Community-Acquired Pneumonia Visualized on CT Scans but Not Chest Radiographs

Accepted Manuscript Community-acquired Pneumonia Visualized on Computed Tomography but Not Chest X-Ray: Pathogens, Severity, and Clinical Outcomes Cameron P. Upchurch, MD, Carlos G. Grijalva, MD, MPH, Richard G. Wunderink, MD, Derek J. Williams, MD, MPH, Grant W. Waterer, MBBS, PhD, Evan J. Anderson, MD, Yuwei Zhu, MD, MS, Eric M. Hart, MD, Frank Carroll, MD, Anna M. Bramley, MPH, Seema Jain, MD, Kathryn M. Edwards, MD, Wesley H. Self, MD, MPH PII:

S0012-3692(17)31392-2

DOI:

10.1016/j.chest.2017.07.035

Reference:

CHEST 1243

To appear in:

CHEST

Received Date: 4 May 2017 Revised Date:

5 July 2017

Accepted Date: 26 July 2017

Please cite this article as: Upchurch CP, Grijalva CG, Wunderink RG, Williams DJ, Waterer GW, Anderson EJ, Zhu Y, Hart EM, Carroll F, Bramley AM, Jain S, Edwards KM, Self WH, Communityacquired Pneumonia Visualized on Computed Tomography but Not Chest X-Ray: Pathogens, Severity, and Clinical Outcomes, CHEST (2017), doi: 10.1016/j.chest.2017.07.035. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Title: Community-acquired Pneumonia Visualized on Computed Tomography but Not Chest X-Ray: Pathogens, Severity, and Clinical Outcomes

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Authors: Cameron P. Upchurch, MD1; Carlos G. Grijalva, MD, MPH2; Richard G. Wunderink, MD3; Derek J. Williams, MD, MPH2; Grant W. Waterer, MBBS, PhD3,4; Evan J. Anderson, MD5; Yuwei Zhu, MD, MS2; Eric M. Hart, MD3; Frank Carroll, MD2; Anna M. Bramley, MPH6; Seema Jain, MD6; Kathryn M. Edwards, MD2; Wesley H. Self, MD, MPH2

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Affiliations: 1 Vanderbilt University School of Medicine, Nashville, TN; 2Vanderbilt University Medical Center, Nashville, TN; 3Northwestern University Feinberg School of Medicine, Chicago, IL; 4 University of Western Australia, Perth, Australia; 5Emory University School of Medicine, Atlanta, GA; 6Centers for Disease Control and Prevention, Atlanta, GA

Running Head: CT pneumonia

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Corresponding Author: Wesley H. Self, MD, MPH. Address: Department of Emergency Medicine, Vanderbilt University Medical Center, 1313 21st Ave South, 703 Oxford House, Nashville, TN 37232. Email: [email protected]

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Potential Conflicts of Interest: CGG reports serving as a consultant for Pfizer, Inc. RGW reports grants from CDC; funds to conduct clinical research from BioMerieux and Vertex Pharmaceuticals; and personal fees from BioMerieux and Visterra Inc. EJA reports funds to conduct clinical research from MedImmune and NovaVax; personal fees from AbbVie and non-financial support from Roche. DJW reports grants from CDC. KME reports grants from CDC and Novartis; and other from Novartis. WHS reports grants from CDC and personal fees from BioFire Diagnostics, Venaxis, Abbott Point of Care, Cempra Pharmaceuticals, and Ferring Pharmaceuticals. Other authors: nothing to disclose.

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Funding/Role of the Sponsors: This work was supported by a cooperative agreement with the Centers for Disease Control and Prevention (U18 IP000299). Investigators from the Centers for Disease Control and Prevent participated in the study as authors. CGG was supported in part by R01AG043471 from the National Institute on Aging. WHS was supported in part by K23GM110469 from the National Institute of General Medical Sciences. Previous Presentation: An abstract reporting preliminary data of this work was presented at the 2014 Society for Academic Emergency Medicine Annual Meeting in Dallas, TX. Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.

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ABSTRACT Background: The clinical significance of pneumonia visualized on computed tomography (CT) in the setting of a normal chest x-ray (CXR) is uncertain.

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Methods: In a multicenter prospective surveillance study of adults hospitalized with communityacquired pneumonia (CAP), we compared the presenting clinical features, pathogens, and

outcomes of patients with pneumonia visualized on CT but not on concurrent CXR (CT-only

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pneumonia) and those with pneumonia visualized on CXR. All patients underwent CXR; the decision to obtain CT imaging was determined by the treating clinicians. CXR and CT images

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were interpreted by study-dedicated thoracic radiologists blinded to clinical data. Results: The study population included 2,251 adults with CAP; 2,185 (97%) patients had pneumonia visualized on CXR while 66 (3%) had pneumonia visualized on CT but not concurrent CXR. Overall, these patients with CT-only pneumonia had a similar clinical profile to

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those with pneumonia visualized on CXR, including comorbidities, vital signs, hospital length of stay, prevalence of viral (30% vs 26%) and bacterial pathogens (12% vs 14%), intensive care unit admission (23% vs 21%), mechanical ventilation (6% vs 5%), septic shock (5% vs 4%), and

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in-hospital mortality (0 vs 2%).

Conclusions: Adults hospitalized with CAP who had radiologic evidence of pneumonia on CT

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but not concurrent CXR had similar pathogens, disease severity, and outcomes compared with patients who had signs of pneumonia on CXR. These findings support using of the same management principles for patients with CT-only pneumonia as those with pneumonia on CXR.

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INTRODUCTION Pneumonia continues to be a major cause of morbidity and mortality in adults, accounting for approximately 55,000 deaths, 1.2 million hospitalizations, and 1.7 million emergency

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department visits annually in the United States (US).1-3 The diagnosis of pneumonia is based on clinical features plus radiologic findings consistent with pulmonary infection.4 Traditionally, chest x-ray (CXR) has been the primary radiographic test used to evaluate for community-

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acquired pneumonia (CAP).4 However, the use of chest computed tomography (CT) to evaluate patients with acute respiratory symptoms has markedly increased during the past two decades as

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clinical practice has evolved to more commonly assess for non-infectious conditions, such as pulmonary embolism and aortic dissection, and to more thoroughly image the lungs for signs of pneumonia.5,6 CT is more sensitive than CXR for identifying radiologic signs of pneumonia, resulting in some patients having pneumonia visualized on CT but not on concurrent CXR (CT-

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only pneumonia).7-11

The clinical significance of radiologic signs of pneumonia visualized only on CT is largely unknown, creating uncertainty about whether these patients should be managed according

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to the same principles as those with pneumonia identified on CXR, or whether CT-only pneumonia is a distinct, less severe disease.12 The purpose of this study was to compare the

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pathogens detected, illness severity, and clinical outcomes of patients with CT-only pneumonia and those with pneumonia visualized on CXR among adults hospitalized with CAP.

MATERIALS AND METHODS This analysis was nested within the Centers for Disease Control and Prevention (CDC) Etiology of Pneumonia in the Community (EPIC) study, a multicenter prospective active

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surveillance study of patients hospitalized with CAP.13 Adults were enrolled from January 1, 2010 to June 30, 2012 at five hospitals, including three in Chicago, Illinois and two in Nashville, Tennessee. Institutional review boards at CDC and each enrolling hospital approved the study

from all enrolled patients or their representatives.

