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Procalcitonin Use in a Pediatric Intensive

Care Unit
Article in The Pediatric Infectious Disease Journal April 2014
DOI: 10.1097/INF.0000000000000370 Source: PubMed

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2 authors:
Jeffrey Cies

Arun Chopra

Drexel University College of Medicine

NYU Langone Medical Center

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The Pediatric Infectious Disease Journal Volume 33, Number 9, September 2014

Cies and Chopra

ACKNOWLEDGMENTS
The authors wish to thank Dr. Stephen Druhan of the
Department of Radiology of Nationwide Childrens Hospital for his
assistance in reviewing the cardiac MRI.
REFERENCES
1. Schutze GE, Jacobs RF. Bartonella species (cat-scratch disease). In: Long
SS, Pickering LK, Prober CG, eds. Principles and Practice of Pediatric
Infectious Diseases. 4th ed. Philadelphia: Elsevier; 2012:856861.
2. Spach DH, Kaplan SL. Microbiology, epidemiology, clinical manifestations, and diagnosis of cat scratch disease. In: Rose BD, ed. UpToDate.
Waltham: UpToDate; 2013.
3. Holmberg M, Wesslen E, Hjelm C, et al. Bartonella spp. in a 60 year-old
Swedish male with myocarditis who succumbed to sudden death [Abstract
31]. In: Program and abstracts of the 13th Sesquiannual Meeting of the
American Society for Rickettsiology. Champion, PA. September 2124, 1997.
4. Meininger GR, Nadasdy T, Hruban RH, et al. Chronic active myocarditis
following acute Bartonella henselae infection (cat scratch disease). Am J
Surg Pathol. 2001;25:12111214.
5. Wesslen L, Ehrenborg C, Holmberg M, et al. Subacute Bartonella infection in Swedish orienteers succumbing to sudden unexpected cardiac
death or having malignant arrhythmias. Scand J Infect Dis. 2001;33:
429438.
6. Pipili C, Katsogridakis K, Cholongitas E. Mycocarditis due to Bartonella
henselae. South Med J. 2008;101:1186.
7. Skouri HN, Dec W, Friedrich MG, et al. Non-invasive imaging in myocarditis. J Am Coll Cardiol. 2006;48:20852093.
8. Kobayashi D, Aggarwal S, Kheiwa A, et al. Myopericarditis in children:
elevated troponin I level does not predict outcome. Pediatr Cardiol.
2012;33:10401045.
9. Holmes AH, Greenough TC, Balady GJ, et al. Bartonella henselae
endocarditis in an immunocompetent adult. Clin Infect Dis. 1995;21:
10041007.

PROCALCITONIN USE IN A PEDIATRIC

INTENSIVE CARE UNIT
Jeffrey J. Cies, PharmD, MPH, BCPS-AQ ID,*
and Arun Chopra, MD
Abstract: We evaluated whether procalcitonin (PCT) might aid diagnosing
serious bacterial infections in a general pediatric intensive care unit population. Two-hundred and one patients accounted for 332 PCT samples. A
PCT 1.45ng/mL had a positive predictive value of 30%, a negative predictive value of 93% and a sensitivity of 72% and a specificity of 75%. These
data suggest PCT can assist in identifying patients without serious bacterial
infections and limit antimicrobial use.
Key Words: procalcitonin, critical care, pediatric
Accepted for publication April 4, 2014.
From the *St. Christophers Hospital for Children, Philadelphia, PA; Drexel
University College of Medicine, Philadelphia, PA; Alfred I duPont Hospital
for Children, Wilmington, DE; NYU Langone Medical Center, New York,
NY; and NYU School of Medicine, New York, NY.
This work, in part, was presented as an abstract at the 22nd Annual Pediatric Pharmacy Advocacy Group Meeting Indianapolis, IN, May 2013.
The authors have no funding or conflicts of interest to disclose.
Address for correspondence: Jeffrey J. Cies, PharmD, MPH, BCPS-AQ ID,
Critical Care and Infectious Diseases Clinical Pharmacist, St. Christophers
Hospital for Children, 3601 A Street, Philadelphia, PA 19134-1095. E-mail:
jeffrey.cies@gmail.com.
Copyright 2014 by Lippincott Williams & Wilkins
DOI: 10.1097/INF.0000000000000370

nfections 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.13 Therefore,

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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 1ng/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 childrens 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 students t test for continuous variables and a
2, Fishers exact test or Mann-Whitney U test for noncontinuous variables. A 2-sided significance level of =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).

