pediatrics 2014 page peds.2013 2112

DOI: 10.1542/peds.2013-2112; originally published online January 20, 2014;Pediatrics

Janssens, Monique Dehoux and Emmanuel BaronAnne-Laure Page, Nathalie de Rekeneire, Sani Sayadi, Sad Aberrane, Ann-Carole

Malnourished ChildrenDiagnostic and Prognostic Value of Procalcitonin and C-Reactive Protein in

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Diagnostic and Prognostic Value of Procalcitonin andC-Reactive Protein in Malnourished Children

WHATS KNOWN ON THIS SUBJECT: Biomarkers such asC-reactive protein (CRP) and procalcitonin are elevated inchildren with severe bacterial infections. Children with severemalnutrition are at increased risk of bacterial infections andearly markers for the diagnosis of infection in these children areneeded.

WHAT THIS STUDY ADDS: Despite elevated values in severelymalnourished children with invasive bacterial infection orinfectious diarrhea, CRP and procalcitonin have limited diagnosticvalue. CRP could predict death in these children with a goodnegative predictive value.

abstractBACKGROUND: Early recognition of bacterial infections is crucial fortheir proper management, but is particularly difcult in children withsevere acute malnutrition (SAM). The objectives of this study were toevaluate the accuracy of C-reactive protein (CRP) and procalcitonin(PCT) for diagnosing bacterial infections and assessing theprognosis of hospitalized children with SAM, and to determine thereliability of CRP and PCT rapid tests suitable for remote settings.

METHODS: From November 2007 to July 2008, we prospectively re-cruited 311 children aged 6 to 59 months hospitalized with SAM plusa medical complication in Maradi, Niger. Blood, urine, and stool cul-tures and chest radiography were performed systematically on admis-sion. CRP and PCT were measured by rapid tests and by referencequantitative methods using frozen serum sent to a reference labora-tory.

RESULTS: Median CRP and PCT levels were higher in children with bac-teremia or pneumonia than in those with no proven bacterial infection(P , .002). However, both markers performed poorly in identifyinginvasive bacterial infection, with areas under the curve of 0.64 and0.67 before and after excluding children with malaria, respectively. Ata threshold of 40 mg/L, CRP was the best predictor of death (81%sensitivity, 58% specicity). Rapid test results were consistent withthose from reference methods.

CONCLUSIONS: CRP and PCT are not sufciently accurate for diagnos-ing invasive bacterial infections in this population of hospitalized chil-dren with complicated SAM. However, a rapid CRP test could be usefulin these settings to identify children most at risk for dying. Pediatrics2014;133:e363e370

AUTHORS: Anne-Laure Page, PhD,a Nathalie de Rekeneire,MD, MSc,a Sani Sayadi, MD,b Sad Aberrane, MD,c

Ann-Carole Janssens, PharmD,b Monique Dehoux,PharmD, PhD,d and Emmanuel Baron, MD, MSca

aEpidemiology and Population Health, Epicentre, Paris, France;bEpidemiology and Population Health, Epicentre, Maradi, Niger;cMicrobiology Laboratory, Centre Hospitalier Intercommunal,Crteil, France; and dBiochemistry Laboratory, Bichat-ClaudeBernard Hospital, Paris, France

KEY WORDSmalnutrition, infectious diseases, C-reactive protein,procalcitonin, developing countries, Sahel, sensitivity, specicity

ABBREVIATIONSAUCarea under the curveCIcondence intervalCRPC-reactive proteinIBIinvasive bacterial infectionIQRinterquartile rangeNBIno proven bacterial infectionPCTprocalcitoninpocpoint-of-careROCreceiver operating characteristicSAMsevere acute malnutritionUTIurinary tract infection

