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Original Research: COPD |

Systemic Inflammatory Pattern of Patients With Community-Acquired Pneumonia With and Without COPDInflammatory Response in Pneumonia with COPD FREE TO VIEW

Ernesto Crisafulli, MD, PhD, FCCP; Rosario Menéndez, MD, PhD; Arturo Huerta, MD; Raquel Martinez, MD; Beatriz Montull, MD; Enrico Clini, MD, FCCP; Antoni Torres, MD, PhD, FCCP
Author and Funding Information

From the Department of Pulmonary Rehabilitation (Drs Crisafulli and Clini), Ospedale Villa Pineta, University of Modena and Reggio Emilia, Modena, Italy; Servicio de Neumología (Drs Menéndez, Martinez, and Montull), Hospital Universitario y politecnico La Fe, CIBERES, Valencia, Spain; and Pneumology Department (Drs Huerta and Torres), Clinic Institute of Thorax, Hospital Clinic of Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain.

Correspondence to: Antoni Torres, MD, PhD, FCCP, Pneumology Department, Clinic Institute of Thorax, Hospital Clinic, Villarroel 170. 08036 Barcelona, Spain; e-mail: ATORRES@clinic.ub.es


Funding/Support: This study was supported by Ciber de Enfermedades Respiratorias [CIBERES (Biomedical Research Centre Network for Respiratory Diseases) CB06/06/0028], Pneumonia Corporate Research Program [2009 SGR 911], and by a grant from Marato TV3, Spain.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2013;143(4):1009-1017. doi:10.1378/chest.12-1684
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Background:  Several clinical studies have evaluated the role of COPD in patients with community-acquired pneumonia (CAP). We investigated the systemic inflammatory response of patients with CAP (CAP + COPD) and patients without associated COPD (CAP only).

Methods:  Clinical, microbiologic, and immunologic data were collected from 367 prospective patients on admission to hospital during a 3-year period. Comparative analyses were performed between patients with CAP + COPD (n = 117) and those with CAP only (n = 250) and between patients with and without domiciliary use of inhaled corticosteroids (ICSs) and oral corticosteroids.

Results:  Detailed characteristics of clinical severity and prognosis (mortality on hospitalization and at 30 and 90 days) were similar between the CAP + COPD and CAP-only groups. The readmission rate and the frequency of previous pneumonia were higher in the group of patients with CAP + COPD. On day 1 (admission to hospital), patients with CAP + COPD had significantly lower serum levels of tumor necrosis factor-α, IL-1, and IL-6 compared with the CAP-only group; levels of the remaining inflammatory biomarkers (C-reactive protein, procalcitonin, IL-8, and IL-10) were similar at days 1 and 3. The exclusion of patients with domiciliary use of ICS and oral corticosteroids confirmed lower levels of TNF-α on day 1 in patients with CAP + COPD. Finally, lower levels of IL-6 were found only among those patients with COPD who were currently using ICS.

Conclusions:  Our prospective study demonstrates a different, disease-specific, early inflammatory pattern between patients with CAP with and without associated COPD. These findings are not completely corticosteroid mediated.

Figures in this Article

Measurement of specific biomarkers in the systemic inflammatory response (SIR) in patients with community-acquired pneumonia (CAP) may be useful for several purposes: Procalcitonin (PCT), C-reactive protein (CRP), IL-6, and IL-8 may aid evaluation of clinical course and treatment efficacy14; IL-6 and IL-10 in identifying etiology5; and IL-6, IL-8, PCT, and CRP in the classification of risk of treatment failure6 and in the prediction of mortality.711

COPD is a disease that progresses slowly, with airflow limitation and a persistent inflammatory pattern.1215 In patients hospitalized due to CAP, COPD represents one of the most frequent comorbidity and risk factors16,17; however, the clinical18,19 and prognostic role18,2024 that COPD seems to play in patients with CAP is still unclear and subject to debate. A correct definition of COPD diagnosis on admission to hospital is probably a confounding factor that leads to difficulties in data interpretation. Moreover, specific immunologic characteristics of inflammatory response in these patients are still unknown.

We hypothesized that patients with COPD have an underlying, characteristic, inflammatory pattern of response to CAP. The aim of our prospective study was to investigate the SIR to CAP in patients with confirmed clinical and functional COPD (CAP + COPD) in comparison with CAP without COPD (CAP only). We, therefore, measured the serum levels of inflammatory biomarkers in these patients on admission to hospital.

We performed a prospective study in two tertiary-care university hospitals in Spain (Hospital La Fe in Valencia and Hospital Clinic in Barcelona). The ethics committee of both hospitals approved the study (Comité Ético De Investigación Clínica project numbers CEIC 2003/0048 and CEIC 2004/1855 for Hospital La Fe and Hospital Clinic, respectively), which was conducted in accordance with the Declaration of Helsinki. Selected patients who gave their written informed consent were considered for the study.

