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Contents lists available at ScienceDirect

Pulmonary Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/ypupt

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The risk and outcomes of pneumonia in patients on inhaled corticosteroids

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Oriol Sibila a, b, Natalia Soto-Gomez c, d, Marcos I. Restrepo c, d, * a

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Servei de Pneumologia, Hospital de la Santa Creu i Sant Pau, Sant Antoni Maria Claret 167, 08025 Barcelona, Spain  Biom  de Sant Frederic, Planta 1, 08025 Barcelona, Spain Institut d'Investigacio edica Sant Pau (IBB Sant Pau), Sant Antoni Maria Claret, 167 Pavello c South Texas Veterans Health Care System, 7400 Merton Minter Boulevard, San Antonio, TX 78229, United States d University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229, United States b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 24 November 2014 Received in revised form 16 April 2015 Accepted 24 April 2015 Available online xxx

Corticosteroids are frequently prescribed anti-inflammatory medications. Inhaled corticosteroids (ICS) are indicated for Chronic Obstructive Pulmonary Disease (COPD) and asthma. ICSs are associated with a decrease in exacerbations and improved quality of life in COPD, however multiple studies have linked the chronic use of ICSs with an increased risk of developing pneumonia, though the effect on mortality is unclear. We review the association of ICS with the risk of pneumonia and the implications on clinical outcomes. © 2015 Published by Elsevier Ltd.

Keywords: Pneumonia Inhaled corticosteroids Chronic obstructive pulmonary disease

1. Introduction Pneumonia is the leading cause of death related to infectious disease in developed countries and the eighth leading cause of death overall in the United States (US). In the US, pneumonia occurs in more than 5 million adults and accounts for more than 1 million admissions a year [1,2]. It is presumed that, in the US, pneumonia and influenza age-adjusted mortality is increasing [3]. Corticosteroids are anti-inflammatory medications commonly prescribed in respiratory medicine. Inhaled corticosteroids (ICS) are currently used for most patients with Chronic Obstructive Pulmonary Disease (COPD) and asthma [4,5]. The combination of ICS and Long Acting Beta Agonists (LABA) is considered a treatment of choice for patients with COPD with forced expiratory volume in the first second (FEV1) lower than 50% of predicted and two or more exacerbations per year [5,6]. Inhaled corticosteroids exert an antiinflammatory and immunosuppressive effect that may affect the pathogenesis of pneumonia [7].

Several studies suggest that in COPD patients receiving chronic ICSs there is a higher risk of developing pneumonia [8e10]. However, the associated impact of ICSs on mortality and poor clinical outcomes among COPD patients who develop pneumonia is a matter of great controversy [11,12]. The purpose of this review is to assess the evidence related to the association of inhaled corticosteroids with the risk of community-acquired pneumonia (CAP) and other related clinical outcomes. 1.1. Methods We reviewed published available manuscripts in PubMed by using the following search terms: “inhaled corticosteroids” and “pneumonia”. We limited the literature search to manuscripts published in the English language. The date of the most recent search was September 1, 2014. 2. Corticosteroids

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* Corresponding author. VERDICT (11C6), South Texas Veterans Health Care System ALMD, 7400 Merton Minter Boulevard, San Antonio, TX 78229, United States. Tel.: þ1 (210) 617 5256; fax: þ1 (210) 567 4423. E-mail addresses: [email protected] (O. Sibila), [email protected] (N. Soto-Gomez), [email protected] (M.I. Restrepo).

Corticosteroids are involved in a wide range of physiological processes, including the regulation of inflammation, immune and stress responses, carbohydrate metabolism, protein catabolism, and serum electrolyte levels [13]. Corticosteroids can be administered through multiple routes, but for the purpose of this review we

http://dx.doi.org/10.1016/j.pupt.2015.04.001 1094-5539/© 2015 Published by Elsevier Ltd.

Please cite this article in press as: O. Sibila, et al., The risk and outcomes of pneumonia in patients on inhaled corticosteroids, Pulmonary Pharmacology & Therapeutics (2015), http://dx.doi.org/10.1016/j.pupt.2015.04.001

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will focus on the corticosteroids that are administered through the inhalational route. Table 1 shows the most relevant ICS available on the market.