Dr Page participated in the study design, carried out theanalyses, and drafted the initial manuscript; Dr de Rekeneireparticipated in the study design and in the elaboration of theplan of analysis, coordinated data collection in the eld, andreviewed and revised the manuscript; Dr Sayadi supervisedclinical data collection in the eld, participated in the datainterpretation, and reviewed and revised the manuscript; DrAberrane participated in the study design, gave expert opinionon all microbiology results, and reviewed and revised themanuscript; Ms Janssens coordinated the laboratory activitiesin the eld, supervised laboratory data collection, and revisedthe manuscript; Dr Dehoux coordinated data collection atHpital Bichat and participated in writing the initial manuscript;Dr Baron participated in the study conceptualization and thedata analysis, and critically reviewed the manuscript; and allauthors approved the nal manuscript as submitted.

www.pediatrics.org/cgi/doi/10.1542/peds.2013-2112

doi:10.1542/peds.2013-2112

Accepted for publication Nov 12, 2013

Address correspondence to Anne-Laure Page, PhD, Epicentre,8 rue Saint-Sabin, 75011 Paris, France. E-mail: [email protected]

(Continued on last page)

PEDIATRICS Volume 133, Number 2, February 2014 e363

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Childrenwithsevereacutemalnutrition(SAM)areat increasedriskof infectionsand malnutrition is estimated to be theunderlying cause of up to 10% of theglobal disease burden in children ,5years of age.1,2 In children hospitalizedwith SAM plus a medical complication,clinical diagnosis of infection is com-plicated by the paucity of clinical signs;classic symptoms of infection (eg, feverin response to bacteremia, or respi-ratory symptoms in children withpneumonia) are not always present inchildren with SAM, who instead oftenpresent with unspecic apathy.3,4 Fur-thermore, laboratory diagnostic ca-pacity is often limited in regions withthe highest burdens of malnutrition.Consequently, treatment is empirical,and broad-spectrum antibiotics arerecommended for all hospitalized chil-dren with complicated SAM.5 In thiscontext, biological markers would bevaluable clinical tools for identifyingchildren with bacterial infections, es-pecially invasive bacterial infections(IBIs), and children most at risk for dy-ing. To be useful in settings with little orno laboratory infrastructure, thesetools must be available as point-of-care(poc) tests.

During theacute phase response, levelsof many proteins in the blood increasein response to inammation, includingC-reactive protein (CRP) and procalci-tonin (PCT). CRP and PCT have beenshown to perform better than othertraditionally used markers, such asleukocyte counts, to differentiate be-tween serious bacterial infections andnonserious or viral infections, but theirdiagnostic accuracy remains contro-versial.610 Nevertheless, they are usedroutinely in some emergency depart-ments and critical care settings inindustrialized countries to identifypatients at high risk for serious bac-terial infections, due to the advantageof being fast and reducing the long waitfor bacteriology results, as well as

their ability to rule out serious bacte-rial infection, particularly for PCT.11,12

Although CRP and PCT have beeninvestigated extensively for differenttypes of infection in industrializedcountries, few studies have evaluatedtheir diagnostic and prognostic value inAfrican settings, where infection pro-les are different.1316 Malaria alsoleads to increased levels of thesemarkers,17,18 which compromises theirusefulness for identifying bacterialinfections in malaria-endemic coun-tries.14 In addition, SAM, particularlyedematous malnutrition, could be as-sociated with reduced levels of acute-phase proteins.19 However, to ourknowledge, the accuracy of CRP andPCT as markers of infection had not yetbeen studied in a population of chil-dren with SAM in Africa.

The aims of this study were to evaluate(1) the diagnostic and prognostic valueof CRP and PCT in identifying childrenwith bacterial infection and those mostat risk for dying, in a population ofchildren with complicated SAM hospi-talized in intensive care; and (2) thereliabilityofCRPandPCTrapid tests thatcould potentially be used in developingcountries with limited laboratory ca-pacity.

