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• Authors' reply:
  Jan Y Verbakel
  Published on: 19 April 2018
• CRP first? : Less is better for education
  Osamu Nomura
  Published on: 19 April 2018
• Testing in relation to timing of illness needs to be considered
  Mitch Blair
  Published on: 19 April 2018

• Published on: 19 April 2018

  Authors' reply:

  • Jan Y Verbakel, General Practitioner, Assistant Professor Nuffield Department of Primary Care Health Sciences, University of Oxford & Department of Public Health and Primary Care, Leuven

  I would like to thank Professor Mitch Blair for his valuable input and bringing up the issue of considering symptoms onset when interpreting point-of-care test results in acute care settings. Recognizing serious infection in children can be challenging, especially at disease onset when the severity of the infection is unclear. Although the choice of biomarker is pivotal in the risk assessment of acutely ill children guided by the point-of-care test result, we had very good rationale to choose C-reactive protein (CRP) as our preferred test.

  Previous research:
  CRP and procalcitonin were identified as the best inflammatory markers for serious infections in children to date in a systematic review, which only identified studies from hospital settings.[1] A CRP <20mg/L and procalcitonin <0.5ng/mL significantly reduce the risk of missing a serious infection in children. Our recent study on point-of-care (POC) CRP in primary care found an even lower threshold of 5mg/L to rule out serious infection in those children, probably due to the early presentation in primary care, when the inflammatory response is still developing, which indeed confirms the importance of setting.[2]
  However, as shown in Figure 6 of the paper by Van den Bruel et al., C-reactive protein and procalcitonin had comparable diagnostic accuracy in the systematic review, as the shape of the curves was roughly similar and the confidence intervals were largely overlapping.[1]

  Practical...

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  I would like to thank Professor Mitch Blair for his valuable input and bringing up the issue of considering symptoms onset when interpreting point-of-care test results in acute care settings. Recognizing serious infection in children can be challenging, especially at disease onset when the severity of the infection is unclear. Although the choice of biomarker is pivotal in the risk assessment of acutely ill children guided by the point-of-care test result, we had very good rationale to choose C-reactive protein (CRP) as our preferred test.

  Previous research:
  CRP and procalcitonin were identified as the best inflammatory markers for serious infections in children to date in a systematic review, which only identified studies from hospital settings.[1] A CRP <20mg/L and procalcitonin <0.5ng/mL significantly reduce the risk of missing a serious infection in children. Our recent study on point-of-care (POC) CRP in primary care found an even lower threshold of 5mg/L to rule out serious infection in those children, probably due to the early presentation in primary care, when the inflammatory response is still developing, which indeed confirms the importance of setting.[2]
  However, as shown in Figure 6 of the paper by Van den Bruel et al., C-reactive protein and procalcitonin had comparable diagnostic accuracy in the systematic review, as the shape of the curves was roughly similar and the confidence intervals were largely overlapping.[1]

  Practical issues:
  At the time of study onset, reliable POC tests were available for CRP only, providing test results within 4 minutes.[3, 4] As mentioned by Professor Blair in his e-letter, other tests such as the Brahms PCT-Q, a semi-quantitative point-of-care procalcitonin test, was available at the time, but required additional manipulation of the sample (centrifugation needed to obtain serum or plasma), a sample volume of 200µL (which was 133 times the volume used in the CRP point-of-care test (merely 1.5 µL, roughly a small drop of blood, especially useful in children)) and an incubation period of at least 30 minutes, which would not be manageable within a single acute care consultation. Therefore, it was not deemed suitable for application in our trial.

  Study characteristics & findings:
  In the present study, we only included children who were not referred by their general practitioner. Taking into account the organization of healthcare services in Belgium, children and parents may present to A&E directly or a consultant paediatrician of their choice, without the need for a letter of referral. This might explain why some children presented at an early stage of their illness to A&E services, potentially reducing the difference in patient spectrum between GP and hospital paediatric settings.
  Furthermore, we found that children with a CRP between 20-75mg/L, should be assessed on seven features, including fever duration <1 day, which reflects the effect of disease onset on the CRP level.
  In this particular CRP range, children could still have a serious infection if fever was only present for 1 day.