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Study Population

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(Vanderbilt University IRB# 091422). Informed consent for study participation was obtained

The EPIC study population of adults hospitalized with CAP has been previously

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described.13 In brief, adults (≥ 18 years old) were eligible if they were admitted to a study hospital, lived in a study catchment area surrounding each participating hospital, had clinical evidence of an acute respiratory infection, and radiologic signs of pneumonia as interpreted by a study-dedicated thoracic radiologist. Exclusion criteria included: recent hospitalization (within

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the previous 28 days for immunocompetent patients and within 90 days for immunosuppressed patients); nursing home resident not functionally independent; tracheostomy; gastrostomy; cystic fibrosis; cancer with neutropenia; solid organ or hematopoietic stem-cell transplant within the

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previous 90 days; active graft-versus-host disease; bronchiolitis obliterans; HIV infection with a CD4 cell count <200 mm3; and those with a non-pneumonia alternative diagnosis causing acute

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respiratory symptoms. The study population for the current analysis included adults in the EPIC study who had adequate etiology testing (≥ 1 test for bacteria and ≥ 1 test for viruses) and a CXR completed within 48 hours of enrollment.

Radiologic Evidence of Pneumonia

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Inclusion in the EPIC study required a CXR or CT within 48 hours before or after hospital admission demonstrating signs of pneumonia.13 The choice of chest imaging (i.e. whether to obtain chest CT in addition to or in lieu of a CXR) was made by the treating clinician

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independent of the study protocol. Initially, patients were enrolled based on interpretation of chest imaging as consistent with acute pneumonia by the clinicians or radiologists interpreting images for routine clinical care. Subsequently, all CXRs and CT scans obtained within 48 hours

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of admission were independently reviewed by a board-certified, study-dedicated thoracic

radiologist blinded to clinical data. The study included two thoracic radiologists (EMH, FC),

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with one reading images from the three Chicago hospitals and the other reading images from the two Nashville hospitals. These radiologists used the same protocol and data collection form when interpreting images and recording their findings. Available chest imaging prior to the current hospitalization was used to help distinguish between acute and chronic findings.

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Only patients with radiologic evidence of pneumonia on CXR and/or CT as interpreted by the study-dedicated radiologists were included in the final EPIC study population. Patients were classified as having CXR evidence of pneumonia if the radiologist identified a new

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consolidation (dense or fluffy opacity with or without air bronchograms), other infiltrate (linear or patchy alveolar or interstitial densities), or pleural effusion on any CXR completed within 48

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hours of hospital presentation.13,14 When interpreting CT scans, radiologists noted their global impression of whether the images were consistent with acute pneumonia by selecting one of four options: 1) no pneumonia, 2) possible pneumonia, 3) probable pneumonia, or 4) definite pneumonia. Patients were classified as having CT evidence of pneumonia if the radiologist indicated possible, probable or definite pneumonia.

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Study Groups for Comparison Patients with CT evidence of pneumonia and CXR without evidence of pneumonia were classified as having CT-only pneumonia. Patients with CXR evidence of pneumonia were

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classified as having CXR pneumonia regardless of whether CT was completed. Patients who were included in the EPIC study based on CT findings without a CXR completed within 48 hours of admission were excluded from the current analysis because the goal was to evaluate

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patients with pneumonia visualized on CT but not on concurrent CXR.

The primary analysis involved a comparison between CT-only pneumonia and CXR

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pneumonia. In secondary analyses, which were reported in supplemental tables, the CXR pneumonia group was divided into three subcategories—CXR pneumonia/CT not done; CXR pneumonia/CT pneumonia; and CXR pneumonia/ CT no pneumonia.

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Outcomes

Patients with CT-only pneumonia and CXR pneumonia were compared based on three categories: initial clinical characteristics and antibiotics received; pathogens detected; and short-

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term clinical outcomes.

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Initial Clinical Characteristics and Antibiotics Patient characteristics were systematically ascertained through patient interview and

medical record abstraction.13 Obesity was defined as a body mass index ≥ 30 kg/m2.15 Pneumonia severity scores, including the Pneumonia Severity Index (PSI),16 CURB-65,17 and American Thoracic Society Minor Criteria for Severe CAP,4 were calculated to summarize each patient’s condition at the time of initial hospital presentation. Patients with residual serum

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collected at hospital presentation also had serum procalcitonin measured for research purposes using the VIDAS BRAHMS PCT immunoassay kit (BioMerieux, Inc. Marcy l’Etoile, France).18,19 The lower limit of detection for this assay was 0.05 ng/ml. Procalcitonin results

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were not available to clinicians and not used for patient management. Prior research suggests a procalcitonin threshold of 0.25 ng/ml can help distinguish between viral and bacterial

infection20,21; therefore, procalcitonin was analyzed on a continuous scale and also dichotomized

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as < 0.25 ng/ml (low) versus ≥ 0.25 ng/ml (high). We also reported the proportion of patients who received antibiotics within 6 and 12 hours of hospital presentation, and the specific

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antibiotics used for initial empirical treatment, defined as antibiotics delivered on the first day of hospitalization, including those given in the emergency department.

Pathogens

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Biological specimens for pathogen detection were systematically collected from each patient as soon as possible after hospital presentation.13 Viral testing as part of the study protocol included real-time polymerase chain reaction (RT-PCR) of nasopharyngeal/oropharyngeal

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(NP/OP) swabs and paired acute and convalescent serology for respiratory viruses, including: adenovirus, coronaviruses (RT-PCR only), human metapneumovirus, human rhinovirus (RT-

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PCR only), influenza, parainfluenza, and respiratory syncytial virus.22-25 Bacterial testing as part of the study protocol included: blood cultures; sputum cultures (limited to high-quality samples26); urinary antigen tests for Streptococcus pneumoniae and Legionella pneumophila27,28; RT-PCR of NP/OP swabs for Chlamydophila pneumoniae and Mycoplasma pneumoniae, and of sputum for Legionella.29 Other respiratory samples, including endotracheal aspirates, pleural

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fluid, and bronchoalveolar lavage, obtained for routine clinical care also underwent bacterial culture.

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Clinical Outcomes

Clinical outcomes during the index hospitalization were ascertained by medical record abstraction.13 These outcomes included: hospital length-of-stay; intensive care unit (ICU)

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admission; invasive mechanical ventilation; vasopressor-dependent septic shock; moderate or severe acute respiratory distress syndrome (ARDS); and in-hospital mortality. Invasive

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mechanical ventilation was defined as new assisted ventilation through an endotracheal tube or tracheostomy. Vasopressor-dependent septic shock was defined as vasopressor administration by continuous infusion at any time during the first 72 hours of the pneumonia hospitalization. Moderate or severe ARDS was defined as meeting all the following criteria within 72 hours of

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hospitalization: bilateral pulmonary opacities, PaO2/FiO2 < 200 mm Hg, and respiratory failure not fully explained by cardiac failure.30

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Statistical Analysis

Outcomes were compared between patients with CT-only pneumonia and CXR

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pneumonia with the Wilcoxon rank-sum test for continuous variables and the Chi-squared or Fisher’s exact test for categorical variables, as appropriate. Analyses were performed with Stata (Version 12.1; StataCorp LP, College Station, TX).