METHODS

Study Population

This work was a substudy of a larger,previously published study on theprevalenceof infections inchildrenwithSAM, conducted in an inpatient thera-peutic feeding center in Maradi, Niger.4

The study population consisted of allconsecutive children aged 6 to 59months with complicated SAM admit-ted to the ICU or transition phase of theinpatient therapeutic feeding center.Children who received antibioticswithin 7 days before admission wereexcluded. SAM was dened as weight-for-height ,3 z-score below themedian, by using the World Health

Organization Child Growth Standardsand/or mid-upper arm circumference,110 mm and/or bilateral edema.20,21

Complicated SAM was dened as SAMaccompanied by anorexia and/orkwashiorkor with major edema and/or another severe medical condition.All patients included in the study hada clinical examination on admission.Blood was systematically collected onthe day of admission (or next day in 4exceptions), urine and stool sampleswere systematically collected within48 hours of admission (72 hours in 3exceptions), and a chest radiographwas performed within 72 hours ofadmission. Two blood samples forculture were collected within 20 to 30minutes of each other and 1 mL ofeach was inoculated in blood culturebottles.4 Urine was collected usinga Foley catheter. Lumbar puncturewas performed when at least 1 clinicalsign of involvement of the centralnervous system was present.

Study Groups

Patients were categorized into 5 in-fection groups based on culture andradiograph results. In case of coin-fections, children were included in thegroup corresponding to the infectionmost likely to trigger the highest in-ammatory response. The bacteremiagroup was composed of children withgrowth of an unambiguous pathogen(Salmonella spp, Escherichia coli,Klebsiella spp, Citrobacter freundii,Haemophilus inuenzae, Pseudomonasaeruginosa, Staphylococcus aureus,Streptococcus pneumoniae, Strepto-coccus pyogenes) in blood culture. The1 child with bacteriology-proven bac-terial meningitis (H inuenzae) alsowas included in this group. The pneu-monia group included children withan alveolar consolidation on chestradiography and no bacteremia, re-gardless of clinical signs, as these areless reliable in children with SAM.3

Bacteremia and pneumonia were also

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grouped together as IBIs. The urinarytract infection (UTI) group includedchildren with a cytology- and culture-proven UTI and no bacteremia orpneumonia. The bacterial diarrheagroup was composed of children withdiarrhea and a bacterial agent identi-ed in stool, and no bacteremia, pneu-monia, or UTI. Finally, childrenwith noneof the above-mentioned laboratory-conrmed infections were included inthe group with no proven bacterial in-fection (NBI) if all other analyses (ie,blood, urine, stool culture, and chestradiography) were negative. Childrenwith inconclusive blood culture results(ie, positive blood culture with bacteriathat could be either a pathogen ora contaminant) and those for whomsome laboratory and/or radiographytests were not performed but all avail-able results were negative, were ex-cluded from these categories.

Laboratory Methods

Blood, urine, and stool cultures wereperformed and interpreted by usingstandard microbiological methods asdescribed elsewhere.4 For the di-agnosis of malaria, thick and thinsmears were stained with Giemsa 10%for 20 minutes and read by trainedtechnicians. Normal range values wereobtained from the Nelson Textbook ofPediatrics.22

CRPwasmeasured on site using a rapidimmunometric method (Nycocard CRPSingleTest;Axis-Shield,Dundee,Scotland)on whole venous blood. This rapidtest uses 5 mL of whole blood, serum,or plasma and provides quantitativeresults within a linear range between 5and 120 mg/L, and qualitative resultsoutside this range. PCT was measuredon site using a rapid immunochroma-tographic test (Brahms PCT-Q; BrahmsDiagnostica, Hennigsdorf, Germany)on 200 mL of plasma, giving semi-quantitative results (,0.5, 0.52, 210,.10 ng/mL). These rapid tests wereperformedand readby trained laboratory

technicians, following themanufacturersrecommendations.

Sera were stored at 80C and sentto the central laboratory of Bichat-Claude Bernard Hospital where mea-surements were performed by usingreference quantitative methods: time-resolved amplied cryptate emissiontechnology (Kryptorprocalcitonin; BrahmsDiagnostica, Hennigsdorf, Germany)for PCT and an immunoturbidimetricassay (Modular P; Roche Diagnostics,Mannheim, Germany) for CRP. Rapidand reference tests were performedindependently, with technicians blin-ded to the results of these and all otherndings.

Statistical Analysis

Double entry was done by using theEpiData 3.0 software (The EpiData As-sociation, Odense, Denmark) and ana-lyzedusingStata 11.0 (StataCorporation,College Station, TX).

