Fluticasone Propionate Research Articles

Allergic bronchopulmonary aspergillosis with chest pain as atypical symptoms

A 43-year-old man with a 1-month history of chest pain was admitted to West China Hospital (Chengdu, China) without cough, fever, or viscous sputum. He had a 36-year history of asthma, treated with inhaled 50 μg salmeterol xinafoate and 250 μg fluticasone propionate (Seretide; GlaxoSmithKline, Brentford, UK), without relapsing for nearly a year. A CT scan showed multiple mucus plugs (figure A). Blood tests showed the peripheral eosinophil count was 1380 cells per uL (normal range, 20–520 cells per uL), the total IgE concentration was 1640 IU/mL (normal range, 5–150 IU/mL), and the results from an Xpert MTB/RIF test, a galactomannan antigen, and a 1,3-β-D glucan antigen test were negative. No sputum pathogenic test was done as the patient had no sputum. According to the Asano criteria, these results suggested a diagnosis of allergic bronchopulmonary aspergillosis. 2 days after admission, a painless fibrobronchoscopy examination was done to obtain mucus plugs for mycology and histopathology tests. Mucus and mucus plugs were detected in the bilateral pulmonary bronchi by bronchoscopy (figure B). Galactomannan antigen test, microscopy, and fungal culture results were negative, but metagenomics next-generation sequencing (mNGS) testing of bronchial lavage and puncture tissue of the endobronchial membrane rapidly detected Aspergillus fumigatus. 4 days after admission, the concentration of specific IgE for filamentous fungi in the blood was 5·67 IU/mL. A pathological test of the puncture tissue of the endobronchial membrane showed infiltration of eosinophils and fungal mycelia and Charcot–Leyden crystals. Thus, the diagnosis was allergic bronchopulmonary aspergillosis and the treatment was intravenous voriconazole (0·4 g twice daily on day 1, then 0·2 g twice daily for 4 days). 8 days after admission, the chest pain eased after therapy. The patient was discharged and the treatment plan switched to oral voriconazole (0·2 g twice daily for 1 month) and prednisone (40 mg once daily for 2 weeks, then 30 mg once daily for 1 week, and 25 mg once daily for another week) for continued treatment. 1 month after being discharged from hospital, the patient received a CT scan review, showing the multiple mucus plugs had almost disappeared (figure C).

Insights into the potential of rheological measurements in development of dry powder inhalation formulations

Study of flow is a key to development of dry powder inhalation formulations. Various static (bulk) and dynamic rheological measurements are used to study different aspects of powder flow and packing. Among rheological measurements, the permeability and the fluidization energy are, conceptually, most relevant to dispersion of dry powder inhalation formulations. The aim of the current study was to test the robustness and the range of applications of the two measurements, among other rheological measurements. To this end, we prepared and studied a series of ternary, carrier-based dry powder inhalation formulations. The formulations were mixtures of coarse-fine excipient (α-lactose monohydrate) blends, with different fine excipient concentrations (0.0–15.0 % w/w), and a spray-dried drug (fluticasone propionate) material. The excipient blends were characterized in terms of morphology, size, crystallinity, and rheological properties. The formulations were evaluated in vitro using a low resistance inhalation device, the Cyclohaler®, and a high resistance inhalation device, the Handihaler®. The study design aimed to complement literature data. Bulk rheological measurements, specifically the bulk density, the compressibility, and the permeability, exhibited satisfactory precision and could demonstrate changes in powder composition and structure. They hold a potential for use as critical material attributes to aid monitoring and optimization of carrier-based dry powder inhalation formulations in quality-by-design systems. On the other hand, dynamic rheological measurements, specifically the basic flowability energy, the specific energy, and the fluidization energy, generally exhibited high variability, which obscured interpretation of the measurements and implied heterogeneous powder structures. The fluidization energy could, nevertheless, convey structural changes taking place during powder fluidization.

