Clinical Microbiology and Infection xxx (xxxx) xxx Contents lists available at ScienceDirect Clinical Microbiology and Infection journal homepage: www.clinicalmicrobiologyandinfection.com Original article Hospitalization due to community-acquired pneumonia in patients with chronic obstructive pulmonary disease: incidence, epidemiology and outcomes J. Bordon 1, *, M. Slomka 2, R. Gupta 3, S. Furmanek 4, R. Cavallazzi 5, S. Sethi 6, M. Niederman 7, J.A. Ramirez 4, on behalf of the University of Louisville Pneumonia Study Group 1) Providence Health Center, Section of Infectious Diseases, Washington, DC, USA University of Maryland Medical Center, Division of Infectious Diseases, Baltimore, MD, USA 3) Cleveland Clinic, Department of Medicine, Division of Hematology and Oncology, Cleveland, OH, USA 4) University of Louisville, Department of Medicine, Division of Infectious Diseases, Louisville, KY, USA 5) University of Louisville, Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Disorders, Louisville, KY, USA 6) University at Buffalo, Jacobs School of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Buffalo, NY, USA 7) Weill Cornell Medical College, Pulmonary and Critical Care Medicine, New York, NY, USA 2) a r t i c l e i n f o a b s t r a c t Article history: Received 21 April 2019 Received in revised form 8 June 2019 Accepted 17 June 2019 Available online xxx Objectives: Community-acquired pneumonia (CAP) is an important complication in patients with chronic obstructive pulmonary disease (COPD). This study aimed to define incidence, and outcomes of COPD patients hospitalized with pneumonia in the city of Louisville, and to estimate the burden of disease in the US population. Methods: This was a secondary analysis of a prospective population-based cohort study of residents in Louisville, Kentucky, 40 years old and older, from 1 June 2014 to 31 May 2016. All adults hospitalized with CAP were enrolled. The annual incidence of pneumonia in COPD patients in Louisville was calculated and the total number of adults with COPD hospitalized in the United States was estimated. Clinical outcomes included time to clinical stability (TCS), length of hospital stay (LOS) and mortality. Results: From a Louisville population of 18 246 patients with COPD, 3419 pneumonia hospitalizations were documented during the 2-year study. The annual incidence was 9369 patients with pneumonia per 100 000 COPD population, corresponding to an estimated 506 953 adults with COPD hospitalized due to pneumonia in the United States. The incidence of CAP in patients without COPD was 509 (95% CI 485 e533) per 100 000. COPD patients had a median (interquartile range) TCS and LOS of 2 (1e4) and 5 (3e9) days respectively. The mortality of COPD patients during hospitalization, at 30 days, 6 months and 1 year was 193 of 3419 (5.6%), 400 of 3374 (11.9%), 816 of 3363 (24.3%) and 1104 of 3349 (33.0%), respectively. Conclusions: There was an annual incidence of 9369 cases of hospitalized CAP per 100 000 COPD patients in the city of Louisville. This was an approximately 18-fold greater incidence of CAP in COPD patients than in those without COPD. J. Bordon, Clin Microbiol Infect 2019;▪:1 © 2019 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved. Editor: L. Leibovici Keywords: COPD Epidemiology Incidence Mortality Pneumonia Introduction Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the United States and is considered the * Corresponding author. J. Bordon, Providence Health System, Section of Infectious Diseases, 1150 Varnum St NE Suite # 203, Washington, DC 20017, USA. E-mail address: [email protected] (J. Bordon). third leading cause of death worldwide [1,2]. Patients with COPD may die due to the progression of airflow limitation leading to respiratory failure, due to deterioration of comorbidities or due to infectious complications such as exacerbations and pneumonia [3e6]. The literature indicates that patients with COPD are at high risk of developing pneumonia [7e9], but the incidence, epidemiology and clinical outcomes of COPD patients hospitalized with community-acquired pneumonia (CAP) are not well defined. The https://doi.org/10.1016/j.cmi.2019.06.025 1198-743X/© 2019 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved. Please cite this article as: Bordon J et al., Hospitalization due to community-acquired pneumonia in patients with chronic obstructive pulmonary disease: incidence, epidemiology and outcomes, Clinical Microbiology and Infection, https://doi.org/10.1016/j.cmi.2019.06.025 2 J. Bordon et al. / Clinical Microbiology and Infection xxx (xxxx) xxx primary objectives of this study were to compare the incidence and clinical outcomes of CAP of hospitalized patients with COPD versus without COPD in Louisville, Kentucky. The secondary objectives were to define the geospatial epidemiology in Louisville and to estimate the