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. CONCLUSIONS: WBC count, ANC, CRP, and procalcitonin are generally not useful to discriminate nonsevere from severe disease in children with CAP, although CRP and procalcitonin may have some utility in predicting the most severe outcomes.

WHAT’S KNOWN ON THIS SUBJECT: Prognostic tools are limited for children aDepartment 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, Childrens Hospital Colorado, associated with severe clinical outcomes in adults with CAP. Data in children c i j Aurora, Colorado; Divisions of Biostatistics and Epidemiology, Emergency Medicine, and Hospital Medicine and are limited. Infectious Diseases and eDepartment of Radiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; dDepartment 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

Downloaded from www.aappublications.org/news by guest on September 24, 2021 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 warranted immediate action (eg, that may improve prognostication of For this analysis, we included low hemoglobin level). Clinicians did children with CAP. The white blood children aged 3 months to 18 years not have access to CRP or cell (WBC) count and absolute with signs and symptoms of LRTI procalcitonin test results in all cases. neutrophil count (ANC) are often who presented to the CCHMC ED Clinical data, including vital signs, evaluated in children with CAP; from July 2013 to December 2017, medications, and interventions, were however, WBC count was not had focal findings on a CXR indicating extracted from the electronic medical associated with disease severity in 1 suspected CAP (defined as CXRs with record. Patients received a follow-up study of children who were focal opacities documented by the 2,3 phone call ∼7 to 15 days after they hospitalized. C-reactive protein (CRP) radiologist during the ED visit), and were discharged from the ED or is an acute-phase reactant produced in had blood drawn. LRTI was defined hospital to assess disease course. response to interleukin-6, an as $1 of the following: new or 4 inflammatory cytokine. Procalcitonin, different cough or sputum Given the variation in CXR a116–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 5 organ dysfunction. 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 6–10 associated with disease severity but disease, malignancy, sickle cell both radiologists classifying CXR 11–15 data in children remain limited. disease, congenital heart disease, findings as atelectasis versus Our objective for this study was to patients dependent on tracheostomy, pneumonia or definite/probable 17 evaluate the association of these host and neuromuscular disorders pneumonia. 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

Downloaded from www.aappublications.org/news by guest on September 24, 2021 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 fl PA) with a functional sensitivity of of IV uids 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 fl B.R.A.H.M.S procalcitonin assay dehydration, the receipt of IV uids 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 fl l’Étoile, France) with a functional sensitivity analyses with no IV uid 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 fi moderate disease was de ned 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 includedinthecompositedisease 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).

Downloaded from www.aappublications.org/news by guest on September 24, 2021 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, 596 Age, y, mean (SD) 5.6 (4.6) children had a focal CXR opacity and Male sex, n (%) 251 (52.6) 477 had blood samples taken and Race (n = 476), n (%) 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) performed. A total of 207 children Public 231 (48.6) 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) fl compare those with mild disease with In uenza 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 . necessitates the examination of its Patients may have been taking 1 class of antibiotic. 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

Downloaded from www.aappublications.org/news by guest on September 24, 2021 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.

Downloaded from www.aappublications.org/news by guest on September 24, 2021 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 Data regarding the association of host (eg, pleural effusion) or were did not differ by disease severity biomarkers and severe disease in insensitive for predicting need for overall, nor did any biomarker children are limited and inconsistent. hospitalization (eg, the British Thoracic adequately discriminate among 31 Studies revealed that both CRP and Society criteria). 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).

Downloaded from www.aappublications.org/news by guest on September 24, 2021 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. ACKNOWLEDGMENTS with these outcomes precludes First, composite outcomes can be 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 fi de nitive 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 fi in predicting the development of speci c 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- markershavearoleinrulingoutthe 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

Downloaded from www.aappublications.org/news by guest on September 24, 2021 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: tafl[email protected] 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, department diagnostic testing and severity in children hospitalized with Kovacevic T, Zaric B. Interleukin-6 and disposition outcomes in pneumonia. community-acquired pneumonia. Front procalcitonin as biomarkers in Pediatrics. 2013;132(2):237–244 Cell Infect Microbiol. 2018;8:382 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 9. Self WH, Grijalva CG, Williams DJ, et al. receptor expressed on myeloid cells-1, 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, 2016;150(4):819–828 community-acquired pneumonia. PLoS 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 by guest on September 24, 2021 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

Downloaded from www.aappublications.org/news by guest on September 24, 2021 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 2020;145; DOI: 10.1542/peds.2019-3728 originally published online May 13, 2020;

Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/145/6/e20193728 References This article cites 31 articles, 5 of which you can access for free at: http://pediatrics.aappublications.org/content/145/6/e20193728#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Emergency Medicine http://www.aappublications.org/cgi/collection/emergency_medicine_ sub Infectious Disease http://www.aappublications.org/cgi/collection/infectious_diseases_su b Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on September 24, 2021 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 2020;145; DOI: 10.1542/peds.2019-3728 originally published online May 13, 2020;

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