Ballot, Daynia E

Cooper, Peter A

Galpin, Jacky

Perovic, Olga

South African Medical Journal (SAMJ)

ORIGINAL ARTICLES851October 2004, Vol. 94, No. 10  SAMJNeonatal sepsis presents a diagnostic problem, as the signs arenonspecific and there is no single reliable laboratory markeravailable on presentation to rule out sepsis.  Many babies areevaluated and treated for presumed sepsis with parenteralantibiotics while awaiting final culture results.  Less than 10%of these babies actually have sepsis, resulting in unnecessaryexpense and hospitalisation — of relevance in developingcountries with limited resources.  Inflammatory markersincluding interleukin 6 (IL6) and interleukin 8 (IL8), C-reactiveprotein (CRP) and serum amyloid alpha have been evaluatedas markers of neonatal sepsis with varying success.  The bestprediction is obtained using a combination of markers.  Serumprocalcitonin (PCT) is one of many inflammatory markers andis now available as a routine laboratory investigation.PCT is the prohormone of calcitonin and occurs in very lowconcentrations in the serum of healthy people. PCT ispreferentially induced in bacterial sepsis, especially in severesepsis and septic shock.1,2 PCT can therefore be used todiscriminate systemic inflammation due to bacterial sepsisfrom other causes and can also be used to monitor the progressand prognosis of patients with sepsis.1,3 PCT levels are higher innon-survivors and decline with a good response to antibiotictherapy.4  PCT has been used as a marker of bacterial sepsis inboth adult and paediatric patients, including neonates. The aim of the present study was to evaluate the role of PCTas a single early marker of neonatal sepsis.  Subjects and methodsThe study was conducted in the neonatal unit of JohannesburgHospital between April and August 2002.  All neonatesundergoing sepsis evaluation were eligible for inclusion in thestudy.  Evaluation for sepsis was done at the discretion of theattending physician for a variety of reasons including maternalrisk factors for sepsis (e.g. prolonged rupture of membranes,chorio-amnionitis, maternal pyrexia, maternal urinary tractinfection, foul-smelling liquor) and signs of neonatal sepsis,e.g. temperature instability, lethargy, feeding intolerance,seizures, ongoing respiratory distress, irritability, blood glucoseabnormalities, hypotension, poor perfusion, acidosis.  A babywas entered in the study after written informed consent wasobtained from the parent or guardian.  The routine sepsisevaluation included a full blood count (FBC) with total anddifferential white cell count (WCC), platelet count, CRP (CRP1)Serum procalcitonin as an early marker of neonatal sepsisDaynia E Ballot, Olga Perovic, Jacky Galpin, Peter A CooperBackground. It has recently been suggested that procalcitonin(PCT) is of value in the diagnosis of neonatal sepsis, withvarying results. This study was to evaluate the role of PCT asa single early marker of neonatal sepsis.Setting. Neonatal Unit, Johannesburg Hospital, andMicrobiology Laboratory, National Health Laboratory Service(NHLS), South Africa.Subjects and methods. Neonates undergoing evaluation forsepsis between April and August 2002 were eligible forinclusion.  Patients were categorised into ‘no infection’,‘possible infection’ and ‘definite infection’ on the basis of C-reactive protein (CRP), white cell count (WCC), plateletcount and blood culture results.  PCT was correlated withinfection categories.  Results. One hundred and eighty-three neonates wereenrolled.  One hundred and eighteen had no infection, 52possible infection and 13 definite infection.  PCT differedsignificantly among infection categories  (p < 0.0001) andcorrelated significantly with CRP at presentation (correlationcoefficient 0.404, p < 0.001) and CRP at 24 hours (correlationcoefficient 0.343, p < 0.001). PCT predicted 89.5% of definiteinfection. Receiver operating characteristic (ROC) analysis forPCT to predict definite infection showed odds ratio (OR)1.145 (95% confidence interval (CI): 1.05 - 1.25) with an areaunder the curve of 0.778.  PCT had a negative predictivevalue of 0.95 (95% CI: 0.915 - 0.988) for definite infection.Conclusions. Although PCT was significantly related to thecategory of infection, it is not sufficiently reliable to be thesole marker of neonatal sepsis.  PCT would be useful as partof a full sepsis evaluation, but is relatively expensive.  