number of COPD patients hospitalized due to CAP in the US and the cost of hospitalization. Methods Study design and participants This was a secondary data analysis of the University of Louisville Pneumonia Study, a prospective population-based cohort study of all hospitalized adults with CAP who were residents in the city of Louisville, Kentucky, from 1 June 2014 to 31 May 2016 [10]. All hospitalized adult patients in Louisville underwent screening for participation in the study. Inclusion criteria Study patients were 40 years old and older with the diagnosis of COPD documented in medical records. Controls were patients 40 years and older without the diagnosis of COPD. Patients were defined as having pneumonia when the following three criteria were met: (1) presence of a new pulmonary infiltrate on chest radiograph and/or chest computed tomography scan at the time of hospitalization, defined by a board-certified radiologist's reading; (2) at least one of the following (a) new cough or increased cough or sputum production, (b) fever >37.8 C (100.0 F) or hypothermia <35.6 C (96.0 F), (c) changes in leucocyte count (leucocytosis >11 000 cells/mm3; left shift >10% band forms/mL; or leucopenia <4000 cells/mm3); and (3) no alternative diagnosis at the time of hospital discharge that justified the presence of criteria 1 and 2 [10]. number of COPD patients hospitalized due to CAP in the US and the cost of hospitalization. Incidence calculation The annual pneumonia incidence rates per 100 000 COPD patients were estimated for unique patients. COPD prevalence in the city of Louisville was derived using data from the 2014 Behavioral Risk Factor Surveillance System (BRFSS) as well as from the 2014 National Health Interview Survey (NHIS) [10]. Time to clinical stability Patients were evaluated daily to determine the day when clinical stability was reached. The following ATS criteria to define a patient as clinically stable were followed: (1) improved cough and shortness of breath, (2) lack of fever for at least 8 hr, (3) improving leucocytosis (decreased at least 10% from the previous day) and (4) tolerating oral intake with adequate gastrointestinal absorption [11]. The day that the patient met criteria for clinical stability minus the day of admission defined time to clinical stability (TCS). Length of hospitalization Length of hospital stay (LOS) was defined in days and calculated for each patient as day of discharge minus the day of admission. Mortality All-cause mortality for all unique hospitalized COPD patients with pneumonia was evaluated during hospitalization, and at 30 days, 6 months and 1 year after hospitalization. After discharge, mortality was evaluated by reviewing medical records and data from the Kentucky Department for Public Health Office of Vital Statistics. Exclusion criteria Geospatial epidemiology With the intent to enrol only hospitalized COPD patients with pneumonia who lived in Louisville, KY, and who were counted in the 2010 US Census, patients were excluded from analysis if they (1) did not have a permanent or valid Louisville address based on US Census Bureau data, (2) did not have a valid Social Security Number (SSN) or (3) were in the correctional system. The geomasked location of each COPD patient's home address was obtained through the US Census Bureau website and a kernel density heatmap was created to show distribution of COPD patients in Louisville. Choropleth maps were created to compare census tract-level demographics and the spatial distribution of CAP. A complete description of the geospatial methods is available (please see supplementary material). Unique COPD patients hospitalized with pneumonia A unique COPD patient hospitalized with pneumonia was counted as the first hospitalization during each study year. A rehospitalization due to a new episode of pneumonia was identified by a repeat of the same SSN of each patient in the same study year. Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the United States and is considered the third leading cause of death worldwide [1,2]. Patients with COPD may die due to the progression of airflow limitation leading to respiratory failure, due to deterioration of comorbidities or due to infectious complications such as exacerbations and pneumonia [3e6]. The literature indicates that patients with COPD are at high risk of developing pneumonia [7e9], but the incidence, epidemiology and clinical outcomes of COPD patients hospitalized with community-acquired pneumonia (CAP) are not well defined. The primary objectives of this study were to compare the incidence and clinical outcomes of CAP of hospitalized patients with COPD versus without COPD in Louisville, KY. The secondary objectives were to define the geospatial epidemiology in Louisville and to estimate the Number of COPD patients hospitalized due to CAP in the United States The