Study Cohort and Definitions

Consecutive adults patients (n = 367) hospitalized with CAP were selected over a period of 3 years (from January 2004 to December 2006). Pneumonia was defined as a new, radiographic, pulmonary infiltrate on admission with signs or symptoms of lower respiratory tract infection. Patients admitted to the hospital in the previous 2 weeks and patients with suspected nosocomial or health-care associated pneumonia were excluded. Furthermore, patients with severe immunosuppression (WBC counts < 1,000/mm3 and/or neutrophil counts < 500/mm3) attributed to a cause other than pneumonia (eg, chemotherapy, bone marrow or solid-organ transplantation, HIV infection, systemic corticosteroid treatment > 20 mg prednisone-equivalent/d for ≥ 2 weeks) were also excluded from the study.

An expert physician specializing in respiratory medicine confirmed diagnosis and severity of COPD, which was defined according to the GOLD (Global Initiative for Chronic Obstructive Lung Disease) guidelines.12 Spirometry was performed prior to CAP-related admission. Forced lung volumes to obtain FEV1 and FVC were assessed by an automated spirometer with predicted values according to the Quanjer equation.25 In the CAP-only group without spirometry, absence of COPD was associated with clinical history, smoking habit (< 10 packs/y), and use of inhaled corticosteroids (ICSs) as a specific medication.

Measurements on Admission

Baseline data gathered on admission included the following primary demographic and functional variables: smoking habit, presence of any comorbid conditions associated with CAP (eg, heart, liver, or renal diseases, diabetes, cancer), and use of domiciliary drugs (including antibiotic treatment and antipneumococcal and/or influenza vaccination). Alcohol abuse was considered in cases with a current intake of ≥ 80 g/d and ≥ 60 g/d in men and women, respectively.26

To obtain a clinical severity score for pneumonia, we calculated the Pneumonia Severity Index (PSI)27 and CURB-6528 (confusion, urea plasma level, respiratory rate, BP, age > 65 years) score on admission. Patient oxygenation was recorded as the ratio of PaO2 to the FIO2 (PaO2/FIO2).

Length of hospital stay (LOS), frequency of patients in whom admission to the ICU or noninvasive mechanical ventilation (NIMV) was required, and frequency of patients in whom severe sepsis with or without septic shock was identified were also recorded. Mortality and rehospitalization were evaluated during follow-up at 30 and 90 days and at 1 year after a hospital admission. However, this study was not powered for mortality.

Microbiologic Evaluation

Samples for microbiologic investigation were collected following a standard protocol: (1) two blood cultures; (2) urine for antigen detection of Streptococcus pneumoniae (Binax NOW S pneumoniae Urinary Antigen Test; Emergo Group Inc) and Legionella pneumophila serogroup 1 (Binax NOW L pneumophila Urinary Antigen Test; Trinity Biotech plc); (3) sputum specimens; (4) nasopharyngeal swabs for respiratory virus detection; and (5) pleural fluid by thoracocentesis. Diagnosis of the following microorganisms was performed by paired serology on admission and during the third or sixth week thereafter: (1) atypical microorganisms, including L pneumophila serogroup 1, Chlamydophila pneumoniae, Chlamydia psittaci, Mycoplasma pneumoniae, and Coxiella burnetii; and (2) respiratory viruses: influenza virus (A and B), parainfluenza virus (1, 2, and 3), respiratory syncytial virus, and adenovirus. High titers of IgM antibodies in the serum during the acute phase was accepted for the diagnosis of atypical microorganisms such as C pneumoniae (≥ 1:32), C burnetii (≥ 1:80), and M pneumoniae (any positive titer).

Determination of Biomarkers

Blood samples were taken from the patients on the morning of admission to hospital, centrifuged, and frozen at −80°C for subsequent analysis. Determination of levels of IL-1, IL-6, IL-8, and IL-10, and tumor necrosis factor α (TNF-α) was performed using an enzyme immunoassay (DIASource ImmunoAssays SA) and the techniques used were in accordance with the manufacturer’s instructions.

Detection limits were as follows: 0.7 pg/mL for IL-8, 1 pg/mL for IL-10, 1.5 pg/mL for IL-1, and 2 pg/mL for IL-6 and TNF-α. An immunoluminometric technique was used to measure procalcitonin (PCT) (Liaison Brahms PCT, DiaSorin SpA) with a detection limit of 0.3 ng/mL. C-reactive protein (CRP) was measured using a commercially available immunoturbidimetric method (Bayer AG) with a detection limit of 0.1 mg/dL.

Statistical Analysis

Analysis of study variables was performed using a statistical software package (SPSS 17 for Windows; IBM). All data were analyzed in the two groups of patients according to the presence or absence of COPD associated with CAP. Results were expressed as mean ± SD or SE for continuous variables and frequency (percentage) for categorical variables. A prior test for normality of data distribution, the Kolmogorov-Smirnov test, was performed. Differences in continuous variables were then analyzed using an independent, two-tailed t test for unpaired variables; otherwise, the nonparametric Mann-Whitney U or Kruskal-Wallis tests were used. Categorical variables were studied using the χ2 test or Fisher exact test when necessary. For all analyses, an α error < 5% was considered statistically significant.

