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Biomarkers and Disease Severity in

Children With
Community-Acquired Pneumonia
Todd A. Florin, MD, MSCE,a Lilliam Ambroggio, PhD, MPH,b Cole Brokamp, PhD,c,d Yin Zhang, MS,c,d Mantosh Rattan, MD,e,f
Eric Crotty, MD,e,f Michael A. Belsky, MS,g Sara Krueger, BA,f Thomas N. Epperson, IV, BA,h Andrea Kachelmeyer, BS,d,i
Richard Ruddy, MD,d,i Samir S. Shah, MD, MSCEd,j

BACKGROUND:Host biomarkers predict disease severity in adults with community-acquired abstract


pneumonia (CAP). We evaluated the association of the white blood cell (WBC) count, absolute
neutrophil count (ANC), C-reactive protein (CRP), and procalcitonin with the development of
severe outcomes in children with CAP.
METHODS: We performed a prospective cohort study of children 3 months to 18 years of age with
CAP in the emergency department. The primary outcome was disease severity: mild
(discharged from the hospital), mild-moderate (hospitalized but not moderate-severe or
severe), moderate-severe (eg, hospitalized with receipt of intravenous fluids, supplemental
oxygen, complicated pneumonia), and severe (eg, intensive care, vasoactive infusions, chest
drainage, severe sepsis). Outcomes were examined within the cohort with suspected CAP and
in a subset with radiographic CAP.
RESULTS: Of 477 children, there were no statistical differences in the median WBC count, ANC,
CRP, or procalcitonin across severity categories. No biomarker had adequate discriminatory
ability between severe and nonsevere disease (area under the curve [AUC]: 0.53–0.6 for
suspected CAP and 0.59–0.64 for radiographic CAP). In analyses adjusted for age, antibiotic
use, fever duration, and viral pathogen detection, CRP was associated with moderate-severe
disease (odds ratio 1.12; 95% confidence interval, 1.0–1.25). CRP and procalcitonin revealed
good discrimination of children with empyema requiring chest drainage (AUC: 0.83) and
sepsis with vasoactive infusions (CRP AUC: 0.74; procalcitonin AUC: 0.78), although
prevalence of these outcomes was low.
WBC count, ANC, CRP, and procalcitonin are generally not useful to discriminate
CONCLUSIONS:
nonsevere from severe disease in children with CAP, although CRP and procalcitonin may
have some utility in predicting the most severe outcomes.

a WHAT’S KNOWN ON THIS SUBJECT: Prognostic tools are limited for children
Department of Pediatrics, Feinberg School of Medicine, Northwestern University and Division of Emergency
with community-acquired pneumonia (CAP). Host biomarkers, including
Medicine, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois; bDepartment of Pediatrics, C-reactive protein (CRP) and procalcitonin, have been shown to be
University of Colorado and Sections of Emergency Medicine and Hospital Medicine, Children’s Hospital Colorado, associated with severe clinical outcomes in adults with CAP. Data in children
Aurora, Colorado; cDivisions of Biostatistics and Epidemiology, iEmergency Medicine, and jHospital Medicine and are limited.
Infectious Diseases and eDepartment of Radiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio;
d
Department of Pediatrics, fCollege of Medicine, University of Cincinnati, Cincinnati, Ohio; gSchool of Medicine, WHAT THIS STUDY ADDS: White blood cell count, CRP, and procalcitonin are
University of Pittsburgh, Pittsburgh, Pennsylvania; and hSchool of Medicine, University of Louisville, Louisville, generally not useful to discriminate overall disease severity in children with
Kentucky CAP. CRP and procalcitonin may have utility in predicting the most severe
outcomes, but research is necessary to validate these findings.
Dr Florin conceptualized and designed the study, supervised participant enrollment and data
acquisition, performed the statistical analysis and interpreted the data, and drafted the initial To cite: Florin TA, Ambroggio L, Brokamp C, et al.
manuscript; Dr Ambroggio conceptualized and designed the study, supervised participant Biomarkers and Disease Severity in Children With
enrollment and data acquisition, and participated in data interpretation; (Continued) Community-Acquired Pneumonia. Pediatrics. 2020;145(6):
e20193728

