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Original Research: Critical Care |

Impact of COPD in the Outcome of ICU-Acquired Pneumonia With and Without Previous IntubationCOPD and ICU-Acquired Pneumonia FREE TO VIEW

Mariano Rinaudo, MD; Miquel Ferrer, MD, PhD; Silvia Terraneo, MD; Francesca De Rosa, MD; Rogelio Peralta, MD; Laia Fernández-Barat, PhD; Gianluigi Li Bassi, MD, PhD; Antoni Torres, MD, PhD
Author and Funding Information

From the Servei de Pneumologia (Drs Rinaudo, Ferrer, Terraneo, De Rosa, Peralta, Fernández-Barat, Li Bassi, and Torres), Institut del Torax, Hospital Clinic, IDIBAPS, Universitat de Barcelona, Barcelona, Spain; the Centro de Investigación Biomedica En Red-Enfermedades Respiratorias (CibeRes, CB06/06/0028) (Drs Ferrer, Fernández-Barat, Li Bassi, and Torres), Barcelona, Spain; and the Department of Pathophysiology and Transplantation (Drs Terraneo and De Rosa), Università degli Studi di Milano, IRCCS Fondazione Ospedale Maggiore Policlinico Cà Granda, Milan, Italy.

CORRESPONDENCE TO: Miquel Ferrer, MD, PhD, UVIR, Servei de Pneumologia, Hospital Clínic, Villarroel 170, 08036 Barcelona, Spain; e-mail: miferrer@clinic.ub.es


Part of this article has been presented in abstract form at the European Respiratory Society Annual Congress, September 7-11, 2013, Barcelona, Spain, and the American Thoracic Society, May 17-22, 2013, Philadelphia, Pennsylvania.

FUNDING/SUPPORT: This study was supported by the Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS) [Grant 2009-SGR-911], ICREA Academia 2013, Juan de la Cierva 2012 [Grant JCI-2012-14801], Ministerio de Economía y Competitividad, Plan Nacional I+D [Grant SAF2012-33744], Centro de Investigación Biomédica en Red-Enfermedades Respiratorias (CibeRes CB06/06/0028)-Instituto de Salud Carlos III (ISCiii), and a European Respiratory Society (ERS) Fellowship.

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


Chest. 2015;147(6):1530-1538. doi:10.1378/chest.14-2005
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BACKGROUND:  COPD seems related to poor outcome in patients with ventilator-associated pneumonia (VAP). However, many patients in the ICU with COPD do not require intubation but can also develop pneumonia in the ICU. We, therefore, compared the characteristics and outcomes of patients with ICU-acquired pneumonia (ICUAP) with and without underlying COPD.

METHODS:  We prospectively assessed the characteristics, microbiology, systemic inflammatory response, and survival of 279 consecutive patients with ICUAP clustered according to underlying COPD or not. The primary end point was 90-day survival.

RESULTS:  Seventy-one patients (25%) had COPD. The proportion of VAP was less frequent in patients with COPD: 30 (42%) compared with 126 (61%) in patients without COPD (P = .011). Patients with COPD were older; were more frequently men, smokers, and alcohol abusers; and more frequently had previous use of noninvasive ventilation. The rate of microbiologic diagnosis was similar between groups, with a higher rate of Aspergillus species and a lower rate of Enterobacteriaceae in patients with COPD. We found lower levels of IL-6 and IL-8 in patients with COPD without previous intubation. The 90-day mortality was higher in patients with COPD (40 [57%] vs 74 [37%] in patients without COPD, P = .003). Among others, COPD was independently associated with decreased 90-day survival in the overall population (adjusted hazard ratio, 1.94; 95% CI, 1.11-3.40; P = .020); this association was observed only in patients with VAP but not in those without previous intubation.

CONCLUSIONS:  COPD was independently associated with decreased 90-day survival in patients with VAP but not in those without previous intubation.