Childrens characteristics and the val-ues of CRP and PCT level were com-pared across infection groups by usingx2, Fisher exact, and Kruskall-Wallistests.

Receiver operating characteristic (ROC)curves were plotted and areas underthe curve (AUC) estimated with 95%condence intervals (95% CI) by usingthe CRP and PCT values measured withreference quantitative methods. Dif-ferent cutoffs were determined to ten-tatively privilege either sensitivity(.80%; ruling out a condition) orspecicity (.80%; ruling in a condi-tion), or to maximize the Youden index(sensitivity + specicity 1). Thesecutoffs, or their closest practicalvalues (ie, values measured by theCRP or PCT rapid tests), were thenused to estimate the diagnostic ac-curacy (sensitivity, specicity, pre-dictive values, and likelihood ratios)of rapid tests to diagnose IBI, anybacterial infection, or to predictdeath.

The values within the CRP rapid testlinear range were compared with thereference values by using the concor-dance correlation coefcient. In addi-tion, to includeall available values in thecomparison, the values were catego-rized (,5, 520, 2040, 4080, 80120,and .120 mg/L) and compared by us-ing the unweighted and linearlyweighted k coefcients.

The PCT rapid test results were com-paredwith the values of the categorizedreference test by using the unweightedand linearly weighted k coefcients.

Ethical Considerations

Ethical approval was obtained fromthe National Ethics Committee of Nigerand the Comit de Protection desPersonnes, Ile de France XI, France.The study was conducted accordingto the principles expressed in theDeclaration of Helsinki. Written in-formed consent was obtained from allstudy participants parents or legalguardian.

RESULTS

Characteristics of the StudyPopulation

Between November 2007 and July 2008,311 children were included in thegeneral study, with a median age of 13months (interquartile range [IQR] 10 to24). There were no subject dropoutsduring the study. Of these, 31 childrendid not have enough serum to performthe pocCRP and pocPCT assays, 3 hadpocPCT but not pocCRP performed onsite, 27 had pocCRP but not pocPCT. Atotal of 261 sera were sent to Bichat-Claude Bernard Hospital for referencetesting, 5 of which were insufcient forperforming any assay and 2 were suf-cient for PCT but not CRP. Finally, thestudy population for the main analysisby using reference results consisted of256 children with a median age of 14months (IQR 10 to 24). Forty-two (16.4%)children had bilateral edema and,

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among the 214 children with maras-mus, the median weight for heightz-score was 3.8 (IQR 4.5 to 3.3),similar to the overall study populationdescribed elsewhere.4 Of these 256children, 21 (8.2%) died, similar to theproportion in the overall cohort. Noneof the 3 HIV-infected children of theoverall cohort were included in ourstudy population.

A total of 51 children could not beclassied in the infection groups; 19were excluded because of inconclusiveblood culture results (9 Leuconostocspp, 2 Enterococcus faecalis, 2 En-terococcus faecium, 1 Streptococcusequinus, 1 Gemella morbillorum, 3positive by Gram stain but no sub-culture), and another 32 children hadnegative but incomplete analyses (Sup-plemental Table 6).

The characteristics of the remaining205 children and infection groups areshown in Table 1. Overall, 68.8% (141/205) of the children presented witha bacterial infection. There were sig-nicant differences in the presence offever, acute diarrhea, and severe de-hydration among the groups. There

was no signicant difference in theproportions of children with hyper-leukocytosis.

Levels of CRP and PCT in EachGroup

Compared with the NBI group, CRP andPCT levels were signicantly higher inthe bacteremia and the pneumonia, butnot the UTI group (Table 2). Levels ofCRP, but not PCT, were signicantlyhigher in the bacterial diarrhea groupthan in the NBI group. Thirteen of the 20children in this group had Shigella sppisolated from their stools; these chil-dren had high CRP values, with a me-dian of 108 mg/L (IQR 35 to 172),compared with a median of 25.9 mg/L(IQR 1 to 111) in the remaining 7 chil-dren with Salmonella spp infection.

