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Re: Procalcitonin as a prognostic marker in children with meningococcal septic shock

Dear Editor

We read with interest the paper from Carrol and coworkers who have demonstrated for the first time that procalcitonin (PCT), even it cannot be presented as a gold standard (7 % of false negative), is a promising marker of meningococcal disease (MCD) in children presenting with fever and rash.[1] Carrol et al. also observed that PCT level was significantly higher (p = 0.001) in children with severe MCD (37/64: 57.8 %) and higher but not significantly (p = 0.299) in those who died (7.8 %).[1] This confirms the findings from Karabocuoglu et al. who reported that PCT level was higher in children with severe meningococcemia (fever, petechia or purpura, and hemodynamic instability) than in children with systemic meningococcal infection without shock (291.29 ± 167 vs. 19.7 ± 23 ng/ml; p < 0.001). [2]

Unfortunately, regarding the children with severe MCD reported by Carrol et al.,[1] several information are missing: a clear definition of severe MCD (defined in their paper as a Glasgow Meningococcal Septicaemia Prognostic Score ³8), median PCT values of survivors and non-survivors and comparison in term of prediction of outcome between PCT level and generic or specific severity scoring systems. Thus, we would like to highlight that admission PCT level is an accurate predictor of mortality in the subgroup of children with meningococcal septic shock (MSS).

We have prospectively compared in 35 children (median age: 16 months; Q1: 9-Q3: 45) with MSS [defined as ecchymotic or necrotic purpura with shock needing fluid expansion (median for the first 24 hrs : 90 ml/kg; Q1- Q3: 48-120) and catecholamine infusion] admitted in our PICU between July 1999 and May 2002 the accuracy in predicting death of the PCT (immunoluminometric assay) and C reactive protein (CRP: nephelometry) [3] levels at admission, and the Pediatric Risk of Mortality (PRISM) score[4] within 24 hrs of admission or at the time of death. Sensitivity, specificity, positive and negative predictive values, and percentage of well-classified children were calculated at the following cutoff values: PCT > 130 ng/ml [the best cutoff value of the PCT level was determined by c2 optimisation (Fisher's test: p=0.0004)], CRP < 100 mg/l 3, PRISM value > 20 and PRISM probability of death > 50 %.[5] For each severity index, we calculated the area under the ROC curve (AUC) and the standard error (SE) [6] and determined the significance of comparisons.[7]

Eleven of 35 children died (31 %) while predicted mortality with the PRISM score was 15.6 (standardised mortality ration: 0.71; 95 % confidence interval: 0.35-1.26). The median (Q1-Q3) PCT and CRP levels and PRISM value and probability of death were the following: (survivors vs. nonsurvivors) PCT 73 (15-210) vs. 277 (208-606) ng/ml (p = 0.001); CRP 92 (44-160) vs. 72 (41-109) mg/l (p = 0.25); PRISM value 17 (8-22) vs. 33 (26 -37) (p < 10^-3); PRISM probability 19 (4-42) vs. 88 (63-95) % (p < 10^-3). Performance characteristics of PCT, CRP and PRISM score are given in the table.

In this study, the PCT level at admission was as accurate as the PRISM value and PRISM probability of death calculated within 24 hrs of admission or at the time of death, and more accurate than the CRP level for classifying survivors and nonsurvivors of MSS. These results are in accordance with those from Hatherill et al. who observed in 37 children with MSS that admission PCT level (values not indicated) was higher in nonsurvivors (11 %) than in survivors (p=0.04) and related to the severity of organ failure (p=0.02); however, in the whole group of children with septic shock whatever the causative organism, the admission PCT functioned worse than the PRISM score [AUC 0.73 (0.59-0.88) vs. 0.83 (0.71-0.93); statistical comparison not performed].[8]

The PRISM score is accepted worldwide in PICUs and has been reported to accurately predict outcome of meningococcal disease. [9, 10] However, as it needs a 24 hour observation period, it cannot be used as inclusion criterion for clinical trials. Admission PCT could represent a good alternative tool if further studies confirm its ability to predict mortality.

