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NIHR Signal C-reactive protein is not useful in diagnosing late-onset infection in newborns

Published on 20 March 2019

doi: 10.3310/signal-000748

The blood level of C-reactive protein (CRP), a marker indicating inflammation in the body, is not accurate enough alone to diagnose late-onset infection in newborn infants.

Late-onset neonatal infection, occurring more than three days after birth, is potentially serious and is relatively common. Tests measuring the blood level of CRP are widely used by physicians to guide their decision on whether or not to start antibiotic treatment for suspected infection.

This NIHR-funded review found 20 studies, including 1,615 hospitalised infants, comparing the use of CRP to bacterial culture of the blood in children with suspected infection. For every 1,000 babies, assuming 40% have an infection, 152 cases of infection would be missed, and 156 would receive unnecessary antibiotics if the decision was just based on CRP.

The findings cast doubt on the use of CRP for this purpose.

Share your views on the research.

Why was this study needed?

Infections in the first three days of life are often associated with maternal infection or complicated childbirth and children at risk are often given antibiotics until given the all clear.

Late-onset neonatal infection is common, especially in children needing intensive care, with prematurity, low birth weight and the need for a central venous catheter. Life-threatening general infection (sepsis) can rapidly develop. Late-onset infection occurs in seven out of every 1,000 births and is responsible for 10% of all newborn deaths in the UK.

Ideally, infections need to be diagnosed early with certainty before antibiotics are prescribed, as widespread use of antibiotics can contribute to antimicrobial resistance. However, early diagnosis can be challenging as bacterial culture typically takes between 24 to 48 hours.

This UK Cochrane review aimed to assess the evidence for the accuracy of C-reactive protein (CRP) measurement when detecting late-onset infection in newborns.

What did this study do?

This systematic review and meta-analysis pooled 20 cohort and cross-sectional studies of 1,615 infants in hospital with suspected infection. The serum CRP threshold level for a ‘positive’ result in the included studies was between 5mg/L and 10mg/L. Diagnosis of infection confirmed using microbial blood culture was the reference standard. Sixteen of the 20 studies were conducted in high-income countries in Europe (16 of the 20). None was based in the UK.

Due to variation between the studies, it was not possible to perform separate analyses according to age, type of infection or infective organism. The risk of bias in the studies was low, and the evidence was of moderate quality so the results should be reliable.

What did it find?

  • C-reactive protein levels are only accurate approximately 6 times out of 10 in correctly identifying late-onset infection.
  • At the average (median) reported specificity of 0.74, when 74% of newborns without infection are correctly identified as free of infection, the sensitivity was 0.62, meaning that 62% of infections are correctly diagnosed (95% confidence interval 0.65 to 0.84).
  • When these values were applied to a hypothetical cohort of 1,000 newborns with suspected late-onset neonatal infection, if the chance of being infected was 40% then 248 babies would be correctly diagnosed (true positives), 152 cases of infection would be missed (false negative) and 156 non-infected newborns would be incorrectly classified as having infection and might receive treatment unnecessarily (false positive). The remaining 444 would test negative and not have a late-onset infection.

Diagram showing diagnostic accuracy of CRP test

 

What does current guidance say on this issue?

At present, there are no relevant UK guidelines available covering the assessment of late-onset neonatal infection.

The 2012 NICE guideline on neonatal infection (early onset): antibiotics for prevention and treatment is currently under review and will be extended to cover late-onset neonatal infection. The expected publication date is August 2020.

What are the implications?

This review casts doubt on the value of CRP testing for the purpose of identifying late-onset infection in newborns.

Clinicians should be reminded of the high number of false positives (unnecessarily treated) and false negatives (missed cases) and are therefore not advised to use CRP as a rule in or out test. There may be a place of CRP alongside other tests and if used in conjunction with clinical signs and symptoms.

It is possible that newer biomarkers such as procalcitonin could prove to be more reliable and further research is likely in this important area.

Citation and Funding

Brown JVE, Meader N, Cleminson J, McGuire W. C-reactive protein for diagnosing late-onset infection in newborn infants. Cochrane Database Syst Rev. 2019;1:CD012126.

This project was funded by the NIHR Cochrane Programme Grant (16/114/03) and the Vermont Oxford Network, USA.

Bibliography

NICE. Neonatal infection. QS75. London: National Institute for Health and Care Excellence; 2014.

NICE. Neonatal infection (early-onset): antibiotics for prevention and treatment. CG149. London: National Institute for Health and Care Excellence; 2012.

Why was this study needed?

Infections in the first three days of life are often associated with maternal infection or complicated childbirth and children at risk are often given antibiotics until given the all clear.

Late-onset neonatal infection is common, especially in children needing intensive care, with prematurity, low birth weight and the need for a central venous catheter. Life-threatening general infection (sepsis) can rapidly develop. Late-onset infection occurs in seven out of every 1,000 births and is responsible for 10% of all newborn deaths in the UK.

Ideally, infections need to be diagnosed early with certainty before antibiotics are prescribed, as widespread use of antibiotics can contribute to antimicrobial resistance. However, early diagnosis can be challenging as bacterial culture typically takes between 24 to 48 hours.

This UK Cochrane review aimed to assess the evidence for the accuracy of C-reactive protein (CRP) measurement when detecting late-onset infection in newborns.

What did this study do?

This systematic review and meta-analysis pooled 20 cohort and cross-sectional studies of 1,615 infants in hospital with suspected infection. The serum CRP threshold level for a ‘positive’ result in the included studies was between 5mg/L and 10mg/L. Diagnosis of infection confirmed using microbial blood culture was the reference standard. Sixteen of the 20 studies were conducted in high-income countries in Europe (16 of the 20). None was based in the UK.