Diagnostic Value of CRP and PCT toIdentify Bacterial Infections

TheROCanalysis to assess the accuracyof CRP and PCT for diagnosing bacter-emia, IBI, or any bacterial infectionshowed low to moderate AUCs, evenafter excluding children with malaria(Table 3 and Fig 1). Accordingly, the

optimal cutoffs maximizing the Youdenindex for the tests showed moderatetheoretical sensitivities and specic-ities (Table 4).

Agreement Between On-Site RapidTests and Reference Method

Within the linear range of the pocCRPrapid test (n = 151), the concordancecoefcient between the pocCRP valuescompared with the reference valuesindicated strong agreement (r = 0.91,95% CI 0.880.94). When categorized(n = 244), pocCRP and reference valuesshowed moderate agreement when us-ing the unweightedk coefcient (69.7%)but good agreement when using thelinear weighted k coefcient (92.3%).The pocPCT values compared with thereference PCT values showed moderateagreement when estimated by using theunweighted k coefcient (69.8%) andgood agreement when using the linearweightedk coefcient (90.8%) (n = 232).

Performance of poc Tests forIdentifying IBIs

Table 5 summarizes the diagnosticperformances of pocCRP and pocPCT to

TABLE 1 Sociodemographic and Clinical Characteristics of Patients by Infection Group

Bacteremia (n = 44) RadiographProvenPneumonia, n = 56

UTI, n = 22 Infectiousdiarrhea, n = 19

NBI, n = 64 P Valuea

Gender: male, n (%) 22 (50.0) 27 (48.2) 14 (63.6) 11 (57.9) 41 (64.1) .38Age, mo, median [IQR] 15.5 [10 to 24] 16.5 [10 to 24] 11 [10 to 24] 20 [11 to 24] 15.5 [9 to 24] .54Malnutrition

Edema, n (%) 10 (22.7) 6 (10.7) 3 (13.6) 1 (5.3) 15 (23.4) .18z-score, median [IQR] 23.6 [4.3 to 3.3] 23.7 [4.5 to 3.2] 24.2 [5.0 to 3.5] 24.3 [5.1 to 3.9] 23.7 [4.6 to 3.2] .15

Albumin, median [IQR] 31 [21 to 36] 31 [25 to 38] 37 [25 to 42] 37 [25 to 40] 34 [25 to 41] .43Fever, n (%) 12 (27.3) 17 (30.4) 3 (13.6) 4 (21.10) 14 (21.9) .58Acute diarrhea, n (%) 26 (59.1) 24 (42.9) 17 (77.3) 19 (100.0) 34 (53.1) ,.001Severe dehydration, n (%) 1 (2.3) 2 (3.6) 2 (9.1) 2 (10.5) 0 (0.0) .041Fast breathing, n (%) 20 (45.5) 30 (53.6) 6 (27.3) 5 926.3) 22 34.4 .08SIRS, n (%) 23 (52.3) 30 (53.6) 9 (40.9) 7 (36.8) 29 (45.3) .64Lethargy, n (%) 19 (43.2) 17 (30.4) 10 (45.5) 11 (57.9) 17 (26.6) .06Hyperleucocytosis, n (%) 5 (12.5) 12 (24.0) 5 (22.7) 4 (21.0) 13 (21.3) .72Deaths, n (%) 7 (15.9) 2 (3.6) 3 (13.6) 1 (5.3) 3 (4.7) .11Coinfections, n (%)

Pneumonia 12 (27.3)UTI 11 (25.0) 4 (7.1)Infectious diarrhea 7 (15.9) 2 (3.6) 2 (9.1)Malaria 3 (6.8) 7 (12.5) 2 (9.1) 0 (0.0) 18 (28.6)

SIRS, systemic inammatory response syndrome.a P value from comparison across infection groups.


identify IBI or any bacterial infectionafter excluding children with malaria,using the cutoffs determined pre-viously (or the closest practical value).Both positive and negative predictivevalues remained low, regardless of thethreshold used.

Prognostic Value of CRP and PCT

Among the 256 children for whom CRPand PCTwere measured, both markerson admission were signicantly higher

in children who died than in those whosurvived (Table 2).