Figures in this Article

ICU-acquired pneumonia (ICUAP) is the leading infection in critically ill patients and a major cause of morbidity and mortality.1,2 Several cofactors, such as disease severity, underlying disease leading to ICU admission, and host response to infection, are likely to affect the course of these patients.35 Specific comorbidities, such as liver cirrhosis6 or prior corticosteroid therapy,7 are also independent predictors for mortality in patients with ICUAP. Knowing specific risk factors for mortality is important for an optimal design and results interpretation in ICUAP trials.

COPD is a frequent comorbidity in patients in the ICU. Previous studies had identified that COPD comorbidity is associated with ICU mortality in patients with ventilator-associated pneumonia (VAP).5,8,9

However, between 15% and 73% of patients with an episode of ICUAP are not previously intubated, namely nonventilator ICUAP.2,10,11 In addition, the number of patients with COPD admitted to the ICU without intubation has increased significantly in recent years with the use of noninvasive ventilation (NIV).12 To our knowledge, no studies have comprehensively assessed nosocomial pneumonia in the ICU setting in patients with COPD without previous intubation. Therefore, whether the association of underlying COPD with worse outcome is restricted to patients with VAP or can be extrapolated to the increasing population of patients with nonventilator ICUAP is unknown. Furthermore, patients from previous studies5,8,9 were not followed to assess mortality beyond ICU discharge. Finally, no studies have assessed the inflammatory response in patients with COPD who present with ICUAP. The aim of the present study was, therefore, to compare the characteristics, microbiology, inflammatory response, and survival up to 90 days of patients with ICUAP with and without COPD in a real-life ICU population, with special emphasis on whether patients were previously intubated or not.

Study Population

The study was conducted in medical and surgical ICUs with overall 45 beds of an 800-bed university hospital. Data were prospectively collected from January 2007 to June 2013. The investigators made daily rounds in all ICUs. Patients were consecutively included, and only the first episode was analyzed. Inclusion criteria were: age ≥ 18 years, with clinical suspicion of pneumonia acquired after 48 h of ICU admission, and written informed consent from patients or their next-of-kin. The only exclusion criteria were severe immunosuppression (neutropenia after chemotherapy or hematopoietic transplant, drug-induced immunosuppression in solid-organ transplant or cytotoxic therapy, and HIV-related disorders). The study was reviewed and approved by the institution’s Ethics Committee of Clinical Research (Comite Etic d’Investigacio Clinica, registry number 2009/5427).

Definition of Pneumonia, Microbiologic Processing, and Antimicrobial Treatment

The clinical suspicion of pneumonia was based on clinical criteria: new or progressive radiologic pulmonary infiltrate together with at least two of the following: temperature > 38°C or < 36°C, leukocytosis > 12,000/μL or leukopenia < 4,000/μL, and purulent respiratory secretions.1,13,14 VAP was considered in patients with previous invasive mechanical ventilation for ≥ 48 h. Patients were classified as VAP or nonventilator ICUAP (ie, cases who do not meet VAP criteria).2

The microbiologic evaluation was extensively addressed in previous reports.15,16 Briefly, we collected at least one lower respiratory airways sample (sputum in nonintubated patients or tracheobronchial aspirates in those intubated), and BAL if possible, within the first 24 h of inclusion. Blood cultures and cultures from pleural fluid if puncture was indicated were also taken. Microbial identification and susceptibility testing were performed by standard methods.17 Polymicrobial pneumonia was defined when more than one pathogen was identified. We also noted the presence of multidrug-resistant pathogens.16

The initial empirical antimicrobial treatment was administered according to local adaptation of guidelines,1 based on the most frequently isolated pathogens and their patterns of antimicrobial sensitivity in our institution, and subsequently revised according to the microbiologic results. We noted the development of predictors of adverse outcomes after 72 to 96 h of antimicrobial treatment to assess the initial response to treatment, as previously described.18,19 In patients with initial nonresponse to treatment, cultures of respiratory samples and blood were repeated, and the empirical antimicrobial treatment was revised.