Anegative PCT on presentation may rule out sepsis, but thisneeds to be evaluated further.  S Afr Med J 2004; 94: 851-854.Department of Paediatrics, University of the Witwatersrand, JohannesburgDaynia E Ballot, PhD, FCP (Paed), MB BCh Peter A Cooper, PhD, FCP (Paed), MB BChDepartment of Clinical Microbiology and Infectious Diseases, National HealthLaboratory Service, University of the Witwatersrand, JohannesburgOlga Perovic, MD, DTM&H, FCPath (SA)Department of Statistics and Actuarial Science, University of the Witwatersrand,JohannesburgJacky Galpin, PhD, BScand blood cultures.  PCT was done at the time of presentationwith the initial sepsis evaluation. The CRP was repeated 24hours after presentation as per the unit policy (CRP2).Cerebrospinal fluid and urine cultures were done as clinicallyindicated at the discretion of the attending physician. Allbabies were started on parenteral antibiotics pending repeatCRP and/or final blood culture results.  If CRP2 remainednegative and the baby was clinically well, antibiotic therapywas discontinued and the baby discharged if eligible, as per theunit policy. AnalysisCategories of infectionBabies were grouped into different categories of infectionbefore obtaining the PCT results, as follows:No infection. Negative blood cultures with normal CRP1,CRP2, platelet count and WCC. As there is a high incidence ofmaternal problems including pregnancy-induced hypertensionand HIV infection, a single low platelet count or abnormalWCC was not considered to be a reliable marker of infectionand such babies would be classified as having no infection. Possible infection. Negative blood cultures with abnormalCRP1 and CRP2 or a combination of at least two of thefollowing: abnormal platelet count, WCC, CRP1 and CRP2.  Definite infection. Positive blood cultures with anyabnormal CRP1, CRP2, platelet count or WCC.Contamination. Positive blood cultures with normal CRP1,CRP2, platelet count and WCC.PCT levels were then compared between the differentcategories of infection.Statistical analysisDescriptive statistics included mean and standard deviation(SD) for continuous variables and proportions for categoricalvariables.  The distribution of the data was skewed so non-parametric statistics were used. Kruskal-Wallis one-wayanalysis of variance was done to determine whether anyvariables differed significantly among infection categories.Spearman’s rank correlation and logistical regression were alsodone to determine the best predictors of infection.  Receiveroperating characteristics (ROC) analysis was done to evaluatethe application of PCT as a diagnostic test for neonatalinfection.  Ethical considerationsThe Committee for Research on Human Subjects of theUniversity of the Witwatersrand approved the study.   Writteninformed consent was obtained from the parent or guardian ofthe infant before entering the study.  ResultsTwo hundred and sixteen patients were entered into the study— 28 were excluded because of incomplete data (e.g. missingblood culture results, no PCT levels obtained).  A further 5babies classified as having contaminated blood cultures werealso excluded. There were therefore 183 babies in the finalanalysis.  The mean birth weight was 1 996 g (SD 893 g) andgestational age 34.6 weeks (SD 4.3 weeks). The majority ofbabies (167/183) were evaluated for sepsis within the first 72hours of life.  There were 13 babies with definite infection, 52with possible infection and 118 with no infection (as definedabove). There were 13 positive microbial isolates including 3Klebsiella pneumoniae (1 with extended beta lactamase activity),3 coagulase-negative staphylococci, 1 Escherichia coli, 2Acinetobacter lwoffi, 1 Viridans streptococcus, 1 Streptococcusagalactiae, 1 Acremonium spp. and 1 Candida albicans. The PCTlevels for the various categories of infection are shown in Table I.One-way analysis of variance (Kruskal-Wallis) showed thatbirth weight (p = 0.001), gestational age (p = 0.0005) and PCT (p < 0.0001) differed significantly among the categories ofinfection.   (Note CRP1, CRP2 and platelet count were used todefine the different categories of infection and so are notincluded in the above analysis.) Spearman’s rank correlationshowed that PCT correlated significantly with CRP1 (p < 0.001correlation coefficient 0.404) and with CRP2 (p < 0.001correlation coefficient 0.343).Because of the likelihood that some babies in the ‘possibleinfection’ group were in fact infected,  logistical regression andROC analysis  was done using ‘no infection’ versus ‘anyinfection’ (possible/definite) and ‘no infection’ v. ‘definiteinfection’.   