estimated number of pneumonia hospitalizations in the US population with COPD was calculated by multiplying the Louisville incidence rate by the estimated 2014 US adult population with COPD estimated from the US Bureau. Full methodological descriptions can be found in the supplementary material. Statistical analysis Descriptive statistics were performed, with medians and interquartile ranges (IQRs) describing continuous data, and frequencies and percentages describing categorical data. Patient groups were compared using ManneWhitney U tests, chi-square tests or the Fisher exact test where appropriate. Clinical outcomes of TCS and LOS were compared using Cox proportional hazards regressions, and clinical outcomes of mortality were compared using logistic regression. In all regression analysis, pneumonia severity index Please cite this article as: Bordon J et al., Hospitalization due to community-acquired pneumonia in patients with chronic obstructive pulmonary disease: incidence, epidemiology and outcomes, Clinical Microbiology and Infection, https://doi.org/10.1016/j.cmi.2019.06.025 J. Bordon et al. / Clinical Microbiology and Infection xxx (xxxx) xxx 3 Table 1 Baseline characteristics of patients Variable Patients; n Demographics Age, median (IQR) Male sex, n (%) Black race, n (%) Social and medical history, n (%) History of CHF BMI >30 History of diabetes mellitus History of renal failure History of neoplastic disease History of stroke History of liver disease History of HIV infection Smoking history Never Former Current Vaccination history, n (%) Pneumococcal vaccination Flu vaccination Cardiovascular risk factors and medications, n (%) Family history of CAD History of CAD History of arterial hypertension History of hyperlipidaemia Prior myocardial infarction Prior percutaneous transluminal coronary angioplasty History of atrial fibrillation Aspirin use Beta-blockers use ACE inhibitors use Warfarin use Heparin use Antiplatelet use Statin use Exam and laboratory values, median (IQR) Temperature, C Respiratory rate, breaths/min Heart rate, beats/min Systolic blood pressure, mmHg Diastolic blood pressure, mmHg Bicarbonate, mEq/L Blood urea nitrogen, mg/dL Glucose, mg/dL Haematocrit, % Sodium, mEq/L Severity of disease at admission ICU admission, n (%) Altered mental status, n (%) Vasopressors, n (%) Ventilatory support, n (%) Pneumonia severity index (PSI), median (IQR) PSI risk class 4 or 5, n (%) Blood culture isolatesa, n (%) Streptococcus pneumonia Staphylococcus other Methicillin-resistant Staphylococcus aureus Methicillin-susceptible Staphylococcus aureus Respiratory culture isolatesa, n (%) Methicillin-resistant Staphylococcus aureus Streptococcus pneumonia Haemophilus influenza Pseudomonas aeruginosa Methicillin-susceptible Staphylococcus aureus COPD treatments, n (%) Oral steroids prior to admission Home oxygen use Group COPD þ COPDe 3419 3476 70 (60e79) 1520 (44) 609 (18) 70 (57e83) 1656 (48) 701 (20) 1225 (36) 1197 (35) 1166 (34) 996 (29) 486 (14) 433 (13) 254 (7) 40 (1) 861 (25) 1197 (34) 1192 (34) 1114 (32) 482 (14) 500 (14) 225 (6) 45 (1) 501 (15) 1540 (45) 1378 (40) 1647 (47) 1148 (33) 681 (20) 1596 (47) 1226 (36) 1308 (38) 1097 (32) 940 (28) 1266 (37) 2520 (74) 1627 (48) 513 (15) 670 (20) 769 (22) 1313 (38) 1391 (41) 998 (29) 419 (12) 56 (2) 268 (8) 1341 (39) 794 (23) 932 (27) 2486 (72) 1572 (45) 392 (11) 507 (15) 685 (20) 1172 (34) 1338 (39) 1005 (29) 416 (12) 66 (2) 201 (6) 1230 (35) 37 (37e38) 24 (20e28) 106 (92e119) 115 (99e134) 56 (48e66) 27 (24e31) 19 (13e29) 149 (118e206) 36 (32e40) 137 (134e140) 37 (37e38) 22 (20e26) 103 (89e117) 117 (99e136) 57 (49e68) 25 (23e28) 20 (14e32) 138 (113e190) 35 (31e39) 137 (134e140) 648 (19) 581 (17) 99 (3) 579 (17) 105 (81e133) 2210 (65) 534 (15) 757 (22) 95 (3) 349 (10) 105 (78e133) 2227 (64) 37 33 22 11 (23) (21) (14) (7) 36 27 20 26 (17) (13) (10) (13) 59 55 39 37 25 (19) (18) (13) (12) (8) 36 21 21 21 20 (21) (12) (12) (12) (11) 568 (17) 834 (24) ACE, angiotensin converting enzyme; BMI, body mass index; CAD, Coronary artery disease; CHF, Congestive heart failure; COPD, chronic obstructive pulmonary disease; HIV, human immunodeficiency virus. a Only isolates with above at least 10% of found isolate frequency for either group are included. Please cite this article as: Bordon J et al., Hospitalization due to community-acquired pneumonia in patients with chronic obstructive pulmonary disease: incidence, epidemiology and outcomes, Clinical Microbiology and Infection, https://doi.org/10.1016/j.cmi.2019.06.025 4 J. Bordon et al. / Clinical Microbiology and Infection xxx (xxxx) xxx (PSI) risk class IV or V was used to adjust for severity of CAP. In addition the following variables not included in the PSI were also adjusted for regression analyses: smoking status, race, obesity, ICU admission on day 0, and active coronary artery disease as defined in the