RESULTS Study Population

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During the 2.5-year study period, 3,634 eligible patients were identified through prospective active surveillance; 2,251 (62%) of these patients were enrolled, had radiologic pneumonia confirmed by a study radiologist, underwent adequate etiologic testing, and had a

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CXR performed (study population for the current analysis) (Figure 1). All 2,251 included

patients underwent a CXR, and 748 (33%) had a concurrent CT scan. Compared with patients who did not undergo CT, those with a CT scan had similar vital signs but fewer comorbidities,

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were more likely to present with hemoptysis, shortness of breath, and chest pain, and had somewhat lower pneumonia severity scores (Supplemental Table 1-3).

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Sixty-six (3%) of the 2,251 included patients had CT-only pneumonia. All 66 of these patients had a CT scan within one calendar day of having a CXR that showed no signs of pneumonia, including 43 (65%) patients with a CT and CXR on the same day and 23 (35%) with a CT completed one calendar later than CXR. Among the 66 cases of CT-only pneumonia, the

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radiologist interpreted CT images as definite pneumonia in 34 (52%), probable pneumonia in 14 (21%), and possible pneumonia in 18 (27%) patients. Of the 2,251 included patients, 2,185 (97%) had CXR pneumonia. Among those with

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CXR pneumonia, 1,503 (69%) did not have a concurrent CT scan, 652 (30%) had pneumonia confirmed on CT, and 30 (1%) had a CT scan without evidence of pneumonia (Supplemental

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Tables 4-6).

Initial Clinical Characteristics and Antibiotics Overall, the presenting clinical profiles of patients with CT-only pneumonia and CXR

pneumonia were similar, including comorbidities, vital signs and laboratory results (Table 1). However, compared with the CXR pneumonia patients, CT-only pneumonia patients were

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younger, and more likely to present with chest pain, wheezing, and low-risk PSI categories I-II. BMI was also higher in the CT-only pneumonia group (median: 30 kg/m2) compared with the CXR pneumonia group (median: 27 kg/m2; p=0.02), thus leading to a higher proportion of

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patients in the CT-only pneumonia group meeting the definition for obesity (49% vs 36%; p=0.04). Serum procalcitonin concentrations were lower in the CT-only pneumonia group

(median: < 0.05 ng/ml; IQR: < 0.05, 0.11 ng/ml) compared with the CXR pneumonia group

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(median 0.16 ng/ml, IQR: < 0.05, 0.85 ng/ml); 18% of CT-only pneumonia patients had a procalcitonin > 0.25 ng/ml, compared with 41% of CXR pneumonia patients (p<0.01).

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A smaller proportion of CT-only pneumonia patients received antibiotics within six hours of hospital presentation than those with CXR pneumonia (59% vs 83%, p < 0.01), but results were similar by 24 hours (97% vs 96%, p=0.80) (Supplemental Table 7). Specific antibiotic regimens were quite similar for patients with CT-only pneumonia and CXR pneumonia, with ß-

groups (Table 2).

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Pathogens

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lactam plus macrolide and fluoroquinolone monotherapy regimens the most common in both

Pathogen detection was similar in the CT-only pneumonia and CXR pneumonia groups,

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with viruses being more commonly detected than bacteria in both groups (Table 3). The prevalence of major CAP pathogens, including S. pneumoniae, M. pneumoniae, Staphylococcus aureus, and influenza, were also similar between groups. However, the detection of human rhinovirus was more common in the CT-only pneumonia group than the CXR pneumonia group (17% vs 8%, p=0.02). Interestingly, two of the eight patients in the CT-only pneumonia group

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with bacterial pathogens detected had PCT < 0.25 ng/ml. Both of these patients had S. pneumoniae detected by urinary antigen test (Supplemental Table 8).

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Clinical Outcomes

Clinical outcomes, including hospital length of stay, ICU admission, mechanical

ventilation, and shock, were similar between CT-only pneumonia and CXR pneumonia (Table

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4). In-hospital death was rare in both the CT-only and CXR pneumonia groups (0 vs 2%).

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Description of CXR pneumonia/CT no pneumonia patients

Thirty patients (1.3% of the full study population, and 4.0% of patients who had a CT completed) had a CXR interpreted as consistent with pneumonia and a CT not consistent with pneumonia. Non-pneumonia abnormalities were identified on CT in each these patients that

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explained why a CXR may have been interpreted as consistent with pneumonia; these findings included: lymphadenopathy (13); pulmonary edema (5); atelectasis (3); pulmonary fibrosis (3); emphysema (3); pulmonary infarct (2); and post-surgical changes (1).

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Compared with the 652 patients who had both a CXR and CT scan interpreted as pneumonia, these 30 patients with CXR pneumonia/CT no pneumonia were older, more likely to

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have asthma or COPD, and had lower white blood cell counts (median: 8.9 vs 11.3 thousand cells/mcl) and lower procalcitonin concentrations (median: < 0.05 vs 0.15 ng/ml) (Supplemental Table 2). Bacterial pathogens and severe infection-related outcomes were rare in these 30 CXR pneumonia/CT no pneumonia patients. Only 4 (13.3%) of these patients had a detected pathogen, including two with parainfluenza virus, one with rhinovirus, and one with Fusobacterium necrophorum (Supplemental Table 5). The patient with F. necrophorum bacteremia presented

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with a two-day history of sore throat and was found to have a pulmonary infarct on CT, suggestive of Lemierre’s syndrome (bacterial pharyngitis, usually caused by F. necrophorum, associated thrombophlebitis of the internal jugular vein)31; this patient recovered with antibiotics

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and was discharged. None of these 30 CXR pneumonia/CT no pneumonia patients developed respiratory failure, septic shock or ARDS (Supplemental Table 4). One of these patients died—a patient with advanced liver disease and metastatic hepatocellular carcinoma who had a

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DISCUSSION

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pulmonary infarct visualized on CT.

In this cohort of 2,251 adults hospitalized with CAP, 66 had radiologic evidence of pneumonia on CT but not on concurrent CXR. Detailed evaluation of these 66 patients with CTonly pneumonia revealed similar illness severity, pathogens, and clinical outcomes compared to

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patients with radiologic pneumonia evident on CXR. These findings support managing patients with CT-only pneumonia according to the same principles as those with CXR pneumonia, including the selection of empirical antibiotics and site of care. Additionally, these results

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suggest pneumonia only visible on CT scan can be associated with significant physiologic abnormalities and morbidity, and hence, support using CT to evaluate for pneumonia when the

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clinical presentation is suggestive of pneumonia but an initial CXR does not demonstrate radiologic signs of pneumonia and identification of pneumonia as the cause of clinical symptoms is important. Examples of such a scenario may include patients with septic shock or fever with altered mental status but no clear source of infection after initial evaluation with a history, physical exam, laboratory work, and CXR.32-34

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Currently, nearly all adults hospitalized with CAP in the US are treated with antibiotics.13 However, only a minority of these patients have detectable bacterial pathogens.13 Hence, many antibiotic stewardship strategies are under development to identify patients who historically have

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been treated with antibiotics but are unlikely to benefit from them.20,35 Our results suggest that stewardship strategies are also needed for CT-only pneumonia. We found that 12% of patients with CT-only pneumonia had a bacterial pathogen; this prevalence is too high to recommend

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withholding antibiotics for all patients with CT-only pneumonia. However, similar to CXR pneumonia, a substantial portion of patients with CT-only pneumonia appear to have non-

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bacterial disease. While more research in this area is needed, stewardship strategies developed for CXR pneumonia, such as PCT-based algorithms for guiding antibiotic prescribing,20 may also be useful for CT-only pneumonia.

