Predictors of pneumonia on routine chest radiographs in patients with COPD: a post hoc analysis of two 1-year randomized controlled trials

Abstract

Background

Patients with COPD are at risk for life-threatening pneumonia. Although anatomical abnormalities in the thorax may predispose to pneumonia, those abnormalities identified on routine chest X-rays (CXRs) in patients with COPD have not been studied to better understand pneumonia risk.

Methods

We conducted a post hoc exploratory analysis of data from two replicate year-long clinical trials assessing the impact of fluticasone furoate–vilanterol versus vilanterol alone on COPD exacerbations (GSK studies: HZC102871/NCT1009463 and HZC102970/NCT1017952). Abnormalities on baseline CXRs from 179 patients who developed pneumonia and 50 randomly selected patients who did not were identified by blinded consensus readings conducted by two radiologists. Positive and negative likelihood ratios and diagnostic odds ratios (ORs) were calculated to evaluate the markers for subsequent pneumonia development during the 1-year study period.

Results

Baseline characteristics distinguishing the pneumonia and non-pneumonia groups included a lower body mass index (24.9 vs 27.5 kg/m², P=0.008), more severe airflow obstruction (mean post-bronchodilator forced expiratory volume in 1 second [FEV₁]/forced vital capacity ratio: 42.3% vs 47.6%, P=0.003), and prior pneumonia (36% vs 20%, P=0.030). Baseline CXR findings with the highest diagnostic ORs were: elevated hemi-diaphragm (OR: 6.87; 95% CI: 0.90, 52.26), thick tracheal-esophageal stripe (OR: 4.39 [0.25, 78.22]), narrow cardiac silhouette (OR: 2.91 [0.85, 9.99]), calcified pleural plaque/mid-chest pleural thickening (OR: 2.82 [0.15, 53.76]), and large/prominent pulmonary artery shadow (OR: 1.94 [0.95, 3.97]). The presence of a narrow cardiac silhouette at baseline was associated with a statistically significant lower mean pre-bronchodilator FEV₁ (P=0.040). There was also a trend for a lower mean pre-bronchodilator FEV₁ in patients with a large/prominent pulmonary artery shadow at baseline (P=0.095).

Conclusion

Findings on routine CXR that relate to pathophysiological mechanisms of pneumonia could help determine pneumonia risk in patients with COPD.

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Keywords:

• COPD
• pneumonia
• chest X-rays
• predictors of risk

Supplementary materials

List of approving institutional review boards/independent ethics committees for GSK study HZC102871 (NCT1009463)

Argentina

Comite de Etica Independiente en Investigacion Clinica (CEIC), Buenos Aires

Comite Independiente de Etica para Ensayos en Farmacologia Clinica, Buenos Aires

Comite de Docencia e Investigacion INSARES, Mendoza

Comite Independiente de revision y etica (CIRE), Buenos Aires

Ave Pulmo.Comite de docencia e investigacion, Mar del Plata, Buenos Aires

Comite de Etica en Investigacion, Insituto de Investigaciones Clinicas, Mar del Plata, Buenos Aires

Comite de Docencia e Investigacion Instituto InAER, Buenos Aires

Comite de Docencia e Investigacion Policlinico, Rio Negro

Australia

ACT Health Human Research Ethics Committee, Canberra, ACT

Austin Health Human Research Ethics Committee, Heidelberg, VIC

Flinders Clinical Research Ethics Committee, Bedford Park, Adelaide, SA

Metro North Health Service District – Redcliffe Caboolture Human Research Ethics Committee, Redcliffe, Brisbane, QLD

Peninsula Health, Human Research and Ethics Committee, Mount Eliza, VIC

Cairns & Hinterland Health Service District Human Research Ethics Committee, Cairns, QLD

Bellberry Human Research Ethics Committee, Dulwich, Adelaide, SA

Canada

IRB Services, Aurora, ON

Comite d’ethique de la recherche de l’hopital, Quebec City, QC

Chile

Comite de Evaluacion Etico Cientifico, Servicio Salud, Valparaiso San Antonio, Valparaiso

Comite de Evaluacion Etica Cientrfica, Temuco

Comite de Etica de la Investigacion Servicio de Salud Metropolitano Norte, Santiago

Comite de etica de Investigacion en seres humanos, Facultad Medicina Universidad de Chile, Santiago

Estonia

Tallinn Medical Research Ethics Committee, National Institute for Health Development, Tallinn

Germany

Ethik-Kommission der Arztekammer Schleswig-Holstein, Bad Segeberg

Italy

Comitato Etico Centrale, Fondazione Salvatore Maugeri I.R.C.C.S, Pavia

Comitato Etico Aziendale A.O. Ospedale S. Martino e Cliniche Universitarie Convenzionate di Genova, Genova

Comitato di Etica della ASL di Salerno, Nocera Inferiore Comitato Etico I.R.C.C.S. San Raffaele Pisana, Roma Comitato Etico dell’Azienda Ospedaliera San Paolo, Milano