Both CRP and PCT (measured with thereference methods) had moderateperformances for the identication ofchildren at risk for dying, with AUC of0.69 (95% CI 0.590.80) and 0.73 (95% CI0.630.83), respectively. The optimalcutoff maximizing the Youden index inthe ROC curve was 41.5 mg/L for CRPand 0.59 ng/mL for PCT (Table 4). Usingcutoffs of 40 mg/L for CRP and 0.5 ng/

mL for PCT, each marker remainedsignicantly associated with death af-ter adjusting for age, gender, and al-bumin levels with odds ratios of 6.6(95% CI 1.431.2, P = .017) and 6.4 (94%CI 1.330.9, P = .020), respectively.

By using the pocCRP test on site, a cutoffof 40 mg/L showed the best perfor-mance for predicting death overall andparticularly for rulingout fatal outcomewith a good negative predictive value of97.4% (Table 5).

DISCUSSION

This study is, to the best of our knowl-edge, the rst to address the diagnosticand prognostic performances of theinammatory markers CRP and PCT ina population of children hospitalizedwith complicated SAM in an ICU inAfrica.

As shown in other contexts for well-nourished children,2325 or even somepopulations with immune decienciessuch as neutropenia,26 PCT and CRPlevels were elevated in our populationof children with SAM and IBIs (bacter-emia and pneumonia), although themedian values found here were lowerthan generally reported inwell-nourishedchildren. Acute pyelonephritis also hasbeen associated with increased CRPand PCT levels in children.27,28 Here, theUTIs could not be classied as upper orlower infections, as renal ultrasoundwas unavailable on site. Whether thelow CRP and PCTvalues in the UTI group

TABLE 2 Median CRP and PCT Reference Values by Infection Group or in Children Who Survived orDied

CRP, mg/L PCT, ng/mL

Median IQR P Valuea Median IQR P Valuea

Infection groupsBacteremia, n = 44 62.6 15.3 to 147.3 .0002 1.3 0.4 to 5.3 .0008Pneumonia, n = 56 40.8 16.1 to 126 .0014 0.7 0.3 to 5.2 .012UTI, n = 22 16.1 7.4 to 52.6 .74 0.5 0.2 to 4.5 .14Infectious diarrhea, n = 19 73.1 14.2 to 164.4 .0087 0.5 0.3 to 3.6 .1NBI, n = 64 12 4.5 to 46.6 ref 0.3 0.1 to 1.8 ref

DeathSurvived, n = 234 26.1 8 to 93.9 ref 0.5 0.2 to 2.8 refDied, n = 20 80.9 42.5 to 186.5 .004 2.2 0.7 to 13.4 .001

a P value for comparison with the group with NBI (Infection groups) or group that survived (Death).

TABLE 3 ROC Analyses Using CRP and PCT Values Measured With Reference Methods

CRP PCT

AUC 95% CI AUC 95% CI

AllBacteremia versus no bacteremia 0.63 (0.530.72) 0.62 (0.530.71)Invasive versus localized or no bacterial infection 0.64 (0.560.72) 0.64 (0.550.72)Bacterial versus no bacterial infection 0.66 (0.590.74) 0.65 (0.560.73)

No malariaBacteremia versus no bacteremia 0.64 (0.550.74) 0.63 (0.540.73)Invasive versus localized or no bacterial infection 0.67 (0.580.76) 0.67 (0.580.75)Bacterial versus no bacterial infection 0.72 (0.630.80) 0.68 (0.590.77)

FIGURE 1ROC curve of the performances of CRP (black dots) and PCT (gray line) to detect bacteremia (A), IBIs (B), or any bacterial infection (C) after exclusion ofmalaria.

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reect limited response or a lowprevalence of acute pyelonephritisremains unclear. Finally, infectious di-arrhea was associated with elevatedlevels of CRP, but not PCT. Our data areconsistent with ndings that gastroin-testinal Shigella infection, and theresulting inammation,29 can lead toincreased CRP levels, as described inadults.30,31 Because diarrhea due toShigella spp requires antibiotic treat-ment, in contrast to most other di-arrhea etiologies, this suggests aninteresting possible use of CRP, whichshould be investigated further.