Intranasal corticosteroid use in patients with allergic rhinitis

Allergic rhinitis (AR) is one of the most common diseases in the world, which is based on IgE-mediated inflammation that develops after exposure to various allergens. About 40% of people suffer from the same or other allergic diseases, every third inhabitant of the Earth has symptoms of AR and every tenth has bronchial asthma. According to the ARIA classification, ARs are divided: by the nature of the flow, by the severity of the flow and by the stage of the flow; for symptoms, the proposed therapy, consisting of sequential steps. Groups of drugs include: systemic or topical blockers of histamine H1 receptors, intranasal and systemic corticosteroids, mast cell stabilizers (intranasal cromones), M-antagonists, antagonists of leukotriene receptors. Medicines do not give a lasting effect after their cancellation, therefore, with persistent AR, treatment should be prolonged; methods of application more often oral or intranasal. The advantages of the pharmacological antiallergic effect of InHCS are the simultaneous inhibition of both the early and late phases of the allergic response and the inhibition of all AR symptoms. The advantage of InHCS over oral administration is the minimal risk of developing systemic side effects against the background of the creation of adequate concentrations of the substance in the nasal mucosa, which allows to control the symptoms of AR. Based on data from a number of studies, the advantages of intrasal corticosteroids for AR, in particular fluticasone propionate, are used.

Inhaled Corticosteroids Alone and in Combination With Long-Acting β2 Receptor Agonists to Treat Reduced Lung Function in Preterm-Born Children

Decreases in future lung function are a hallmark of preterm birth, but studies for management of decreased lung function are limited. To determine whether 12 weeks of treatment with inhaled corticosteroids (ICS) alone or in combination with long-acting β2 agonists (LABA) improves spirometry and exercise capacity in school-aged preterm-born children who had percent predicted forced expiratory volume in 1 second (%FEV1) less than or equal to 85% compared with inhaled placebo treatment. A double-blind, randomized, placebo-controlled trial was conducted to evaluate ICS and ICS/LABA against placebo. Preterm-born children (age, 7-12 years; gestation ≤34 weeks at birth) who did not have clinically significant congenital, cardiopulmonary, or neurodevelopmental abnormalities underwent spirometry, exercise testing, and measurement of fractional exhaled nitric oxide before and after treatment. A total of 144 preterm-born children at the Children's Hospital for Wales in Cardiff, UK, were identified and enrolled between July 1, 2017, and August 31, 2019. Each child was randomized to 1 of 3 cohorts: fluticasone propionate, 50 μg, with placebo; fluticasone propionate, 50 μg, with salmeterol, 25 μg; or placebo inhalers, all given as 2 puffs twice daily for 12 weeks. Children receiving preexisting ICS treatment underwent washout prior to randomization to ICS or ICS/LABA. The primary outcome was between-group differences assessed by adjusted pretreatment and posttreatment differences of %FEV1 using analysis of covariance. Intention-to-treat analysis was conducted. Of 144 preterm-born children who were identified with %FEV1 less than or equal to 85%, 53 were randomized. Treatment allocation was 20 children receiving ICS (including 5 with prerandomization ICS), 19 children receiving ICS/LABA (including 4 with prerandomization ICS), and 14 children receiving placebo. The mean (SD) age of children was 10.8 (1.2) years, and 29 of the randomized children (55%) were female. The posttreatment %FEV1 was adjusted for sex, gestation, bronchopulmonary dysplasia, intrauterine growth restriction, pretreatment corticosteroid status, treatment group, and pretreatment values. Posttreatment adjusted means for %FEV1, using analysis of covariance, were 7.7% (95% CI, -0.27% to 15.72%; P = .16) higher in the ICS group and 14.1% (95% CI, 7.3% to 21.0%; P = .002) higher in the ICS/LABA group compared with the placebo group. Active treatment decreased the fractional exhaled nitric oxide and improved postexercise bronchodilator response but did not improve exercise capacity. One child developed cough when starting inhaler treatment; no other adverse events reported during the trial could be attributed to the inhaler treatment. The results of this randomized clinical trial suggest that combined ICS/LABA treatment is beneficial for prematurity-associated lung disease in children. EudraCT number: 2015-003712-20.

