Inhaled corticosteroid effects on pneumonia severity and antimicrobial. resistance

Transcription

1 Inhaled corticosteroid effects on pneumonia severity and antimicrobial resistance Oriol Sibila MD 1,2, Elena Laserna MD 1,3, Eric M. Mortensen MD, MSc 4,5, Antonio Anzueto MD 1,6 and Marcos I. Restrepo, MD, MSc. 1,6,7. 1 University of Texas Health Science Center at San Antonio, San Antonio, TX; 2 Servei de Pneumologia, Hospital de la Santa CreuiSant Pau, Barcelona, Spain; 3 Hospital Comarcal de Mollet, Mollet del Valles, Spain; 4 VA North Texas Health Care System, 5 University of Texas Southwestern Medical Center, 6 South Texas Veterans Health Care System and 7 Veterans Evidence Based Research Dissemination and Implementation Center (VERDICT). Corresponding author: Marcos I. Restrepo, MD, MSc; VERDICT (11C6) South Texas Veterans Health Care System ALMD Merton Minter Boulevard - San Antonio Texas, 78229; Phone: (210) ext Fax: (210) ; restrepom@uthscsa.edu

2 Running Head: Inhaled corticosteroids in CAP Keywords: Drug resistance, Inhaled Corticosteroids, Pneumonia, Severity of illness index. Word count of the abstract: 194 Word count of the body of the manuscript: 1912 Conflict of Interest disclosures: DrsSibila, Laserna, and Mortensen have reported that no potential conflicts of interest exists with any companies/organisms whose products or services may be discussed in this article. DrAnzueto has participated as a speaker in scientific meetings or courses organized and financed by various pharmaceutical companies including: BoehringerIngelheim, Bayer Healthcare, GlaxoSmithKline, Forest Laboratories. DrAnzueto has being a consultant for Astra-Zeneca, BoehringerIngelheim, Pfizer, GlaxoSmithKline, Bayer Healthcare, Forest Laboratories, Intermune, Amgen. DrAnzueto has being the principal investigator for research grants and the University of Texas Health Science Center at San Antonio was paid for participing in multi-center clinical trials sponsored by GlaxoSmithKline, Bayer-Schering Pharma, Lilly, National Institutes of Health. Dr. Restrepo has participated in advisory boards for Theravance, Forest Laboratories, Johnson & Johnson, Trius and Novartis. Consultant for Theravance, Trius and Pfizer (Wyeth). Summary at a glance: Prior inhaled corticosteroid use is associated with higher severity of illness and increased incidence of antimicrobial drug-resistant pathogens in patients admitted with community-acquired pneumonia.

3 ABSTRACT Background: Limited information is available regarding the impact of prior use of inhaled corticosteroids (ICS) in patients subsequently developing community-acquired pneumonia (CAP). We assessed the effects of prior ICS on severity of illness and microbiology for CAP hospitalized patients. Methods: A retrospective cohort study of subjects with CAP (by International classifications of the diseases, 9 th edition, codes) was conducted over a 4-year period at two tertiary teaching hospitals. Subjects were considered to be ICS users if they received inhaled corticosteroids prior to admission. Primary outcomes were severity of illness and microbiology at admission. Results: Data were abstracted on 664 patients (prior ICS users, 89 [13.4%] vs. prior non- ICS users 575 [86.6%], respectively). Prior ICS users had more severity of illness at admission compared to non-ics users (mean ± SD, PSI ± 31.4 vs ± 33.4, p=0.001, and CURB ± 1.02 vs ± 1.02, p=0.002). In addition, prior ICS were independently associated with antimicrobial resistant pathogens (11.2% vs. 5.9%, OR=2.61, 95%CI , p=0.04). Conclusions: Our results suggest that prior ICS use is associated with higher severity of illness at admission and increased incidence of antimicrobial drug-resistant pathogens in CAP hospitalized patients.