Definition of COPD

We defined COPD according to American Thoracic Society/European Respiratory Society criteria,20 and COPD severity was assessed by the GOLD (Global Initiative for Chronic Obstructive Lung Disease) criteria.21 The diagnosis of COPD was always confirmed with premorbid pulmonary function testing (PFT); otherwise, patients were not analyzed.

In patients without clinical diagnosis of COPD, those who were current or former smokers (≥ 10 pack-years) without PFT were also excluded to avoid the possible inclusion of undiagnosed COPD in this group. Conversely, those with a forced spirometry without obstructive ventilatory pattern were included.

Assessment of Severity

We calculated the APACHE (Acute Physiology and Chronic Health Evaluation) II22 on ICU admission. The simplified Clinical Pulmonary Infectious Score23 and the Sepsis-Related Organ Failure Assessment (SOFA)24 score were also evaluated on ICU admission and up to 9 days after the onset of pneumonia. Septic shock25 and ARDS26 were defined according to previously described criteria.

Assessment of Systemic Inflammatory Response

We evaluated the serum levels of IL-6, IL-8, tumor necrosis factor-α, C-reactive protein, procalcitonin, and midregional proadrenomedullin within the first 24 h and the third day after the diagnosis of pneumonia. All methods of these analyses have been described in detail.27,28

Data Collection

All relevant data were collected at admission and at the onset of pneumonia from the medical records and bedside flow charts, including clinical, laboratory, radiology, and microbiologic information. Patients were followed until death or up to 90 days after the diagnosis of pneumonia.

Outcome Measures

The primary outcome was comparison of 90-day survival after diagnosis of ICUAP. Secondary outcomes included length of ICU and hospital stay and initial nonresponse to treatment.

Statistical Analysis

The main clinical, laboratory, radiologic, and etiologic characteristics as well as the outcomes of patients with COPD were compared with those without COPD. For the purpose of the study we analyzed separately patients with VAP and nonventilator ICUAP. In addition, the overall population results are also reported.

Data are presented as number (proportions) and mean ± SD. Qualitative or categorical variables were compared between groups with the χ2 or Fisher exact test when appropriate. Quantitative continuous variables were compared using the Student t test or nonparametric Mann-Whitney test when appropriate.

The Kaplan-Meier curves were used to compare 90-day survival in the two groups; survival curves were compared with a log-rank test. Crude survival between groups was analyzed using Cox regression with 90-day survival as the dependent variables. All variables associated with survival in the univariate analysis (P < .10) were entered in a stepwise forward Cox proportional hazard regression to determine factors independently associated with survival. Adjusted hazard ratio and 95% CIs were calculated.

Data were processed with SPSS Statistics, version 20 (IBM). The level of significance was set at 0.05 (two-tailed).

Patients

We prospectively collected 446 consecutive patients with criteria of ICUAP. Among 108 patients previously diagnosed with COPD, we excluded 37 without PFT. Among 338 without diagnosis of COPD, we excluded 130 current or former smokers without PFT. Therefore, we analyzed 279 patients with ICUAP, 71 (25%) of them with COPD (Fig 1). According to the GOLD stages of COPD severity, nine (13%) were stage I, 24 (34%) stage II, 30 (42%) stage III, and eight (11%) stage IV. The FEV1 was 52% ± 21% predicted.

Figure Jump LinkFigure 1 –  Trial profile of included and excluded patients. NV-ICUAP = nonventilator ICU-acquired pneumonia; PFT = pulmonary function test; VAP = ventilator-associated pneumonia.Grahic Jump Location

The proportion of VAP was less frequent in patients with COPD: 30 (42%) compared with 126 (61%) in patients without COPD (P = .011). The characteristics of patients at ICU admission and at onset of pneumonia, according to previous intubation or not, are shown in Tables 1 and 2. Patients with COPD were older; were more frequently men, smokers, and alcohol abusers; and more frequently had hypercapnic respiratory failure as the cause for ICU admission compared with patients without COPD. Cardiac comorbidity and tracheostomy at admission were more frequent, and recent surgery was less frequent, in patients with COPD with VAP only. In contrast, organ system dysfunction assessed by the SOFA score was lower, and previous use of NIV and corticosteroids were more frequent, in patients without COPD with nonventilator ICUAP only.

