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  Original Contributions DOES THIS CHILD HAVE BACTERIAL MENINGITIS? A SYSTEMATIC REVIEW OFCLINICAL PREDICTION RULES FOR CHILDREN WITH SUSPECTED BACTERIALMENINGITIS Dina M. Kulik,  MD ,  FRCPC ,* Elizabeth M. Uleryk,  BA  ,  MLS ,† and Jonathon L. Maguire,  MSC FRCPC ‡§ jj{ #** *DivisionofPaediatricEmergencyMedicine,HospitalforSickChildren,Toronto,Ontario,Canada,†HospitalforSickChildren,HospitalLibrary, Toronto, Ontario, Canada, ‡Department of Pediatrics, St. Michael’s Hospital, Toronto, Ontario, Canada, §Keenan Research Centre, Li KaShing Knowledge Institute of St. Michael’s Hospital, Toronto, Ontario, Canada,  jj Division of Pediatric Medicine and the Pediatric OutcomesResearch Team (PORT), Hospital for Sick Children, Toronto, Ontario, Canada,  { Child Health Evaluative Sciences, Hospital for Sick ChildrenResearch Institute, Toronto, Ontario, Canada, #Department of Health Policy Management and Evaluation, University of Toronto, Toronto,Ontario, Canada, and **Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada Reprint Address:  Dina M. Kulik,  MD ,  FRCPC , Pediatric Emergency Medicine, The Hospital for Sick Children, 555 University Avenue, Toronto,Ontario, Canada M5G 1X8 , Abstract—Background: Acute meningitis is a relativelycommon phenomenon in children. Identifying which chil-dren are most likely to have bacterial meningitis vs. self-limiting aseptic meningitis is important, as these childrenrequire investigation and antibiotic treatment. Objective:Our aim was to systematically identify and review the qual-ity and performance of published clinical prediction rules(CPRs) for children with suspected bacterial meningitis.Methods: Medline and Embase were searched for CPRs in-volving children 0–18 years of age with suspected bacterialmeningitis, with cerebral spinal fluid (CSF) culture used asthe reference diagnostic standard. CPR quality was assessedusing 17 previously published items. CPR performance wasevaluatedusing sensitivity, negative likelihood ratio, and thetreatment frequency that would result if the rule was used.Results: Eleven studies involving 6675 children with acutemeningitis fulfilled all inclusion criteria and were enteredin the study. They all describe the derivation or validation of six unique CPRs. A rigorously developed, high-performing,andwell-validated CPR readyforclinical use to guide whichchildren with suspected bacterial meningitis should be hos-pitalized and treated with intravenous antibiotics and whichcan be safely discharged home was not identified. Areas forquality improvement for future CPR studies include pro-spective validation using standardized inclusion criteria,adequate blinding, predictor reproducibility assessment,andmeticulousfollow-upofoutcomes.TheBacterialMenin-gitis Score had the highest quality and performance and isthe best candidate for prospective validation. Conclusions:Until consistently high methodological quality and diagnos-tic performance are demonstrated through prospectivevalidation, caution is warranted in the routine clinical useof existing CPRs for children with suspected bacterialmeningitis.   2013 Elsevier Inc. , Keywords—meningitis; clinical predictionrule; decisiontrees; predictive value of tests; multivariate analysis INTRODUCTION  Background  Acute meningitis is a relatively common and potentiallysevere infection in childhood, with approximately 3000new cases each year in children younger than 18 yearsof age in the United States (1–3). Fortunately, mostinfections are aseptic and resolve spontaneously, but6–18% are bacterial in srcin and require i.v. antibiotictreatment, hospitalization, and close monitoring (4,5).R ECEIVED : 30 March 2012; F INAL SUBMISSION RECEIVED : 3 October 2012;A CCEPTED : 15 March 2013 508 The Journal of Emergency Medicine, Vol. 45, No. 4, pp. 508–519, 2013Copyright  2013 Elsevier Inc.Printed in the USA. All rights reserved0736-4679/$ - see front matter  Accuratelydiagnosing bacterial meningitisinchildrenis imperativeto avoid severe