Inhaled fluticasone propionate impairs pulmonary clearance of Klebsiella Pneumoniae in mice

Patterson, Craig M; Morrison, Richard L.; D’Souza, Alain; Teng, Xu; Happel, Kyle I.

doi:10.1186/1465-9921-13-40

Cited by 45 publications

(34 citation statements)

References 34 publications

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“…There is good evidence supporting the effect of ICS on human pulmonary host defence, acting through several biological pathways, such as an inhibitory action on macrophage functions, a decrease in cytokine production and nitric oxide expression, which may lead to a failure to control infection 29 30. Although there have been no studies directly comparing the effects of fluticasone and budesonide on host defence, differences are likely related to their contrasting pharmacokinetic and pharmacodynamic properties.…”

Section: Discussionmentioning

confidence: 99%

“…Although there have been no studies directly comparing the effects of fluticasone and budesonide on host defence, differences are likely related to their contrasting pharmacokinetic and pharmacodynamic properties. Fluticasone is known to be more potent (ie, greater effect on intracellular steroid receptors), more lipophilic and has a longer half life than budesonide 29. Accordingly, fluticasone has a better penetration at the site of action and a more prolonged effect.…”

Section: Discussionmentioning

confidence: 99%

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Inhaled corticosteroids in COPD and the risk of serious pneumonia

Suissa

Patenaude

Lapi

et al. 2013

Thorax

405

298

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BackgroundInhaled corticosteroids (ICS) are known to increase the risk of pneumonia in patients with chronic obstructive pulmonary disease (COPD). It is unclear whether the risk of pneumonia varies for different inhaled agents, particularly fluticasone and budesonide, and increases with the dose and long-term duration of use.MethodsWe formed a new-user cohort of patients with COPD treated during 1990–2005. Subjects were identified using the Quebec health insurance databases and followed through 2007 or until a serious pneumonia event, defined as a first hospitalisation for or death from pneumonia. A nested case–control analysis was used to estimate the rate ratio (RR) of serious pneumonia associated with current ICS use, adjusted for age, sex, respiratory disease severity and comorbidity.ResultsThe cohort included 163 514 patients, of which 20 344 had a serious pneumonia event during the 5.4 years of follow-up (incidence rate 2.4/100/year). Current use of ICS was associated with a 69% increase in the rate of serious pneumonia (RR 1.69; 95% CI 1.63 to 1.75). The risk was sustained with long-term use and declined gradually after stopping ICS use, disappearing after 6 months (RR 1.08; 95% CI 0.99 to 1.17). The rate of serious pneumonia was higher with fluticasone (RR 2.01; 95% CI 1.93 to 2.10), increasing with the daily dose, but was much lower with budesonide (RR 1.17; 95% CI 1.09 to 1.26).ConclusionsICS use by patients with COPD increases the risk of serious pneumonia. The risk is particularly elevated and dose related with fluticasone. While residual confounding cannot be ruled out, the results are consistent with those from recent randomised trials.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Inhaled corticosteroids in COPD and the risk of serious pneumonia

Suissa

Patenaude

Lapi

et al. 2013

Thorax

405

298

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“…They postulated that steroid-induced suppression of the host immune response might act in conjunction with extensive mucoid occlusion of the peripheral airways to increase the probability of infection in the lower respiratory tract. In a mouse model, fluticasone was reported to reduce innate pulmonary host defenses and clearance of the bacterial pathogen, causing greater systemic bacterial burden and increased mortality 41. There may be difference in immunosuppressive potency between different corticosteroids; based on a meta-analysis of clinical trial data, budesonide was reported to be associated with fewer pneumonia events than fluticasone 42.…”

Section: Discussionmentioning

confidence: 99%

Inhaled corticosteroid use in patients with chronic obstructive pulmonary disease and the risk of pneumonia: a retrospective claims data analysis

Yawn¹,

Li²,

Tian³

et al. 2013

COPD

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BackgroundThe use of inhaled corticosteroids in patients with chronic obstructive pulmonary disease (COPD) has been associated with an increased risk of pneumonia in controlled clinical trials and case-control analyses.ObjectiveUsing claims databases as a research model of real-world diagnosis and treatment, to determine if the use and dose of inhaled corticosteroids (ICS) among patients with newly diagnosed COPD are associated with increased risk of pneumonia.Patients and methodsThis was a retrospective cohort analysis of patients diagnosed with COPD between January 01, 2006 and September 30, 2010, drawn from databases (years 2006–2010). Patients (aged ≥45 years) were followed until first pneumonia diagnosis, end of benefit enrollment, or December 31, 2010, whichever was earliest. A Cox proportional hazard model was used to assess the association of ICS use and risk of pneumonia, controlling for baseline characteristics. Daily ICS use was classified into low, medium, and high doses (1 μg–499 μg, 500 μg–999 μg, and ≥1000 μg fluticasone equivalents daily) and was modeled as a time-dependent variable.ResultsAmong 135,445 qualifying patients with a total of 243,097 person-years, there were 1020 pneumonia incidences out of 5677 person-years on ICS (crude incidence rate, 0.180 per person-year), and 27,730 pneumonia incidences out of 237,420 person-years not on ICS (crude incidence rate, 0.117 per person-year). ICS use was associated with a dose-related increase in risk of pneumonia, with adjusted hazard ratios (versus no use; (95% confidence interval) of 1.38 (1.27–1.49) for low-dose users, 1.69 (1.52–1.88) for medium-dose users, and 2.57 (1.98–3.33) for high-dose users (P < 0.01 versus no use and between doses).ConclusionThe use of ICS in newly diagnosed patients with COPD is potentially associated with a dose-related increase in the risk of pneumonia.