4 INTRODUCTION Inhaled corticosteroids (ICS) are anti-inflammatory agents widely used in patients with obstructive airways diseases. Their established efficacy and adequate safety profile have placed these medications in the treatment recommendations for the most prevalent chronic respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD)[1, 2]. In COPD, the fourth leading cause of death in the US [3], ICS have been demonstrated to reduce the overall frequency of exacerbations and improve quality of life [4, 5]. Paradoxically, several large trials have demonstrated that the use of ICS was associated with an increased incidence of community-acquired pneumonia (CAP) in these patients [6-12]. There is significant controversy regarding the association of poor clinical outcomes in CAP patients with prior use of ICS [9, 13-15]. Although recent and numerous randomized trials and meta-analyses have evaluated the impact of ICS on pneumonia-related or overall mortality [6-15], limited data are available regarding the association of prior ICS with the severity of illness at admission or its impact on antimicrobial resistance. Although, chronic systemic corticosteroids use has been associated with higher opportunistic infections [16-18] and potentially highly drug resistant pathogens [19, 20], these associations are not clear in patients treated with ICS. Therefore, our aim was to investigate the association of prior outpatient ICS use with severity of illness and pathogens antimicrobial resistance among in hospitalized patients with CAP at the time of admission.

5 METHODS This is a cross-sectional study of patients hospitalized with CAP at two academic teaching tertiary care hospitals in San Antonio, Texas. The Institutional Review Board of the University Health Science Center at San Antonio approved the research protocol with exempt status. Study Sites/Inclusion and Exclusion Criteria We identified all patients admitted to the study hospitals between January 1, 1999 and December 31, 2002 with a primary discharge diagnosis of pneumonia (ICD-9 codes or ) or secondary discharge diagnosis of pneumonia with a primary diagnosis of respiratory failure (518.81) or sepsis (038.xx). Subjects were included if they were 1) greater than 18 years of age, 2) had an admission diagnosis of CAP, and 3) had a radiographically confirmed infiltrate or other finding consistent with pneumonia on chest x-ray or CT obtained within 24 hours of admission. Exclusion criteria included 1) having been discharged from an acute care facility within 14 days of admission, 2) transfer after being admitted to another acute care hospital, 3) being comfort measures only on this admission, and 4) using systemic corticosteroids. If a subject was admitted more than once during the study period, only the first hospitalization was abstracted Data Abstraction Chart review data included: demographics, co-morbid conditions, physical examination findings, laboratory data, chest radiographic reports, guideline-concordant empirical antibiotic

6 therapy and prior antibiotic use. Comorbid conditions were identified from either the admission or discharge notes or outpatient problem lists. Antimicrobial therapy was considered guidelineconcordant if it agreed with either the American Thoracic Society (ATS) guidelines [21]. Prior antibiotic use was considered if patients were taking any kind of antibiotic 15 days before admission. Information on all inhaled corticosteroid outpatient medications that were either 1) reported as currently being taken by the patient at presentation, or 2) listed in the electronic medical record, were recorded. Inhaled corticosteroid (ICS) therapy was defined if the patient was receiving inhaled beclomethasonedipropionate, triamcinolone, budesonide or fluticasone propionate at the time of admission. Diagnostic criteria Microbiologic data results were reviewed, and a microbiologic cause was assigned independently by two of the investigators (E.M.M. and M.I.R.). The cause of pneumonia was considered if one of the following conditions were met: (1) positive blood cultures for bacterial or fungal pathogens (in the absence of extra-pulmonary source of infection); (2) pleural fluid cultures yielding a bacterial pathogen; (3) endotracheal aspirates with moderate or heavy growth of bacterial pathogens; (4) significant quantitative culture growth from bronchoscopic respiratory samples (protected specimen brush cultures of at least 10 3 cfu/ml, and in bronchoalveolar lavage of at least 10 4 cfu/ml). When two or more microbiologic causes were present, the patient was considered to have a polymicrobial infection. A patient was considered to have CAP of unknown cause if microbiologic studies were not performed or inconclusive.