outcomes, such as neurolog-ical impairment or death, and minimize unnecessaryantibiotic use and hospitalization in children with self-limiting illness (6–13). Although diagnostic techniques,such as cerebral spinal fluid (CSF) culture and poly-merase chain reaction (PCR) are reliable, physiciansmust decide which patients to treat with i.v. antibioticsempirically before culture or PCR results are reported48 h later (14,15). Weighing the risk of missing atrue case of bacterial meningitis with unnecessarilyadmitting patients without bacterial meningitis for 48 hof i.v. antibiotics remains a major challenge (16).Clinicians often review results of CSF glucose, pro-tein, white blood cell (WBC) count, Gram stain, andserum WBC count to guide diagnostic decisions (17).Gram stain is highly specific but it is falsely negative inupto40%ofcasesandthereforecannotbeexclusivelyre-lied upon (2,18–20). Elevated CSF WBC count is morecommon in aseptic rather than bacterial meningitis(21–27). Widespread use of vaccines against Strepto-coccus pneumonia and Hemophilus influenza type Bhave decreased the probability of bacterial meningitis inchildren, further decreasing the likelihood that elevatedCSF WBC count is the result of bacterial meningitis(28–31).Clinicalpredictionrules(CPRs)arepotentiallypower-ful evidence-based tools for reducing uncertainty andimproving accuracy in medical decision making by stan-dardizing the collection and interpretation of clinical data(32). They can also minimize the use of potentially harm-ful diagnostic tests, such as lumbar puncture, and reduceadmissions and adverse events from antibiotic use. Theyhave been defined as clinical decision-making tools thatquantify the relative importance of 3 or more variablesfrom history,physicalexamination,orsimpleteststopro-vide the probability of an outcome or suggest a singlediagnostic or therapeutic course of action for an individ-ual patient (32–34).This study aimed to systematically identify CPRs forchildrenwithsuspected bacterial meningitisandcomparetheir methodological quality and performance for diag-nosing bacterial meningitis using a recently developedframework to evaluate CPRs for children (35). METHODS Search Strategy Potentially relevant studies were identified through elec-tronic searches of Medline and Embase from January1950 up to September 2012 (Appendix 1). Because thereisnomedicalsubjectheading(MeSH)thatspecifiesclinicalprediction rules, a previously developed electronic searchstrategy for CPRs was used with the addition of theMeSH term  bacterial meningitis  (35,36). The referencelists of identified clinical prediction rule publicationswere searched manually to identify additional studies.Our search was limited to English publications.  Inclusion Criteria Only prospective or retrospective studies that derived,validated, or assessed the impact of CPRs were included.ACPRwasdefinedasaclinicaldecision-makingtoolthat1) includes three or more predictive variables obtainedfrom the history, physical examination, or simple diag-nostic tests; 2) provides the probability of an outcomeor suggests a diagnostic or therapeutic course of actionfor an individual patient; and 3) is not a decision analysisor practice guideline (32,33,35–37)Only studies involving children (term birth–18 years)with suspected or proven bacterial meningitis were in-cluded. Studies that did not include positive CSF culture(defined as a positive bacterial pathogen isolated in theCSF) as the outcome were not included. Studies involv-ing both adults and children were included if a separateanalysis was performed for children. Studies requiringthe use of artificial neural networks or that assessed pre-dictors with no obvious goal of creating a prediction rulewere not included. Studies that did not include positiveCSF culture (defined as a positive bacterial pathogenisolated in the CSF) as the outcome were not included.We did not exclude studies that included patients whoreceived antibiotics; however, no such studies met inclu-sion criteria. Selection of Studies Two reviewers (D. M. Kulik and J. L. Maguire) inde-pendently assessed the inclusion of potentially relevantarticles through a two-step process. First, the titles andabstracts from each article identified through the elec-tronic search were assessed for inclusion. Second, pub-lications identified as relevant by title or abstract werereviewed manually. Discrepancies between the tworeviewers were discussed and included by consensus.Discrepancies occurred <5% of the time and consensuswas reached for every discrepancy.  