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“…This is likely because the airway infections responsible for the exacerbation, and the consequent airway inflammation, are not adequately controlled by the innate immune system and the ICS treatment, thus allowing infection/inflammation to penetrate to alveoli and pleural space. While all ICS can suppress local innate immunity, immunosuppression with fluticasone against pneumonia pathogens has been demonstrated [42]. This may be explained by the high lipophilicity of fluticasone mentioned above, which results in a high retention time in the mucus and therefore higher airway concentrations than ICS like budesonide [10].…”

Section: Potential Side Effects Of Ics In Copd: the Risk Of Pneumoniamentioning

confidence: 98%

Differences in the efficacy and safety among inhaled corticosteroids (ICS)/long-acting beta2-agonists (LABA) combinations in the treatment of chronic obstructive pulmonary disease (COPD): Role of ICS

Latorre

Novelli

Vagaggini

et al. 2015

Pulmonary Pharmacology & Therapeutics

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a b s t r a c tInhaled corticosteroids (ICS) are frequently recommended for the treatment of asthma and COPD, often in combination with long-acting beta2-agonists (LABA), depending on the severity of the disease and/or on the specific phenotype. Several ICS/LABA combinations are currently available that differ in their pharmacokinetic characteristics and dose of both components. Thus, this review assesses differences in the efficacy and the safety profiles of the ICS components in the two more frequently used ICS/LABA combinations (budesonide/formoterol and fluticasone/salmeterol) for the management of COPD.Whereas the basic mechanism of action is similar for all ICS (binding with the intracellular glucocorticoid receptor, which mediates both genomic and non genomic effects), the pharmacokinetic and characteristics of ICS are quite different in terms of receptor affinity, bioavailability, lipophilicity and drug persistence in the airways. Fluticasone persists longer in airway mucus and requires more time to dissolve in the lining fluid and then enter the airway wall, whereas budesonide is cleared more quickly from the airways.Comparative efficacy of the two major ICS/LABA combinations recommended for the treatment of COPD show similar efficacy in terms of reduction of exacerbations, improvement in forced expiratory volume in the first second (FEV1) and quality of life. One retrospective cohort study suggested a greater efficacy for the budesonide/formoterol combination on hospital or emergency department admissions, oral corticosteroid courses, and addition of tiotropium, and an observational real-life study reported a greater reduction of COPD exacerbations with budesonide/formoterol than with fluticasom/salmeterol combination.Among the potential side effects of chronic ICS treatment in patients with COPD, recently the use of fluticasone or fluticasone/salmeterol combination has been associated with a higher prevalence of pneumonia in the major long-term studies. On the other hand, no similar increased risk of pneumonia has been reported in patients with COPD treated with the budesonide/formoterol combination. A recent population-based cohort study from the Quebec database showed that the adjusted odds ratio for having severe pneumonia was higher for fluticasone (2.1) than for budesonide (1.17) or other ICS (1.41). Of the ICS studied, only fluticasone demonstrated a dose-related increase in risk of pneumonia in patients with COPD. This difference between fluticasone and budesonide may be explained by the longer retention of fluticasone in the airways, with potentially greater inhibition of type-1 innate immunity.Therefore, the risk:benefit ratio should be evaluated thoroughly when choosing an ICS/LABA combination for patients with COPD.

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Inhaled fluticasone propionate impairs pulmonary clearance of Klebsiella Pneumoniae in mice

Cited by 45 publications

References 34 publications

Inhaled corticosteroids in COPD and the risk of serious pneumonia

Inhaled corticosteroids in COPD and the risk of serious pneumonia

Inhaled corticosteroid use in patients with chronic obstructive pulmonary disease and the risk of pneumonia: a retrospective claims data analysis

Differences in the efficacy and safety among inhaled corticosteroids (ICS)/long-acting beta2-agonists (LABA) combinations in the treatment of chronic obstructive pulmonary disease (COPD): Role of ICS

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