medical record. KaplaneMeier curves were also produced to for clinical outcomes of TCS, LOS and mortality. Time to clinical stability and length of stay were right truncated at eight and 14 days, respectively. In the event that patients died or left the hospital before becoming clinically stable, they were given the worst outcome (8 days). Patients that died before they left the hospital were given the worst outcome (14 days). Human subjects protection The study was approved by the University of Louisville (UofL) Institutional Review Board (IRB #11.0613) and by the research offices at each participating hospital. Study consents were waived. Study coordinating centre The study-coordinating centre, located at the UofL Division of Infectious Diseases, directed all operational and data aspects of the study [10]. Results Study population A total of 18 246 individuals aged 40 and older with COPD were estimated to live in Louisville, KY. Our study revealed a total of 3419 COPD patients hospitalized due to CAP in Louisville, KY, during the 2-year study period. Characteristics of our study patients are shown in Table 1. COPD patients, compared with non-COPD patients, had more history of heart failure, more ICU admission and use of mechanical ventilation, yet had similar PSI score and 17% received oral steroids prior to admission. They also had more pneumococcal pneumonia, in spite of receiving pneumococcal vaccine significantly more often. Incidence of CAP The annual incidence of CAP was 9369 (95% CI 8925e9813) in patients with COPD versus 509 (95% CI 486e533) in patients without COPD per 100 000 population in the city of Louisville. The incidence of CAP among COPD and non-COPD patients for ages 40e64 years and older than 65 years, by sex, are shown in Fig. 1. Clinical outcomes TCS and LOS were similar for patients with and without COPD hospitalized due to CAP. Median TCS was 2 (IQR 1e4) days and median LOS was 5 (IQR 3e8) days in both patient groups. The mortality of patients with COPD and CAP during hospitalization was 5.6%. Furthermore, the mortality of patients with COPD at 30 days, 6 months and 1 year was 11.9%, 24.3% and 33.0%, respectively versus 6.6%, 14.2%, 24.2% and 30.1% in non-COPD respectively. KaplaneMeier curves are shown in Fig. 2. The adjusted model outcomes are shown in Table 2. Geospatial epidemiology The kernel density heat map according to the home address of each COPD patient hospitalized with CAP is shown in Fig. 3A. Clusters of COPD patients hospitalized with CAP were identified in the western northern area of the city of Louisville were individuals with low-income and Black/African American are concentrated (Fig. 3B and C). Clusters of COPD patients hospitalized with CAP did not appear to be associated with areas with increased elderly population as shown in Fig. 3D. Number of COPD patients hospitalized due to CAP in the USA The projected number of individuals with COPD hospitalized due to CAP in United States was 506 953 (95% CI 482 923e530 983). Discussion This study revealed a CAP incidence of 9369 individuals per 100 000 population aged 40 years and older with COPD in the city Fig. 1. Incidence of patients hospitalized for community-acquired pneumonia by age groups and gender per 100 000 population for patients with and without COPD (chronic obstructive pulmonary disease). Please cite this article as: Bordon J et al., Hospitalization due to community-acquired pneumonia in patients with chronic obstructive pulmonary disease: incidence, epidemiology and outcomes, Clinical Microbiology and Infection, https://doi.org/10.1016/j.cmi.2019.06.025 J. Bordon et al. / Clinical Microbiology and Infection xxx (xxxx) xxx 5 Table 2 Adjusted model results for clinical outcomes of CAP patients hospitalized with and without COPD Outcome Estimate 95% Confidence interval p Time to clinical stabilitya Length of staya Mortality, all causes In-hospital mortalityb 30-day mortalityb 6-month mortalityb 1-year mortalityb 0.92 0.90 0.87e0.97 0.85e0.95 0.002 <0.001 0.86 0.85 1.08 1.25 0.69e1.07 0.73e1.00 0.95e1.22 1.11e1.41 0.165 0.052 0.262 <0.001 a b Fig. 2. KaplaneMeier curves for hospitalized community-acquired pneumonia patients with and without chronic obstructive pulmonary disease (COPD) according to time to reach clinical stability, hospital discharge, and mortality. of Louisville. These observations mean that nearly one in ten persons with COPD will be hospitalized annually due to CAP. This translates into approximately 500 000 COPD patients hospitalized with CAP every year in the United States, resulting in a substantial Adjusted hazard ratio for negative outcome reported. Adjusted odds ratio for negative outcome reported. burden of approximately 5 billion US dollars in hospitalization costs. Furthermore, our study showed that patients with COPD have an approximately 18-fold greater incidence of CAP