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PEDIATRICS Volume 145, number 6, June 2020:e20193728 ARTICLE
Community-acquired pneumonia (CARPE DIEM) study was parent by using a structured
(CAP) is one of the most common a prospective cohort study of children questionnaire. Clinicians completed
serious infections in children, resulting aged 3 months to 18 years who a case report form assessing clinical
in a substantial number of emergency presented to the ED with signs and signs and severity impressions. Blood,
department (ED) visits and symptoms of lower respiratory tract urine, and/or nasopharyngeal swabs
hospitalizations.1 Accurate assessment infection (LRTI) and received a chest were collected at enrollment from
of disease severity is essential to radiograph (CXR) for clinical those who consented to collection of
clinical decision-making. Although the suspicion of CAP. The study was each specimen type. Complete blood
site-of-care decision is one of the most approved by the Cincinnati Children’s cell count, CRP and procalcitonin
important in the management of CAP, Hospital Medical Center (CCHMC) assays were performed within 1 hour
there are no validated prognostic tools Institutional Review Board. Written after blood collection. Clinicians
to assist with this determination. informed consent was obtained from caring for enrolled patients were
Biomarkers reflecting the host’s all legal guardians, and assent was blinded to all study laboratory test
response to an infection offer an obtained from children $11 years results, with the exception of values
objective measure of disease severity of age. from the complete blood cell count
that may improve prognostication of that warranted immediate action (eg,
For this analysis, we included
children with CAP. The white blood low hemoglobin level). Clinicians did
children aged 3 months to 18 years
cell (WBC) count and absolute not have access to CRP or
with signs and symptoms of LRTI
neutrophil count (ANC) are often procalcitonin test results in all cases.
who presented to the CCHMC ED
evaluated in children with CAP; Clinical data, including vital signs,
from July 2013 to December 2017,
medications, and interventions, were
however, WBC count was not had focal findings on a CXR indicating
associated with disease severity in 1 extracted from the electronic medical
suspected CAP (defined as CXRs with
study of children who were record. Patients received a follow-up
focal opacities documented by the
hospitalized.2,3 C-reactive protein (CRP) phone call ∼7 to 15 days after they
radiologist during the ED visit), and
is an acute-phase reactant produced in were discharged from the ED or
had blood drawn. LRTI was defined
hospital to assess disease course.
response to interleukin-6, an as $1 of the following: new or
inflammatory cytokine.4 Procalcitonin, different cough or sputum Given the variation in CXR
a 116–amino acid precursor of production, chest pain, dyspnea, interpretation, a subset of the cohort
calcitonin, is barely detectable in the tachypnea, or abnormal auscultatory with suspected CAP was defined as
blood of healthy individuals but findings.16 We excluded children having radiographic CAP, which was
increases in response to severe hospitalized for #14 days before the defined on the basis of the
bacterial infection, sepsis, and multiple- index ED visit, those with a history of evaluations of 2 independent study
organ dysfunction.5 Both CRP and aspiration or aspiration pneumonia, radiologists blinded to clinical
procalcitonin have been studied as and those with information after the study visit.
a means of differentiating viral from immunocompromising or chronic Radiographs were classified as
bacterial etiology; less work has been medical conditions that predispose to normal, definite/probable atelectasis,
done to understand their prognostic severe or recurrent pneumonia (eg, atelectasis versus pneumonia, or
abilities. Studies in adults with CAP immunodeficiency, chronic definite/probable pneumonia.
have revealed that these markers are corticosteroid use, chronic lung Radiographic CAP was defined as
associated with disease severity6–10 but disease, malignancy, sickle cell both radiologists classifying CXR
data in children remain limited.11–15 disease, congenital heart disease, findings as atelectasis versus
Our objective for this study was to patients dependent on tracheostomy, pneumonia or definite/probable
evaluate the association of these host and neuromuscular disorders pneumonia.17 In cases of
biomarkers with the development of impacting respiration). Patients disagreement, the attending
severe outcomes in a prospective enrolled within 30 days before the ED radiologist’s reading from the ED visit
cohort of children with CAP. visit were excluded to ensure was used as a tiebreaker. If there was
a distinct infection episode. persistent disagreement, consensus
was reached during an in-person
METHODS
Study Procedures meeting with the study radiologists.
Study Design, Setting, and Potential participants were identified
Participants by trained research coordinators. Outcome Measurements
The Catalyzing Ambulatory Research After informed consent, demographic The primary outcome, assessed after
in Pneumonia Etiology and Diagnostic and historical information were the ED visit, was disease severity.
Innovations in Emergency Medicine obtained from the patient and/or Mild disease was defined as discharge

