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Three Part Question

In [children under three with a temperature >38.5°C and no clinical focus of infection], is [measurement of procalcitonin] a [good screening test to exclude serious bacterial illness]?

Clinical Scenario

A 4-month-old boy presents with a fever of 38.9°C and no focus on clinical examination. He does not appear septic and clean catch urine is normal. There are no respiratory symptoms and no clinical signs of meningitis. You think he has a low risk of a serious bacterial illness. You wonder if procalcitonin can help you exclude serious bacterial illness that may need antibiotics?

Search Strategy

The primary source was Medline using PubMed:
(("procalcitonin"[Substance Name] OR procalcitonin[Text Word]) AND ("infant"[MeSH Terms:noexp] OR "child, preschool"[MeSH Terms])) OR (("procalcitonin"[Substance Name] OR procalcitonin[Text Word]) AND ("Child*")).

Search Outcome

Outcome: 127 articles (last check 13th May 2006) were found. Five studies which addressed the clinical scenario were selected. One narrative review article was found which identified four of these five papers (one was published after the review) (Hsaio). Several other papers using procalcitonin for specific presentations with a fever (rash, diarrhoea) were not included.
Secondary search methods: Search replicated on Cochrane library, EMBASE, CINAHL, BestBETs, CatCrawler. Article reference lists were reviewed, and manufacturer's website and clinical trial registers searched. No additional relevant articles were found. One systematic review on procalcitonin as a marker for bacterial illness was found but it did not focus on children under age three (Simon).

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Gendrel, D 1999 France	1500 children age 1 month to 15 year presenting to single children's hospital with temp > 38.5. Exclusions were children known to have a chronic disease.	Exploratory prospective cohort with blind allocation (level 2b).	Invasive bacterial versus localised or viral illness for PCT = 1 (44,2,75,239) Bacteraemia 34/360	Sensitivity 0.96 (0.86-0.99). Specificity 0.76 (0.71-0.81). Negative likelihood ratio = 0.05 (0.02-0.20)	Potential selection (spectrum) bias as only children with bloods taken were included. Only 360 causal agents were found from 700. The outcome for this 340 remaining is not mentioned.
Lacour, AG 2001 Switzerland	124 children age 7 days to 36 months presenting to a single children's hospital with a temperature > 38 degrees without an obvious focus. Excluded fever > 7 days, antibiotics 48 hours prior, immunodeficiencies.	Exploratory prospective cohort with blind allocation (level 2b).	Serious Bacterial Illness versus benign infection using PCT = 0.9 (26,2,21,75) Bacteraemia 4/124.	Sensitivity 0.93 (0.77-0.98). Specificity 0.78 (0.69-0.85). Negative likelihood ratio = 0.09 (0.02-0.35)	Selected group had a blood culture received antibiotics for 48 hours. In a response to a letter pointing out this criticism the authors analysed the data with only those children who had a blood culture and there was no change in findings [Procalcitonin Study:Methodological errors]. Temperature cut off lower than other studies and our three-part question.
Fernandez Lopez, A. 2003 Spain	445 children age 1 to 36 months in nine paediatric emergency departments, temperature > 38°C. Exclusions were antibiotics treatment in previous 48 hours, vaccination, recent surgery, chronic pathology that might affect CRP, history of prior UTI, VUR or renal malformation.	Exploratory prospective cohort with blind allocation (level 2b).	Invasive bacterial versus localised or viral illness using PCT = 0.59 (13, 7, 13, 13, 189) Bacteraemia 56/445.	Sensitivity 0.91 (0.86-0.95), Specificity 0.94 (0.89-0.96), Negative likelihood ratio 0.09 (0.06-0.15)	Large multicentre study in paediatric emergency departments (352 febrile children and 93 controls). High prevalence of invasive bacterial illness (150/445, 34%). Lobar pneumonia treated as invasive (17/445, 3.8%), pyelonephritis (48/445, 10.7%), meningococcal B (33/445, 7.4%) and C (17/445, 3.8%). Few weaknesses. Collaboration with PCT diagnostic test manufacturer.
Galetto-Lacour, A. 2003 Switzerland	99 children age 7 days to 36 months presenting to a single childrens hospital with a temperature of >38°C without localising signs. Excluded fever > 7 days, antibiotics 48 hours prior, immunodeficiencies. Evaluated PCT, CRP, WBC, Bands, IL6 and Yale Observation Score.	Exploratory prospective cohort with blind allocation (level 2b).	Serious Bacterial Illness versus benign infection using PCT = 0.5 (27,2,18,52) Bacteraemia 4/99.	Sensitivity 0.93 (0.78-0.98). Specificity 0.74 (0.63-0.83), Negative likelihood ratio 0.09 (0.02-0.36)	Selected group had a blood culture received antibiotics for 48 hours. Temperature cut off lower than other studies and our three part question. High incidence of pyelonephritis.
Thayyil S 2005 England	72 children 1 to 36 months with temperature > 39°C without localising signs presenting at two university hospitals. All had blood cultures, urine, WBC, CXR, CRP and PCT. Excluded children with fever > 7 days, immunodeficiency or on antibiotics in the preceding 72 hours.	Exploratory prospective cohort with blind allocation (level 2b).	Serious Bacterial Illness versus Possible Serious Bacterial illness or Viral illness using PCT = 0.5 (7,1,32,32) Bacteraemia 5/86.	Sensitivity 0.87 (0.53-0.98), Specificity 0.50 (0.38-0.62), Negative likelihood ratio 0.25 (0.04-1.59).	Inconsistency in data between figure 1 and text. Number of SBI cases reported as 8 yet 9 diseases listed and 9 SBI cases in figure 1. Smallest study based on a power estimate (90% power to detect a 15% difference between CRP and PCT at 0.05 power level). This creates large 95% confidence intervals. The difference between 87.5% sensitivity (-LR 0.25) and 94.4% sensitivity (-LR 0.11) would be one patient.