than non-COPD patients. Risk factors for this high incidence may include use of inhaled corticosteroid (ICS), smoking and suboptimal immunization [12e15]. The use of ICS has been associated with a 69% increase of the rate of pneumonia [16]. The UPLIFT trial established that use of ICS increases pneumonia events by 22% in COPD patients [17]. A Cochrane review of 43 RCTs concluded that ICS were associated with a 1.78-fold increase in the odds of pneumonia [18]. The high rate of tobacco smoking of our COPD patients is expected to be a major contributing factor to the high incidence of CAP [19,20]. The tobacco smoking rate of our patient population was similar to that reported by Mullerova et al. in the UK [21]. Modifiable factors associated with CAP such us tobacco smoking and immunizations should be health interventions to prevent the burden of CAP in COPD patients. However, pneumococcal vaccination was used more often in our COPD population than in other CAP patients, but pneumococcal pneumonia still occurred at a numerically higher rate. In relation to underserved populations, our study showed a substantial burden of CAP in COPD among African Americans and those living in poverty. Other studies of CAP among patients with COPD did not examine epidemiology factors such as race/ethnicity and poverty level [19,22,23]. Health interventions to prevent CAP should be maximized in underserved population as revealed by our study. No clinical differences were found among patients with versus without COPD in regard to time to reach clinical improvement, time of hospital discharge. Except for the 1-year mortality that was 25% greater among COPD patients, the in-hospital mortality, 30-day mortality and 6-month mortality did not have statistically significant differences between groups (Table 2). Though patients with COPD would be expected to have poorer outcomes, others reported similar results to ours [18,24e26]. In our study, the lower than expected mortality among COPD patients could be due to multiple factors including the aggressive medical management for COPD. Factors contributing to the outcomes of CAP among COPD patients are poorly characterized. Corticosteroid therapy may play a role in the lack of poor outcomes of COPD patients [27,28]. Similar to the immune response following vaccination, chronic bacterial lung colonization may contribute to the priming of the host response favouring the outcomes of CAP in COPD patients [29,30]. Even though we did not find evidence of increased mortality at earlier time points, we documented an increase in the odds of 1-year allcause mortality by 25% among our COPD patients compared to those without COPD. Our study has several limitations. Our study was not designed to identify risk factors for the incidence of CAP among COPD patients. Please cite this article as: Bordon J et al., Hospitalization due to community-acquired pneumonia in patients with chronic obstructive pulmonary disease: incidence, epidemiology and outcomes, Clinical Microbiology and Infection, https://doi.org/10.1016/j.cmi.2019.06.025 6 J. Bordon et al. / Clinical Microbiology and Infection xxx (xxxx) xxx Fig. 3. Heatmap representation of the home address of each chronic obstructive pulmonary disease (COPD) patient hospitalized with community-acquired pneumonia (CAP) in the city of Louisville (A). Maps indicating the home address (dots) of COPD patients hospitalized with CAP superimposed on maps indicating poverty (B), Black/African American (C), and population over 65 years of age (D) according to census tracts in the city of Louisville. In this regard, our study does not include validation of corticosteroid therapy and of influenza and pneumococcal immunizations. Our study also did not include the confirmation of COPD diagnosis by lung function test. We also did not evaluate CAP in COPD patients that did not lead to hospitalization. Major strengths of our study include the prospective population-based design, the inclusion of all adult hospitals of a major US city, and the identification of patients hospitalized multiple times by using the patients' social security numbers as a unique identifier. In summary, our study revealed an incidence of 9369 cases of CAP per 100 000 COPD patients resulting in an approximately 18fold greater incidence of CAP than those patients without COPD. This substantial incidence of CAP among COPD patients results in a high health and financial burden. Acknowledgements The authors would like to acknowledge the efforts of all healthcare workers, administrators, and members of the research offices at each of the participating facilities who made this study possible. The authors appreciate the manuscript review by Jessica Lynn Petrey, Clinical Librarian, Kornhauser Health Sciences Library, University of Louisville. Appendix A. 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