PCT alone correctly predicted 72.5% of anyinfection and 89.2% of definite infection.  If birth weight,gestational age and platelets were added into the equation, theprediction improved to 79.1% and 90.4% respectively.  Thepredictive values for PCT using a cut off of 0.5 ng/ml areshown in Table II. ROC analysis using PCT to predict ‘noinfection’ v. ‘any infection’ gave an odds ratio (OR) of 1.148(95% CIs 1.06 - 1.23) with an area under the ROC curve of 0.75(Fig. 1).  The OR for the prediction of PCT for ‘no infection’ v.‘definite infection’ was 1.145 (95% CI: 1.05 - 1.25).  The areaunder this ROC curve was 0.778 (Fig. 2).  Table I. Procalcitonin levels among the different infection categoriesPCT  Number of level (median)Category subjects (ng/ml) Range IQRNone 118 0.4 33.6 0.65Possible 52 2.55 187.6 10.05Definite 13 7.0 34.8 12.55IQR = interquartile range (non-parametric equivalent of standard deviation).October 2004, Vol. 94, No. 10  SAMJORIGINAL ARTICLES852ORIGINAL ARTICLES853October 2004, Vol. 94, No. 10  SAMJDiscussionThe value of PCT in the diagnosis of neonatal sepsis is stillunder evaluation. PCT has been shown to be useful in thediagnosis, prognosis and response to treatment of patients withneonatal sepsis.3,5 PCT may be a more reliable marker for earlyonset neonatal sepsis within the first 12 hours of life than eitherCRP or IL6.6,7  Also, umbilical cord blood PCT may be a usefulindicator in the diagnosis of early onset neonatal sepsis.8However, specific cut-off values of PCT may be required in thefirst 48 hours of life, as various maternal and perinatal factorsaffect the PCT level.9 However, Blommendahl et al.10 report thatPCT does not offer any advantage over more conventionalmarkers of sepsis in neonates, especially CRP and theimmature-to-total neutrophil ratio.  PCT has also been shownto have no value in predicting infection in paediatric patients.11Our results show that although PCT is reasonably predictiveof neonatal sepsis, it is not sufficiently reliable to be used as thesole marker of infection.  PCT would be useful as part of acomplete laboratory work-up for sepsis, rather than as a singlemarker, as suggested by Giamarellos-Bourboulis et al.3The negative predictive value for definite infection in ourstudy was 95%.  This is in agreement with Guibourdenche etal.12 who have suggested that a negative PCT on presentationmay be useful to rule out sepsis in neonates.  This approach issimilar to our current unit policy where we discontinueantibiotic therapy if the CRP2 (done at 24 hours) is negative.13The high negative predictive value of PCT may allow anegative PCT on presentation to rule out sepsis and limithospital stay and antibiotic use in neonates treated forsuspected sepsis. The PCT assay costs approximately R130compared with approximately R30 for CRP.  Potential savingsin antibiotic use and hospital admissions, however, couldbalance the relatively high cost of PCT.  This approach andpossible cost benefits need to be evaluated further before beingrecommended as standard management.Comments and criticismsThese data once again confirm the low incidence of actualinfection in neonates evaluated for sepsis and highlight thelarge numbers of babies unnecessarily treated for thiscondition.  A single reliable marker of infection at presentationwould solve this problem.  Unfortunately, our results do notconfirm that PCT is such a marker. Two of the isolates from the blood cultures in this study werefungal and not bacterial.  We did not exclude these results fromthe analysis, as these babies were clinically septic and PCT hasbeen reported to correlate with the severity and outcome offungal infection.14Babies were categorised into 3 groups of infection, ratherthan just present and absent infection as it is acknowledgedthat some babies with sepsis will have negative blood cultures.Therefore some of the babies with ‘possible’ sepsis will haveFig. 1. ROC analysis for ‘no infection’ v. ‘any infection’.Fig. 2. ROC analysis for ‘no infection’ v. ‘definite infection’.Table II. Predictive values for PCT < 0.5 ng/ml (95% CI)Infection category Sensitivity Specificity Positive predictive value Negative predictive valueNone v. any 0.78 0.5 0.46 0.8(0.725 - 0.844) (0.427 - 0.572) (0.391 - 0.535) (0.751 - 0.865)None v. definite 0.769 0.5 0.14 0.95(0.697 - 0.841) (0.414 - 0.586) (0.085 - 0.205) (0.915 - 0.988)actual sepsis.  