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2 FLORIN et al
disease required at least 1 of the ORs to compare 3 groups: (1) mild
following: treatment in the ICU, versus mild-moderate, moderate-
positive-pressure ventilation severe, and severe, (2) mild and mild-
(including continuous positive- moderate versus moderate-severe and
pressure ventilation, bilevel positive- severe, and (3) nonsevere (mild, mild-
pressure ventilation, and intubation moderate, and moderate-severe) versus
with mechanical ventilation), severe disease in children with CAP and
vasoactive infusions, chest drainage, radiographic CAP. Proportional odds
extracorporeal membrane logistic regression models were used by
oxygenation, severe sepsis or septic considering disease severity an ordered
shock (by using validated factor, with proportionally similar
International Classification of differences in multiplicative risks
Diseases, Ninth Revision diagnosis between mild, mild-moderate, moderate-
codes), or death.18 severe, and severe disease states.
Multivariate models were adjusted for
Biomarker Measurements age (as a natural cubic spline with 3
WBC count and ANC assays were degrees of freedom), receipt of
performed on the CELL-DYN Sapphire antibiotics before arrival, and duration of
(Abbott Diagnostics, Lake Forest, IL). fever because these variables were
CRP assays were performed on the hypothesized a priori to affect biomarker
Dimension Vista 1500 (Siemens concentrations and disease severity
Medical Solutions USA, Inc, Malvern, outcomes. In addition, although receipt
PA) with a functional sensitivity of of IV fluids as an inpatient (bolus or
0.29 mg/dL. Procalcitonin was continuous for .12 hours) is often in
measured by using the VIDAS response to lack of oral intake or
B.R.A.H.M.S procalcitonin assay dehydration, the receipt of IV fluids may
FIGURE 1 performed on the MINI VIDAS also be due to other, sometimes arbitrary,
Study flow diagram. instrument (BioMerieux, Marcy- factors. Therefore, we performed
l’Étoile, France) with a functional sensitivity analyses with no IV fluid
sensitivity of 0.1 ng/mL. Biomarker variables in the composite outcome.
from the ED and not returning for measurements less than the limit of
hospitalization within 7 days. Mild- detection were replaced with We characterized the discriminatory
moderate disease was defined as estimates equal to the limit of ability of each biomarker by creating
those hospitalized (including those detection divided by the square root receiver operating characteristic (ROC)
initially discharged who were of 2.19 curves and calculating the area under
subsequently hospitalized within 7 the curve (AUC). Using an empirical cut
days) but not meeting moderate- Statistical Analysis point estimation method for
severe or severe criteria. Moderate- maximizing classification accuracy, we
The median biomarker
severe disease was classified as calculated the optimal threshold for
concentrations with 25th and 75th
hospitalization with at least 1 of the classification and calculated the
percentiles were reported.
following occurring as an inpatient: resulting test characteristics with 95%
Differences across outcome
receipt of at least 1 intravenous (IV) confidence intervals (CIs) at the
categories were tested by using
fluid bolus, continuous IV fluids for nearest point to the upper left corner of
a Wilcoxon rank test. Statistical tests
.12 hours, supplemental oxygen, the ROC curve. All analyses were
were not conducted if any outcome
broadening of antibiotics from repeated for the individual outcomes
category had a prevalence of ,5%.20
aminopenicillin to any other included in the composite disease
antibiotic class, complicated Biomarker concentrations were log- severity outcome.
pneumonia (moderate-large pleural base-2 transformed for modeling
effusion, metastatic infection because they were right-skewed. Statistical computing was conducted
associated with pneumonia, lung Odds ratios (ORs) were thus in R (version 3.5.3; R Foundation for
abscess, or lung necrosis), or interpreted as the multiplicative Statistical Computing, Vienna,
presumed sepsis (systemic change in odds for a doubling of each Austria), SAS (version 9.4; SAS
inflammatory response syndrome biomarker concentration. Logistic Institute, Inc, Cary, NC), and Stata
with receipt of antibiotics and regression models were used to (version 14.2; Stata Corp, College
$40 mL/kg of IV bolus fluid). Severe calculate unadjusted and adjusted Station, TX).

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PEDIATRICS Volume 145, number 6, June 2020 3
RESULTS TABLE 1 Cohort Characteristics
A total of 1142 children were enrolled N = 477
in CARPE DIEM. Of these, 603 Age, y, mean (SD) 5.6 (4.6)
children had a focal CXR opacity and Male sex, n (%) 251 (52.6)
Race (n = 476), n (%)
477 had blood samples taken and
White 319 (67)
were included in this analysis. All 477 African American 128 (26.9)
children had a WBC count and ANC Other 29 (6.1)
performed; 456 children had CRP and Insurance (n = 475), n (%)
procalcitonin measurements Private 236 (49.7)
Public 231 (48.6)
performed. A total of 207 children
Self-pay 8 (1.7)
had radiographic CAP and blood Home antibiotics (n = 470), n (%) 189 (40.2)
drawn (Fig 1). The mean age of the Home antibiotic class, n (%)a
cohort was 5.6 years, and 52.6% (n = Aminopenicillin 106 (56.1)
251) of children were boys (Table 1). Cephalosporin 32 (16.9)
Macrolide 27 (14.3)
Of the 477 children included, 121 Other 48 (25.4)
Fever 418 (87.6)
(25.4%) had mild disease, 126 Duration of fever, d, mean (SD) 4.56 (4.85)
(26.4%) had mild-moderate disease, CXR results, n (%)b
179 (37.5%) had moderate-severe Normal 34 (7.1)
disease, and 51 (10.7%) had severe Definite or probable atelectasis 236 (49.5)
disease. There were no statistical Atelectasis versus pneumonia 39 (8.2)
Definite or probable pneumonia 168 (35.2)
differences in the median WBC count, Pathogen detected, n (%) 276 (57.9)
ANC, CRP level, or procalcitonin level Virus 248 (52.0)
across the 4 severity categories Rhinovirus or enterovirus 109 (22.9)
(Fig 2). In sensitivity analyses used to Respiratory syncytial virus 83 (17.4)
compare those with mild disease with Influenza 29 (6.1)
Parainfluenza 14 (2.9)
the rest of the cohort, those with mild Human metapneumovirus 23 (4.8)
and mild-moderate disease with Adenovirus 4 (0.8)
those with moderate-severe and Bocavirus 8 (1.7)
severe disease, and those with Coronavirus 10 (2.1)
nonsevere (ie, mild, mild-moderate, Mycoplasma pneumoniae 35 (7.3)
Typical bacteria 3 (0.6)
and moderate-severe) disease with Staphylococcus aureus 3 (0.6)
those with severe disease, results did Streptococcus pneumoniae 0 (0.0)
not change. When IV fluids were Disease severity, n (%)
removed from the composite Mild 121 (25.4)
outcome, results also did not change. Mild-moderate 126 (26.4)
Moderate-severe 179 (37.5)
Severe 51 (10.7)
Use of composite outcomes
a Patients may have been taking .1 class of antibiotic.
necessitates the examination of its b As determined by 2 radiologists independently assessing CXRs.
individual components. WBC count
and ANC were largely not associated
with the presence of most individual procalcitonin values were higher in [95% CI, 1.04–1.35]; mild 1 mild-
outcomes (Supplemental Table 4). children who had sepsis and required moderate versus moderate-severe 1
CRP and procalcitonin did reveal vasoactive infusions. severe: OR 1.12 [95% CI, 1.00–1.25]).
statistical association with several of Similarly, CRP was associated with
the components of the composite In analyses adjusted for age, disease severity of radiographic CAP
severity outcome. Small sample sizes antibiotic receipt before arrival, fever only when comparing mild severity with
precluded statistical testing on duration, and viral pathogen more severe groups (OR 1.23 [95% CI,
several individual outcomes; detection, WBC count, ANC, and 1.01–1.51]). In adjusted proportional
however, higher median values of all procalcitonin were not associated odds regression models of the ordinal 4-
biomarkers were found in children with disease severity in suspected or tiered severity outcome, WBC count and
who developed complicated radiographic CAP (Table 2). CRP was ANC were not associated with disease
pneumonia or received chest- modestly associated with disease severity, whereas CRP and procalcitonin
drainage procedures or positive- severity in suspected CAP (mild were modestly associated
pressure ventilation. Median CRP and severity versus more severe: OR 1.19 (Supplemental Table 5). In radiographic