While patients with CT-only pneumonia and CXR pneumonia were largely similar, our

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analysis identified some potential differences that will be important to explore in future studies. For example, CT-only pneumonia appeared to be more common in obese patients, perhaps due to lower CXR sensitivity associated with x-ray beam attenuation by adipose tissues in obese

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patients.36,37 Also, CT-only pneumonia patients as a group appeared to have lower procalcitonin levels and a higher prevalence of human rhinovirus detection, suggesting that viral pathogens

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may be more common in CT-only pneumonia than CXR pneumonia. However, it is important to note that 12% of CT-only pneumonia patients had a bacterial pathogen detected, which was similar to that observed in the CXR pneumonia group. Additionally, two patients with CT-only pneumonia and a serum PCT concentration < 0.25 ng/ml had pneumococcal infection, highlighting that the combination of CXR and PCT does not identify all bacterial pneumonia.

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Claessens et al7 recently published a study evaluating the effect of routine CT use for patients with suspected CAP in the emergency department. While we focused on identifying the pathogens and clinical outcomes of patients with CT-only pneumonia, Claessens et al7 focused

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on understanding how CT scans performed on patients with suspected pneumonia changed clinical management. Among the 308 patients with clinically-suspected pneumonia in the

Claessens et al study7, 40 (13%) had CT-only pneumonia, and clinicians typically responded to a

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positive CT for pneumonia after a normal CXR by administering antibiotics.7 Our results

complement those of Claessens et al7 by suggesting that the pathogens and clinical outcomes

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associated with CT-only pneumonia do indeed warrant consideration for antibiotic therapy. Claessens et al7 also found that 18% of patients in their study had a CXR suggestive of pneumonia but a CT without evidence of pneumonia, and clinicians were likely to discontinue antibiotics and change disposition from inpatient to outpatient based on results of the CT scan

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demonstrating no pneumonia. Our data also support a clinical decision to use negative CT scans to de-escalate care initiated based on a CXR suggestive of pneumonia. In our study, only 1 of 30 patients with a CXR suggestive of pneumonia and a CT scan without evidence of pneumonia had

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a bacterial pathogen detected, and CT images often clarified the abnormality seen on CXR as a non-pneumonia finding.

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There were limitations to our study. First, the use of CT was determined by treating

clinicians independent of the study protocol; clinicians elected to perform CT in approximately one-third of the patients in the cohort. As noted in Supplemental Table 1, patients with chest pain, shortness of breath and hemoptysis were more likely to undergo CT, likely due to clinicians’ concern for pulmonary embolism or cancer in patients with these symptoms; therefore, study results may not be generalizable to patients who clinicians are not concerned

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enough about to order chest CT imaging. Second, because radiologic evidence of pneumonia on CXR or CT was required for cohort inclusion, we did not evaluate patients with clinicallysuspected pneumonia who had a CXR without evidence of pneumonia and no CT completed. If

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CT were systematically completed on these patients, additional cases of CT-only pneumonia would likely have been discovered. Third, patients were considered to have CT-only pneumonia if a CT scan showing evidence of pneumonia was completed on the same day or the following

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day as a CXR showing no signs of pneumonia, and both imaging studies were completed within two days of hospital admission. Only including patients who had a CT performed immediately

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after a CXR (within minutes or hours) may have decreased the discordance between CXR and CT; however, considering a CT and CXR performed within one calendar day of each other as concurrent imaging is consistent with clinical practice, in which routine chest imaging more frequently than once per day is not recommended.4 Fourth, multiple comparisons between

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groups were performed and differences observed should be considered hypothesis generating. Fifth, while this is the largest study to date assessing clinical outcomes of patients with CT-only pneumonia, our sample size was somewhat limited, precluding multivariable analyses, and

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robust comparisons of rare outcomes, such as mortality. Sixth, nearly all patients were treated with antibiotics; hence, the impact of antibiotics on clinical outcomes could not be evaluated.

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Finally, only hospitalized patients were included in this study and generalizability to the outpatient setting is unknown.

Conclusions

In this large prospective cohort study of adults hospitalized with CAP who underwent systematic etiology testing, patients with pneumonia visualized on CT but not on CXR had

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similar pathogens and clinical outcomes compared with those who had pneumonia visualized on CXR. These findings support the management of patients with pneumonia visualized only on CT

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according to the same principles as those with pneumonia visualized on CXR.

ACKNOWLEDGMENTS

Author Contributions: WHS had full access to the data and takes responsibility for the integrity

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of the data and accuracy of the analysis.

Study concept and design: CPU, CGG, RGW, SJ, KME, WHS.

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Acquisition of data: RGW, DJW, EJA, EJH, FC, AMB, SJ, KME, WHS. Statistical analysis: CPU, CGG, YZ, AMB, WHS.

Interpretation of data: CPU, CGG, RJW, DJW, GWW, EJA, SJ, KME, WHS. Drafting of the initial manuscript: CPU, WHS.

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Critical revision of manuscript: All authors. Obtained Funding: KME, RGW.

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Study supervision: RGW, SJ, KME, WHS.

Funding/Role of the Sponsors: This work was supported by a cooperative agreement with the

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Centers for Disease Control and Prevention (U18 IP000299). Investigators from the Centers for Disease Control and Prevent participated in the study as authors. CGG was supported in part by R01AG043471 from the National Institute on Aging. WHS was supported in part by K23GM110469 from the National Institute of General Medical Sciences.

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17. Lim WS, van der Eerden MM, Laing R, et al. Defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study. Thorax. 2003; 58: 377-82.

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18. Self WH, Grijalva CG, Williams DJ, et al. Procalcitonin as an early marker of the need for invasive respiratory or vasopressor support in adults with community-acquired pneumonia. Chest 2016; in press. DOI: 10.1016/j.chest.2016.04.010

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19. BioMerieux, Inc. VIDAS BRAHMS PCT. Available at: http://www.biomerieuxdiagnostics.com/vidas-brahms-pct. Accessed: 15 July 2016.

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20. Schuetz P, Christ-Crain M, Thomann R, Falconnier C, Wolbers M, Widmer I, et al. Effect of procalcitonin-based guidelines vs standard guidelines on antibiotic use in lower respiratory tract infections: The ProHOSP randomized controlled trial. JAMA 2009; 302:1059-66.

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21. Self WH, Balk RA, Grijalva CG, et al. Procalcitonin as a marker of etiology in adults hospitalized with community-acquired pneumonia. Clin Infect Dis 2017; in press. doi: 10.1093/cid/cix317.

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22. Weinberg GA, Schnabel KC, Erdman DD, et al. Field evaluation of TaqMan Array Card (TAC) for the simultaneous detection of multiple respiratory viruses in children with

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acute respiratory infection. J Clin Virol 2013; 57: 254-60.