RESULTS
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 1ng/mL
(Table2). Of the patients with a PCT 1ng/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 1ng/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 1ng/mL and
a positive bacterial culture, Spearmans Rho=0.253, P<0.01. There
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The Pediatric Infectious Disease Journal Volume 33, Number 9, September 2014

TABLE 1. Baseline Demographic Information

Characteristic
Sample
Median age(yrs), range
Admit diagnosis
Asthma
BSI
CNS
Heart disease
Other
PNA
Respiratory failure
Sepsis
Trauma
Mean PCT (ng/mL)
Max PCT (ng/mL)
Median PCT levels per patient (range)
# patients with > 1 PCT level, %
Positive bacterial culture, %
Blood, %
Urine, %
Respiratory, %
Other, %
Positive viral culture, %
Antibiotics > 5 days, %

Number, %
201
1.7 (0 days to 24 yrs)
36 (18)
6 (3)
4 (2)
25 (12)
14 (7)
40 (20)
46 (23)
28 (14)
2 (1)
6.44 (17.7)
190.3
1 (114)
65 (32.3)
47 (23.4)
7 (3.5)
6 (3)
27 (13.4)
15 (7.5)
63 (31.3)
63 (31.3)

BSI, blood stream infection; PNA, pneumonia; CNS, central nervous system process
(seizures, abscess); SD, standard deviation; yrs, years.

TABLE 2. Culture Breakdown for Patients With

PCT 1ng/mL
PCT 1

Number

# patients
Positive bacterial culture, %
Blood, %
Urine, %
Respiratory, %
Other, %
Positive viral culture, %
Positive bacterial and viral culture, %
Antibiotics > 5 days, %

75
28 (37.3)
7 (25)
3 (10.7)
11 (39.2)
11 (39.2)
24 (32)
7 (9.3)
46 (61.3)

was also a positive correlation between a PCT 1ng/mL and receiving a treatment course of antimicrobials (Spearmans Rho=0.48,
P<0.01). There was no correlation between PCT and a positive viral
culture, Spearmans Rho=0.04, P=0.56. Logistic regression analysis demonstrated that a PCT 1ng/mL predicted having a SBI, odds
ratio=1.18, 95% confidence interval: 1.071.49. A PCT 1ng/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 1.45ng/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 26.6ng/mL. In the subset of patients with positive
blood cultures, the lowest PCT value was 1.8ng/mL and no patient
with a positive blood culture had a PCT value < 1ng/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 12.1ng/mL. Of 15 patients in the other classification, 3 (20%)
had PCT values < 1ng/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
2014 Lippincott Williams & Wilkins

Procalcitonin

radiographic evidence of pneumonia and no other positive bacterial

cultures. The mean PCT in this subgroup was 5.28ng/mL and 12
(60%) had a PCT < 1ng/mL and 8 (40%) had a PCT 1ng/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.

DISCUSSION
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.810 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 1.45ng/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 0.6mg/mL (range 016.7)
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.
REFERENCES
1. Uzzan B, Cohen R, Nicolas P, et al. Procalcitonin as a diagnostic test for
sepsis in critically ill adults and after surgery or trauma: a systematic review
and meta-analysis. Crit Care Med. 2006;34:19962003.
2. Clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock: 2007 update from the American College of Critical Care
Medicine. Crit Care Med 2009;37:666688.
3. Muszynski JA, Knatz NL, Sargel CL, et al. Timing of correct parenteral antibiotic initiation and outcomes from severe bacterial community-acquired
pneumonia in children. Pediatr Infect Dis J. 2011;30:295301.

