Infections are a major cause of death among critically ill patients.1 Early diagnosis and administration of antimicrobial agents for bacterial infections are paramount and have been shown to reduce morbidity and mortality in the pediatric and adult population.1–3 Therefore, assessment of the systemic inflammatory response to infection, crucial to management and outcome of these patients, is difficult with usual markers (ie, fever, leukocytosis, C-reactive protein). Even though a bacterial culture is the best method for diagnosing an infection, it does not indicate the host response well or differentiate between bacterial colonization and systemic complications like a systemic inflammatory response to infection or invasive bacterial infections.1 There are data demonstrating that procalcitonin (PCT), a precursor peptide of the hormone calcitonin,4 which rises specifically in bacterial processes,5 has utility in a wide range of adult bacterial infections.6,7 However, there are limited data on the general use of PCT in children and neonates. Therefore, the purpose of this study was to evaluate the utility of a cutoff value of 1 ng/mL as a marker of serious bacterial infection (SBI) in pediatric intensive care unit (ICU) patients.
MATERIALS AND METHODS
This was a single-center, retrospective study that was conducted in a 189-bed freestanding children’s tertiary care teaching hospital with 33 critical care beds that provide care for children with burns, trauma, congenital heart disease and children on extra corporeal membrane oxygenation. This study protocol was approved by the Medical Institutional Review Board.
All patients admitted to the pediatric ICU that had a PCT level obtained from December 1, 2011, through April 30, 2012, were included. After a literature review, in mid-2010, the use of PCT was adopted for use in patients admitted to any of the ICUs (eg, general ICU, cardiac ICU, burn ICU and step-down unit). There was no specific protocol, and PCT levels were obtained at the discretion of the primary critical care team caring for the patient in an effort to guide treatment and differentiate bacterial from nonbacterial infections. For the purpose of this study, a patient was considered to have a SBI if they had either a positive blood culture, a positive urine culture and a urinalysis with positive nitrites or leukocyte esterase and at least 10 white blood cells per high power field, a positive tracheal culture and gram stain with moderate or many white blood cells and a positive chest radiogram or a patient that received >5 days of therapeutic antibiotics. PCT concentrations were obtained using the VIDAS Brahms Mini-Vidas instrument (Biomerieux Inc, Durham, NC).
Demographic and clinical characteristics were compared between the groups with a student’s t test for continuous variables and a χ2, Fisher’s exact test or Mann-Whitney U test for noncontinuous variables. A 2-sided significance level of α = 0.05 was used to determine statistical significance. Simple linear regression and a correlation analysis were used to test the association between PCT and bacterial infection. A receiver operator characteristic curve was also generated. All analyses were performed using IBM SPSS Version 20 (SPSS Inc., Chicago, IL).
Two-hundred one patients with 332 PCT samples met inclusion criteria and were analyzed (Table 1). The median age of the population was 1.7 years (range 0 days to 24 years). Forty-seven (23.4%) patients had a positive bacterial culture and 63 (31.3%) patients had a positive viral culture leaving 91 (45.3%) patients without any positive culture in the population. Overall, 63 (31.3%) patients received a full treatment course of antimicrobials.