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4 FLORIN et al
FIGURE 2
Blood biomarkers and disease severity. The median biomarker concentration is represented by the middle line in each box. The lower and upper
boarders of the box represent the 25th and 75th percentiles, respectively. A, WBC count (P = .24). B, ANC (P = .26). C, CRP (P = .6). D, Procalcitonin (P = .21).

CAP, none of the biomarkers were examined remained poor to fair


improved slightly in children with
associated with increasing severity in (Supplemental Tables 6 and 7).
radiographic CAP, particularly for WBC
adjusted analyses.
count, ANC, and procalcitonin. When the When test characteristics of
None of the 4 biomarkers examined had mild group was compared with all biomarkers for individual outcomes
adequate discriminatory ability (ie, AUC) others and when the mild and mild- were examined, WBC count and ANC
for severe versus nonsevere disease, moderate groups were compared with generally did not discriminate from
with only fair sensitivity and specificity the moderate-severe and severe groups, those who did and did not develop
(Table 3). Discriminatory ability test characteristics of all 4 biomarkers individual severe outcomes. CRP and

TABLE 2 Association of Biomarkers With Disease Severity in Children With CAP, Adjusted for Age, Receipt of Antibiotics Before Arrival, Fever Duration, and
Viral Pathogen Detected
Biomarker Suspected CAP, OR (95% CI) Radiographic CAP, OR (95% CI)
Mild Versus Mild- Mild 1 Mild-Moderate Mild 1 Mild- Mild Versus Mild- Mild 1 Mild-Moderate Mild 1 Mild-
Moderate 1 Versus Moderate- Moderate 1 Moderate 1 Versus Moderate- Moderate 1
Moderate-Severe Severe Moderate-Severe Moderate-Severe Severe Moderate-Severe
1 Severe 1 Severe Versus Severe 1 Severe 1 Severe Versus Severe
WBC count 1.06 (0.81–1.38) 0.95 (0.75–1.2) 1.3 (0.87–1.97) 1.11 (0.75–1.63) 1.05 (0.94–1.18) 1.13 (0.69–1.96)
ANC 1.06 (0.87–1.29) 1.01 (0.85–1.2) 1.31 (0.97–1.82) 1.11 (0.82–1.48) 1.11 (0.85–1.46) 1.14 (0.77–1.76)
CRP 1.19 (1.04–1.35) 1.12 (1.00–1.25) 1.22 (0.99–1.51) 1.23 (1.01–1.51) 1.08 (0.91–1.3) 1.28 (0.93–1.82)
Procalcitonin 1.11 (1.00–1.23) 1.06 (0.98–1.16) 1.13 (0.98–1.29) 1.11 (0.97–1.28) 1.05 (0.94–1.18) 1.15 (0.96–1.37)
Biomarkers were analyzed by using log2 transformation. OR is interpreted as the odds of developing the more severe outcome for every doubling of the biomarker value.