Assessment of Methodological Quality The quality of the included studies was assessed usinga 17-item checklist from published guidelines for use inthe derivation or validation of clinical prediction rules forchildren (see Appendix 2) (32–36,38,39). Each item was notedtobepresent(1)orabsent(0).Themaximumnumberof quality items was 17. Two reviewers (D. M. Kulik and Does This Child Have Bacterial Meningitis? 509  J. L. Maguire) independently abstracted data from in-cluded papers using a standardized data collection form.Discrepancies between the reviewers were discussed andresolved by consensus. Given the importance of rule vali-dation,hierarchyofrulevalidationwasassessedseparately(see Assessment of Hierarchy of Rule Validation section).  Assessment of Rule Performance Data were extracted from each publication to constructa 2  2 table to calculate sensitivity (Sn), specificity, neg-ativelikelihood ratio (LR  ) and their 95% confidence in-tervals (CIs) for the diagnosis of bacterial meningitis(33,40). Calculations were performed using SAS 9.1(SAS Institute Inc., Cary, NC). The predicted frequencyof empiric i.v. antibiotic treatment and hospitalizationthat would result if the rule were applied to everypatient (rule predicted treatment frequency) was alsodetermined. Rule predicted treatment frequencycaptures both sensitivity and specificity and providesa sensible quantification of the degree of overtreatmentthat the CPR would produce when compared with theactual frequency of bacterial meningitis in each study.Given that physicians are not likely to feel comfortableusing a rule that misses more than a very small numberof children with bacterial meningitis and that sucha rule should not substantially inflate the risk of i.v.antibiotics and hospital admission, the following 4 rule-performance benchmarks were used to identify high-performing CPRs: Sn > 0.95; lower limit of sensitivity95% CI > 0.95; LR   < 0.1; and upper limit of the LR  95% CI < 0.1 (32,33,35–37,40,41). Sensitivity andLR   are also independent of disease prevalence, whichmakes them useful measures for comparing CPRs fromdifferent populations with different frequencies of bacterial meningitis (40,42).  Assessment of Hierarchy of Rule Validation The degree of validation for CPRs that met inclusion cri-teria was assessed according to the hierarchy of evidencefor CPRs published by the Evidence-Based MedicineWorking Group (32). In this hierarchy, prediction rulesthat have been derived but not prospectively validatedare the lowest level of evidence (level 4), rules thathave been prospectively validated in only one sampleare level 3, rules that have been broadly validated in mul-tiple settings are level 2, and rules that have had impactanalysis performed that demonstrated a change in clini-cian behavior with beneficial consequences are level 1.Although performing a meta-analysis would havebeen ideal, due to heterogeneity of the populations andpredictors used in many of the rules, we believed that itwould not be appropriate to do. RESULTS Study Selection A total of 6387 titles and abstracts were identified andscreened by the search strategy as potentially relevant(Figure 1). Of these, 379 were extracted as full textarticles and assessed for inclusion; 11 studies fulfilledall inclusion criteria. These studies were derivation orvalidation studies of six unique CPRs.  