7 Drug-Resistant pathogens were defined as having one of the following microorganisms: Drug-Resistant Streptococcus pneumoniae(drsp), Methicillin-resistant Staphylococcus aureus(mrsa), Acinetobacterbaumanii, Extendended Spectrum Beta Lactamases (ESBL) or multidrug-resistant Pseudomonas aeruginosa (resistance to three or more antimicrobial categories) [22]. Clinical outcomes Primary outcomes were 1) severity of illness at the time of presentation defined by the Pneumonia Severity Index (PSI)[23] and CURB-65 [24], and 2) presence of resistant or opportunistic pathogens. Statistical analyses For the statistical analyses, subjects were stratified according to the prior ICS use. Categorical variables were analyzed using the chi-square test and continuous variables were analyzed using Student t test. Multivariable analysis was performed using a logistic regression model with drug-resistant pathogens as the dependent variables, and those with p<0.1 as independent variables (Age, gender, COPD, congestive heart failure and history of malignancy). Logistic regression results are reported as odds ratio (OR) and 95% confidence interval (95% CI). Subgroup analyses were performed for patients with and without COPD according to the primary outcomes.copd represents one the largest group of ICS users among elderly patients and it is the cohort where significant interest related to complications with ICS has emerged

8 (25). Two-side p-value <0.05 were considered statistically significant. All analyses were performed using SPSS version 19.0 for Windows (SPSS Inc; Chicago, IL). RESULTS We identified 664 patients who met the inclusion criteria, 89 (13.4%) received ICS prior to admission vs. 575 (86.6%) did not receive ICS. Patient Characteristics Subject characteristics by whether or not they received outpatient ICS therapy are shown in Table 1. Prior ICS users were older, more likely men and had more preexisting comorbid conditions such as congestive heart failure, history of malignancy and COPD. No significant differences were found among groups regarding physical exam, laboratory, radiological data and processes of care measures. Microbiological findings An etiologic diagnosis was found in 161 (24.2%) of hospitalized CAP patients (table 2). Prior ICS users had similar rates of isolated pathogens including S. pneumoniae,s. aureus and P. aeruginosacompared to non-ics users. Opportunistic pathogens such Aspergillusspp, Pneumocystis jirovecci and Nocardiaspp and ESBL pathogens were not found in outpatient ICS users. Clinical outcomes

9 Patients receiving ICS had higher PSI and CURB-65 scores at the time of clinical presentation compared to non-ics users (mean ± SD, PSI ± 31.4 vs ± 33.4, p=0.001, and CURB ± 1.02 vs ± 1.02, p=0.002). In the multivariate analyses, after adjusting for potential confounders, the use of outpatient ICS were independently associated with drugresistant pathogens (11.2% vs. 5.9%, OR=2.6, 95%CI , p=0.04) (figure 1). Subgroup Analyses COPD patients who received outpatient ICS (n=58/176, 33.0%) were more likely to be associated with drug resistant pathogens (12.1% vs. 3.4%, OR 3.9, 95%IC , p=0.03) compared to COPD patients without prior ICS use (n=118/176, 67.0%). However, COPD patients treated with prior ICS had no statistical significant differences regarding severity of illness at presentation (mean PSI ± SD, ± 30.0 vs ± 30.8, p= 0.6; and mean CURB-65 ± SD, 1.6 ± 0.9 vs. 1.6 ± 1.1, p=0.9) when compared to no prior ICS use. Non-COPD patients managed with ICS (n=31/488, 6.4%) were not associated with drug resistant pathogens (9.7% vs. 6.6%, p=0.4). However, non-copd patients had higher severity of the disease based on PSI score (mean ± SD, 96.5 ± vs ± 33.2, p= 0.04) compared to non-copd patients without prior ICS use (n=457/488, 93.6%). DISCUSSION The main findings of our study suggest that in hospitalized CAP patients the outpatient use of ICS was associated with a higher severity of illness at admission and increased incidence of antimicrobial drug-resistant pathogens.