Our prospective study cohort included 367 patients admitted to two university hospitals for CAP. Of these, 250 (68%) showed no associated COPD, and 117 patients (32%) with CAP also had clinically and functionally confirmed COPD. As expected, patients in the CAP + COPD group (mean FEV1, 54 ± 17% predicted) were predominantly men (94%), older (mean age, 72 ± 10 years), and with greater prevalence of heart disease, smoking, and alcoholic habit in comparison with the CAP-only group of patients. In terms of domiciliary pharmacotherapy, patients with CAP + COPD presented considerable use of bronchodilators, ICS, and oral corticosteroids on admission; however, the percentage of patients who had received antibiotic treatment (data not shown) and/or an antipneumococcal or influenza vaccination before developing CAP was similar in both groups. Table 1 shows the values of these main characteristics of the patients studied.

Table Graphic Jump Location
Table 1 —Main Characteristics of Cohort Study

Data given as No. (%) unless otherwise indicated. CAP = community-acquired pneumonia; GOLD = Global Initiative for Chronic Obstructive Lung Disease; LABA = long-acting β2 agonist; SABA = short-acting β2 agonist.

a 

Values in bold indicate P < .05.

b 

Stage I was defined as FEV1/FVC ratio ≤ 70% and FEV1 > 80% predicted; stage II as FEV1/FVC ratio ≤ 70% and FEV1 50%-80% predicted; stage III as FEV1/FVC ratio ≤ 70% and FEV1 30%-50% predicted; stage IV as FEV1/FVC ratio ≤ 70% and FEV1 < 30% predicted.

In terms of the clinical features and outcomes of pneumonia on hospitalization (Table 2), patients with CAP + COPD had higher values for specific scores (ie, PSI and CURB-65) compared with patients in the CAP-only group; however, the comparison of detailed characteristics of clinical severity (Pao2/FIo2, LOS, admission directly to ICU, need for NIMV, and sepsis with and without shock) were similar in both groups (CAP only and CAP + COPD). Furthermore, the mortality rate calculated on hospitalization and at 30 and 90 days was also similar. Readmission to hospital and frequency of previous pneumonia were more prevalent in the CAP+COPD group.

Table Graphic Jump Location
Table 2 —Clinical Features and Outcomes of Pneumonia

Data given as No. (%) unless otherwise indicated. CURB-65 = confusion, elevated blood urea nitrogen, respiratory rate, and BP, plus age ≥ 65 y score; LOS = length of hospital stay; NIMV = noninvasive mechanical ventilation; PSI = Pneumonia Severity Index. See Table 1 legend for expansion of other abbreviations.

a 

Values in bold indicate P < .05.

The rate of microbiologic diagnosis (Table 3), confirmed in 44% and 49% of patients in the CAP-only and CAP + COPD groups, respectively, was similar in both groups, with S pneumoniae being the most frequent pathogen; however, P aeruginosa was less frequent in the CAP-only group than in the CAP + COPD group (n = 4 vs n = 14; P < .05). An additional analysis that excluded patients with domiciliary use of inhaled and oral corticosteroids showed a similar prevalence of P aeruginosa (2.0% and 2.4% in patients with CAP or CAP + COPD, respectively; P = .881). Furthermore, in patients with CAP + COPD, the prevalence of P aeruginosa was 1.8% and 11% in patients without and with domiciliary use of ICS, respectively (P = .048).

Table Graphic Jump Location
Table 3 —Microbiologic Diagnosis According to Presence or Absence of COPD

Data given as No. (%) relative to the number of patients with etiologic diagnosis in each group. See Table 1 legend for expansion of abbreviations.

a 

Etiologic diagnosis confirmed in n = 112 (44.8%) and n = 58 (49.6%) of patients with CAP only and patients with CAP + COPD, respectively (P = .393).

b 

Including methicillin-sensitive and methicillin-resistant S aureus.

c 

Including Mycoplasmapneumoniae, Coxiellaburnettii, and Chlamydia.

d 

P < .05.

e 

Including Escherichia coli, Klebsiella oxytoca, and Proteus mirabilis.

On admission to hospital (day 1), patients with CAP + COPD had lower serum levels of TNF-α (P < .001), IL-1 (P < .05), and IL-6 (P < .05) compared with the CAP-only group (mean ± SE, 21.6 ± 1.8, 14.8 ± 2.9, and 331.9 ± 81.3 vs 33.0 ± 2.5, 24.7 ± 4.3, and 341.9 ± 48.2 for TNF-α, IL-1, and IL-6, respectively). The remaining inflammatory biomarkers (CRP, PCT, IL-8, and IL-10) were similar in patients from both groups on day 1 and day 3 (Fig 1).