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The Pediatric Infectious Disease Journal Volume 33, Number 9, September 2014

4. Becker KL, Nyln ES, White JC, et al. Clinical review 167: Procalcitonin
and the calcitonin gene family of peptides in inflammation, infection, and
sepsis: a journey from calcitonin back to its precursors. J Clin Endocrinol
Metab. 2004;89:15121525.
5. Schneider HG, Lam QT. Procalcitonin for the clinical laboratory: a review.
Pathology. 2007;39:383390.
6. Castelli GP, Pognani C, Meisner M, et al. Procalcitonin and C-reactive protein during systemic inflammatory response syndrome, sepsis and organ
dysfunction. Crit Care. 2004;8:R234R242.
7. Clech C, Ferriere F, Karoubi P, et al. Diagnostic and prognostic value of procalcitonin in patients with septic shock. Crit Care Med. 2004;32:11661169.
8. Leroy S, Fernandez-Lopez A, Nikfar R, et al. Association of procalcitonin
with acute pyelonephritis and renal scars in pediatric UTI. Pediatrics.
2013;131:870879.
9. Lopez AF, Cubells CL, Garcia JJG, et al; the Spanish Society of Pediatric
Emergencies. Procalcitonin in pediatric emergency departments for the
early diagnosis of invasive bacterial infections in febrile infants: results of
a multicenter study and utility of a rapid qualitative test for this marker.
Pediatr Infect Dis J, 2003;22:895903.
10. Hatzistilianou M, Rekliti A, Athanassiadou F, et al. Procalcitonin as an
early marker of bacterial infection in neutropenic febrile children with acute
lymphoblastic leukemia. Inflamm Res. 2010;59:339347.

11. Esposito S, Tagliabue C, Picciolli I, et al. Procalcitonin measurements
for guiding antibiotic treatment in pediatric pneumonia. Respir Med.
2011;105:19391945.
12. Vouloumanou EK, Plessa E, Karageorgopoulos DE, et al. Serum procalcitonin as a diagnostic marker for neonatal sepsis: a systematic review and
meta-analysis. Intensive Care Med. 2011;37:747762.
13. Garcia IJ, Gargallo MB, Torn EE, et al. Procalcitonin: a useful biomarker
to discriminate infection after cardiopulmonary bypass in children. Pediatr
Crit Care Med. 2012;13:441445.
14. Heffner AC, Horton JM, Marchick MR, et al. Etiology of illness in patients
with severe sepsis admitted to the hospital from the emergency department.
Clin Infect Dis. 2010;50:814820.
15. Connell TG, Rele M, Cowley D, et al. How reliable is a negative blood culture result? Volume of blood submitted for culture in routine practice in a
childrens hospital. Pediatrics. 2007;119:891896.

ASSOCIATION BETWEEN BREAST-FEEDING AND

SEVERITY OF ACUTE VIRAL RESPIRATORY TRACT
INFECTION
Shanda Vereen, MSPH,* Tebeb Gebretsadik, MPH,
Tina V. Hartert, MD, MPH, Patricia Minton, RN,,
Kimberly Woodward, RN, BSN, Zhouwen Liu, MS,
and Kecia N. Carroll, MD, MPH*
Abstract: In a cross-sectional analysis of 629 mother-infants dyads, breastfeeding (ever vs. never) was associated with decreased relative odds of a
lower versus upper respiratory tract infection (adjusted odds ratio: 0.64;
95% confidence interval: 0.420.99). There was not a significant association between breast-feeding and bronchiolitis severity score or length of
hospital stay.
Key Words: breast-feeding, acute respiratory infection severity, upper respiratory tract infection, lower respiratory tract infection
Accepted for publication April 9, 2014.
From the *Department of Pediatrics; Division of General Pediatrics; Center for
Asthma and Environmental Health Research; Department of Biostatistics;
Department of Medicine; and Division of Allergy, Pulmonary and Critical
Care Medicine, Vanderbilt University School of Medicine, N
ashville, TN.
This work was supported by K01 AI070808, Thrasher Research Fund Clinical
Research Grant (TVH), NIH HL072471, and UL1 RR024975.
The authors have no other funding or conflict of interest to disclose.
Address for correspondence: Kecia N. Carroll, MD, MPH, Vanderbilt University
School of Medicine, 313 Oxford House, Nashville, TN 37232-4313. E-mail:
Kecia.carroll@vanderbilt.edu.
Copyright 2014 by Lippincott Williams & Wilkins
DOI: 10.1097/INF.0000000000000364