10 The relationship between ICS and pneumonia is one of the most important questions that has still yet to be resolved since Calverley et al [6] reported in 2007 the results of the TORCH (Towards a Revolution in Chronic Obstructive Pulmonary Disease Health) Study. Multiple studies have confirmed that COPD patients treated with ICS have an increased likelihood of developing pneumonia [7-12]. However, COPD patients receiving ICS and required treatment for pneumonia may or not have increased poor outcomes, such as higher mortality as compared with patients not receiving ICS [6-15]. This observation has led to speculation that ICS use may increase CAP risk, but because ICS immunomodulatory effects, patients may be protected against severe pneumonia or pneumonia-related complications [26, 27]. Our results suggested that prior ICS users that develop pneumonia and required hospitalization have more severe CAP than non-ics users, by having higher PSI [23] and CURB65 [24] scores at admission. These results are hypothesis generating, that require further exploration with larger databases and adjusting for other possible confounding variables. One previous study reported the impact of previous ICS in pneumonia severity. Singanayagam et al. [14] did not find differences in severity of illness at admission in their cohort of COPD patients admitted with pneumonia. These findings are consistent with our subgroup analysis limited to COPD patients. These data suggest that chronic prior ICS use may play an important role in the lungs defense mechanisms against infections. We hypothesized that in addition to the immunomodulatory effects observed in patients treated with ICS, is possible that an immunosuppressive effect might be the cause of having a higher severity of the disease. These immunomodulatory may be different among COPD and non-copd patients. However, further studies are needed to assess the effect of ICS on different airway protective mechanisms against infections such as local inflammatory

11 response, mucins and antimicrobials peptides and different patient populations exposed to ICS [28]. Different studies have identified an increase incidence of potentially highly resistant bacteria [19, 20] and opportunistic infections of the lung, such as Aspergillusspp [17], Pneumocystis jirovecci[18] and Nocardiaspp [29] in patients taking systemic corticosteroids. However, the association of antimicrobial resistant bacteria in patients treated with outpatient ICS was unknown. Our study results suggest that the prior ICS use in patients admitted to the hospital with CAP may have drug-resistant pathogens, particularly in the COPD group of patients managed with ICS. Liapikou et al. [30] reported that COPD patients treated with chronic ICS had a higher rate of pneumonia due to P aeruginosa, but less Legionellasppinfection. However, antimicrobial resistance was not assessed in COPD patients treated with ICS. We hypothesized that ICS may alter habitual flora and antimicrobial susceptibility particularly in COPD patients with chronic airway infections [31]. Previous antimicrobial courses have been associated with development of MDR pathogens (32), and is an important variable to be considered in future assessment of the risk of antimicrobial resistance related to the use of ICS. Our study has several limitations. First, this is a retrospective study involving only two centers with a relatively small simple size. Second, our sample was predominately male due to the higher population of veterans enrolled in this cohort. It is unknown if prior ICS use in females would have similar results. Third, our cohort did not have information regarding the exact dose of the ICS, ICS clinical indication and length of ICS therapy as outpatients. Fourth,

12 our database did not include data on multiple courses of antibiotic prescriptions unrelated to the pneumonia hospitalization event. Finally, diagnosis of COPD was not based on spirometry. In conclusion, hospitalized CAP patients receiving prior ICS were associated with higher severity of disease at presentation and antimicrobial drug-resistant pathogens. Further studies are needed to study mechanisms involved in these important findings, which may affect the current indications of the ICS. ACKNOWLEDGMENTS Funding sources This research was supported by Howard Hughes Medical Institute faculty-start up grant and a Department of Veteran Affairs Veterans Integrated Service Network 17 new faculty grant. Dr. Sibila is supported by Instituto de Salud Carlos III (BAE11/00102). DrSibila and DrLaserna are supported by Sociedad Espanola de Neumologia y CirugiaToracica (SEPAR), SocietatCatalana de Pneumologia (SOCAP) and FundacioCatalana de Pneumologia (FUCAP). Dr. Restrepo time is partially protected by Award Number K23HL from the National Heart, Lung, and Blood Institute. The funding agencies had no role in the preparation, review, or approval of the manuscript. The views expressed in this article are those of the author and do not necessarily represent the views of the Department of Veterans Affairs.