Figure Jump LinkFigure 1. Panel of inflammatory response according to presence or absence of COPD associated with community-acquired pneumonia (CAP) (sample tested, n = 367). In white and gray: patients with CAP only and CAP + COPD, respectively. The horizontal bar and box length represent the median and the interquartile range, respectively. Circles and asterisks indicate outliers (1.5 and 3 times the interquartile range, respectively). §P < 0.05; §§P < .001. CRP = C-reactive protein; TNF-α = tumor necrosis factor-α.Grahic Jump Location

Repetition of the analyses selecting patients < 65 years and those ≥ 65 years and patients with or without chronic heart disease (presence or absence) confirmed a significantly (P < .05) lower level of early inflammatory response in patients with CAP + COPD in comparison with patients with CAP only, especially in terms of serum levels of TNF-α and IL-1 (Table 4).

Table Graphic Jump Location
Table 4 —Additional Analyses of Early Inflammatory Response According to Patient Age and Presence or Absence of Chronic Heart Disease

Data given as mean ± SE. TNF = tumor necrosis factor. See Table 1 legend for expansion of other abbreviations.

a 

P < .05 in comparison with CAP only.

b 

P < .001 in comparison with CAP only.

Analysis of inflammatory response, excluding patients with domiciliary use of ICS and oral corticosteroids (total sample, n = 282; n = 241 and n = 41 for CAP only and CAP + COPD, respectively), confirmed lower levels of TNF-α (mean ± SE, 23.1 ± 3.2 vs 33.7 ± 2.6; P < .05) and IL-1 (mean ± SE, 9.6 ± 2.1 vs 25.5 ± 4.6 P < .05) on day 1 in patients with CAP + COPD (Fig 2).

Figure Jump LinkFigure 2. Panel of inflammatory response according to presence or absence of COPD with exclusion of patients with domiciliary use of inhaled and oral corticosteroids (sample tested, n = 282). In white and gray: patients with community-acquired pneumonia (CAP) only and CAP + COPD, respectively. The horizontal bar and box length represent the median and the interquartile range, respectively. Circles and asterisks indicate outliers (1.5 and 3 times the interquartile range, respectively). §P < .05. See Figure 1 legend for expansion of abbreviations.Grahic Jump Location

The exclusion of patients with CAP only (COPD total sample, n = 117; with ICS, n = 63; without ICS, n = 54) showed lower levels of IL-6 on day 1 in patients currently using corticosteroids (mean ± SE, 241.8 ± 61.5 vs 642.9 ± 42.2; P < .05) (Fig 3).

Figure Jump LinkFigure 3. Panel of inflammatory response performed in patients with COPD only (sample tested, n = 117). In white and gray: patients with COPD without and with inhaled corticosteroid domiciliary use, respectively. The horizontal bar and box length represent the median and the interquartile range, respectively. Circles and asterisks indicate outliers (1.5 and 3 times the interquartile range, respectively). §P < .05. See Figure 1 legend for expansion of abbreviations.Grahic Jump Location

The main finding of our prospective research refers to the different and disease-specific early inflammatory pattern of patients with CAP + COPD compared with patients with CAP only. Indeed, we showed that, on the first day of hospitalization, the systemic response to bacterial infection (not completely corticosteroid mediated) in patients with COPD is lower, especially in terms of levels of TNF-α, IL-1, and IL-6 cytokines.

Clinical Characteristics and Etiologic Diagnosis

As expected, the epidemiologic characteristics of patients with COPD were specific and distinct from other patients with CAP. Clinical manifestations of patients with CAP + COPD, as reported by other authors,1719 appear worse according to specific pneumonia scales that are mainly linked to age (older), sex (higher percentage of men), and number of comorbidities. However, in a detailed evaluation of clinical severity characteristics on admission to hospital as well as of Pao2/FIo2, LOS, ICU admission, and need for NIMV, we found no significant differences between the groups (Table 2).19 This apparent incongruity regarding severity in patients with CAP + COPD suggests that PSI and CURB-65 may not be good markers of severity of CAP in patients with COPD. Hospital mortality rates and mortality rates during short-term and long-term follow-up were similar, thus confirming the lack of effect of COPD on prognosis in patients with CAP.18,24 However, it should be noted that this study was not powered for mortality.

In the spectrum of etiology diagnosis,19 we found a higher prevalence of P aeruginosa in the CAP + COPD group (Table 3). As shown in the literature, impairment of the lung parenchyma and/or airways is a risk factor for infection29; however, we found a significantly higher prevalence of P aeruginosa infection due to chronic and prior use of corticosteroids.

Early SIR to CAP

Generally, in CAP, the first host defense against bacterial infection is linked to the activation and recruitment of phagocytes, macrophages, and monocyte-derived macrophages, thereby producing multiple proinflammatory mediators, especially in the early phase.3032 Cellular observations33,34 of different mechanisms involving alveolar macrophages and/or phagocytosis response to infection concur with the finding of a reduced and specific inflammatory pattern in these patients with CAP + COPD.