Table Graphic Jump Location
TABLE 1 ]  Characteristics of Patients at ICU Admission, According to Previous Intubation or Not

Data are presented as No. (%) or mean ± SD unless otherwise noted. APACHE = Acute Physiology and Chronic Health Evaluation; SOFA = Sepsis-Related Organ Failure Assessment.

Table Graphic Jump Location
TABLE 2 ]  Characteristics of Patients at Onset of Pneumonia, According to Previous Intubation or Not

Data are presented as No. (%) or mean ± SD. CPIS = Clinical Pulmonary Infection Score. See Table 1 legend for expansion of other abbreviation.

Microbiologic Findings

In the overall population, a microbial etiology could be determined in 165 patients (59%) (Table 3). The rate of etiologic diagnosis was similar between both groups. The most frequently identified pathogens were Pseudomonas aeruginosa, Enterobacteriaceae, and methicillin-sensitive Staphylococcus aureus. There was a higher rate of Aspergillus species and a lower rate of Enterobacteriaceae in patients with COPD.

Table Graphic Jump Location
TABLE 3 ]  Etiologic Diagnosis of Pneumonia

Data are presented as No. (%).

a 

In two patients without COPD, more than one Enterobacteriaceae was identified.

Inflammatory Biomarkers

Patients with COPD had lower levels of C-reactive protein than those without COPD in the subset of VAP only (Table 4). In addition, we found lower levels of IL-6 and IL-8 in patients with COPD with nonventilator ICUAP. The remaining biomarkers were not significantly different between patients with and without COPD.

Table Graphic Jump Location
TABLE 4 ]  Serum Levels of Inflammatory Response Markers at the Onset of Pneumonia, According to Previous Intubation or Not

Data are presented as median (interquartile range). MR-proADM = mid-regional proadrenomedullin; TNF = tumor necrosis factor.

Outcome Variables

In the overall population, the initial nonresponse to treatment and the length of stay was similar between both groups, regardless of whether patients were previously intubated or not (Table 5). However, the 90-day mortality rate was significantly higher (40 [57%] vs 74 [37%], P = .003) and the 90-day survival significantly lower (Fig 2) in COPD compared with patients without COPD. The multivariate analysis showed that COPD, together with older age, liver cirrhosis, shock at onset of pneumonia, and lower prothrombin time were independently associated with decreased 90-day survival (Table 6).

Table Graphic Jump Location
TABLE 5 ]  Response to Treatment and Length of Stay in the Overall Population
Figure Jump LinkFigure 2 –  Kaplan-Meier survival curves at 90 d of the study cohort comparing patients with or without COPD.Grahic Jump Location
Table Graphic Jump Location
TABLE 6 ]  Factors Associated With Decreased 90-Day Survival in the Overall Population

HR = hazard ratio. See Table 1 legend for expansion of other abbreviations.

a 

HRs are calculated for each unit of measure.

Similar to the overall population, the 90-day mortality rate was significantly higher (18 [62%] vs 45 [37%], P = .015), and the 90-day survival (Fig 3A) remained significantly lower in patients with COPD with VAP. Conversely, in patients with nonventilator ICUAP, the 90-day mortality rate of patients with and without COPD just fell to be significantly different (22 [54%] vs 29 [36%], respectively; P = .059), whereas the 90-day survival between both groups was not significantly different (Fig 3B).

Figure Jump LinkFigure 3 –  A, B, Kaplan-Meier survival curves at 90 d of patients with ventilator-associated pneumonia (A) and nonventilator ICU-acquired pneumonia (B), comparing patients with or without COPD.Grahic Jump Location

COPD is a frequent comorbidity in patients with hospital-acquired pneumonia, ranging between 20% and 30%.9,29,30 In our study we found a 25% proportion, which is in line with previous studies. Although underlying COPD as comorbidity was independently associated with decreased 90-day survival in patients with ICUAP, differences in survival were observed in patients with VAP but not in those with nonventilator ICUAP.