23. Dare RK, Fry AM, Chittaganpitch M, Sawanpanyalert P, Olsen SJ, Erdman DD. Human coronavirus infections in rural Thailand: a comprehensive study using real-time reversetranscription polymerase chain reaction assays. J Infect Dis 2007; 196: 1321-8.

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24. Sawatwong P, Chittaganpitch M, Hall H, et al. Serology as an adjunct to polymerase chain reaction assays for surveillance of acute respiratory virus infections. Clin Infect Dis 2012; 54: 445-6.

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25. Feikin DR, Njenga MK, Bigogo G, et al. Additional diagnostic yield of adding serology to PCR in diagnosing viral acute respiratory infections in Kenyan patients 5 years of age and older. Clin Vaccine Immunol 2013; 20: 113-4.

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26. Bartlett RC. Medical microbiology: quality, cost and clinical relevance. New York: John Wiley, 1974: 24-31.

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27. Murdoch DR, Laing RTR, Mills GD, et al. Evaluation of a rapid

immunochromatographic test for detection of Streptococcus pneumoniae antigen in urine samples from adults with community-acquired pneumonia. J Clin Microbiol 2001; 39: 3495-8.

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28. Murdoch DR. Diagnosis of Legionella infection. Clin Infect Dis 2003; 36: 64-9. 29. Thurman KA, Warner AK, Cowart KC, Benitez AJ, Winchell JM. Detection of Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella spp. in clinical

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specimens using a single-tube multiplex real-time PCR assay. Diagn Microbiol Infect Dis 2011; 70: 1-9.

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30. ARDS Definition Task Force. Acute respiratory distress syndrome: The Berlin Definition. JAMA 2012; 307(23): 2526-33.

31. Karkos PD, Asrani S, Karkos CD, Leong SC, Theochari EG, Alexopoulou TD, and Assimakopoulous AD. Lemierre’s syndrome: a systematic review. Laryngoscope 2009;119(8):1552-1559.

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32. Heussel CP, Kauczor HU, Heussel G, Fischer B, Mildenberger P, Thelen M. Early detection of pneumonia in febrile neutropenic patients: Use of thin-section CT. AJR Am J Roentgenol 1997;169:1347-53.

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33. Ahmed WA, de Heredia LL, Hughes RJ, Belci M, Meagher TM. Outcomes of wholebody computed tomography in spinal cord patients with sepsis. Spinal Cord 2014; 52:536-40.

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34. Karhu JM, Ala-Kokko TI, Ahvenjarvi LK, Rauvala E, Ohtonen P, and Syrjala HP. Early chest computed tomography in adult acute severe community-acquired pneumonia

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patients treated in the intensive care unit. Acta Anesthesiol Scand 2016;60(8):1102-1110. 35. Dellit TH, Owens RC, McGowan JE Jr, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis 2007; 44:

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159-77.

36. Uppot RN. Impact of obesity on radiology. Radiol Clin North Am. 2007;45:231-46. 37. Uppot RN, Sahani DV, Hahn PF, Kalra MK, Saini SS, and Mueller PR. Effect of obesity

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on image quality: fifteen-year longitudinal study for evaluation of dictated radiology

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reports. Radiology. 2006;240(2):435-439.

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FIGURE LEGEND

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Figure 1. Flow diagram for generation of the study population.

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TABLES Table 1. Clinical characteristics at hospital presentation. p

53 (40-63) 39 (59.1)

58 (47-71) 1111 (50.9)

<0.01 0.18

100 (88-118) 140 (126-157) 20 (18-24) 98.4 (97.3-100.3) 96 (94-98)

100 (87-114) 131 (114-148) 20 (18-24) 98.5 (97.2-100.1) 95 (92-97)

0.51 <0.01 0.62 0.73 0.07

39 (59.1) 5 (7.6) 49 (74.2) 44 (66.7) 11 (16.7) 37 (56.1)

1206 (55.2) 192 (8.8) 1703 (77.9) 1065 (48.7) 438 (20.1) 937 (42.9)

0.53 0.73 0.48 <0.01 0.50 0.03

21 (31.8) 14 (21.2) 8 (12.1) 21 (31.9) 9 (13.6) 3 (4.6) 32 (48.5) 17 (25.8)

561 (25.7) 505 (23.1) 422 (19.3) 563 (25.8) 344 (15.7) 122 (5.6) 789 (36.1) 577 (26.4)

0.26 0.72 0.14 0.27 0.64 0.72 0.04 0.91

11.05 (6.9-14.2) 12 (9-19) 120 (102-144) <0.05 (<0.05-0.11)

11.4 (8-14.9) 15 (10-24) 115 (99-145) 0.16 (<0.05-0.85)

0.13 <0.01 0.46 <0.01

41 (62.1) 11 (16.7) 14 (21.2)

979 (44.8) 439 (20.1) 767 (35.1)

0.02

53 (80.3) 7 (10.6) 6 (9.1)

1517 (69.4) 422 (19.3) 246 (11.3)

0.14

63 (95.5) 3 (4.5)

2028 (92.8) 157 (7.2)

0.62

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CXR pneumonia (n=2185)

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Demographics Age [years], median (IQR) Female, n (%) Vital signs, median (IQR) Heart Rate [beats/min] Systolic blood pressure [mm Hg] Respiratory rate [breaths/min] Temperature [ºF] Oxygen saturation [%] Signs and Symptoms, n (%) Cough with sputum production Hemoptysis Shortness of breath Chest pain Confusion Wheezing Comorbidities, n (%) Asthma Chronic Obstructive Pulmonary Disease Chronic Heart Failure Diabetes mellitus Chronic kidney disease Chronic liver disease Obesity (Body Mass Index ≥30 kg/m2) Current tobacco smoker Laboratory values, median (IQR) White blood cell count [thous cells/ mcL] Blood urea nitrogen [mg/dL] Blood glucose [mg/dL] Procalcitonin [ng/ml] * Pneumonia Severity Index risk class, n (%) I-II (low risk) III (moderate risk) IV-V (high risk) CURB-65 score, n (%) 0-1 (low risk) 2 (moderate risk) 3-5 (high risk) ATS severe pneumonia criteria, n (%) < 3 criteria (non-severe) ≥ 3 criteria (severe)

CT-only pneumonia (n=66)

* 520 patients did not have procalcitonin measured, including 17 (25.8%) in the CT-only pneumonia group and 503 (23.0%) in the CXR pneumonia group. 23

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Abbreviations: CT computed tomography; CXR chest x-ray; n number; IQR interquartile range; min minute; mm millimeter; Hg mercury; F Fahrenheit; mcL microliter; mg milligram; dL deciliter; ng nanogram; ml milliliter; CURB-65 confusion, uremia, respiratory rate, blood pressure, age ≥ 65 years; ATS American Thoracic Society.