When comparing patients with CAP with and without COPD, Gutierrez and colleagues33 showed that the microenvironment in the lungs may modify the common inflammatory response by inducing different types of activation and phenotypes of alveolar macrophages. Macrophages incubated in sputum obtained from patients with CAP showed increased expression of inflammatory biomarkers with a classic M1 activation pathway35; in patients with COPD associated with CAP, however, the authors observed a moderate, nonsignificant expression of cytokines, especially TNF-α, with a clear absence of M1 or M2 activation. This different activation and phenotype macrophage response may be interrelated with the specific peripheral inflammatory pattern of these patients with CAP + COPD.

According to the study by Taylor et al,34 however, patients with COPD show an immune deficit in terms of bacterial clearance, particularly in the alveolar phagocytosis response of macrophages and monocyte-derived macrophages for common airway pathogens, especially bacteria. Moreover, this reduced phagocyte activity, probably linked to a chronic adaptation, was not correlated and was suppressed by ICS medication, thereby suggesting that it is innate in patients with COPD. In these patients, TNF-α and IL-1 levels on day 1 were lower in the overall sample (Fig 1) and were unmodified after exclusion of patients using corticosteroids (Fig 2), thus confirming this underlying behavior of alveolar macrophages in patients with CAP + COPD. However, the significant differences observed in the levels of blood cytokines between the two groups were small and, therefore, probably not clinically meaningful.

Furthermore, the clearance dysfunction of phagocytes due to limited ability to remove pathogenic bacteria36,37 may lead to colonization of the lower airways with frequent acute bacterial infections, usually shown by an increase in frequency of COPD exacerbation17; our data showed an increased risk of pneumonia in patients with COPD (Table 2). However, we cannot rule out the possibility that prolonged use of ICS (commonly used by patients with COPD [Table 1]) increases the risk of developing pneumonia.38,39

Regarding the inflammatory effect of ICS medication on cytokine detection, our data demonstrate that this systemic modulation, widely reported in patients with COPD40,41 and severe pneumonia alone,42 can exist in the association of both conditions (CAP + COPD). Indeed, when comparing samples of patients with (Fig 1) and without (Fig 2) domiciliary steroid therapy, we found a loss of significance of IL-6 on day 1 in attenuating effects on systemic inflammatory levels. Moreover, to confirm these results in the COPD sample only (Fig 3), we found lower values of this biomarker in patients using domiciliary ICS.

Clinical Considerations

From the perspective of current clinical practice, our results in patients with CAP + COPD lead to some important considerations. As reported by studies that correlated SIR and clinical outcomes of patients with CAP,1,4,69 we can hypothesize that, in these patients with CAP + COPD, the low levels of circulating inflammatory biomarkers may have a nondetrimental effect on the hospital course and prognosis of these patients (Table 2), as previously reported18. However, our study is not intended or statistically powered to evaluate the clinical and prognostic effects of a different, early inflammatory response between patients with CAP only and those with CAP + COPD; further prospective studies are needed to clarify the possible correlation between immunologic and clinical/prognostic aspects of patients with COPD.

Regarding the hypothetical baseline bias of advanced age and comorbidities on the measurement of early inflammatory response (Table 1), we did not find any modulation effect of age and cardiovascular disease when comparing patients with CAP + COPD and the CAP-only group (Table 4). However, regarding IL-6 on day-1 (increased levels in patients with CAP + COPD who also had heart disease), we can exclude an effect of this comorbidity.

Strengths and Limitations

Although several articles have evaluated the clinical role of COPD in CAP,1724 to our knowledge, our study cohort is the first in which the specific inflammatory pattern of patients with both conditions has been investigated. Furthermore, diagnosis of COPD made before hospital admission and in a stable phase of the disease was confirmed by spirometry; this functional approach (FEV1/FVC < 0.70 for all patients) correctly and considerably increases the prevalence of patients with COPD. Conversely, in patients with CAP only, absence of COPD was diagnosed by clinical history, smoking habit, and home medication only. For that reason, we cannot exclude the presence of patients with airflow obstruction in this sample. Another limitation of our study is that it was not sufficiently powered to detect potential differences in mortality when comparing COPD with CAP to CAP alone.

In conclusion, our study shows that patients hospitalized with CAP + COPD show a different early inflammatory pattern than patients with CAP and without COPD; in particular, a systemic reduction of cytokine levels is likely. This finding seems to be specifically associated with COPD and is partially explained by the use of corticosteroids.

Author contributions: Dr Crisafulli had full access to the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Dr Crisafulli: contributed to the study concept and design, data analysis, and drafting of the manuscript and served as principal author.

Dr. Menéndez: contributed to the study concept and design, data analysis, and drafting of the manuscript.

