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