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Table 2. Antibiotics administered during the first day of hospitalization. CXR pneumonia

(n=66)

(n=2185)

ß -lactam + macrolide

12 (18.2)

488 (22.3)

Respiratory fluoroquinolone* alone

12 (18.2)

470 (21.5)

Respiratory fluoroquinolone* + ß-lactam

6 (9.1)

113 (5.2)

ß -lactam + macrolide + glycopeptide

5 (7.6)

151 (6.9)

Respiratory fluoroquinolone* + ß -lactam + macrolide

3 (4.6)

202 (9.2)

Respiratory fluoroquinolone* + ß-lactam + glycopeptide

3 (4.6)

92 (4.2)

ß -lactam alone

ß-lactam + glycopeptide Respiratory fluoroquinolone* + macrolide Respiratory fluoroquinolone* + glycopeptide Macrolide alone

Respiratory fluoroquinolone* + macrolide + glycopeptide Glycopeptide alone

65 (3.0)

2 (3.0)

52 (2.4)

2 (3.0)

50 (2.3)

1 (1.5)

42 (1.9)

2 (3.0)

32 (1.5)

3 (4.6)

22 (1.0)

0 (0)

5 (0.2)

1 (1.5)

2 (0.1)

11 (16.7)

349 (16.0)

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Other regimens

2 (3.0)

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Respiratory fluoroquinolone* + ß-lactam + macrolide + glycopeptide

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CT-only pneumonia

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Antibiotic Regimen during Hospital Day #1

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*Respiratory fluoroquinolones: gemifloxacin, levofloxacin, moxifloxacin

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Table 3. Pathogens detected. CXR pneumonia

pneumonia (n=66)

(n=2185)

27 (40.9)

822 (37.6)

0.59

Co-detection of ≥ 1 pathogen

2 (3.0)

108 (4.9)

0.48

Any Bacteria

8 (12.1)

297 (13.6)

0.86

3 (4.6)

111 (5.1)

1.00

Group A Streptococcus

0 (0)

7 (0.32)

0.65

Viridans group Streptococci

0 (0)

8 (0.37)

0.62

Other Streptococci species

0 (0)

Staphylococcus aureus

0 (0)

Haemophilus influenzae

0 (0)

Any pathogen

Streptococcus pneumoniae

p

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CT-only

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Pathogens Detected, n (%)

0.62

37 (1.7)

0.63

13 (0.6)

1.00

1 (1.5)

16 (0.7)

0.47

1 (1.5)

7 (0.3)

0.11

2 (3.0)

10 (0.5)

0.01

0 (0)

43 (2.0)

0.64

1 (1.5)

8 (0.4)

0.24

0 (0)

32 (1.5)

0.62

0

9 (0.4)

0.60

20 (30.3)

570 (26.1)

0.44

4 (6.1)

126 (5.8)

0.92

1 (1.5)

66 (3.0)

0.72

0 (0)

53 (2.4)

0.41

Human metapneumovirus

4 (6.1)

84 (3.8)

0.36

Respiratory syncytial virus

0 (0)

68 (3.1)

0.26

11 (16.7)

182 (8.3)

0.02

1 (1.5)

31 (1.4)

0.62

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8 (0.4)

Escherichia coli Pseudomonas aeruginosa Klebsiella pneumoniae Mycoplasma pneumoniae Chlamydia pneumoniae

Other bacteria * Any Virus Influenza

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Coronavirus

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Parainfluenza virus

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Legionella pneumophila

Human rhinovirus Adenovirus

* Other bacteria included: Fusobacteria (3), Enterobacter (2), Neisseria, Bacteroides, Pasteurella, Proteus. Abbreviations: n number; CT computed tomography; CXR chest x-ray

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Table 4. Clinical outcomes. CXR pneumonia

pneumonia (n=66)

(n=2185)

0 (0)

49 (2.2)

0.40

3.5 (2-5)

3 (2-6)

0.90

15 (22.7)

467 (21.4)

0.80

Invasive mechanical ventilation, n (%)

4 (6.1)

113 (5.2)

0.76

Vasopressor-dependent septic shock, n (%)

3 (4.6)

84 (3.8)

0.74

Moderate-severe ARDS, n (%)

1 (1.5)

In-hospital death, n (%) Hospital length-of-stay (days) among survivors, median (IQR) ICU admission, n (%)

p

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CT-only

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Clinical Outcome

89 (4.1)

0.52

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Abbreviations: CT computed tomography; CXR chest x-ray; n number; IQR interquartile range; ICU intensive care unit; ARDS acute respiratory distress syndrome

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e-Table 1. Clinical characteristics of patients who underwent computed tomography (CT) and those who did not undergo CT. All included patients underwent chest x-ray (CXR). CT Completed CT not p (n=748) Completed (n=1503) Demographics Age [years], median (IQR) 56 (46, 67) 59 (47, 73) < 0.01 Female, n (%) 353 (53.0) 797 (47.2) < 0.01 Vital signs, median (IQR) Heart Rate [beats/min] 101 (88, 114) 99 (86, 114) 0.11 Systolic blood pressure [mm Hg] 131 (116, 149) 132 (114, 149) 0.96 Respiratory rate [breaths/min] 20 (18, 22) 20 (18, 24) 0.74 Temperature [ºF] 98.4 (97.3, 99.7) 98.6 (97.1, 0.05 100.3) Oxygen saturation [%] 95 (93, 98) 95 (92, 97) 0.51 Signs and Symptoms, n (%) Cough with sputum production 348 (46.5) 658 (43.4) 0.22 Hemoptysis 91 (12.2) 106 (7.1) <0.01 Shortness of breath 612 (81.8) 1140 (75.9) <0.01 Chest pain 428 (57.2) 681 (45.3) <0.01 Confusion 117 (15.6) 332 (22.1) <0.01 Wheezing 317 (42.4) 657 (43.7) 0.55 Comorbidities, n (%) Asthma 181 (24.2) 401 (26.7) 0.21 Chronic Obstructive Pulmonary Disease 163 (21.8) 356 (23.7) 0.31 Chronic Heart Failure 115 (15.4) 315 (21.0) <0.01 Diabetes mellitus 166 (22.2) 418 (27.8) <0.01 Chronic kidney disease 94 (12.6) 259 (17.2) <0.01 Chronic liver disease 43 (5.8) 82 (5.5) 0.78 270 (36.1) 551 (36.7) 0.79 Obesity (Body Mass Index ≥30 kg/m2) Laboratory values, median (IQR) White blood cell count [thous cells/ mcL] 11.2 (7.7, 14.7) 11.5 (8.2, 15.0) 0.06 Blood urea nitrogen [mg/dL] 14 (10, 20) 16 (10, 25) <0.01 Blood glucose [mg/dL] 114 (98, 139) 116 (99, 148) 0.10 Procalcitonin [ng/ml] * 0.13 (<0.05, 0.16 (<0.05, 0.01 0.64) 1.01) Pneumonia Severity Index risk class, n (%) I-II (low risk) 366 (48.9) 654 (43.5) 0.02 III (moderate risk) 150 (20.1) 300 (20.0) IV-V (high risk) 232 (31.0) 549 (36.5) CURB-65 score, n (%) 0-1 (low risk) 579 (77.4) 991 (65.9) < 0.01 2 (moderate risk) 121 (16.2) 308 (20.5) 3-5 (high risk) 48 (6.4) 204 (13.6) ATS severe pneumonia criteria, n (%) < 3 criteria (non-severe) 711 (95.1) 1380 (91.8) 0.01 ≥ 3 criteria (severe) 37 (4.9) 123 (8.2) * 520 patients did not have procalcitonin measured, including 162 (21.7%) with CT completed and 358 (23.9%) with CT not completed. Abbreviations: CT computed tomography; CXR chest x-ray; n number; IQR interquartile range; min minute; mm millimeter; Hg mercury; F Fahrenheit; mcL microliter; mg milligram; dL deciliter; ng nanogram; ml milliliter; CURB-65 confusion, uremia, respiratory rate, blood pressure, age ≥ 65 years; ATS American Thoracic Society. Online supplements are not copyedited prior to posting and the author(s) take full responsibility for the accuracy of all data.