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18 FIGURE LEGENDS Figure 1- Percentage of drug-resistant pathogens among non-inhaled Corticosteroids users (No ICS) and Inhaled Corticosteroids users (ICS) with Community-Acquired Pneumonia*. * Multivariate analysis adjusted for potential confounders (Age, gender, COPD, congestive heart failure and history of malignancy).

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20 TABLES Table 1- Subject demographic and clinical characteristics by the use of inhaled corticosteroids (ICS). Non-ICS users ICS users (n=575) (n=89) p-value Men 446 (77.6) 81 (91.0) Age / / <0.001 Preexisting comorbid conditions Congestive heart failure 79 (13.7) 20 (22.5) 0.03 Chronic pulmonary disease 118 (20.5) 58 (65.2) <0.001 History of stroke 62 (10.8) 15 (16.9) 0.1 Chronic liver disease 76 (13.2) 6 (6.7) 0.1 History of malignancy 49 (8.5) 14 (15.7) 0.04 Renal insufficiency 53 (9.2) 10 (11.2) 0.5 History, physical, laboratory and radiographic data Altered mental status 59 (10.3) 5 (5.6) 0.2 Respiratory rate > 30 per minute 53 (9.2) 8 (9.0) 1.0 Systolic blood pressure <90 mmhg 14 (2.4) 3 (3.4) 0.4 Heart rate > 125 per minute 76 (13.2) 8 (9.0) 0.3 Temperature < 95 º or > 104 º 15 (2.6) 1 (1.1) 0.7 Arterial ph < (6.3) 3 (3.4) 0.4 Arterial oxygenation saturation < 90% 122 (21.2) 23 (25.8) 0.3 Hematocrit < 30% 52 (9.0) 9 (10.1) 0.6 Serum blood urea nitrogen > 30 mg/dl 109 (19.0) 20 (22.5) 0.4 Serum glucose > 250 mg/dl 57 (9.9) 6 (6.7) 0.4 Serum sodium < 130 meq/l 93 (16.2) 11 (12.4) 0.4 Pleural effusion 144 (25.0) 20 (22.5) 0.6 Multilobar infiltrates 207 (36.3) 30 (34.1) 0.7 Processes of care Initial antibiotics within 4 hours 157 (27.3) 29 (32.6) 0.3 Guideline-concordant antibiotics 435 (75.7) 65 (73.0) 0.5 Prior antibiotic use 88 (15.3) 18 (20.2) 0.2 Note: Data are presented as number (%) or mean +/- standard deviation

21 Table 2- Etiologic diagnosis in patients with CAP by the use of outpatient inhaled corticosteroids (ICS). Non-ICS users ICS users p-value (n=575) (n=89) Streptococcus pneumoniae 49 (8.5) 8 (9.0) DRSP 27 (4.7) 6 (6.7) 0.4 Others Streptococcus 3 (0.5) Staphylococcus aureus 29 (5.0) 5 (5.6) MRSA 6 (1.0) 3 (3.4) 0.1 Pseudomonas aeruginosa 11 (1.9) 3 (3.4) MDR-P. aeruginosa 1 (0.2) Haemophilus influenzae 13 (2.3) 4 (4.5) 0.2 Escherichia coli 7 (1.2) 1 (1.1) 1.0 Klebsiella pneumoniae 7 (1.2) Proteus mirabilis 3 (0.5) Acinetobacter baumanii 0 1 (1.1) 0.1 Aspergillus ssp. 4 (0.7) Polymicrobial 8 (1.4) 3 (3.4) 0.1 Total pathogens isolated 135 (23.5) 26 (29.2) 0.2 Note: Data are presented as number (percentage) of patients. DRSP: Drug-Resistant S. pneumoniae (resistant to cephalosporins, penicillins, macrolides or fluoroquinolones). MRSA: Methicillin resistant S. aureus. MDR-P. aeruginosa: multidrug resistant P. aeruginosa ( 3 antimicrobials categories [22]).

22 Drug-resistant Pathogens 20 For Peer Review p= 0.04 Percent % 11.2% 0 No ICS ICS