  Conclusion:
  Procalcitonin has been introduced as an earlier and more accurate diagnostic markers than currently available tests, however evidence of superior clinical accuracy in diagnosing serious infection in children in ambulatory care is still lacking.
  I agree with Professor Blair that further prospective studies are needed to compare the clinical effectiveness of using point-of-care CRP and procalcitonin to guide clinical assessment in acute paediatric care.

  REFERENCES

  1. Van den Bruel A, Thompson M, Haj-Hassan T, et al. Diagnostic value of laboratory tests in identifying serious infections in febrile children: systematic review. BMJ 2011;342:d3082
  2. Verbakel JY, Lemiengre MB, De Burghgraeve T, et al. Should all acutely ill children in primary care be tested with point-of-care CRP: a cluster randomised trial. BMC Med. 2016;14(1):131 doi: 10.1186/s12916-016-0679-2published Online First: Epub Date]|.
  3. Minnaard MC, van de Pol AC, Broekhuizen BD, et al. Analytical performance, agreement and user-friendliness of five C-reactive protein point-of-care tests. Scand. J. Clin. Lab. Invest. 2013;73(8):627-34 doi: 10.3109/00365513.2013.841985published Online First: Epub Date]|.
  4. Verbakel JY, Aertgeerts B, Lemiengre MB, De Sutter A, Bullens DM, Buntinx F. Analytical accuracy and user-friendliness of the Afinion point-of-care CRP test. J. Clin. Pathol. 2014;67:83 - 86

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  Conflict of Interest:
  None declared.

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• Published on: 19 April 2018

  CRP first? : Less is better for education

  • Osamu Nomura, Pediatric Emergency Physician Tokyo Metropolitan Children's Medical Center, Division of Pediatric Emergency Medicine

  With great interest, I read a recent study by Verakel et al (1). illustrating the utility of a newly developed algorithm for excluding serious infections (SI) in acutely ill children. Their algorithm stratifies patients into three risk groups based on the values of point-of-care C reactive protein (POC CRP) and is meant to assist the decision making of physicians, especially trainees. This method demonstrated excellent diagnostic performance and enabled physicians to rule out 36% of SI in children visiting outpatient clinics and emergency departments. However, their proposed method does raise some concerns about potential negative consequences in the educational context.
  The algorithm requires physicians to perform the POC CRP test for all patients regardless of their pre-test probability of SIs. In addition, their model may lead young physicians to draw conclusions about the patients’ clinical features only after estimating the risk of SI based on the POC CRP value and may cause them to neglect the importance of history taking and physical examinations.
  As the authors state, the POC CRP is an innovative tool in pediatric acute care; a POC sample can be obtained by a simple finger prick and the test results can be obtained within several minutes. Nevertheless, in pediatric practice sometimes “doing nothing” is better than “doing something”. This may well be one of the most important principles in pediatrics (2-4). Our role as senior physicians is to show traine...

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  With great interest, I read a recent study by Verakel et al (1). illustrating the utility of a newly developed algorithm for excluding serious infections (SI) in acutely ill children. Their algorithm stratifies patients into three risk groups based on the values of point-of-care C reactive protein (POC CRP) and is meant to assist the decision making of physicians, especially trainees. This method demonstrated excellent diagnostic performance and enabled physicians to rule out 36% of SI in children visiting outpatient clinics and emergency departments. However, their proposed method does raise some concerns about potential negative consequences in the educational context.
  The algorithm requires physicians to perform the POC CRP test for all patients regardless of their pre-test probability of SIs. In addition, their model may lead young physicians to draw conclusions about the patients’ clinical features only after estimating the risk of SI based on the POC CRP value and may cause them to neglect the importance of history taking and physical examinations.
  As the authors state, the POC CRP is an innovative tool in pediatric acute care; a POC sample can be obtained by a simple finger prick and the test results can be obtained within several minutes. Nevertheless, in pediatric practice sometimes “doing nothing” is better than “doing something”. This may well be one of the most important principles in pediatrics (2-4). Our role as senior physicians is to show trainees how they can assess the pre-test probability for SI in acutely ill children without resorting to pricking children’s fingers to obtain their “inorganic” CRP value.
  I assume that the authors' algorithm will function as insurance for children with suspected SI; however, debriefing and reflection by trainees and attending physicians alike after each patient encounter is essential even after implementing this technique.