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  e-Table 2. Pathogens detected among patients who underwent computed tomography (CT) and those who did not undergo CT.

256 (34.2) 31 (4.1) 89 (11.9) 32 (4.3) 4 (0.5) 7 (0.9) 4 (0.5) 10 (1.3) 5 (0.7) 7 (0.9) 2 (0.3) 6 (0.8) 6 (0.8) 2 (0.3) 7 (0.9) 5 (0.7) 167 (22.3) 36 (4.8) 21 (2.8) 17 (2.3) 25 (3.3) 17 (2.3) 53 (7.1) 9 (1.2)

593 (39.5) 79 (5.3) 216 (14.4) 82 (5.5) 3 (0.2) 1 (0.1) 4 (0.3) 27 (1.8) 8 (0.5) 10 (0.7) 6 (0.4) 6 (0.4) 37 (2.5) 7 (0.5) 25 (1.7) 0 (0) 423 (28.1) 94 (6.3) 46 (3.1) 36 (2.4) 63 (4.2) 51 (3.4) 140 (9.3) 23 (1.5)

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CT not Completed (n=1503)

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Any pathogen Co-detection of ≥ 1 pathogen Any Bacteria Streptococcus pneumoniae Group A Streptococcus Viridans group Streptococci Other Streptococci species Staphylococcus aureus Haemophilus influenzae Escherichia coli Pseudomonas aeruginosa Klebsiella pneumoniae Mycoplasma pneumoniae Chlamydia pneumoniae Legionella pneumophila Other bacteria Any Virus Influenza Parainfluenza virus Coronavirus Human metapneumovirus Respiratory syncytial virus Human rhinovirus Adenovirus

CT completed (n=748)

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Pathogens Detected, n (%)

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Abbreviations: n number; CT computed tomography; CXR chest x-ray

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  e-Table 3. Clinical outcomes among patients who underwent computed tomography (CT) and those who did not undergo CT.

In-hospital death, n (%) Hospital length-of-stay (days) among survivors, median (IQR)

166 (22) 45 (0.6) 35 (4.7) 24 (3.2)

316 (21) 72 (4.8) 52 (3.5) 66 (4.4)

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ICU admission, n (%) Invasive mechanical ventilation, n (%) Vasopressor-dependent septic shock, n (%) Moderate-severe ARDS, n (%)

CT not Completed (n=1503) 33 (2.2) 3 (2-5)

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CT-completed (n=748) 16 (2.1) 4 (2-7)

Clinical Outcome

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  e-Table 4. Clinical characteristics at hospital presentation, with the CXR pneumonia group subclassified based on CT results: CXR pneumonia / CT not done (CXR+/CT not done); CXR pneumonia / CT pneumonia (CXR+/CT+); CXR pneumonia / CT no pneumonia (CXR+/CT-).

59 (47-73)

56 (47-67)

63.5 (55-73)

53 (40-63)

797 (53)

299 (45.9)

15 (50)

39 (59.1)

99 (86-114) 132 (114139) 20 (18-24)

101 (88-114) 130 (115-147)

103 (78-123) 133 (124-149)

100 (88-118) 140 (126-157)

20 (18-22)

20 (18-24)

98.4 (97.399.7) 95 (93-98)

97.7 (96.399.2) 95 (93-98)

98.4 (97.3100.3) 96 (94-98)

344 (52.8)

17 (56.7)

39 (59.1)

84 (12.9) 537 (82.4) 365 (55.8) 99 (15.2) 260 (39.9)

2 (6.7) 26 (86.7) 20 (66.7) 7 (23.3) 20 (66.7)

5 49 44 11 37

401 (26.7) 356 (23.7)

149 (22.9) 135 (20.7)

11 (36.7) 14 (46.7)

21 (31.8) 14 (21.2)

315 (21) 418 (27.8) 259 (17.2) 82 (5.5) 551 (36.7)

100 (15.3) 137 (21) 81 (12.4) 37 (5.7) 228 (35)

7 (23.3) 8 (26.7) 4 (13.3) 3 (10) 10 (33.3)

8 (12.1) 21 (31.9) 9 (13.6) 3 (4.6) 32 (48.5)

11.5 (8.2-15)

11.3 (7.914.8) 14 (10-20)

8.9 (5.5-11.9)

11.1 (6.9-14.2)

14 (12-17)

12 (9-19)

113.5 (98139) 0.15 (<0.050.64)

114 (102-136)

120 (102-144)

<0.05 (<0.05<0.05)

<0.05 (<0.050.11)

845 (56.2) 106 (7.1) 1140 (75.9) 681 (45.3) 332 (22.1) 657 (43.7)

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Procalcitonin [ng/ml] *

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98.6 (97.1100.3) 95 (92-97)

20 (18-22)

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CXR+/CT(n=30)

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Oxygen saturation [%] Signs and Symptoms, n (%) Cough with sputum production Hemoptysis Shortness of breath Chest pain Confusion Wheezing Comorbidities, n (%) Asthma Chronic Obstructive Pulmonary Disease Chronic Heart Failure Diabetes mellitus Chronic kidney disease Chronic liver disease Obesity (Body Mass Index ≥30 kg/m2) Laboratory values, median (IQR) White blood cell count [thous cells/ mcL] Blood urea nitrogen [mg/dL] Blood glucose [mg/dL]

CXR+/CT+ (n=652)

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Demographics Age [years], median (IQR) Female, n (%) Vital signs, median (IQR) Heart Rate [beats/min] Systolic blood pressure [mm Hg] Respiratory rate [breaths/min] Temperature [ºF]

CT-only pneumonia (CXR-/CT+) (n=66)

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CXR pneumonia CXR+/CT not done (n=1503)

16 (10-25)

116 (99-148) 0.16 (<0.05 1.01)

(7.6) (74.2) (66.7) (16.7) (56.1)

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654 (43.5) 300 (20) 549 (36.5)

316 (48.5) 131 (20.1) 205 (31.4)

9 (30) 8 (26.7) 13 (43.3)

41 (62.1) 11 (16.7) 14 (21.2)

991 (65.9) 308 (20.5) 204 (13.6)

503 (77.2) 109 (16.7) 40 (6.1)

23 (76.7) 5 (16.7) 2 (6.7)

53 (80.3) 7 (10.6) 6 (9.1)

1387 (92.3) 116 (7.7) 1284 (85.4)

619 (94.9) 33 (5.1) 501 (76.8)

63 (95.5) 3 (4.5) 39 (59.1)

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Pneumonia Severity Index risk class, n (%) I-II (low risk) III (moderate risk) IV-V (high risk) Index score, median (IQR) CURB-65 score, n (%) 0-1 (low risk) 2 (moderate risk) 3-5 (high risk) ATS severe pneumonia criteria, n (%) < 3 criteria (non-severe) ≥ 3 criteria (severe) Antibiotics within six hours

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30 (100) 0 (0) 26 (86.7)

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Abbreviations: CT computed tomography; CXR chest x-ray; n number; IQR interquartile range; min minute; mm millimeter; Hg mercury; F Fahrenheit; mcL microliter; mg milligram; dL deciliter; ng nanogram; ml milliliter; CURB-65 confusion, uremia, respiratory rate, blood pressure, age ≥ 65 years; ATS American Thoracic Society.

