SCH Journal ClubUse of time from fever onset improves the diagnostic accuracy of C-reactive protein in identifying bacterial infections

Wednesday 13th May 2015

Nic Seneviratne

Case Presentation• A 6 month old presents to the hospital with evidence of a

LRTI and fever of 38.5oC • 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 2014 99: 974-978

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 Chart1158 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;99:974-978

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;99:974-978

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;99:974-978

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 (%)

<12hN = 74 (*2.1mg/dL)

76 (63-88) 72 (52-87) 77 (64-86) 3.1 (1.8-5.5) 76 (62-89)

>12-24hN=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 (85-97.5)

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