2.1. Mechanism of action Corticosteroids inhibit the expression and action of many cytokines involved in the inflammatory response associated with pneumonia. At the cellular level, corticosteroids bind to a heterocomplex receptor located in the cytoplasm present in all human cells. This receptor is known as the glucocorticoid receptor (alphaGR) [14], which is activated by corticosteroids, resulting in a drugereceptor complex that moves into the nucleus of the cell and binds this complex to the DNA. This will directly or indirectly regulate the transcription of target genes [15]. However, the antiinflammatory and immunosuppressive effects of corticosteroids are due to three molecular mechanisms [7]. First, the ligandactivated alpha-GR binds as a homodimer to specific DNA sequences located in the promoter regions of target genes inducing transcription (transactivation). Second, an indirect negative regulation of gene expression (transrepression) is achieved by GRprotein interaction. The ligand activated receptor binds as a monomer to key pro-inflammatory transcription factors such as activator protein (AP)-1 and nuclear factor (NF)-kB. The resulting complex inhibits the initiation of transcription of relevant genes that play a central role in inflammation [7]. Corticosteroids inhibit the synthesis of several cytokines (e.g. tumor necrosis factor alfa [(TNF-alfa] and interleukins [IL] 4, 5, 6 and 13), adhesion molecules (e.g. ICAM-1, VCAM-1) and chemokines (e.g. eotaxin, IL-8) [15]. The third mechanism is corticosteroid signaling through membraneassociated receptors and second messengers (so-called non genomic pathways). The best-described non-genomic mechanism involves the activation of endothelial nitric oxide synthetase (eNOS), which is responsible for a rapid vasodilatory effect [16]. Other mechanism of action includes histone acetylation and deacetylation [17]. The mechanisms that could explain why ICSs may cause pneumonia are a matter of scientific interest. We hypothesized several possible explanations based on our review of the literature. The immunosuppressive effect caused by high local lung concentrations found with the use of ICSs may potentially increase the risk of pneumonia [47,48]. Barnes et al. [49] showed that in bronchial biopsies from patients receiving ICS/LABA (fluticasone propionate and salmeterol) the number of inflammatory cells was reduced and the expression of pro-inflammatory mediators was decreased. This suggests a possible decrease in local cellular defense mechanisms. This observation was confirmed in a multicenter randomized placebo-controlled trial, which also found a reduction of lungspecific inflammatory biomarkers [50]. The use of an ICS alone or in combination with LABA was associated with lower lung C-reactive protein (CRP), IL-6, and Surfactant protein D (SP-D) levels, but not systemic inflammatory biomarkers, except SP-D, when

Table 1 Types of inhaled corticosteroids. Inhaled corticosteroids

Combination inhaled corticosteroids/ long-acting beta-agonists

Beclomethasone dipropionate Budesonide Flunisolide Fluticasone propionate Mometasone furoate Triamcinolone acetonide Ciclesonide

Fluticasone/Salmeterol Budesonide/Formoterol Mometasone/Formoterol Fluticasone/Vilanterol

compared to placebo. Barbier et al. [51] demonstrated that fluticasone reduces bacterial airway epithelial invasion in a murine model of lung infection. And finally, as mentioned before it is possible that lipophilic ICS, such as fluticasone, may exert a stronger immunosuppressive effect, increasing mucosal and epithelial exposure facilitating pneumonic events. 3. Inhaled corticosteroids Inhaled corticosteroids (ICS) are commonly prescribed medications for the management of patients with COPD and asthma [4,5,22]. In COPD, they are recommended for patients with severe obstruction (GOLD III or IV) and/or frequent exacerbations [5]. ICSs are recommended for patients with asthma and persistent symptoms [4,23]. The pharmacokinetics of the available inhaled corticosteroids has been described extensively [24,25]. Briefly, the use of ICSs, as opposed to systemic corticosteroids, improves the therapeutic index by decreasing systemic bioavailability, increasing systemic clearance, and prolonging residence time within the lung volume of distribution [26]. All available ICSs may produce systemic effects when administered in the high-dose range as defined by the guidelines [4,5]. Multiple studies have recognized an increased risk of pneumonia associated with the chronic use of inhaled corticosteroids [8e10]. Pneumonia is associated with increased morbidity and mortality. In COPD, it is also associated with worsening quality of life and a decline in lung function [27]. Given their broad use, this has become a significant safety concern. 3.1. Inhaled corticosteroids and pneumonia We reviewed the relevant literature assessing the association of ICSs and the risk of developing pneumonia among patients with COPD (Table 2). The Towards a Revolution in Chronic Obstructive Pulmonary Disease Health (TORCH) study [8], was the landmark randomized controlled trial (RCT) that suggested an associated increased risk of developing pneumonia among COPD patients treated with ICSs. The TORCH study compared the efficacy of salmeterol, fluticasone propionate, or a combination regimen (salmeterol/fluticasone 50/500 mg twice daily) against placebo in COPD patients over a 3-year period. COPD patients who received an ICS, as monotherapy or in combination therapy, had a higher rate of physician-reported pneumonia (19.6% and 18.3%, respectively) when compared to placebo (12.3%, p < 0.001). However, this study was limited by the lack of radiographic confirmation of the diagnosis of pneumonia. A post hoc analysis of the TORCH study reported by Crim et al. [28] confirmed these results, identifying advanced age, low body mass index, low FEV1, and the presence of an exacerbation in the previous year as risk factors for the development of pneumonia in COPD patients taking ICSs. After the publication of the TORCH trial, interest in assessing this association emerged around the world. Kardos et al. [9], assessed the impact of combination therapy with salmeterol/fluticasone propionate 50/500 mg, twice daily, compared with LABA alone on the rates of moderate and severe acute exacerbations of COPD (AECOPD). The authors concluded that combination LABA/ICS therapy reduces the rate of moderate and severe AECOPD by 35% in patients with severe COPD (p < 0.001). However, the authors also found that pneumonia events were more likely to occur between COPD patients managed with LABA/ICS when compared to the LABA-only group (4.5 vs. 1.4%; p ¼ 0.005). In addition, Wedzicha et al. [10], evaluated the effect of combination salmeterol/fluticasone propionate 50/500 mg twice daily vs. tiotropium on reducing exacerbations among patients with COPD. The authors conclude that pneumonia events were more common