Comment(s)

Estimating pretest probability and then applying the likelihood ratios to determine post-test risk is the optimal method to utilise a test. Treatment decisions are then based on post-test risk and how serious the outcome would be if the illness were left untreated. In the post Haemophilis influenzae b era, Streptococcus pneumoniae and Neiserria meningiditis (in its epidemic forms) are the main pathogens with rapid and sometimes serious effects. The incidence of serious bacterial illness depends on the definition used, the height of the fever, the source population, local organisms and immunisation practices, and most importantly the age of the child. In the five studies reviewed, the prevalence of serious bacterial illness ranged from 11% all the way up to 43% during a meningococcal epidemic. There are hundreds of studies demonstrating a much lower incidence in many settings. The commonest occult source was the urinary tract and a two of these studies used DMSA to differentiate pyelonephritis from simple lower UTI. Pneumonia is rarely present without clinical symptoms or signs but these may include vague symptoms such as abdominal pain and vomiting. One study defined consolidation as a local infection [Gendrel] while another classified it as an invasive infection [Fernandez Lopez]. Meningitis will be present in a few and if suspected CSF examination is required and often recommended in the first 6 weeks of life where the signs of meningitis can be difficult to detect. Skin, bone and other infections may sometimes present and a careful examination is required. A small number of remaining children will have occult bacteraemia. In the five studies occult bacteraemia was diagnosed in 9.4%, 3.2%, 12.5%, 4% and 5.8% of cases (table). In the post Hib vaccination era the risk of bacteraemia may be less than 2% [Alpern] and may be reduced further by pneumococcal vaccination [Klein] and targeted meningococcal vaccine programs. [Oster]. Our local incidence of serious bacterial infection is low and in the clinical scenario above in a fully vaccinated child with a clear urine and no respiratory symptoms, I would estimate the pretest probability to be around 1% in our population. The fear of missing a case has lead to widespread use of antibiotics and admissions to hospital although many children with occult bacteraemia will recover without treatment (Trautner). A diagnostic test to separate the serious bacterial illnesses from the more common virus has long been sought (whether it be a clinical scoring system, a single test or a group of tests). C-reactive protein (CRP) had been the best test to date but may not be elevated in the first 24 h of a serious bacterial illness but is raised in many viral illnesses. Many of these studies included CRP, but this was not the focus of this critical appraisal. Procalcitonin is the latest candidate that has shown the most promise in these papers. No one previous screening tool has reached the sensitivity of procalcitonin, although combinations of clinical scoring tests and laboratory tests may (Thayyil ). Unfortunately, the lack of a true gold-standard for "serious bacterial illness" has created heterogeneity in these studies which makes meta-analysis difficult, but attempts have been made in other settings (Simon). As a 'rule-out' test Procalcitonin is currently limited by the laboratory tests available [Nylen]. Normal procalcitonin is likely to be around 0.05 ng/ml in healthy individuals. Current assays have a functional detection range down to 0.5 ng/ml. Having the ability to set lower cut off points in the future could mean procalcitonin may have even better sensitivity. A procalcitonin level of around 0.5–1.0 had a negative likelihood ratio (95% CI) in the five studies reviewed being 0.05 (0.02 to 0.20), 0.09 (0.02 to 0.35), 0.09 (0.06 to 0.15), 0.09 (0.02 to 0.36) and 0.25 (0.04 to 1.59). This allows a practitioner to reduce the pretest probability by between 4- and 20-fold. If your pretest probability were 10%, then with a procalcitonin level of less than 0.5 the post-test risk of serious bacterial illness would be between 0.5% and 2.5%. Somewhere between 40 and 200 children would need to be treated to ensure you were treating the one child with a serious bacterial illness.