Due to variation between the studies, it was not possible to perform separate analyses according to age, type of infection or infective organism. The risk of bias in the studies was low, and the evidence was of moderate quality so the results should be reliable.

What did it find?

  • C-reactive protein levels are only accurate approximately 6 times out of 10 in correctly identifying late-onset infection.
  • At the average (median) reported specificity of 0.74, when 74% of newborns without infection are correctly identified as free of infection, the sensitivity was 0.62, meaning that 62% of infections are correctly diagnosed (95% confidence interval 0.65 to 0.84).
  • When these values were applied to a hypothetical cohort of 1,000 newborns with suspected late-onset neonatal infection, if the chance of being infected was 40% then 248 babies would be correctly diagnosed (true positives), 152 cases of infection would be missed (false negative) and 156 non-infected newborns would be incorrectly classified as having infection and might receive treatment unnecessarily (false positive). The remaining 444 would test negative and not have a late-onset infection.

Diagram showing diagnostic accuracy of CRP test

 

What does current guidance say on this issue?

At present, there are no relevant UK guidelines available covering the assessment of late-onset neonatal infection.

The 2012 NICE guideline on neonatal infection (early onset): antibiotics for prevention and treatment is currently under review and will be extended to cover late-onset neonatal infection. The expected publication date is August 2020.

What are the implications?

This review casts doubt on the value of CRP testing for the purpose of identifying late-onset infection in newborns.

Clinicians should be reminded of the high number of false positives (unnecessarily treated) and false negatives (missed cases) and are therefore not advised to use CRP as a rule in or out test. There may be a place of CRP alongside other tests and if used in conjunction with clinical signs and symptoms.

It is possible that newer biomarkers such as procalcitonin could prove to be more reliable and further research is likely in this important area.

Citation and Funding

Brown JVE, Meader N, Cleminson J, McGuire W. C-reactive protein for diagnosing late-onset infection in newborn infants. Cochrane Database Syst Rev. 2019;1:CD012126.

This project was funded by the NIHR Cochrane Programme Grant (16/114/03) and the Vermont Oxford Network, USA.

Bibliography

NICE. Neonatal infection. QS75. London: National Institute for Health and Care Excellence; 2014.

NICE. Neonatal infection (early-onset): antibiotics for prevention and treatment. CG149. London: National Institute for Health and Care Excellence; 2012.

C-reactive protein for diagnosing late-onset infection in newborn infants

Published on 15 January 2019

Brown, J. V. E.,Meader, N.,Cleminson, J.,McGuire, W.

Cochrane Database Syst Rev Volume 1 , 2019

BACKGROUND: Late-onset infection is the most common serious complication associated with hospital care for newborn infants. Because confirming the diagnosis by microbiological culture typically takes 24 to 48 hours, the serum level of the inflammatory marker C-reactive protein (CRP) measured as part of the initial investigation is used as an adjunctive rapid test to guide management in infants with suspected late-onset infection. OBJECTIVES: To determine the diagnostic accuracy of serum CRP measurement in detecting late-onset infection in newborn infants. SEARCH METHODS: We searched electronic databases (MEDLINE, Embase, and Science Citation Index to September 2017), conference proceedings, previous reviews, and the reference lists of retrieved articles. SELECTION CRITERIA: We included cohort and cross-sectional studies evaluating the diagnostic accuracy of serum CRP levels for the detection of late-onset infection (occurring more than 72 hours after birth) in newborn infants. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed eligibility for inclusion, evaluated the methodological quality of included studies, and extracted data to estimate diagnostic accuracy using hierarchical summary receiver operating characteristic (SROC) models. We assessed heterogeneity by examining variability of study estimates and overlap of the 95% confidence interval (CI) in forest plots of sensitivity and specificity. MAIN RESULTS: The search identified 20 studies (1615 infants). Most were small, single-centre, prospective cohort studies conducted in neonatal units in high- or middle-income countries since the late 1990s. Risk of bias in the included studies was generally low with independent assessment of index and reference tests. Most studies used a prespecified serum CRP threshold level as the definition of a 'positive' index test (typical cut-off level between 5 mg/L and 10 mg/L) and the culture of a pathogenic micro-organism from blood as the reference standard.At median specificity (0.74), sensitivity was 0.62 (95% CI 0.50 to 0.73). Heterogeneity was evident in the forest plots but it was not possible to conduct subgroup or meta-regression analyses by gestational ages, types of infection, or types of infecting micro-organism. Covariates for whether studies used a predefined threshold or not, and whether studies used a standard threshold of between 5 mg/L and 10 mg/L, were not statistically significant. AUTHORS' CONCLUSIONS: The serum CRP level at initial evaluation of an infant with suspected late-onset infection is unlikely to be considered sufficiently accurate to aid early diagnosis or select infants to undergo further investigation or treatment with antimicrobial therapy or other interventions.

Expert commentary

C-reactive protein (CRP) is commonly used in neonatal units to help identify if a baby has sepsis or not, but the review by Brown et al. places doubt on this practice. Where does this leave clinicians?

Treating a baby suspected of infection is clearly important, so all aspects of the baby need to be assessed when making a diagnosis of infection. For the future, however, robust studies are urgently required to evaluate not only CRP but newer agents such as procalcitonin to make an accurate diagnosis of infection in newborn babies.

Sailesh Kotecha, Professor of Child Health, Cardiff University School of Medicine

The commentator declares no conflicting interests