Online supplements are not copyedited prior to posting and the author(s) take full responsibility for the accuracy of all data.

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  e-Table 5. Pathogens detected, with the CXR pneumonia group sub-classified based on CT results: CXR pneumonia / CT not done (CXR+/CT not done); CXR pneumonia / CT pneumonia (CXR+/CT+); CXR pneumonia / CT no pneumonia (CXR+/CT-). CT-only pneumonia (CXR-/CT+) (n=66)

CXR+/CT(n=30)

225 (34.5) 29 (4.5)

4 (13.3) 0 (0)

27 (40.9) 2 (3.0)

1 (3.3) 0 (0)

8 (12.1) 3 (4.6)

0 (0)

0 (0)

7 (1.1)

0 (0)

0 (0)

4 (0.6)

0 (0)

0 (0)

10 (1.5)

0 (0)

0 (0)

5 (0.8)

0 (0)

0 (0)

10 (0.7) 6 (0.4)

6 (0.9) 1 (0.2)

0 (0) 0 (0)

1 (1.5) 1 (1.5)

6 (0.4)

4 (0.6)

0 (0)

2 (3.0)

37 (2.5)

6 (0.9)

0 (0)

0 (0)

7 (0.5)

1 (0.2)

0 (0)

1 (1.5)

25 (1.7)

7 (1.1)

0 (0)

0 (0)

0 (0) 423 (28.1) 94 (6.3) 46 (3.1) 36 (2.4) 63 (4.2)

4 (0.6) 144 (22.1) 32 (4.9) 18 (2.8) 17 (2.6) 21 (3.2)

1 (3.3) 3 (10) 0 (0) 2 (6.7) 0 (0) 0 (0)

0 (0) 20 (30.3) 4 (6.1) 1 (1.5) 0 (0) 4 (6.1)

51 (3.4)

17 (2.6)

0 (0)

0 (0)

140 (9.3) 23 (1.5)

41 (6.3) 8 (1.2)

1 (3.3) 0 (0)

11 (16.7) 1 (1.5)

80 (12.3) 29 (4.5)

3 (0.2)

4 (0.6)

1 (0.1) 4 (0.3) 27 (1.8)

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8 (0.5)

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216 (14.4) 82 (5.5)

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CXR+/CT+ (n=652)

AC C

Any pathogen Co-detection of ≥ 1 pathogen Any Bacteria Streptococcus pneumoniae Group A Streptococcus Viridans group Streptococci Other Streptococci species Staphylococcus aureus Haemophilus influenzae Escherichia coli Pseudomonas aeruginosa Klebsiella pneumoniae Mycoplasma pneumoniae Chlamydia pneumoniae Legionella pneumophila Other bacteria Any Virus Influenza Parainfluenza virus Coronavirus Human metapneumovirus Respiratory syncytial virus Human rhinovirus Adenovirus

CXR+/CT not done (n=1503) 593 (39.5) 79 (5.3)

EP

Pathogens Detected, n (%)

RI PT

CXR pneumonia

Abbreviations: n number; CT computed tomography; CXR chest x-ray

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ACCEPTED MANUSCRIPT

  e-Table 6. Clinical outcomes, with the CXR pneumonia group sub-classified based on CT results: CXR pneumonia / CT not done (CXR+/CT not done); CXR pneumonia / CT pneumonia (CXR+/CT+); CXR pneumonia / CT no pneumonia (CXR+/CT-).

ICU admission, n (%) Invasive mechanical ventilation, n (%) Vasopressor-dependent septic shock, n (%) Moderate-severe ARDS, n (%)

316 (21) 72 (4.8) 52 (3.5) 66 (4.4)

143 41 32 23

(21.9) (6.3) (4.9) (3.5)

CT-only pneumonia (CXR-/CT+) (n=66) 0 (0) 3.5 (2-5)

RI PT

In-hospital death, n (%) Hospital length-of-stay (days) among survivors, median (IQR)

8 (26.7) 0 (0) 0 (0) 0 (0)

SC

Clinical Outcome

CXR pneumonia CXR+/CT CXR+/CT CXR+/CT not done + - (n=30) (n=1503) (n=652) 33 (2.2) 15 (2.3) 1 (3.3) 3 (2-5) 4 (2.5-7) 3 (2-6)

15 4 3 1

(22.7) (6.1) (4.6) (1.5)

EP

TE D

M AN U

Abbreviations: CT computed tomography; CXR chest x-ray; n number; IQR interquartile range; ICU intensive care unit; ARDS acute respiratory distress syndrome

AC C

e-Table 7. Timing of in-hospital antibiotics.

Antibiotics ≤ 6 hours, n (%) Antibiotics ≤ 12 hours, n (%) Antibiotics ≤ 24 hours, n (%) Median (IQR) time to first antibiotics, hours

CT-only pneumonia (n = 66) 39 (59%) 58 (88%) 64 (97%) 4.7 (2.6, 6.8)

CXR pneumonia (n = 2185) 1815 (83%) 2046 (94%) 2106 (96%) 2.9 (2.0, 4.5)

Online supplements are not copyedited prior to posting and the author(s) take full responsibility for the accuracy of all data.

ACCEPTED MANUSCRIPT

  e-Table 8. Among patients with CT-only pneumonia [n=66], pathogens detected in patients with probable or definite pneumonia on CT and an elevated PCT (≥ 0.25 ng/ml) [n=5] and patients not meeting these criteria. Fourteen patients could not be classified by these criteria due to missing procalcitonin (PCT) values; these patients are displayed separately in the table. Probable/definite pneumonia on CT and missing PCT (n = 14) 6 (43)

Possible pneumonia on CT and/or PCT <0.25 ng/ml (n = 47) 19 (40)

Bacterial pathogen, n (%)

1 (20)

3 (21)

4 (9)

Bacterial pathogens detected

E. coli

S. pneumoniae K pneumoniae C. pneumoniae

Viral Pathogen, n (%)

1 (20)

3 (21)

16 (34)

Viral pathogens detected

HPMV

HRV x 2 Flu A

HRV x 8 HMPV x 3 Flu A x 3 PIV AdV

S. pneumoniae x 2 K pneumoniae P. aeruginosa

SC

M AN U

Any pathogen detected, n (%)

RI PT

Probable/definite pneumonia on CT and PCT ≥ 0.25 ng/ml (n = 5) 2 (40)

AC C

EP

TE D

Abbreviations: CT: computed tomography; PCT: procalcitonin; HPMV: human metapneumovirus; HRV: human rhinovirus; Flu A: influenza A virus; PIV: parainfluenza virus; AdV: adenovirus

171083

Online supplements are not copyedited prior to posting and the author(s) take full responsibility for the accuracy of all data.