Editor Comment

Dr Herd is supported by the Joan Mary Reynolds fellowship. CRP, C-reactive protein; CXR, chest x ray; fn, false negative; fp, false positive; PCT, procalcitonin; SBI, serious bacterial infection; tn, true negative; tp, true positive; UTI, urinary tract infection; VUR, vesicoureteral reflux; WBC, white blood cell.

Clinical Bottom Line

Procalcitonin can be used to help differentiate serious bacterial illness from viral infection in children under age three with fever without focus (grade B). Procalcitonin is still not sensitive enough to be used solely as an exclusion test for serious bacterial illness but can reduce your pretest probability by between 4- and 20-fold (grade B). More sensitive and rapid procalcitonin assays are being developed.

References

1. Gendrel D, Raymond J, Coste J, Moulin F, Lorrot M, Guerin S, Ravilly S, Lefevre H, Royer C, Lacombe C, Palmer P, Bohuon C. Comparison of procalcitonin with C-reactive protein, interleukin 6 and interferon-alpha for differentiation of bacterial vs. viral infections LWW Online Pediatr Infect Dis J. 1999 Oct;18(10):875-81.
2. Lacour AG, Gervaix A, Zamora SA, Vadas L, Lombard PR, Dayer JM, Suter S. Procalcitonin, IL-6, IL-8, IL-1 receptor antagonist and C-reactive protein as identificators of serious bacterial infections in children with fever without localising signs Spinger Eur J Pediatr. 2001 Feb;160(2):95-100.
3. Fernandez Lopez A, Luaces Cubells C, Garcia Garcia JJ, Fernandez Pou J; Spanish Society of Pediatric Emergencies. Procalcitonin in pediatric emergency departments for the early diagnosis of invasive bacterial infections in febrile infants: results of a multicenter study and utility of a rapid qualitative test... LWW Online Pediatr Infect Dis J. 2003 Oct;22(10):895-903.
4. Galetto-Lacour A, Zamora SA, Gervaix A. Bedside procalcitonin and C-reactive protein tests in children with fever without localizing signs of infection seen in a referral center. Pediatrics (free full-text online) Pediatrics. 2003 Nov;112(5):1054-60.
5. Thayyil S, Shenoy M, Hamaluba M, Gupta A, Frater J, Verber IG. Is procalcitonin useful in early diagnosis of serious bacterial infections in children? MetaPress Acta Paediatr. 2005 Feb;94(2):155-8.
6. Nylen E, Muller B, Becker KL, Snider R. The future diagnostic role of procalcitonin levels: the need for improved sensitivity. Clin Infect Dis 2003 Mar 15;36(6):823-4; author reply 6-7.
7. Hsiao AL, Baker MD. Fever in the new millennium: a review of recent studies of markers of serious bacterial infection in febrile children. Curr Opin Pediatr 2005, 17(1):56-61.
8. Alpern ER, Alessandrini EA, Bell LM, Shaw KN, McGowan KL. Occult bacteremia from a pediatric emergency department: current prevalence, time to detection, and outcome. Pediatrics 2000, 106(3):505-511.
9. Klein JO. Management of the febrile child without a focus of infection in the era of universal pneumococcal immunization. Pediatr Infect Dis J 2002, 21(6):584-588; discussion 613-584.
10. Oster P, Lennon D, O'Hallahan J, Mulholland K, Reid S, Martin D. MeNZB: a safe and highly immunogenic tailor-made vaccine against the New Zealand Neisseria meningitidis serogroup B disease epidemic strain. Vaccine 2005, 23(17-18):2191-2196.
11. Post-publication Peer Reviews. Procalcitonin Study: Methadological errors. Pediatrics[Online] 2004 - Jan-Feb[Accessed 7th July 2006]
12. Simon L, Gauvin F, Amre DK, et al. Serum procalcitonin and C-reactive protein levels as markers of bacterial infection: a systematic review and meta-analysis. Clin Infect Dis 2004;39(2):206-17.
13. Trautner BW, Caviness AC, Gerlacher GR, et al. Prospective evaluation of the risk of serious bacterial infection in children who present to the emergency department with hyperpyrexia (temperature of 106 degrees F or higher). Pediatrics 2006;118(1):34-40.