Comitato Etico dell’Azienda Ospedaliera Complesso San Filippo Neri di Roma, Roma

Comitato Etico A.O. Umberto I e Facolta’ di Medicina e Chirurgia Università degli Studi di Ancona, Torette

Comitato Etico Provincia di Ferrara-Azienda Ospedaliero Universitaria, Corso della Giovecca, Ferrara

Mexico

Comite de Etica Cardiolink Clin Trials, Monterrey Comite da Bioetlca del Instituto, IMER de Oocidente, Guadalajara, Jalisco

Comite de Etica dellnstituto Jalisciense de Investigacion Clfnica, Guadalajara, Jalisco

Cornite de Etica del Hospital General de Tijuana, Baja California Norte

Comite Bioeticopara Ia lnvestigacion Clinica, Roma

The Netherlands

Independent Review Board, Amsterdam

Peru

Comite Institucional de Etica, Universidad Peruana Cayetano Heredia, San Martin de Porres, Lima

Comite Inslitucional de Etica en la Investigacion, del Hospital Nacional Cayetano Heredia, San Martin de Porres, Lima

Comite de Etica del Hospital Edgardo Rebagliati Martins, Jesus Maria, Lima

Philippines

Research And Ethics Committee, Veterans Memorial Medical Center, Quezon City

Ethics Committee, Lung Centre of the Philippines, Quezon City

Hospital Ethics Committee, Quirino Memorial Medical Centre, Quezon City

Ethics Committee, Dagupan Doctors Villaflor Memorial Hospital, Dagupan City

South Africa

Pharma Ethics Committee, Pretoria

Medicines Control Council, Clinical Trials Unit, Pretoria Health Research Ethics Committee, University Of Stellenbosch, Tygerberg

Sweden

Regionala Etikprovningsnamnden i Goteborg, Goteberg

United Kingdom

Oxfordshire Research Ethics Committee B, Bicester

United States

Quorum Review, Inc., Seattle, WA

University of Texas Health Science Center San Antonio, San Antonio, TX

Birmingham VA Institutional Review Board, Department of Veterans Affairs Medical Centre, Birmingham, AL

Human Studies Subcommittee, Bay Pines VA

Healthcare System, Research & Development Service (151), Bay Pines, FL

Western Institutional Review Board, Olympia, WA

Research Compliance Office, Stanford, CA

Committee for the Protection of Human Subjects, Dartmouth College, Hanover, NH

Human Studies Subcommittee, VA Long Beach Health Care System, Long Beach, CA

Phoenix VA Health Care System IRB, Phoenix, AZ

Institutional Review Board, Program for the Protection of Human Subjects, Mount Sinai School of Medicine, New York, NY

University of Florida Institutional Review Board-01, Gainesville Health Science Centre, Gainesville, FL

University of Miami, Human Subject Research Office, Miami, FL

Scott & White Institutional Review Board, Temple, TX

List of approving institutional review boards/independent ethics committees for GSK study HZC102970 (NCT1017952)

Argentina

Comite de Etica Independiente en Investigacion Clinica, Buenos Aires

Comite de Docencia e Investigacion Fundacion CIDEA, Buenos Aires

Comite de Revision Institutional del Instituto Medico Especializado, Buenos Aires

Comite de Docencia e Investlgacion CEMIT, Medicos Investigatores Tucuman, Tucuman

Comite de Docencia e Investigacion de Investigaciones en Patologias Respiratorias, Tucuman

Australia

Uniting Care Health Human Research Ethics Committee, The Wesley Hospital, Auchenflower, QLD

Royal Adelaide Hospital Research Ethics Committee, Adelaide, SA

Bellberry Human Research Ethics Committee, Dulwich, Adelaide, SA

Sir Charles Gairdner Group Human Research Ethics Committee, Sir Charles Gairdner Hospital, Nedlands, WA

Gold Coast Health Service District Human Research Ethics Committee, Southport, QLD

Eastern Health Research and Ethics Committee, Box Hill, VIC

Sydney West Area Health Service Human Research Ethics Committee, Westmead Hospital, Westmead, NSW

Tasmania Health & Medical Human Research Ethics Committee, University of Tasmania, Hobart, TAS

Canada

REB Biomedical-C, Montreal Chest Institute, Montreal, QC

Institutional Review Board Services, Aurora, ON

Colchester East Health Authority Ethics Board, Truro, NS

Concordia Hospital Ethics Committee, Concordia Hospital, Winnipeg, MB

Chile

Comite Etico Cientifico, Servicio de Salud Metropolitano Oriente, Santiago

Comite Etico Cientifico, Secretaria Ministerial de Salud, Concepcion

Denmark

Videnskabsetiske Komiteer for Region Hovedstaden, Hillerod

Germany

Ethik-Kommission der Landesarztekammer Hessen, Frankfurt

Italy

Comitato di Etica A.S.L. Salemo, Nocera Inferiore, Salemo

Comitato Etico Aziende Sanitarie dell’Umbria, Segreteria

Scientifico-Amministrativa, Ellera di Corciano (PG)

