Clinical Microbiology and Infection xxx (xxxx) xxx

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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
2)
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

a r t i c l e i n f o a b s t r a c t

Article history: Objectives: Community-acquired pneumonia (CAP) is an important complication in patients with chronic
Received 21 April 2019 obstructive pulmonary disease (COPD). This study aimed to define incidence, and outcomes of COPD
Received in revised form patients hospitalized with pneumonia in the city of Louisville, and to estimate the burden of disease in
8 June 2019
the US population.
Accepted 17 June 2019
Methods: This was a secondary analysis of a prospective population-based cohort study of residents in
Available online xxx
Louisville, Kentucky, 40 years old and older, from 1 June 2014 to 31 May 2016. All adults hospitalized with
Editor: L. Leibovici 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
Keywords: included time to clinical stability (TCS), length of hospital stay (LOS) and mortality.
COPD Results: From a Louisville population of 18 246 patients with COPD, 3419 pneumonia hospitalizations
Epidemiology were documented during the 2-year study. The annual incidence was 9369 patients with pneumonia per
Incidence 100 000 COPD population, corresponding to an estimated 506 953 adults with COPD hospitalized due to
Mortality
pneumonia in the United States. The incidence of CAP in patients without COPD was 509 (95% CI 485
Pneumonia
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.

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 Infec-
tious Diseases, 1150 Varnum St NE Suite # 203, Washington, DC 20017, USA.
E-mail address: jbordon@dc-whi.org (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, epidemi-
ology 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].
Exclusion criteria
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.
Unique COPD patients hospitalized with pneumonia
A unique COPD patient hospitalized with pneumonia was
counted as the first hospitalization during each study year. A re-
hospitalization 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, epidemi-
ology 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
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
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 pa-
tients 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 clin-
ical 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.
Geospatial epidemiology
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).
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 de-
scriptions can be found in the supplementary material.
Statistical analysis
Descriptive statistics were performed, with medians and inter-
quartile 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
 J. Bordon et al. / Clinical Microbiology and Infection xxx (xxxx) xxx 3

Table 1
Baseline characteristics of patients

Variable Group

COPD þ COPDe

Patients; n 3419 3476

Demographics
Age, median (IQR) 70 (60e79) 70 (57e83)
Male sex, n (%) 1520 (44) 1656 (48)
Black race, n (%) 609 (18) 701 (20)
Social and medical history, n (%)
History of CHF 1225 (36) 861 (25)
BMI >30 1197 (35) 1197 (34)
History of diabetes mellitus 1166 (34) 1192 (34)
History of renal failure 996 (29) 1114 (32)
History of neoplastic disease 486 (14) 482 (14)
History of stroke 433 (13) 500 (14)
History of liver disease 254 (7) 225 (6)
History of HIV infection 40 (1) 45 (1)
Smoking history
Never 501 (15) 1647 (47)
Former 1540 (45) 1148 (33)
Current 1378 (40) 681 (20)
Vaccination history, n (%)
Pneumococcal vaccination 1596 (47) 1308 (38)
Flu vaccination 1226 (36) 1097 (32)
Cardiovascular risk factors and medications, n (%)
Family history of CAD 940 (28) 794 (23)
History of CAD 1266 (37) 932 (27)
History of arterial hypertension 2520 (74) 2486 (72)
History of hyperlipidaemia 1627 (48) 1572 (45)
Prior myocardial infarction 513 (15) 392 (11)
Prior percutaneous transluminal coronary angioplasty 670 (20) 507 (15)
History of atrial fibrillation 769 (22) 685 (20)
Aspirin use 1313 (38) 1172 (34)
Beta-blockers use 1391 (41) 1338 (39)
ACE inhibitors use 998 (29) 1005 (29)
Warfarin use 419 (12) 416 (12)
Heparin use 56 (2) 66 (2)
Antiplatelet use 268 (8) 201 (6)
Statin use 1341 (39) 1230 (35)
Exam and laboratory values, median (IQR)
Temperature,
C 37 (37e38) 37 (37e38)
Respiratory rate, breaths/min 24 (20e28) 22 (20e26)
Heart rate, beats/min 106 (92e119) 103 (89e117)
Systolic blood pressure, mmHg 115 (99e134) 117 (99e136)
Diastolic blood pressure, mmHg 56 (48e66) 57 (49e68)
Bicarbonate, mEq/L 27 (24e31) 25 (23e28)
Blood urea nitrogen, mg/dL 19 (13e29) 20 (14e32)
Glucose, mg/dL 149 (118e206) 138 (113e190)
Haematocrit, % 36 (32e40) 35 (31e39)
Sodium, mEq/L 137 (134e140) 137 (134e140)
Severity of disease at admission
ICU admission, n (%) 648 (19) 534 (15)
Altered mental status, n (%) 581 (17) 757 (22)
Vasopressors, n (%) 99 (3) 95 (3)
Ventilatory support, n (%) 579 (17) 349 (10)
Pneumonia severity index (PSI), median (IQR) 105 (81e133) 105 (78e133)
PSI risk class 4 or 5, n (%) 2210 (65) 2227 (64)
Blood culture isolatesa, n (%)
Streptococcus pneumonia 37 (23) 36 (17)
Staphylococcus other 33 (21) 27 (13)
Methicillin-resistant Staphylococcus aureus 22 (14) 20 (10)
Methicillin-susceptible Staphylococcus aureus 11 (7) 26 (13)
Respiratory culture isolatesa, n (%)
Methicillin-resistant Staphylococcus aureus 59 (19) 36 (21)
Streptococcus pneumonia 55 (18) 21 (12)
Haemophilus influenza 39 (13) 21 (12)
Pseudomonas aeruginosa 37 (12) 21 (12)
Methicillin-susceptible Staphylococcus aureus 25 (8) 20 (11)
COPD treatments, n (%)
Oral steroids prior to admission 568 (17)
Home oxygen use 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 sta-
bility 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 of-
fices 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 me-
chanical 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 signifi-
cantly more often.
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
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%, respec-
tively 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
 J. Bordon et al. / Clinical Microbiology and Infection xxx (xxxx) xxx
Fig. 2. KaplaneMeier curves for hospitalized community-acquired pneumonia pa-
tients 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 per-
sons 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
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
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 0.92 0.87e0.97 0.002
Length of staya 0.90 0.85e0.95 <0.001
Mortality, all causes
In-hospital mortalityb 0.86 0.69e1.07 0.165
30-day mortalityb 0.85 0.73e1.00 0.052
6-month mortalityb 1.08 0.95e1.22 0.262
1-year mortalityb 1.25 1.11e1.41 <0.001
a
Adjusted hazard ratio for negative outcome reported.
b
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 signifi-
cant 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 all-
cause 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.
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 corticoste-
roid 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 pa-
tients that did not lead to hospitalization. Major strengths of our
study include the prospective population-based design, the inclu-
sion 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 18-
fold 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. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.cmi.2019.06.025.
References

Transparency declaration
This work was supported primarily by the Division of Infectious
Diseases, University of Louisville, Kentucky. Partial support was
given by Pfizer Inc. All authors do not report conflicts of interest. All
authors submitted the CMI form for disclosure of Potential Conflict
of Interest. Conflicts that the journal consider relevant to the con-
tent of the manuscript have been disclosed.
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