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PEDIATRICS Volume 145, number 6, June 2020 5
procalcitonin had moderately good such as mortality, complicated procalcitonin were associated with
ability to discriminate those who pneumonia, positive-pressure severe disease, as defined by the British
developed complicated pneumonia, ventilation, and inotropic support, Thoracic Society pneumonia guideline
required chest drainage, or received whereas others have revealed no criteria.14 However, at cutoffs of
vasoactive infusions (Supplemental association with severity or no value 1.04 mg/L for CRP and 0.093 ng/mL
Table 8). in adding CRP to existing clinical for procalcitonin, the sensitivity (77.2%
severity scores.6,7,22–24 Procalcitonin for CRP and 76.8% for procalcitonin),
has been shown to be superior to CRP specificity (41.2% for CRP and 57.7%
DISCUSSION
in predicting mortality and severe for procalcitonin), and discriminatory
We evaluated the association with outcomes in adults.9,21,25–28 Recently, performance (AUC: 0.58 for CRP and
and predictive ability for disease a large prospective cohort study of 0.65 for procalcitonin) for both
severity of 4 widely available 1770 adults revealed that markers were only fair. These previous
conventional host biomarkers (WBC procalcitonin was strongly associated studies were limited by smaller sample
count, ANC, CRP, and procalcitonin) with the risk of requiring invasive sizes, a focus on children who were
in a prospective cohort of children respiratory or vasopressor support.9 hospitalized, and use of outcomes that
with ED encounters for suspected or were either focused on specific entities
radiographic CAP. Biomarker levels (eg, pleural effusion) or were
Data regarding the association of host
did not differ by disease severity insensitive for predicting need for
biomarkers and severe disease in
overall, nor did any biomarker hospitalization (eg, the British Thoracic
children are limited and inconsistent.
adequately discriminate among
Studies revealed that both CRP and Society criteria).31
various degrees of severity. A modest
procalcitonin levels are elevated in
association was observed for CRP and
children with complicated compared In our study, we examined not only
disease severity in models adjusted
with uncomplicated CAP.29,30 Agnello complications of CAP, such as
for age, previous antibiotic use, fever
et al15 found that CRP, but not empyema or sepsis, but also more
duration, and viral pathogen
procalcitonin, was a predictor of common indicators of disease
detection. In individual clinical
pleural effusion in 119 hospitalized severity and requirements for
outcomes, host biomarker levels,
children with CAP 1 to 14 years old in hospitalization, such as use of IV
particularly CRP and procalcitonin,
Italy. In contrast, Stockmann et al12 fluids, supplemental oxygen, positive-
were higher in those who developed
found that increasing procalcitonin pressure ventilation, and broadening
rare, but serious, outcomes, including
levels were associated with ICU of antibiotics. We therefore looked at
empyema requiring chest-drainage
admission, empyema requiring chest CAP severity more broadly than most
procedures and sepsis requiring
drainage, and longer hospital length of previous studies by focusing on both
vasoactive infusions; however, we
stay in 532 hospitalized children with interventions and diagnoses that
cannot reach definitive conclusions.
CAP in the United States. In 100 required hospitalization. We found that
Consistent with previous literature, children with CAP, Don et al11 found CRP and procalcitonin were statistically
we found that WBC count has limited that procalcitonin levels were higher in associated with use of IV fluids and
ability to predict severity in children children who were hospitalized and that CRP was associated with
with suspected CAP.3,21,22 Studies of those with alveolar, as opposed to broadening of antibiotics. Interquartile
CRP and disease severity in adults interstitial, CAP. A study of 265 ranges (IQRs) were overlapping,
with CAP yield conflicting results.6,7 children 4 months to 14 years old making the clinical significance of these
Some studies have revealed that CRP hospitalized for suspected CAP differences unclear. Similar to previous
is associated with severe outcomes, revealed that both CRP and results, we also found elevated CRP

TABLE 3 Performance Characteristics of Biomarkers To Predict Severe Versus Nonsevere Disease in Children With CAP
Biomarker Thresholda AUC (95% CI) Sensitivity (95% CI) Specificity (95% CI) PPV (95% CI) NPV (95% CI) LR1 (95% CI) LR2 (95% CI)
Suspected CAP
WBC count 16.8 0.6 (0.54–0.67) 0.4 (0.28–0.54) 0.8 (0.77–0.84) 0.2 (0.13–0.28) 0.92 (0.89–0.94) 2.03 (1.42–2.91) 0.75 (0.6–0.92)
ANC 9.6 0.58 (0.51–0.64) 0.52 (0.38–0.65) 0.64 (0.6–0.68) 0.15 (0.1–0.2) 0.92 (0.88–0.94) 1.43 (1.09–1.87) 0.76 (0.58–0.99)
CRP 3.3 0.56 (0.48–0.63) 0.54 (0.39–0.68) 0.57 (0.48–0.63) 0.13 (0.09–0.19) 0.91 (0.87–0.94) 1.26 (0.96–1.67) 0.8 (0.59–1.1)
Procalcitonin 0.35 0.53 (0.46–0.61) 0.48 (0.34–0.62) 0.59 (0.54–0.64) 0.13 (0.09–0.19) 0.9 (0.86–0.93) 1.17 (0.86–1.58) 0.88 (0.67–1.16)
Radiographic CAP
WBC count (n = 206) 15 0.62 (0.51–0.73) 0.52 (0.31–0.73) 0.71 (0.64–0.78) 0.19 (0.1–0.3) 0.92 (0.87–0.96) 1.8 (1.15–2.83) 0.67 (0.43–1.04)
ANC (n = 206) 11.2 0.63 (0.52–0.74) 0.57 (0.35–0.77) 0.69 (0.62–0.76) 0.19 (0.1–0.3) 0.93 (0.87–0.96) 1.81 (1.19–2.76) 0.63 (0.39–1.02)
CRP (n = 200) 6.23 0.59 (0.47–0.7) 0.57 (0.34–0.78) 0.60 (0.53–0.68) 0.15 (0.08–0.24) 0.92 (0.86–0.96) 1.4 (0.95–2.2) 0.71 (0.43–1.18)
Procalcitonin (n = 205) 0.52 0.64 (0.53–0.76) 0.62 (0.38–0.82) 0.67 (0.6–0.74) 0.18 (0.1–0.28) 0.94 (0.88–0.97) 1.87 (1.26–2.77) 0.57 (0.33–0.99)
LR1, positive likelihood ratio; LR2, negative likelihood ratio.
a Empirical cut point estimation at the point closest to perfect sensitivity and specificity (ie, upper left-hand corner of the ROC curve).