Despite these increased levels, thevalue of CRP and PCT for identifying

bacterial infections, or specically in-vasive infections, is lower in our studypopulation than in other studies frompediatric emergency departments orICUs,32 or from another study in Africanchildren (where the AUCs in the ROCanalysis were 0.81 and 0.86 for CRP andPCT, respectively).16 This nding wasconrmed within our study by the lowdiagnostic performances of the rapidtests, even after excluding malaria,which can be done in the eld usingmalaria rapid diagnostic tests. Wecould not identify a threshold withsufcient positive predictive value torule-in an IBI or with sufcient negativepredictive value to rule it out and

thereby avoid the use of unnecessaryantibiotics, or even to use as a screen-ing tool for children needing bloodculture, as proposed elsewhere.15

Combining both rapid tests alsofailed to improve classication (datanot shown).

The relationship between malnutritionand the acute phase inammatoryresponse remains unclear. Severalauthors have suggested that malnu-trition does not affect CRP productionin response to infections.33,34 In a studyin Malawi, although children withkwashiorkor had reduced rates ofprotein breakdown and synthesis,their CRP levels were similar to thosewithout kwashiorkor.35 To our knowl-edge, only 1 study found that CRPlevels in response to infection arelower in malnourished than in well-nourished children.36 In our study, allchildren were malnourished, andwe could not detect an associationbetween the level (z-score) or type(marasmus versus kwashiorkor) ofmalnutrition and CRP or PCT levels inthe group with IBIs (data not shown).However, the fact that the medianlevels of CRP and PCT in the childrenwith IBIs found here were lower thangenerally reported elsewhere in non-malnourished children, suggests re-duced responses to infection.

TABLE 4 Cutoffs and Corresponding Theoretical Sensitivity and Specicity Determined Using theROC Curves for Identifying Bacterial Infection or Predicting Death

CRP PCT

Cutoff, mg/L Se, % Sp, % Cutoff, ng/mL Se, % Sp, %

IBIsa

Rule-in, specicity .80% 85.0 37.3 80.0 2.2 40.0 80.0Rule-out, sensitivity .80% 13.7 83.2 49.2 0.3 81.1 43.1Youden index 13.7 83.2 49.2 0.4 71.1 56.9

Bacterial infectionsa


Deathb


Se, sensitivity; sp, specicity.a Children with malaria excluded, n = 173 for CRP, n = 175 for PCT.b Children with malaria included, n = 254 for CRP, n = 256 for PCT.

TABLE 5 Performance of On-site pocCRP and pocPCT Tests to Identify Invasive or Any Bacterial Infection or Predict Death Using Different Cut-offs

Sensitivity Specicity PPV NPV LR+ LR

% 95% CI % 95% CI % 95% CI % 95% CI % 95% CI % 95% CI

IBIsa

pocCRP $10 mg/L 84.5 75.891.1 27.8 17.939.6 61.2 52.469.5 57.1 39.473.7 1.17 0.991.38 0.56 0.311.01pocCRP $90 mg/L 39.2 29.449.6 86.1 75.993.1 79.2 65.089.5 51.2 42.060.4 2.82 1.515.28 0.71 0.590.85pocPCT $0.5 ng/mL 51.8 40.762.7 63.5 50.475.3 65.7 53.176.8 49.4 38.160.7 1.42 0.962.08 0.76 0.571.01pocPCT $2 ng/mL 34.1 24.245.2 77.8 65.587.3 67.4 51.580.9 46.7 36.956.7 1.54 0.892.66 0.85 0.691.04

Bacterial infectionsa

pocCRP $10 mg/L 82.5 75.188.4 32.1 19.946.3 75.8 68.282.5 41.5 26.357.9 1.21 0.991.48 0.55 0.320.93pocCRP $50 mg/L 46.7 38.155.4 81.1 68.090.6 86.5 76.593.3 37.1 28.346.5 2.48 1.384.45 0.66 0.540.81pocPCT $0.5 ng/mL 48.8 39.857.9 65.9 50.179.5 80.3 69.588.5 31.2 22.041.6 1.43 0.912.24 0.78 0.591.02pocPCT $2 ng/mL 34.4 26.143.4 84.1 69.993.4 86 73.394.2 31.1 22.940.2 2.16 1.054.45 0.78 0.650.93