Dr. Huerta: contributed to the coordination of data acquisition and to critical revision of the manuscript.

Dr. Martinez: contributed to the coordination of data acquisition and to critical revision of the manuscript.

Dr. Montull: contributed to the coordination of data acquisition and to critical revision of the manuscript.

Dr Clini: contributed to the interpretation of the data and critical revision of the manuscript.

Dr Torres: contributed to the study concept and design, interpretation of the data, and critical revision of the manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsor: CIBERES is a stable funding from the Ministry of Health mainly for personnel. Marato TV3 supported all the nonpersonnal budget (supplies) for this study.

CAP

community-acquired pneumonia

CRP

C-reactive protein

CURB-65

confusion, elevated blood urea nitrogen, respiratory rate, and BP, plus age ≥ 65 y

ICS

inhaled corticosteroid

LOS

length of hospital stay

NIMV

noninvasive mechanical ventilation

PCT

procalcitonin

PSI

Pneumonia Severity Index

SIR

systemic inflammatory response

TNF-α

tumor necrosis factor α

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Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault JC; Official Statement of the European Respiratory Society Official Statement of the European Respiratory Society. Lung volumes and forced ventilatory flows. Report Working Party Standardization of Lung Function Tests, European Community for Steel and Coal. Official statement of the European Respiratory Society Eur Respir J Suppl. 1993;16:5-40. [PubMed]
 
de Roux A, Cavalcanti M, Marcos MA, et al. Impact of alcohol abuse in the etiology and severity of community-acquired pneumonia. Chest. 2006;129(5):1219-1225. [CrossRef] [PubMed]
 
Fine MJ, Auble TE, Yealy DM, et al. A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J Med. 1997;336(4):243-250. [CrossRef] [PubMed]
 
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(5):377-382. [CrossRef] [PubMed]
 
Arancibia F, Bauer TT, Ewig S, et al. Community-acquired pneumonia due to gram-negative bacteria and pseudomonas aeruginosa: incidence, risk, and prognosis. Arch Intern Med. 2002;162(16):1849-1858. [CrossRef] [PubMed]
 
Endeman H, Meijvis SC, Rijkers GT, et al. Systemic cytokine response in patients with community-acquired pneumonia. Eur Respir J. 2011;37(6):1431-1438. [CrossRef] [PubMed]
 
Kolling UK, Hansen F, Braun J, Rink L, Katus HA, Dalhoff K. Leucocyte response and anti-inflammatory cytokines in community acquired pneumonia. Thorax. 2001;56(2):121-125. [CrossRef] [PubMed]
 
Nelson S. Novel nonantibiotic therapies for pneumonia: cytokines and host defense. Chest. 2001;119(suppl 2):419S-425S. [CrossRef] [PubMed]
 
Gutierrez P, Closa D, Piñer R, Bulbena O, Menéndez R, Torres A. Macrophage activation in exacerbated COPD with and without community-acquired pneumonia. Eur Respir J. 2010;36(2):285-291. [CrossRef] [PubMed]
 
Taylor AE, Finney-Hayward TK, Quint JK, et al. Defective macrophage phagocytosis of bacteria in COPD. Eur Respir J. 2010;35(5):1039-1047. [CrossRef] [PubMed]
 
Gordon S. Alternative activation of macrophages. Nat Rev Immunol. 2003;3(1):23-35. [CrossRef] [PubMed]
 
Donnelly LE, Barnes PJ. Defective phagocytosis in airways disease. Chest. 2012;141(4):1055-1062. [CrossRef] [PubMed]
 
Berenson CS, Garlipp MA, Grove LJ, Maloney J, Sethi S. Impaired phagocytosis of nontypeable Haemophilus influenzae by human alveolar macrophages in chronic obstructive pulmonary disease. J Infect Dis. 2006;194(10):1375-1384. [CrossRef] [PubMed]
 
Calverley PMA, Stockley RA, Seemungal TA, et al;; Investigating New Standards for Prophylaxis in Reduction of Exacerbations (INSPIRE) Investigators Investigating New Standards for Prophylaxis in Reduction of Exacerbations (INSPIRE) Investigators. Reported pneumonia in patients with COPD: findings from the INSPIRE study. Chest. 2011;139(3):505-512. [CrossRef] [PubMed]
 
Almirall J, Bolíbar I, Serra-Prat M, et al;; Community-Acquired Pneumonia in Catalan Countries Community-Acquired Pneumonia in Catalan Countries. Inhaled drugs as risk factors for community-acquired pneumonia. Eur Respir J. 2010;36(5):1080-1087. [CrossRef] [PubMed]
 
Sin DD, Lacy P, York E, Man SF. Effects of fluticasone on systemic markers of inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2004;170(7):760-765. [CrossRef] [PubMed]
 
Antoniu SA. Effects of inhaled therapy on biomarkers of systemic inflammation in stable chronic obstructive pulmonary disease. Biomarkers. 2010;15(2):97-103. [CrossRef] [PubMed]
 