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6 FLORIN et al
and procalcitonin levels in children severity outcomes. Finally, detailed outcomes) in which these biomarkers
with complicated pneumonia, clinical outcomes data allowed for improve current predictive ability,
empyema requiring chest drainage, examination of a breadth of severity allowing for targeted interventions in
positive-pressure ventilation, sepsis, outcomes. high-risk children.
and receipt of vasoactive infusions;
however, smaller numbers of children Our study also has several limitations.
with these outcomes precludes First, composite outcomes can be ACKNOWLEDGMENTS
definitive conclusions. challenging to interpret because of We acknowledge Judd Jacobs and
potential heterogeneity and the impact of Jessi Lipscomb for their role in data
Clinicians making site-of-care and initial individual outcomes on the whole. We management for the CARPE DIEM
treatment decisions often do not make performed several sensitivity analyses, study. Elizabeth Moneka provided
choices with a single individual outcome including proportional odds logistic administrative assistance in
in mind, but rather by considering regression and different groupings of the manuscript preparation. Stacey Tobin
a group of outcomes indicating the need severity outcomes, and found similar provided editorial support. We are
for hospitalization or focused therapies. results. We also analyzed each outcome grateful to the entire research team
Therefore, we believe it more clinically individually, although sample sizes were and patient services staff in the
relevant to examine disease severity as small for some. We cannot draw Divisions of Emergency Medicine and
a composite outcome encompassing definitive conclusions for these outcomes Hospital Medicine at CCHMC for their
many facets of severity. There were no (eg, severe sepsis). This was a single- assistance with study procedures.
differences in biomarker levels for center study, and results may not be Finally, we are especially grateful to
increasing degrees of severity. These generalizable; validation across centers is the patients and families who
biomarkers were not able to adequately important. Finally, we did not examine enrolled in the CARPE DIEM study.
discriminate children who would go on serial biomarker measurements, making
to develop more severe outcomes from us unable to draw conclusions on
those who would not. Our data suggest temporal changes or the impact of repeat
that CRP and procalcitonin may be useful studies during hospitalization on
in predicting the development of specific outcomes. Only 30 children had repeat ABBREVIATIONS
severe outcomes, such as complicated WBC count, CRP measurement, or ANC: absolute neutrophil count
pneumonia and sepsis. Given the higher procalcitonin measurement performed, AUC: area under the curve
negative predictive values (NPVs) of and many of the components of the CAP: community-acquired
these markers in discriminating severe composite outcome are not dependent pneumonia
from nonsevere disease, it may be these on these values (eg, development of CARPE DIEM: Catalyzing Ambula-
markers have a role in ruling out the complicated pneumonia and use of tory Research in
most severe outcomes. positive predictive value [PPV]), Pneumonia Etiology
Our study has several important therefore it is unlikely that these and Diagnostic
strengths. Our study is larger than repeated studies played a substantial Innovations in
most previous studies, and it began in role in the results. To account for illness Emergency
the ED (the setting of most site-of-care duration and the effect of antibiotic use Medicine
decisions) and included children on biomarker measurement, we adjusted CCHMC: Cincinnati Children’s
regardless of their disposition. We were for these in our multivariable analyses, Hospital Medical Center
also able to examine the role of these with similar results. CI: confidence interval
biomarkers in patients with clinically CRP: C-reactive protein
suspected CAP and the subset with CXR: chest radiograph
radiographic CAP, which is important CONCLUSIONS ED: emergency department
because CAP is often diagnosed Our results suggest that IQR: interquartile range
without a radiograph, yet radiographs conventionally measured biomarkers, IV: intravenous
are considered the current reference including CRP and procalcitonin, are LRTI: lower respiratory tract
standard for diagnosis. Our results are not generally useful for predicting infection
not substantively different between illness severity in children evaluated NPV: negative predictive value
those with suspected CAP and those for CAP in the ED. Given their high PPV: positive predictive value
with radiographic CAP confirmed by NPV, these markers may be helpful in OR: odds ratio
independent radiologist review. ruling out the most severe outcomes. ROC: receiver operating
Temporal associations may be inferred Further research is required to characteristic
because these biomarkers were understand if there are specific WBC: white blood cell
measured before occurrence of the clinical situations (eg, severe