Deathb

pocCRP $40 mg/L 81.0 58.194.6 58.6 52.364.7 13.8 8.321.2 97.4 93.599.3 1.96 1.522.52 0.33 0.130.79pocPCT $0.5 ng/mL 64.7 38.385.8 57.2 50.663.6 9.8 5.016.9 95.7 91.098.4 1.51 1.032.21 0.62 0.321.19

LR, likelihood ratio; NPV, negative predictive value; PPV, predictive positive value.a Children with malaria excluded, n = 190 for pocCRP and n = 169 for pocPCT.b Children with malaria included, n = 277 for pocCRP and n = 253 for pocPCT.


Increased CRP and PCT levels remainedfair indicators of condition severity, assuggested by their association withfatal outcome. This contrasts with datafrom a study on malnourished childrenin Bangladesh, which found that CRPwas not a predictor of death, but thenumber of children in this study wassmall and the cutoff level (10mg/L) wasnot very discriminatory.37 Here, thebest predictor of death was CRP witha threshold of 40 mg/L, and the pocCRPtest showed good performance forruling out the risk of fatal outcome inthe eld. Although this test requiressome equipment and manipulation, itcan be set up in a simple laboratoryand provide results rapidly.

Our study presented several limitations.One major challenge in evaluating bac-terial infectionmarkers is in constitutingappropriatecategories,andthevarietyofreference standards used in differentstudies probably partly explains thevariable results.32 Despite our effortsto establish an appropriate diagnosticlaboratory, the available tests andexaminations were limited, and manychildren had no laboratory-conrmed

diagnosis. In addition, multiple infec-tions were frequent in our study pop-ulation.4 Finally, the less-than-optimalsensitivity of blood cultures, and thehigh prevalence of bacterial infections inthis population,might have caused someserious infections to be misclassied,possibly leading to underestimation ofthemarkers performance. It also shouldbe noted that our study included allchildren regardless of fever, whereasmost other studies focus only on fe-brile children. Our rationale was thatchildren with SAM show indetermi-nate clinical signs, as illustrated bythe fact that fewer than a quarter ofthose with bloodstream infection hadfever.4 However, repeating the analysison the subset of febrile children did notchange our results signicantly (datanot shown).

CONCLUSIONS

The inammatory proteins CRP andPCT do not appear to be adequatemarkers of IBIs in a sub-Saharan Afri-can population of hospitalized childrenwith SAM plus medical complications,and therefore cannot help reduce an-

tibiotic use. Whether the markers lowperformances in this context are dueto malnutrition, high prevalence of in-fections, and/or other factors specicto this population, remains unclear.However, these markers could behelpful in identifying children most atrisk for dying, which could potentiallybe useful for triage purposes. Theavailability of a simple, reliable test formeasuring CRP makes it a good can-didate for such a use in settings withaccess to some laboratory capacity.

ACKNOWLEDGMENTSWe thank all the children who partici-pated in the study and their parents.We are grateful to all the personswho made the study possible, fromthe Mdecins Sans Frontires andEpicentre teams in Niger and Paris,as well as the Nigerien health au-thorities in Niamey and Maradi. Wethank Prof Dominique Gendrel, DrFabienne Nackers, and Dr RebeccaGrais for their critical review of themanuscript, as well as Dr PatriciaKahn for her helpful comments andcorrections.

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(Continued from rst page)

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright 2014 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The authors have indicated they have no nancial relationships relevant to this article to disclose.

FUNDING: Funded by Mdecins Sans Frontires, France.

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conicts of interest to disclose.


DOI: 10.1542/peds.2013-2112; originally published online January 20, 2014;Pediatrics

Janssens, Monique Dehoux and Emmanuel BaronAnne-Laure Page, Nathalie de Rekeneire, Sani Sayadi, Sad Aberrane, Ann-Carole

Malnourished ChildrenDiagnostic and Prognostic Value of Procalcitonin and C-Reactive Protein in

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