Description of Studies Included studies were published between 2001 and 2010and involved a total of 6675 children (see Table 1 forpopulation characteristics for each study). The mediannumber of children enrolled in each study was 286 (range74–2903). Five studies were published in general pediat-ric journals, two in infectious disease journals, two ingeneral medicine journals, and one in each of emergencymedicine and epidemiology journals. Three studies weremulticentered and eight were single centered. Fivecohorts were from the Unite States, two were fromFrance, three were from the Netherlands, and one wasmulticentered across Europe (France, Poland, Turkey,Spain, and Switzerland). Eight of 11 studies were per-formed in the emergency department (ED). Three studieswere completed on the pediatric ward. There was consid-erable variation in the population age (28 days–18 years).Three studies included patients presenting with the clini-cal suspicion for meningitis in the ED, and eight studiesincluded only children who had a final diagnosis of viralor bacterial meningitis. Two studies used post-dischargefollow-up methods to ensure no missed cases of bacterialmeningitis (43,44). The frequency of acute bacterialmeningitis in each study population varied between0.04 and 0.48 (median 0.19).Six studies described derivations of a rule and 5 wererule validation studies. None assessed the rule’s clinical Figure1. Selectionprocessformeningitisclinicalpredictionrules. 510 D. M. Kulik et al.  Table 1. Study Characteristics Study Setting Rule Name n Study Type Age Population Outcomes Assessment CountryNo. of SitesBonsu, 2008 (47) ED Modified Bonsu 1107 Derivation 4 wk  18 y Children diagnosed with acuteviral or bacterial meningitis orchildren who underwent LP*Bacteria grown from CSF US 1Bonsu 2004 (50) ED Bonsu 142 Derivation 5 wk  18y Children diagnosed with acuteviral or bacterial meningitis orchildren who underwent LP*Bacteria grown from CSF US 1Chavanet 2007 (51) Ward Meningitest 175 Derivation 3 mos  15 y Childrenhospitalizedwith LP*and7 WBC/mL in CSFBacteria grown from CSF France 1Dubos 2006* (45) ED Bonsu 161 Validation 28 d  16 y Children with acute meningitis(CSF WBC $ 7/mm 3  )Bacteria grown from CSF France 1Dubos 2006* (45) ED BMS 151 Validation 28 d  16 y Children with acute meningitis(CSF WBC $ 7/mm 3  )Bacteria grown from CSF France 1Dubos 2006* (45) ED Oostenbrink 119 Validation 28 d  16 y Children with acute meningitis(CSF WBC $ 7/mm 3  )Bacteria grown from CSF France 1Dubos 2010* (46) ED Meningitest 198 Validation 29 d  18 y CSF WBC $ 7    10 6  /L and CSFculture/PCR or blood culturepositive and procalcitonin leveldoneBacteria grown from CSF 5 Europeancountries6Dubos 2010* (46) ED BMS 198 Validation 29 d  18 y CSF WBC $ 7    10 6  /L and CSFculture/PCR or blood culturepositive and procalcitonin leveldoneBacteria grown from CSF 5 Europeancountries6Fine 2007 (27) Ward Modified BMS 696 Derivation 29 d  19 y Children with a final diagnosis of meningitis who had LPperformedBacteria grown from CSFor CSF meningitis CSFWBC $ 7/mm withpositive blood cultureUS 1Nigrovic 2002 (2) Ward BMS 696 Derivation 29 d  19 y Children with a final diagnosis of meningitis who had LPperformedBacteria grown from CSF US 1Nigrovic 2007 (48) ED BMS 2903 Validation 29 d  19 y Children with a final diagnosis of meningitis who had LPperformedBacteria grown from CSF US 20Oostenbrink 2001 (43) ED Oostenbrink 286 Derivation 1 mos  15 y Children visiting the ED withmeningeal signsBacteria grown from CSF Netherlands 1Oostenbrink 2002 (44) ED Oostenbrink 74 Validation 2 mos  15 y Children visiting the ED withmeningeal signsBacteria grown from CSF Netherlands 1Oostenbrink 2004 (49) ED Oostenbrink 226 Validation 2 mos  15 y Children visiting the ED withmeningeal signsBacteria grown from CSF Netherlands 4BMS=BacterialMeningitisScore;CSF=cerebrospinalfluid;ED=emergencydepartment;LP=lumbarpuncture;PCR=polymerasechainreaction;WBC=whitebloodcellcount;US=United States.* Assessed the performance of more than one rule. D  o e  s T  h  i     s  C h  i    l     d H  a v  e B  a  c  t    e r  i     a l    M e ni    n  gi     t   i     s ?   5 1 1 
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