Comitato Etico, Azienda Sanitaria Locale 1, Caserta

Comitato Etico Unico per la Provincia di Parma, Azienda

Ospedaliero-Universitaria di Parma, Parma

Comitato Etico dell’Azienda Ospedaliera Universitaria

Policlinico Paolo Giaccone dee’Universita degi Studi di Palermo, Palermo

Comitato Etico Provinciale di Modena, Azienda

Ospedaliera universitaria Poloclinico di Modena, Modena

Comitato Etico, Azienda Ospedaliero-Universiatria, Ospedali Reuniti di Foggia, Foggia

Comitato Etico Azienda Ospedaliera Universitaria Pisana, Pisa

Comitato Etico dell’Universita’ Cattolica del Sacro

Cuore – Policlinico Universitario A. Gemelli di Roma, Roma

Comitato Etico Per La Sperimentazione Clinica Dei Medicinali Azienda Ospedaliera Universitaria Pisana, Pisa

Mexico

Comite de Bioetica del Instituto IMER de Occidente, Guadalajara, Jalisco

Comite de Etica del Instituto Jalisciense de Investigacion Clinica, Guadalajara, Jalisco

Comite de Etico de la Facultad de Medicina de Medicina de la UANL y Hospital Universitario, Monterrey

The Netherlands

Independent Review Board, Amsterdam

Peru

Comite Institucional de Etica de la Universidad Peruana

Cayetano Heredia, San Martin de Porres, Lima

Comite de Bioetica de la Red Asistencial Sabogal, Essalud, Callao

South Africa

Pharma Ethics Committee, Pretoria

Medicines Control Council, Pretoria

University of Cape Town, Human Research Ethics Committee, Cape Town

University of the Witwatersrand, Human Research Ethics Committee, WITS Health Consortium, Parktown

Spain

Comite Etico de Investigacion Clinica, Hospital Clínico San Carlos, Madrid

Comite Etico de Investigacion Clinica, Hospital General Santa Maria del Rosell, Cartegena, Murcia

Comite Etico de Investigacion Clinica, Hospital de Elda, Elda, Alicante

Comite Etico de Investigacion Clinica, Clinica Mediterranea de Neurociencias, Camino Viejo Alicante-Elche, Alicante

Comite Etico de Investigacion Clinica, Hospital Universitario Puerta de Hierro, Majadahonda

CEIC Hospital de Galdakano, Galdakano, Vizcaya

CEIC Autonomica Pais Vasco, Dpto. Sanidad Gobierno Vasco, Vitoria, Alava

Comite Etico de Investigacion Clinica de Cáceres, Hospital San Pedro de Alcántara, Caceres

Comite Etico de Investigacion Clinica, Islas Baleares Consell, Palma de Mallorca

Sweden

Regionala etikprovningsnamnden i Linkoping, Halsouniversitetets Kansli, Linkoping

United Kingdom

Oxfordshire Research Ethics Committee B, Bicester

United States

Quorum Review, Inc., Seattle, WA

Dean Institutional Review Board, Middleton, WI

Health Sciences Institutional Review Board, Columbia, MO

Berkshire Medical Center Institutional Review Board, Pittsfield, MA

Western Institutional Review Board, Olympia, WA

McGuire Institutional Review Board, McGuire VA

Medical Center, Richmond, VA

Institutional Review Board Committee, University of Arizona Human Subjects Protection Program, Tucson, AZ

Department for Human Research Protections, University of Toledo Medical Center, Toledo, OH

Institutional Review Board for Human Subject Research for Baylor College of Medicine and Affiliated Hospitals, Houston, TX

Vanderbilt Institutional Review Board, Nashville, TN

Texas Health Resources, Institutional Review Board, Arlington, TX

Saint Francis Hospital and Medical Centre IRB, Hartford, CT

Table S1 Patients’ medical history

Table S2 Demographics and baseline characteristics in the randomly selected non-pneumonia group and in all patients without on-treatment pneumonia

Table S3 Relationship between localization of CXR findings and subsequent pneumonia in lung tissue

Acknowledgments

Editorial support (in the form of writing assistance, collating author comments, assembling tables and figures, grammatical editing, and referencing) during the development of this manuscript was provided by Emma Landers, PhD, of Gardiner-Caldwell Communications, Macclesfield, UK, and was funded by GSK. The authors were fully responsible for the decision to submit the article for publication and for all content and editorial decisions, were involved at all stages of manuscript development, and approved the final version for submission. This analysis was funded by GSK (data were derived from GSK studies HZC102871/NCT1009463 and HZC102970/NCT1017952). Employees of the sponsor were involved in study concept, data collection, data analysis/review, and manuscript writing/review. Medical writing support during the development of this manuscript was funded by GSK.

Disclosure

DBR, SL, DVG, and CC: employment and stock ownership (GSK). SB: employment (GSK) at the time the analysis was conducted. HAA: employment and shareholder (Bristol-Myers Squibb). The current affiliation for HAA is Headquarters Medical, Immunoscience Marketed Products Development, Bristol-Myers Squibb, Princeton, NJ, USA. The authors report no other conflicts of interest in this work.