Please cite this article in press as: O. Sibila, et al., The risk and outcomes of pneumonia in patients on inhaled corticosteroids, Pulmonary Pharmacology & Therapeutics (2015), http://dx.doi.org/10.1016/j.pupt.2015.04.001

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Table 2 Studies evaluating the risk of pneumonia in COPD patients treated with inhaled corticosteroids. Association of ICS use and risk of pneumonia in COPD patients Author/year

Study design

Comments

Increased risk of pneumonia Kardos et al. [9] e 2006

Randomized controlled trial

Calverley et al. [8] e 2007

Randomized controlled trial

Wedzicha et al. [10] e 2007

Randomized controlled trial

Ernst et al. [27] e 2007

Observational

Nannini et al. [42] e 2007

Meta-analysis

Drummond et al. [36] e 2008

Meta-analysis

Singh et al. [37] e 2009

Meta-analysis

Rodrigo et al. [38] e 2009

Meta-analysis

Singh et al. [39] e 2010

Meta-analysis

Müllerova et al. [30] e 2012 Nannini et al. [41] e 2012

Observational Meta-analysis

Jansson et al. [33] e 2013

Observational

Suissa et al. [31] e 2013

Observational

DiSantostefano et al. [34] e 2014

Cluster analysis of RCTs

Kew et al. [43] e 2014

Meta-analysis

Ferrer et al. [46] e 2014

Prospective Cohort Study

4% of patients in the salmeterol/fluticasone group and 1% of patients in the salmeterol group were reported to have suspected pneumonia, however there was no radiographic confirmation. Probability of pneumonia increased with LABA/ICS compared to placebo, though pneumonia-related mortality was similar among all groups. No prospective definition for pneumonia on study protocol (e.g. no radiographic confirmation), as this was an unexpected event. Increased rates of pneumonia with LABA/ICS, as opposed to tiotropium, though the LABA/ICS group had a lower rate of death. Diagnosis of pneumonia was clinical (e.g. radiographic confirmation was not required). ICS use is associated with an excess risk of pneumonia hospitalization and pneumonia hospitalization leading to death. Definition of pneumonia based on diagnostic codes. Combined LABA/ICS therapy led to fewer exacerbations and a reduction in all-cause mortality, though an increased risk of pneumonia was noted (OR 1.62) with a three-year NNTH of 17 (mostly based on the results of the TORCH trial). In patients with COPD, ICS use was associated with an increased risk of pneumonia, especially in the following subgroups: higher ICS dose, shorter duration of ICS use, lower baseline FEV1, and combined LABA/ICS. ICS use was associated with increased rates of pneumonia and serious pneumonia events when comparing to placebo vs. ICS-alone or LABA alone vs. combination LABA/ ICS. Combination LABA/ICS was associated with an increased risk of pneumonia (RR 1.65), although it did significantly reduce the number of moderate exacerbations and improved St. George Respiratory Questionnaire scores. ICS use was associated with an increase in mortality, particularly in the elderly and patients with more severe disease and lower FEV1. Definition of pneumonia based on diagnostic codes. Pneumonia was more frequent with LABA/ICS combination (4%) than LABA alone (3%), but no significant differences in rates of hospitalization or mortality. Higher rates of pneumonia and pneumonia-related mortality were seen in patients on fluticasone/salmeterol when compared to those on budesonide/formoterol. Diagnosis of pneumonia based on diagnostic codes. ICSs were associated with increased rates of serious pneumonia events, particularly with fluticasone when compared with budesonide. ICS use was associated with an increased risk of pneumonia and serious pneumonia events independent of cluster. ICS use, alone or in combination with LABA, was associated with an increased risk of pneumonia events, without significant differences in mortality. Fluticasone was associated with higher rates of pneumonia, though not serious pneumonia events, when compared with budesonide. Use of ICSs prior to admission for community-acquired pneumonia was associated with a reduced inflammatory response, but with no difference in long-term mortality.

No increased risk of pneumonia Welte et al. [32] e 2009

Randomized controlled trial

Sin et al. [40] e 2009

Meta-analysis

Cheng et al. [45] e 2014

Randomized controlled trial

Festic et al. [44] e 2014

Cohort study

Patients in the budesonide/formoterol plus tiotropium had less exacerbations and improved lung function, health status, and morning symptoms, when compared to tiotropium alone, however rates of pneumonia were similar among both groups (