SCH Journal Club Use of time from fever onset improves the diagnostic accuracy of C-reactive protein in identifying bacterial infections Wednesday 13 th May 2015 Nic Seneviratne

Case Presentation A 6 month old presents to the hospital with evidence of a LRTI and fever of 38.5 o C They are not clinically septic How will you decide whether this needs treatment with antibiotics or is likely to be viral? Will initial inflammatory markers help? Does consideration of the duration of their fever prior to presentation make any difference?

The Clinical Question In a feverish child, does the use of time of onset of fever improve the ability of CRP to differentiate between bacterial & viral infections? P- feverish children I – time from onset of fever & CRP C – CRP alone O – differentiation between bacterial & viral infections

Paper Use of time from fever onset improves the diagnostic accuracy of C- reactive protein in identifying bacterial infections. Idan Segal, Matityahu Ehrlichman, Joseph Urbach Arch Dis Child :

Current Practice / Guidelines NICE Guidelines for Early Onset Neonatal Sepsis recommends a repeat CRP at 18-24h as the initial result may be falsely reassuring Can the same presumption be made about older patients? NICE guidelines for feverish children cautions that a low CRP at presentation does not rule out serious infection

Methods A prospective observational study Single hospital Children with fever where it was felt blood tests were clinically appropriate Only enrolled when study investigators were available WBC and differential, CRP, blood cultures, and time from fever onset in all patients CXR, urine & CSF culture semi-dependent on clinical picture, although some guidance

Study Flow Chart 1158 children with fever 229 met exclusion criteria 929 eligible patients 373 enrolled 0-28 days Full septic screen (blood, urine & CSF cultures) 28 days to 8 weeks Focus of infection or WBC >15,000 or <5,000 or white cells in urine Full septic screen >8 weeks Abnormal urinalysis or symptoms of urine infection Urine culture Signs of pneumonia Chest X-ray No focus of infection Chest X-ray Appeared unwell Full septic screen All enrolled patients had blood culture and WBC with differential sent CRP was sent and parents determined time from fever onset

Outcome Measures Patients classified as –Bacterial infection –Presumed viral infection –Acute otitis media –Inconclusive CRP value at different time points compared between bacteria & viral groups Sensitivity, specificity & likelihood ratios calculated for diagnosis of bacterial infection.

C-reactive protein (CRP) values by time from fever onset for bacterial (circles) and viral (crosses) infections. Idan Segal et al. Arch Dis Child 2014;99: Copyright © BMJ Publishing Group Ltd & Royal College of Paediatrics and Child Health. All rights reserved.

Receiver operating characteristic curves for C-reactive protein at different time points from fever onset. Idan Segal et al. Arch Dis Child 2014;99: Copyright © BMJ Publishing Group Ltd & Royal College of Paediatrics and Child Health. All rights reserved.

Positive & Negative Post Test Probability for Bacterial Infection by CRP value and time from fever onset. C – rule in, D - rule out. Idan Segal et al. Arch Dis Child 2014;99: Copyright © BMJ Publishing Group Ltd & Royal College of Paediatrics and Child Health. All rights reserved.

CASP Was there a clear question for the study to address? »Clear regarding the setting and the test »Less so about the population or the outcomes and how these were defined Was there a comparison with an appropriate reference standard? »Unclear »The definition of viral infection is the absence of evidence of bacterial infection

CASP 2 Did all the patients get the diagnostic test and reference standard?Yes Could the results of the tests have been influenced by the results of the reference test?No Is the disease status of the tested population clearly defined?No Were the methods for performing the test described in sufficient details?Not really

What Are the Results? CRP at different time points AUC % (95% CI) Sensitivity % (95% CI) Specificity % (95% CI)+LR (95% CI) Post test Probability (%) <12h N = 74 (*2.1mg/dL) 76 (63-88)72 (52-87)77 (64-86)3.1 ( )76 (62-89) >12-24h N=67 (*6mg/dL) 81 (69-92)68 (48-83)83 (69-92)4.2 (2-8.4)80 (63-96) >24-48h N=51 (*10.7mg/dL) 87 (77-96)68 (47-84)90 (73-96)6.8 (2.1-20)87 (62-99) >48h N=98 (*12.6mg/dL) 90 (84-97)80 (64-90)94 ( ) 13.3 (4.8-33)93 (82-99) Pre-test probability = 27% * Cut off

Are the results of the trial valid? Sensitivity, specificity and likelihood ratios presented, including confidence intervals, but unclear how these were calculated How sure are we about the results? Positive post test probability from this study suggests that a CRP >16 in the first 24h is always a bacterial infection

Are the Results of the Trial Valid? Only a small proportion of eligible pts enrolled –Was there a significant difference between those who had bloods done & those that did not –Higher rate of bacterial infection than expected How accurate was the differentiation between bacterial & viral infection? –Definition of viral infection includes recovery without antibitoics, therefore are those with severe infection presumed bacterial?

Will the Results Help Locally? Can the results be applied to our patients / population? –Unclear. –What is their threshold for doing blood tests on children? –Likelihood is that these are the children that we have diagnostic uncertainty about Can the test be applied to our population? –Yes Will knowledge of the test result improve patient well being or lead to a change in management? –Unlikely

Bottom Line Conclusion A high CRP can be used to rule in bacterial infection A low CRP does not rule out bacterial infection, especially if it is done early on in the illness The addition of time from onset of fever adds little to the management of a child, with a single CRP Knowledge of the expected rise in CRP over the first 24 hours is a useful reminder not to be too reassured by an early low CRP

Summary & Conclusion