Montón C, Ewig S, Torres A, et al. Role of glucocorticoids on inflammatory response in nonimmunosuppressed patients with pneumonia: a pilot study. Eur Respir J. 1999;14(1):218-220. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1. Panel of inflammatory response according to presence or absence of COPD associated with community-acquired pneumonia (CAP) (sample tested, n = 367). In white and gray: patients with CAP only and CAP + COPD, respectively. The horizontal bar and box length represent the median and the interquartile range, respectively. Circles and asterisks indicate outliers (1.5 and 3 times the interquartile range, respectively). §P < 0.05; §§P < .001. CRP = C-reactive protein; TNF-α = tumor necrosis factor-α.Grahic Jump Location
Figure Jump LinkFigure 2. Panel of inflammatory response according to presence or absence of COPD with exclusion of patients with domiciliary use of inhaled and oral corticosteroids (sample tested, n = 282). In white and gray: patients with community-acquired pneumonia (CAP) only and CAP + COPD, respectively. The horizontal bar and box length represent the median and the interquartile range, respectively. Circles and asterisks indicate outliers (1.5 and 3 times the interquartile range, respectively). §P < .05. See Figure 1 legend for expansion of abbreviations.Grahic Jump Location
Figure Jump LinkFigure 3. Panel of inflammatory response performed in patients with COPD only (sample tested, n = 117). In white and gray: patients with COPD without and with inhaled corticosteroid domiciliary use, respectively. The horizontal bar and box length represent the median and the interquartile range, respectively. Circles and asterisks indicate outliers (1.5 and 3 times the interquartile range, respectively). §P < .05. See Figure 1 legend for expansion of abbreviations.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Main Characteristics of Cohort Study

Data given as No. (%) unless otherwise indicated. CAP = community-acquired pneumonia; GOLD = Global Initiative for Chronic Obstructive Lung Disease; LABA = long-acting β2 agonist; SABA = short-acting β2 agonist.

a 

Values in bold indicate P < .05.

b 

Stage I was defined as FEV1/FVC ratio ≤ 70% and FEV1 > 80% predicted; stage II as FEV1/FVC ratio ≤ 70% and FEV1 50%-80% predicted; stage III as FEV1/FVC ratio ≤ 70% and FEV1 30%-50% predicted; stage IV as FEV1/FVC ratio ≤ 70% and FEV1 < 30% predicted.

Table Graphic Jump Location
Table 2 —Clinical Features and Outcomes of Pneumonia

Data given as No. (%) unless otherwise indicated. CURB-65 = confusion, elevated blood urea nitrogen, respiratory rate, and BP, plus age ≥ 65 y score; LOS = length of hospital stay; NIMV = noninvasive mechanical ventilation; PSI = Pneumonia Severity Index. See Table 1 legend for expansion of other abbreviations.

a 

Values in bold indicate P < .05.

Table Graphic Jump Location
Table 3 —Microbiologic Diagnosis According to Presence or Absence of COPD

Data given as No. (%) relative to the number of patients with etiologic diagnosis in each group. See Table 1 legend for expansion of abbreviations.

a 

Etiologic diagnosis confirmed in n = 112 (44.8%) and n = 58 (49.6%) of patients with CAP only and patients with CAP + COPD, respectively (P = .393).

b 

Including methicillin-sensitive and methicillin-resistant S aureus.

c 

Including Mycoplasmapneumoniae, Coxiellaburnettii, and Chlamydia.

d 

P < .05.

e 

Including Escherichia coli, Klebsiella oxytoca, and Proteus mirabilis.

Table Graphic Jump Location
Table 4 —Additional Analyses of Early Inflammatory Response According to Patient Age and Presence or Absence of Chronic Heart Disease

Data given as mean ± SE. TNF = tumor necrosis factor. See Table 1 legend for expansion of other abbreviations.

a 

P < .05 in comparison with CAP only.

b 

P < .001 in comparison with CAP only.

References

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Liapikou A, Polverino E, Ewig S, et al. Severity and outcomes of hospitalised community-acquired pneumonia in COPD patients. Eur Respir J. 2012;39(4):855-861. [CrossRef] [PubMed]
 
Pifarre R, Falguera M, Vicente-de-Vera C, Nogues A. Characteristics of community-acquired pneumonia in patients with chronic obstructive pulmonary disease. Respir Med. 2007;101(10):2139-2144. [CrossRef] [PubMed]
 
Rello J, Rodriguez A, Torres A, et al. Implications of COPD in patients admitted to the intensive care unit by community-acquired pneumonia. Eur Respir J. 2006;27(6):1210-1216. [CrossRef] [PubMed]
 
Restrepo MI, Mortensen EM, Pugh JA, Anzueto A. COPD is associated with increased mortality in patients with community-acquired pneumonia. Eur Respir J. 2006;28(2):346-351. [CrossRef] [PubMed]
 