References

(1) Carrol ED, Newland P, Riordan FAI, Thomson APJ, Curtis N, Hart CA. Procalcitonin as a diagnostic marker of meningococcal disease in children presenting with fever and a rash. Arch Dis Child 2002;86: 282-5.

(2) Karabocuoglu M, Kaya O. Plasma procalcitonin levels correlated with the severity of systemic meningococcal disease in children. Crit Care Med 2000;28(Suppl.): A170.

(3) Leclerc F, Chenaud M, Delepoulle F, et al. Prognostic value of C-reactive protein level in severe infectious purpura: a comparison with eight other scores. Crit Care Med 1991;19:430-2.

(4) Pollack MM, Ruttimann UE, Getson PR. Pediatric risk of mortality (PRISM) score. Crit Care Med 1988;16:1110-6.

(5) Mok Q, Butt W. The outcome of children admitted to intensive care with meningococcal septicaemia. Intensive Care Med 1996;22:259-63.

(6) Hanley JA, McNeil BJ. The meaning and use of the area under a receiver operating characteristic (ROC) curve. Radiology 1982;143:29-36.

(7) Hanley JA, McNeil BJ. A method of comparing the areas under receiver operating characteristic curves derived from the same cases. Radiology 1983;148:839-43.

(8) Hatherill M, Tibby SM, Turner C, Ratnavel N, Murdoch IA. Crit Care Med 2000;28: 2591-4.

(9) Castellanos-Ortega A, Delgado-Rodriguez M. Comparison of the performance of two general and two specific scoring systems for meningococcal septic shock in children. Crit Care Med 2000; 28: 2967-2973.

(10) Leteurtre S, Leclerc F, Martinot A et al. Can generic scores (Pediatric Risk of Mortality and Pediatric Index of Mortality) replace specific scores in predicting the outcome of presumed meningococcal septic shock in children? Crit Care Med 2001; 29: 1239-1246.

Table Performance characteristics of PCT, CRP and PRISM score in 35 children with MSS

Send letter to journal:
Re: Procalcitonin as a marker of meningococcal disease

Dear Editor

We thank Professor Leclerc for his interest in our paper. We disagree with some of his comments, however.

Firstly, the definition of severe meningococcal disease (MCD) is defined in the methods section as a Glasgow Meningococcal Septicaemia Prognostic Score GMSPS >= 8.[1] This is a well recognised and validated definition,[2] and one that has been used as entry criteria for randomised controlled trials in MCD.[3]

Second, the aim of the study was to determine if procalcitonin (PCT) might be a useful marker of MCD in children presenting with fever and a rash, and not to use PCT for prediction of outcome.

The data that he presents are interesting, and we would be in general agreement with his findings. We have additional data on PCT in children with confirmed MCD, but as these data are being submitted for publication, we are unable to discuss it here.

Enitan D Carrol
Paul Newland
F Andrew Riordan
Alistair PJ Thomson
Nicola Curtis
C Anthony Hart

References

(1) Carrol ED, Newland P, Riordan FA, Thomson AP, Curtis N, Hart CA. Procalcitonin as a diagnostic marker of meningococcal disease in children presenting with fever and a rash. Arch Dis Child 2002;86:282-5. (2) Riordan FAI Marzouk O, Thomson APJ, Sills JA, Hart CA. Prospective validation of the Glasgow Meningococcal Septicaemia Prognostic Score. Comparison with other scoring methods. Eur J Paediatr 2002;In Press. 3. Levin M, Quint PA, Goldstein B, Barton P, Bradley JS, Shemie SD, et al. Recombinant bactericidal/permeability-increasing protein (rBPI21) as adjunctive treatment for children with severe meningococcal sepsis: a randomised trial. rBPI21 Meningococcal Sepsis Study Group. Lancet 2000;356:961-7.