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cute viral respiratory infections (ARIs) are a leading cause of

infant morbidity.1 Although viral upper respiratory tract infections (URIs) are common in infancy; currently, there are no effective vaccines to prevent the most common viral etiologies of ARIs,
such as respiratory syncytial virus (RSV).2 Viral lower respiratory
tract infections (LRTIs) are a leading cause of hospitalizations during infancy in the United States2,3 and are associated with subsequent wheeze and asthma.3
Breast-feeding is a protective factor for ARI.4,5 Exclusive
breast-feeding has been associated with decreased risk of ARI;47
however, findings have been less consistent regarding partial breastfeeding.4,6,7 Our objective was to assess the association between history of breast-feeding (ever vs. never) and ARI severity in a cohort
of 629 mother-infant dyads enrolled in the Tennessee Childrens
Research Initiative (TCRI).

METHODS
We investigated the association between history of
breast-feeding and infant ARI severity, as measured by involvement of the lower respiratory tract and bronchiolitis severity
score, using a cross-sectional analysis of data from the TCRI
cohort.8 Briefly, TCRI is a prospective study of mother-infant
dyads designed to assess the association between infant ARI
and childhood asthma.8 Participants were recruited from September through May 20042008 during an acute visit (ambulatory or inpatient) for a URI or LRTI. Term infants without
chronic medical conditions were eligible, with oversampling
for hospitalized infants.8 At enrollment, trained research personnel administered a structured questionnaire to collect data
on infant feeding, sociodemographics, medical history, environmental exposures and family history. Informed consent was
obtained from the women. The Vanderbilt University Institutional Review Board approved the study.
Infants were classified as having a URI or LRTI based on
physician discharge diagnosis and chart review, with LRTI considered as more severe.8 Symptoms indicative of a URI included
fever, cough, congestion, hoarse cry, otitis media and/or rhinorrhea without lower respiratory symptoms. Infants with a LRTI
had symptoms including grunting, nasal flaring and/or chest wall
retractions, diffuse wheezing, rales or rhonchi. LRTI severity was
assessed using the ordinal bronchiolitis severity score (BSS) and
length of stay (LOS) for hospitalized infants. The BSS ranges from
0 to 12 (12 most severe) and scores (03) flaring/retraction, respiratory rate, wheezing and oxygen saturation.8 Length of hospital stay
was measured in days.8 Viral testing for RSV and other viruses was
conducted on infant nasopharyngeal specimens obtained at enrollment using RT-PCR.8
We obtained infant breast-feeding history using the questions, was your child ever breastfed? and If yes, for how long?
(specify in weeks). Responses were dichotomized as ever and
never breast-fed. Ever breast-fed was categorized by a history of any breast-feeding and the minimum duration recorded
was 1week. We derived current breast-feeding by report of breastfeeding with length reported as current. We a priori selected covariates based on association with breast-feeding and ARI severity,9,10
including: maternal factors (ethnicity/race, age, asthma, enrollment
year) and infant factors (estimated gestational age, birth weight,
age at enrollment, insurance, daycare attendance, secondhand
smoke exposure and siblings).
Univariate analyses compared breast-feeding and ARI
severity using Pearson 2 tests for categorical variables and Wilcoxon rank sum tests for continuous variables. We used multivariable regression models to investigate the association of
breast-feeding with ARI severity. When our regression sample
2014 Lippincott Williams & Wilkins