Microbiologic Results

Similar to a previous study dealing with COPD and VAP,4P aeruginosa was the main pathogen in patients with COPD, without significant differences with patients without COPD. We found a lower overall rate of Enterobacteriaceae in patients with COPD; however, the rate of all individual pathogens from this group was similar between patients with and without COPD.

We also found a higher rate of Aspergillus species in patients with COPD. Isolation of Aspergillus species from the respiratory tract is very common in patients with COPD, both during stable clinical conditions31,32 and in the ICU.33 In the last population, isolation of Aspergillus was a marker of poor prognosis and was associated with high mortality irrespective of invasion or colonization.33 The clinical relevance of this finding in critically ill patients, and whether this isolation should be considered as a pathogen or simply colonization, is uncertain, since we did not find a different mortality between patients with and without isolation of Aspergillus species.

COPD as Predictor of Mortality in Patients With ICUAP

Several studies have found a relationship between COPD, VAP, and mortality. In critically ill patients who are ventilated without evidence of respiratory infection at admission, underlying COPD was independently associated with higher mortality in the ICU.34 COPD was an independent variable associated with higher risk of death that was included in a clinical score proposed for predicting ICU mortality and health-care resources use in patients with VAP.5 A 2011 prospective observational study on 215 patients with VAP, with 30% of patients with COPD comorbidity, found again that COPD was independently associated with ICU mortality.9 In addition, patients with severe COPD (ie, GOLD stage IV) had longer duration of ventilation and stay than patients without COPD in this study. In contrast, other authors did not find an association between COPD and mortality in patients with VAP.30

In our study, COPD was independently associated with worse survival in the multivariate analysis. Different from previous studies that followed patients up to ICU discharge,5,9 the worse outcome of patients with COPD was observed when follow-up was extended up to 90 days in our study.

The potential reasons for the worse outcome associated with COPD comorbidity in patients with VAP have been previously discussed. These include an adverse impact of COPD on respiratory muscle function and nutritional status21 and the complex pathobiology of inflammation in advanced COPD with various underlying mechanisms implicated.9,35 Other factors such as older age and more frequent previous use of corticosteroids7 may also influence the worse outcome of patients with COPD; however, these variables were included in the adjustment of survival in our population.

The association between COPD comorbidity and worse survival was found only for patients with VAP. In contrast, COPD was not related to worse outcome in those patients without intubation before the onset of pneumonia. Patients with COPD had lower rate of VAP instead of nonventilator ICUAP, probably due to more frequent previous use of NIV in this population. Several reasons may explain why COPD was not related to survival in patients with nonventilator ICUAP. At onset of pneumonia, patients with COPD had much lower organ system dysfunction, assessed by the SOFA score, less frequent previous use of corticosteroids, and lower serum levels of IL-6 and IL-8. The association of these variables with worse survival, observed in previous studies,7,18,19 may have counterbalanced the effect of COPD on increased mortality in patients with nonventilator ICUAP. In contrast, SOFA score, previous use of corticosteroids, and serum levels of IL-6 and IL-8 were similar between patients with and without COPD with VAP. This explains that the association of COPD with mortality was observed only in VAP, as in previous investigations.5,8,9

Strengths and Limitations

Several issues of the present study have not been addressed previously. First, we analyzed separately patients with VAP and nonventilator ICUAP, which resulted in different association of COPD with outcome. Second, the analysis of mortality was performed at 90 days; the survival curves in Figure 2 show that the different outcome of patients with and without COPD appears more evident with time. Third, different from previous reports, we included only patients with COPD confirmed with PFT, and we excluded all current or former smokers in whom COPD could not be excluded because of absence of PFT. This resulted in very well-defined population of patients with and without COPD. Previous reports did not systematically confirm COPD with forced spirometry9,34 or did not mention PFT.4,5,8 Fourth, we assessed systemic inflammatory biomarkers in the patients.