  References:
  1. Verbakel JY, Lemiengre MB, DeBurghgraeve T, et al. Arch Dis Child 2017;0:1–7. doi:10.1136/archdischild-2016-312384.
  2. Williams HS and Zenel JA. Commentary: When Doing Less Is Best. Pediatr Rev. 2013;34;423-8.
  3. Cornfield DN. Bronchiolitis: Doing Less and Still Getting Better. Pediatrics. 2014;133: e213-4.
  4. Taylor JA. Oral rehydration: in pediatrics, less is often better. Arch Pediatr Adolesc Med. 2004;158:420-1.

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  Conflict of Interest:
  None declared.

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• Published on: 19 April 2018

  Testing in relation to timing of illness needs to be considered

  • Mitch Blair, Professor of Paediatrics and Child Public Health Imperial College London

  The authors have added an interesting opportunity to refine our clinical decision making with the addition of a point of care test (POC) . However I would argue that choice of POC test might be a critical factor here and very much dependent on initial onset of symptoms. Some years ago published data on the then relatively new POC test for Procalcitonin (PCT-Q) indicated that children presenting within 24 h, PCT performed significantly better (AUC 0.96, SE 0.05) than CRP (0.74, 0.12).(1) This could well explain the differences the authors found in the primary care arm of their study. Setting for these tests becomes increasingly important as we see a shift of more children being seen in GP run Urgent Care Centres with a possibly a different spectrum of illness severity.(2) Prospective studies in different settings comparing both of these biomarkers as POCs would be worth further cosideration.

  References
  1 K. Brent, S .M. Hughes, S .Kumar, A. Gupta, A. Trewick,
  S. Rainbow, R. Wall and M. Blair
  Is procalcitonin a discriminant marker of early
  invasive bacterial infection in children?
  Current Paediatrics (2003) 13, 399

  2 . Gritz A, Sen A, Hiles S, Mackenzie G, Blair M. G241(P) More under-fives now seen in urgent care centre than A&amp;E- should we shift our focus? Arch Dis Child [Internet]. 2016 Apr 27 [cited 2016 Aug 3];101(Suppl 1):A132.1-A132. Available from:...

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  The authors have added an interesting opportunity to refine our clinical decision making with the addition of a point of care test (POC) . However I would argue that choice of POC test might be a critical factor here and very much dependent on initial onset of symptoms. Some years ago published data on the then relatively new POC test for Procalcitonin (PCT-Q) indicated that children presenting within 24 h, PCT performed significantly better (AUC 0.96, SE 0.05) than CRP (0.74, 0.12).(1) This could well explain the differences the authors found in the primary care arm of their study. Setting for these tests becomes increasingly important as we see a shift of more children being seen in GP run Urgent Care Centres with a possibly a different spectrum of illness severity.(2) Prospective studies in different settings comparing both of these biomarkers as POCs would be worth further cosideration.

  References
  1 K. Brent, S .M. Hughes, S .Kumar, A. Gupta, A. Trewick,
  S. Rainbow, R. Wall and M. Blair
  Is procalcitonin a discriminant marker of early
  invasive bacterial infection in children?
  Current Paediatrics (2003) 13, 399

  2 . Gritz A, Sen A, Hiles S, Mackenzie G, Blair M. G241(P) More under-fives now seen in urgent care centre than A&amp;E- should we shift our focus? Arch Dis Child [Internet]. 2016 Apr 27 [cited 2016 Aug 3];101(Suppl 1):A132.1-A132. Available from: http://adc.bmj.com/lookup/doi/10.1136/archdischild-2016-310863.232

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  Conflict of Interest:
  None declared.

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