The analysis using ‘no infection’ v. ‘anyinfection’ (possible and definite sepsis) and ‘no infection’  v.‘definite infection’ was done  to cover this possibility.Excluding the patients with possible infection would result inthe potential  exclusion of some patients with actual infection. Six of the organisms isolated in our study are of lowvirulence (Acinetobacter lwoffi, streptococci viridans andcoagulase-negative staphylococci (CoNS)).  These organismsmay contaminate blood cultures.  These isolates were regardedas significant in the present study because there were otherabnormal markers of infection.  Of interest is that the PCT levelwas low in 3 of these patients.  This may indicate that thesewere indeed contaminants, although the PCT response is lessmarked in low-virulence organisms.5ConclusionsOur results confirm the low incidence of culture-provenneonatal sepsis.  Although PCT is reasonably predictive ofneonatal sepsis, it is not sufficiently reliable to be used as thesole marker. PCT would be more useful as part of a full sepsisevaluation.  A negative PCT on presentation may be useful torule out sepsis, but this should be evaluated further.We wish to thank Humor Diagnostica Laboratories forproviding the kits for the PCT assay.References1. Meisner M. Pathobiochemistry and clinical use of procalcitonin. Clin Chim Acta 2002; 323: 17-29.2. Delevaux I, Andre M, Colombier M, et al. Can procalcitonin measurement help indifferentiating between bacterial infection and other kinds of inflammatory process? AnnRheum Dis 2003; 62: 337-340.3. Giamarellos-Bourboulis EJ, Mega A, Grecka P, et al. Procalcitonin: a marker to clearlydifferentiate systemic inflammatory response syndrome and sepsis in the critically ill patient?Intensive Care Med 2002; 28: 1351 - 1356.4. Athan F, Akagunduz B, Genel F, Bak M, Can D. Procalcitonin: a marker of neonatal sepsis.    JTrop Pediatr 2002; 48: 10 - 14. 5. Chiesa C, Pacifico L, Rossi N, Panero A, Matrunola M, Mansuco G. Procalcitonin as a markerof nosocomial infections in the neonatal intensive care unit. Intensive Care Med 2000; 26: S 175-178.6. Enguix A, Rey C, Concha A, Medina A, Coto D, Dieguez MA. Comparison of procalcitoninwith C reactive protein and serum amyloid for the diagnosis of bacterial sepsis in critically illneonates and children. Intensive Care Med 2001: 27: 211 - 215.7. Resch B, Gusenleitner W, Muller WD. Procalcitonin and interleukin 6 in the diagnosis ofearly onset sepsis of the neonate.  Acta Paediatr 2003; 92: 243-245.8. Kordek A, Giedrys-Kalemba S, Pawlus B, Podraza W, Czajka R. Umbilical cord blood serumprocalcitonin concentration in the diagnosis of early neonatal infection. J Perinatol 2003; 23:148-153.9. Chiesa C, Pellegrinin G, Panero A, et al. C reactive protein, interleukin 6 and procalcitonin inthe immediate postnatal period: influence of illness severity, risk status, antenatal andperinatal complications and infection. Clin Chem 2003; 49: 60 - 68. 10. Blommendahl J, Janas M, Laine S, Miettinen A, Ashorn P.  Comparison of procalcitonin withCRP and differential white blood cell count for diagnosis of culture-proven neonatal sepsis.Scand J Infect Dis 2002; 24: 620 - 622. 11. Korppi M, Remes S, Heiskanen-Kosma T.  Serum procalcitonin concentrations in bacterialpneumonia in children: A negative result in primary healthcare settings.  Pediatr Pulmonol2003; 35: 56 -61.12. Guibourdenche J, Bedu A, Petzold L, et al. Biochemical markers of neonatal sepsis: value ofprocalcitonin in the emergency setting. Ann Clin Biochem 2002; 39: 130 -135.13. Bomela HN, Ballot DE, Cory BJ, Cooper PA.  Use of C reactive protein to guide duration ofempiric antibiotic therapy in suspected early neonatal sepsis.  Pediatr Infect Dis J 2000; 19:531-535.14. Chrisofilopoulou S, Charvalos E, Petrikkos G.  Could procalcitonin be a predictive biologicalmarker in systemic fungal infections? Study of 14 cases. Eur J Intern Med 2002; 13: 493 - 495.Accepted 24 June 2004.October 2004, Vol. 94, No. 10  SAMJORIGINAL ARTICLES854

Serum procalcitonin as an early marker of neonatal sepsis

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Serum procalcitonin as an early marker of neonatal sepsis

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