There were 75 (37.3%) patients with a PCT ≥ 1 ng/mL (Table 2). Of the patients with a PCT ≥ 1 ng/mL, 24 (32%) had a positive viral culture and 28 (37.3%) had a positive bacterial culture. The type of positive bacterial culture were as follows; 7 blood, 3 urine, 11 tracheal aspirate and 11 other. Forty-six (61.3%) patients with a PCT ≥ 1 ng/mL received a full treatment course of at least one antimicrobial. When evaluating PCT against all positive cultures, there was a positive correlation between a PCT ≥1 ng/mL and a positive bacterial culture, Spearman’s Rho = 0.253, P< 0.01. There was also a positive correlation between a PCT ≥1 ng/mL and receiving a treatment course of antimicrobials (Spearman’s Rho = 0.48, P < 0.01). There was no correlation between PCT and a positive viral culture, Spearman’s Rho = 0.04, P = 0.56. Logistic regression analysis demonstrated that a PCT ≥1 ng/mL predicted having a SBI, odds ratio = 1.18, 95% confidence interval: 1.07–1.49. A PCT ≥ 1 ng/mL exhibited a positive predictive value (PPV) of 28%, a negative predictive value of 93%, a sensitivity of 70% and a specificity of 68%. A receiver operator curve curve was generated and demonstrated a PCT of 1.45 ng/mL as the optimal cut-point with a PPV of 30%, a negative predictive value of 93%, a sensitivity of 72% and a specificity of 75%
For the 7 patients with positive blood cultures, the mean PCT value was 26.6 ng/mL. In the subset of patients with positive blood cultures, the lowest PCT value was 1.8 ng/mL and no patient with a positive blood culture had a PCT value < 1 ng/mL. There were 15 patients that had positive cultures labeled as other, which included pleural fluid/tissue, pericardial fluid, wounds and one patient that was polymerase chain reaction positive for pertussis through nasopharyngeal swab. The mean PCT value in this group was 12.1 ng/mL. Of 15 patients in the other classification, 3 (20%) had PCT values < 1 ng/mL. Of these 3 patients, 2 had positive wound cultures and the last patient was pertussis positive. There were 20 patients that had positive tracheal aspirate cultures with no radiographic evidence of pneumonia and no other positive bacterial cultures. The mean PCT in this subgroup was 5.28 ng/mL and 12 (60%) had a PCT < 1 ng/mL and 8 (40%) had a PCT ≥ 1 ng/mL.
Of the 201 patients, 53 had a PCT value obtained for the primary purpose of determining whether antimicrobials should be started or broadened from their current regimen. Of these 53 patients, 46 (87%) did not have antimicrobials started or broadened based on the results of the PCT and did not clinically deteriorate necessitating escalation of care with antimicrobials at a later point in time during their hospitalization.
There is a growing body of literature using PCT in adults but the data using PCT within the pediatric population is relatively limited to a few distinct populations such a febrile neutropenia, young febrile infants, pediatric urinary tract infections and appendicitis.8–10 More recently, a PCT guided study was reported in the setting of pediatric community-acquired pneumonia.11
The use of PCT in a pediatric ICU setting is limited to neonatal sepsis and neonates post-cardiopulmonary bypass for surgical correction or palliation from congenital heart disease.12,13 Our hypothesis, a PCT of 1 ng/mL, would be useful in discriminating for SBI; however, after performing a receiver operator curve analysis, a PCT cutoff of 1.45 ng/mL demonstrated the same negative predictive value of 93% with enhanced sensitivity, specificity and PPV. The low PPV of 30% could be partially explained by several factors. First, as a pediatric tertiary/quaternary referral center, we may experience decreased diagnostic sensitivity of any culture since many are drawn after receipt of anti-microbials prior to transfer. Second, the ability of microbial testing methodologies to return a positive result could greatly affect the ability to acquire a positive culture. One adult study evaluated the etiology of illness in patients with severe sepsis admitted through the emergency department14 found that 55% of adult patients identified, admitted and treated for severe sepsis had negative culture results. Many factors can influence the yield of a blood culture but the single most important factor is blood volume. When the volume of blood submitted for culture is inadequate, a negative blood culture result is potentially misleading in falsely excluding significant bacteremia.15 Lastly, initial procalcitonin levels in viral infections can be elevated, which is likely demonstrated in this cohort with levels for patients with known virus who were not treated with antibiotics were elevated with a mean (standard deviation) of 1.97 (3.58) and a median of 0.6 mg/mL (range 0–16.7)
This was a retrospective investigation and as such has all the attendant limitations associated with retrospective studies. Also, this study was performed as a single-center, retrospective study and, as such causation cannot be inferred, nor generalization to other pediatric hospitals or settings recommended.
Our data suggest PCT can assist in identifying patients without SBI and may help guide when to limit antimicrobial use. In addition, when a patient has a worsening clinical course in the face of a low PCT, other diagnostic possibilities than SBI for that clinical deterioration should be evaluated.
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