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PEDIATRICS Volume 145, number 6, June 2020 7
Dr Brokamp and Mr Zhang performed the statistical analysis and interpreted the data; Drs Rattan and Crotty interpreted all chest radiographs and participated in
data interpretation; Mr Belsky, Ms Krueger, and Mr Epperson participated in data acquisition and interpretation; Ms Kachelmeyer supervised participant
enrollment, coordinated the study activities, and interpreted the data; Drs Ruddy and Shah conceptualized and designed the study and participated in data
interpretation; and all authors reviewed and revised the manuscript, approved the final manuscript as submitted, and agree to be accountable for all aspects of
the work.
DOI: https://doi.org/10.1542/peds.2019-3728
Accepted for publication Mar 13, 2020
Address correspondence to Todd A. Florin, MD, MSCE, Division of Emergency Medicine, Ann and Robert H. Lurie Children’s Hospital of Chicago, 225 E Chicago Ave, Box
62, Chicago, IL 60611. E-mail: taflorin@luriechildrens.org
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2020 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: Supported by the National Institutes of Health National Institute of Allergy and Infectious Diseases (K23AI121325 to Dr Florin and K01AI125413 to Dr
Ambroggio), the Gerber Foundation (to Dr Florin), the National Institutes of Health National Center for Research Resources, and the Cincinnati Center for Clinical
and Translational Science and Training (5KL2TR000078 to Dr Florin). The funders did not have any role in the study design, data collection, statistical analysis, or
manuscript preparation. Funded by the National Institutes of Health (NIH).
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

REFERENCES
1. Keren R, Luan X, Localio R, et al; acquired pneumonia. Clin Chem Lab 12. Stockmann C, Ampofo K, Killpack J, et al.
Pediatric Research in Inpatient Settings Med. 2015;53(4):559–566 Procalcitonin accurately identifies
(PRIS) Network. Prioritization of hospitalized children with low risk of
7. Hohenthal U, Hurme S, Helenius H, et al.
comparative effectiveness research bacterial community-acquired
Utility of C-reactive protein in assessing
topics in hospital pediatrics. Arch pneumonia. J Pediatric Infect Dis Soc.
the disease severity and complications
Pediatr Adolesc Med. 2012;166(12): 2018;7(1):46–53
of community-acquired pneumonia.
1155–1164
Clinical Microbiol Infect. 2009;15(11): 13. Wallihan RG, Suárez NM, Cohen DM,
2. Florin TA, French B, Zorc JJ, Alpern ER, 1026–1032 et al. Molecular distance to health
Shah SS. Variation in emergency transcriptional score and disease
8. Andrijevic I, Matijasevic J, Andrijevic L, severity in children hospitalized with
department diagnostic testing and
Kovacevic T, Zaric B. Interleukin-6 and community-acquired pneumonia. Front
disposition outcomes in pneumonia.
procalcitonin as biomarkers in Cell Infect Microbiol. 2018;8:382
Pediatrics. 2013;132(2):237–244
mortality prediction of hospitalized
3. Williams DJ, Zhu Y, Grijalva CG, et al. patients with community acquired 14. Esposito S, Di Gangi M, Cardinale F,
Predicting severe pneumonia outcomes pneumonia. Ann Thorac Med. 2014;9(3): et al; Ita-CAP Study Group. Sensitivity
in children. Pediatrics. 2016;138(4): 162–167 and specificity of soluble triggering
e20161019 receptor expressed on myeloid cells-1,
9. Self WH, Grijalva CG, Williams DJ, et al.
4. Luna CM. C-reactive protein in Procalcitonin as an early marker of the midregional proatrial natriuretic
pneumonia: let me try again. Chest. need for invasive respiratory or peptide and midregional
2004;125(4):1192–1195 vasopressor support in adults with proadrenomedullin for distinguishing
community-acquired pneumonia. Chest. etiology and to assess severity in
5. Becker KL, Nylén ES, White JC, Müller B, community-acquired pneumonia. PLoS
2016;150(4):819–828
Snider RH Jr.. Clinical review 167: One. 2016;11(11):e0163262
procalcitonin and the calcitonin gene 10. Bello S, Lasierra AB, Minchole E, et al.
family of peptides in inflammation, Prognostic power of 15. Agnello L, Bellia C, Di Gangi M, et al.
infection, and sepsis: a journey from proadrenomedullin in community- Utility of serum procalcitonin and
calcitonin back to its precursors. J Clin acquired pneumonia is independent of C-reactive protein in severity
Endocrinol Metab. 2004;89(4): aetiology. Eur Respir J. 2012;39(5): assessment of community-acquired
1512–1525 1144–1155 pneumonia in children. Clin Biochem.
2016;49(1–2):47–50
6. Zhydkov A, Christ-Crain M, Thomann R, 11. Don M, Valent F, Korppi M, et al.
et al; ProHOSP Study Group. Utility of Efficacy of serum procalcitonin in 16. Jain S, Williams DJ, Arnold SR, et al;
procalcitonin, C-reactive protein and evaluating severity of community- CDC EPIC Study Team. Community-
white blood cells alone and in acquired pneumonia in childhood. acquired pneumonia requiring
combination for the prediction of Scand J Infect Dis. 2007;39(2): hospitalization among U.S. children.
clinical outcomes in community- 129–137 N Engl J Med. 2015;372(9):835–845