Acupoint thread-embedding as adjuvant therapy for bronchial asthma in children and its effect on pulmonary function, serum IgA and IgE levels

To observe the efficacy of acupoint thread-embedding combined with fluticasone propionate aerosol for chronic persistent bronchial asthma of lung-spleen qi deficiency and spleen-kidney yang deficiency in children and its effect on pulmonary function and serum levels of IgA and IgE. A total of 120 children with chronic persistent bronchial asthma were randomly divided into an observation group (60 cases, 9 cases dropped off) and a control group (60 cases, 7 cases dropped off). The control group was treated with fluticasone propionate aerosol (125 μg per inhalation), twice a day; based on the control group treatment, the observation group was treated with acupoint thread-embedding at Dingchuan (EX-B 1), Feishu (BL 13), Zusanli (ST 36) and Danzhong (CV 17), once half a month. Both groups were treated for 3 months. The pulmonary function, serum IgA, IgE levels and TCM symptom score were compared between the two groups before and after treatment, and the clinical efficacy was evaluated. After treatment, the large airway function (peak expiratory flow [PEF], forced expiratory volume at the first second [FEV1]) and small airway function (maximal expiratory flow at 25% of the forced capacity [MEF25%], maximal expiratory flow at 50% of the forced capacity [MEF50%], maximal expiratory flow at 75% of the forced capacity [MEF75%] and midexpiratory flow 25%-75% [MEF25%-75%]) were higher than those before treatment (P<0.05), and the pulmonary function in the observation group was higher than that in the control group (P<0.05). After treatment, the serum IgA levels in the two groups were higher than those before treatment (P<0.05), and the serum IgE levels and TCM symptom scores were lower than those before treatment (P<0.05); the serum IgA level in the observation group was higher than that in the control group (P<0.05), and the serum IgE level and TCM symptom score in the observation group were lower than those in the control group (P<0.05). The total effective rate was 94.1% (48/51) in the observation group, which was higher than 88.7% (47/53) in the control group (P<0.05). Acupoint thread-embedding combined with fluticasone propionate aerosol could improve the pulmonary function, TCM symptoms and serum IgA and IgE levels in children with chronic persistent bronchial asthma of lung-spleen qi deficiency and spleen-kidney yang deficiency. The curative effect is better than fluticasone propionate aerosol alone.

Pharmacology Versus Convenience: A Benefit/Risk Analysis of Regular Maintenance Versus Infrequent or As-Needed Inhaled Corticosteroid Use in Mild Asthma.

IntroductionThis study compared the bronchoprotective and benefit/risk profiles of various inhaled corticosteroid (ICS) dosing regimens in mild asthma.MethodsA pharmacokinetic/pharmacodynamic model was developed and validated describing the relationship between ICS dose and time-course for airway bronchoprotection, [provocative concentration of adenosine monophosphate (AMP) causing ≥ 20% decline in forced expiratory volume in 1 s (FEV1) (AMP PC20)], for fluticasone furoate (FF), fluticasone propionate (FP) and budesonide (BUD). For regular ICS maintenance therapy (100% and 50% adherence) and infrequent or as-needed use (dosing 3–4 times per week), treatment effectiveness was expressed as percent time during 28 days when bronchoprotection exceeded either the threshold for a treatment-related bronchoprotective effect (AMP PC20 ≥ 0.25 doubling dose) or the threshold for a clinically significant bronchoprotective effect (AMP PC20 ≥ 1.0 doubling dose). This value was divided by the total ICS dose administered expressed in prednisolone equivalents to give a therapeutic index (TI).ResultsThe model-predicted time course of ICS-induced bronchoprotection with regular daily maintenance dosing and 100% adherence showed that all ICS at the highest recommended doses for mild asthma exceeded the threshold for clinically significant bronchoprotective effect for all or most of the 28-day dosing period, mean (90% CI); 100% (96.1–100), 99.9% (8.0–100) and 100% (58.2–100) with TI values of 16.9, 6.6 and 5.4 for FF 100 µg OD, FP 200 µg BID and BUD 200 µg BID, respectively. For simulated poor adherence (50%) to regular daily maintenance therapy, corresponding mean (90% CI) values were; 75.7% (39.4–89.1), 52.3% (0.7–69.2) and 51.3% (28.6–58.3) with TI values of 25.7, 6.9 and 5.6. For simulated infrequent/as needed use the corresponding values were; 77.0% (37.6–87.0), 25.5% (0.0–38.0) and 26.2% (14.3–31.5) with TI values of 26.1, 6.7 and 5.7. For all regimen/scenarios, FF had the most sustained efficacy and favourable TI followed by FP and BUD.ConclusionsAt doses recommended for mild asthma, all ICS regimens provide sustained bronchoprotective efficacy when dosed regularly with high adherence. With poor adherence or use 3–4 times per week (infrequent/as needed), longer-acting ICS molecules will more likely provide sustained protection and a better TI versus shorter duration of action molecules (FF > FP ≥ BUD). These data highlight the benefits of using ICS as regular daily maintenance dosing in mild asthma and the potential risks of under-treatment with ICS (which may occur with ICS/formoterol as-needed approach in mild persistent asthma) associated with reduced levels of bronchoprotection.