Molinos L, Clemente MG, Miranda B, et al;; ASTURPAR Group ASTURPAR Group. Community-acquired pneumonia in patients with and without chronic obstructive pulmonary disease. J Infect. 2009;58(6):417-424. [CrossRef] [PubMed]
 
Menéndez R, Torres A, Zalacaín R, et al;; Neumofail Group Neumofail Group. Risk factors of treatment failure in community acquired pneumonia: implications for disease outcome. Thorax. 2004;59(11):960-965. [CrossRef] [PubMed]
 
Snijders D, van der Eerden M, de Graaff C, Boersma W. The influence of COPD on mortality and severity scoring in community-acquired pneumonia. Respiration. 2010;79(1):46-53. [CrossRef] [PubMed]
 
Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault JC; Official Statement of the European Respiratory Society Official Statement of the European Respiratory Society. Lung volumes and forced ventilatory flows. Report Working Party Standardization of Lung Function Tests, European Community for Steel and Coal. Official statement of the European Respiratory Society Eur Respir J Suppl. 1993;16:5-40. [PubMed]
 
de Roux A, Cavalcanti M, Marcos MA, et al. Impact of alcohol abuse in the etiology and severity of community-acquired pneumonia. Chest. 2006;129(5):1219-1225. [CrossRef] [PubMed]
 
Fine MJ, Auble TE, Yealy DM, et al. A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J Med. 1997;336(4):243-250. [CrossRef] [PubMed]
 
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(5):377-382. [CrossRef] [PubMed]
 
Arancibia F, Bauer TT, Ewig S, et al. Community-acquired pneumonia due to gram-negative bacteria and pseudomonas aeruginosa: incidence, risk, and prognosis. Arch Intern Med. 2002;162(16):1849-1858. [CrossRef] [PubMed]
 
Endeman H, Meijvis SC, Rijkers GT, et al. Systemic cytokine response in patients with community-acquired pneumonia. Eur Respir J. 2011;37(6):1431-1438. [CrossRef] [PubMed]
 
Kolling UK, Hansen F, Braun J, Rink L, Katus HA, Dalhoff K. Leucocyte response and anti-inflammatory cytokines in community acquired pneumonia. Thorax. 2001;56(2):121-125. [CrossRef] [PubMed]
 
Nelson S. Novel nonantibiotic therapies for pneumonia: cytokines and host defense. Chest. 2001;119(suppl 2):419S-425S. [CrossRef] [PubMed]
 
Gutierrez P, Closa D, Piñer R, Bulbena O, Menéndez R, Torres A. Macrophage activation in exacerbated COPD with and without community-acquired pneumonia. Eur Respir J. 2010;36(2):285-291. [CrossRef] [PubMed]
 
Taylor AE, Finney-Hayward TK, Quint JK, et al. Defective macrophage phagocytosis of bacteria in COPD. Eur Respir J. 2010;35(5):1039-1047. [CrossRef] [PubMed]
 
Gordon S. Alternative activation of macrophages. Nat Rev Immunol. 2003;3(1):23-35. [CrossRef] [PubMed]
 
Donnelly LE, Barnes PJ. Defective phagocytosis in airways disease. Chest. 2012;141(4):1055-1062. [CrossRef] [PubMed]
 
Berenson CS, Garlipp MA, Grove LJ, Maloney J, Sethi S. Impaired phagocytosis of nontypeable Haemophilus influenzae by human alveolar macrophages in chronic obstructive pulmonary disease. J Infect Dis. 2006;194(10):1375-1384. [CrossRef] [PubMed]
 
Calverley PMA, Stockley RA, Seemungal TA, et al;; Investigating New Standards for Prophylaxis in Reduction of Exacerbations (INSPIRE) Investigators Investigating New Standards for Prophylaxis in Reduction of Exacerbations (INSPIRE) Investigators. Reported pneumonia in patients with COPD: findings from the INSPIRE study. Chest. 2011;139(3):505-512. [CrossRef] [PubMed]
 
Almirall J, Bolíbar I, Serra-Prat M, et al;; Community-Acquired Pneumonia in Catalan Countries Community-Acquired Pneumonia in Catalan Countries. Inhaled drugs as risk factors for community-acquired pneumonia. Eur Respir J. 2010;36(5):1080-1087. [CrossRef] [PubMed]
 
Sin DD, Lacy P, York E, Man SF. Effects of fluticasone on systemic markers of inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2004;170(7):760-765. [CrossRef] [PubMed]
 
Antoniu SA. Effects of inhaled therapy on biomarkers of systemic inflammation in stable chronic obstructive pulmonary disease. Biomarkers. 2010;15(2):97-103. [CrossRef] [PubMed]
 
Montón C, Ewig S, Torres A, et al. Role of glucocorticoids on inflammatory response in nonimmunosuppressed patients with pneumonia: a pilot study. Eur Respir J. 1999;14(1):218-220. [CrossRef] [PubMed]
 
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