Several limitations of the present study should also be addressed. First, this study was conducted in a single center, and therefore extrapolation of the findings to other setting must be done cautiously. Second, there was no microbiologic documentation in 41%. However, this is a usual situation in clinical practice.36 We have suggested that some of these cases with negative microbiology might also represent, at least in part, fluid overload added to the underlying inflammatory process potentially mimicking pneumonia.15 Third, the lack of association of COPD with survival in patients with nonventilator ICUAP should be taken cautiously because of the smaller number of patients analyzed. However, the shape of the survival curves was clearly different from that of patients with VAP (Fig 3).

In conclusion, COPD was independently associated with decreased 90-day survival. This association occurred in patients with VAP, whereas in those with nonventilator ICUAP, COPD was not associated with different outcomes.

Author contributions: M. F. is the guarantor of, and takes responsibility for the content of the manuscript, including the data and analysis. M. R., M. F., S. T., F. D. R., and R. P. participated in the recruitment of patients; L. F.-B. processed the microbiologic samples; M. R., M. F., and G. L. B. participated in the data analysis; M. R., M. F., and A. T. participated in writing of the manuscript; and all authors revised the final version 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 sponsors: The sponsors contributed to financial and logistic support of the research group.

Other contributions: Rebeca Domingo, RN; Encarna Moreno, RN; and Montserrat Sola RN, participated in the study as research nurses collecting and processing blood and respiratory samples. I. Rovira, MD, Cardiovascular ICU; E. Zavala, MD, Surgical ICU; X. Bosch, MD, Coronary Unit; Pedro Castro, MD, Medical ICU; and A. Escorsell, MD, Hepatology and Gastroenterology ICU, helped with screening and recruitment of patients.

GOLD

Global Initiative for Chronic Obstructive Lung Disease

ICUAP

ICU-acquired pneumonia

NIV

noninvasive ventilation

PFT

pulmonary function testing

SOFA

Sepsis-Related Organ Failure Assessment

VAP

ventilator-associated pneumonia

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Figures

Figure Jump LinkFigure 1 –  Trial profile of included and excluded patients. NV-ICUAP = nonventilator ICU-acquired pneumonia; PFT = pulmonary function test; VAP = ventilator-associated pneumonia.Grahic Jump Location
Figure Jump LinkFigure 2 –  Kaplan-Meier survival curves at 90 d of the study cohort comparing patients with or without COPD.Grahic Jump Location
Figure Jump LinkFigure 3 –  A, B, Kaplan-Meier survival curves at 90 d of patients with ventilator-associated pneumonia (A) and nonventilator ICU-acquired pneumonia (B), comparing patients with or without COPD.Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1 ]  Characteristics of Patients at ICU Admission, According to Previous Intubation or Not

Data are presented as No. (%) or mean ± SD unless otherwise noted. APACHE = Acute Physiology and Chronic Health Evaluation; SOFA = Sepsis-Related Organ Failure Assessment.

Table Graphic Jump Location
TABLE 2 ]  Characteristics of Patients at Onset of Pneumonia, According to Previous Intubation or Not

Data are presented as No. (%) or mean ± SD. CPIS = Clinical Pulmonary Infection Score. See Table 1 legend for expansion of other abbreviation.

Table Graphic Jump Location
TABLE 3 ]  Etiologic Diagnosis of Pneumonia

Data are presented as No. (%).

a 

In two patients without COPD, more than one Enterobacteriaceae was identified.

Table Graphic Jump Location
TABLE 4 ]  Serum Levels of Inflammatory Response Markers at the Onset of Pneumonia, According to Previous Intubation or Not

Data are presented as median (interquartile range). MR-proADM = mid-regional proadrenomedullin; TNF = tumor necrosis factor.

Table Graphic Jump Location
TABLE 5 ]  Response to Treatment and Length of Stay in the Overall Population
Table Graphic Jump Location
TABLE 6 ]  Factors Associated With Decreased 90-Day Survival in the Overall Population

HR = hazard ratio. See Table 1 legend for expansion of other abbreviations.

a 

HRs are calculated for each unit of measure.

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