Downloaded from www.aappublications.org/news at Ukraine:AAP Sponsored on May 13, 2020


8 FLORIN et al
17. Neuman MI, Monuteaux MC, Scully KJ, community-acquired pneumonia. BMC 27. Lacoma A, Rodríguez N, Prat C, et al.
Bachur RG. Prediction of pneumonia in Infect Dis. 2007;7:10 Usefulness of consecutive biomarkers
a pediatric emergency department. measurement in the management of
23. Chalmers JD, Singanayagam A, Hill AT.
Pediatrics. 2011;128(2):246–253 community-acquired pneumonia. Eur
C-reactive protein is an independent
J Clin Microbiol Infect Dis. 2012;31(5):
18. Balamuth F, Weiss SL, Hall M, et al. predictor of severity in community-
825–833
Identifying pediatric severe sepsis and acquired pneumonia. Am J Med. 2008;
septic shock: accuracy of diagnosis 121(3):219–225 28. Huang DT, Weissfeld LA, Kellum JA, et al;
codes. J Pediatr. 2015;167(6): GenIMS Investigators. Risk prediction
24. Krüger S, Ewig S, Papassotiriou J, et al;
1295–1300.e4 with procalcitonin and clinical rules in
CAPNETZ Study Group. Inflammatory
community-acquired pneumonia. Ann
19. Hornung RW, Reed LD. Estimation of parameters predict etiologic patterns
Emerg Med. 2008;52(1):48–58.e2
average concentration in the presence but do not allow for individual
of nondetectable values. Appl Occup prediction of etiology in patients with 29. Fonseca TS, Gendrel D, Ruuskanen O,
Environ Hyg. 1990;5(1):46–51 CAP: results from the German Nascimento-Carvalho CM. Pleural
competence network CAPNETZ. Respir effusion increases serum procalcitonin
20. Peduzzi P, Concato J, Kemper E, Holford
Res. 2009;10:65 values in children with community-
TR, Feinstein AR. A simulation study of
acquired pneumonia. Pediatr Infect Dis
the number of events per variable in 25. Krüger S, Ewig S, Marre R, et al;
J. 2015;34(8):914–915
logistic regression analysis. J Clin CAPNETZ Study Group. Procalcitonin
Epidemiol. 1996;49(12):1373–1379 predicts patients at low risk of death 30. Lahti E, Peltola V, Virkki R, Alanen M,
from community-acquired pneumonia Ruuskanen O. Development of
21. Park JH, Wee JH, Choi SP, Oh SH. The
across all CRB-65 classes. Eur Respir J. parapneumonic empyema in children.
value of procalcitonin level in
2008;31(2):349–355 Acta Paediatr. 2007;96(11):1686–1692
community-acquired pneumonia in the
ED. Am J Emerg Med. 2012;30(7): 26. Masiá M, Gutiérrez F, Shum C, et al. 31. Ambroggio L, Brokamp C, Mantyla R,
1248–1254 Usefulness of procalcitonin levels in et al. Validation of the British Thoracic
community-acquired pneumonia Society severity criteria for pediatric
22. Müller B, Harbarth S, Stolz D, et al. according to the patients outcome community-acquired pneumonia.
Diagnostic and prognostic accuracy of research team pneumonia severity Pediatr Infect Dis J. 2019;38(9):
clinical and laboratory parameters in index. Chest. 2005;128(4):2223–2229 894–899

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PEDIATRICS Volume 145, number 6, June 2020 9
Biomarkers and Disease Severity in Children With Community-Acquired
Pneumonia
Todd A. Florin, Lilliam Ambroggio, Cole Brokamp, Yin Zhang, Mantosh Rattan, Eric
Crotty, Michael A. Belsky, Sara Krueger, Thomas N. Epperson IV, Andrea
Kachelmeyer, Richard Ruddy and Samir S. Shah
Pediatrics originally published online May 13, 2020;

Updated Information & including high resolution figures, can be found at:
Services http://pediatrics.aappublications.org/content/early/2020/05/11/peds.2
019-3728
References This article cites 31 articles, 5 of which you can access for free at:
http://pediatrics.aappublications.org/content/early/2020/05/11/peds.2
019-3728#BIBL
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Biomarkers and Disease Severity in Children With Community-Acquired
Pneumonia
Todd A. Florin, Lilliam Ambroggio, Cole Brokamp, Yin Zhang, Mantosh Rattan, Eric
Crotty, Michael A. Belsky, Sara Krueger, Thomas N. Epperson IV, Andrea
Kachelmeyer, Richard Ruddy and Samir S. Shah
Pediatrics originally published online May 13, 2020;

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/early/2020/05/11/peds.2019-3728

Data Supplement at:


http://pediatrics.aappublications.org/content/suppl/2020/05/12/peds.2019-3728.DCSupplemental

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