The effect of treatment with fexofenadine and fluticasone propionate on the gene expression levels of Th9 transcription factors in patients with allergic rhinitis

T helper-9 (Th9) is a new T cell subset involved in allergic rhinitis (AR) pathogenesis. Fexofenadine and fluticasone propionate are the first effective line of AR treatment. This study aimed to evaluate the effect of fexofenadine and fluticasone propionate on the gene expression levels of Interferon regulatory factor 4 (IRF4), B cell-activating transcription factor-like (BATF), and SPI1 gene-encoded protein (PU.1), essential transcription factors for Th9 cell differentiation, in AR patients. Twenty-six AR patients (aged 32.8 ± 9.1 years, 13 men and 13 women) were treated with fexofenadine and fluticasone propionate for one month. Expression levels of PU.1, IRF4, and BATF genes were measured using Real-Time PCR. Our results showed that after one month of treatment, the expression level of IRF4 and BATF genes decreased significantly (P < 0.001, P < 0.01, respectively), while PU.1 gene expression was not remarkably different. Overall, our results showed that after one month of treatment with fexofenadine and fluticasone propionate, the expression levels of IRF4 and BATF genes in AR patients decreased, which may be due to this treatment regimen. However, the exact mechanism of action of fexofenadine and fluticasone propionate needs further study.

Trends in Medicaid spending on inhalers in the United States, 2012-2018.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) and asthma are common respiratory diseases that impose a significant economic burden on Medicaid. Inhalers are the mainstay treatment for relieving symptoms and improving outcomes for COPD and asthma patients. OBJECTIVE: To describe the total spending and trends of Medicaid expenditures on inhalers between 2012 and 2018 in the United States. METHODS: We analyzed the deidentified data from the Medicaid Drug Spending Dashboard and utilization datasets from 2012 to 2018. We identified 9 classes of inhalers and described the Medicaid total spending on and relative annual changes for those inhalers. We also described the spending on available generic inhalers and compared the Medicaid spending by manufacturers during this time frame. RESULTS: Medicaid spent $26.2 billion on inhalers from 2012 to 2018. This spending increased by $2.5 billion (120%) over this time frame. During this specified period, the highest Medicaid spending was on the group of inhaled corticosteroid (ICS)-containing inhalers ($14.9 billion). Within this group, the inhaler class of ICS/long-acting beta-2 adrenoceptor agonists contributed to the highest Medicaid spending (53%), with a growth of 607% between 2012 and 2018. Of the $26.2 billion that Medicaid spent on inhalers, $35.5 million (less than 0.01%) was spent on 2 generic inhalers: fluticasone propionate with salmeterol and levalbuterol tartrate hydrofluoroalkane. CONCLUSIONS: Between 2012 and 2018, on average, $3.5 billion per year was spent by Medicaid on inhalers. Decreasing the price of inhalers by introducing more generic inhalers in the market can potentially reduce the cost burden on Medicaid. DISCLOSURES: This study was funded by the American Foundation for Pharmaceutical Education (AFPE). The funders had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript. The authors declare no conflicts of interest.

Effect of Vitamin D3 Supplementation on Severe Asthma Exacerbations in Children With Asthma and Low Vitamin D Levels: The VDKA Randomized Clinical Trial

To investigate if supplementation with vitamin D3 would improve the time to a severe exacerbation in children at high risk with vitamin D insufficiency and taking low-dose inhaled corticosteroids (ICSs) for persistent asthma.The participants were recruited from 7 children’s hospitals across the United States. Participants, 6 to 16 years of age, had to have physician-diagnosed asthma for at least 1 year, being treated with low-dose ICSs, and have a serum 25-hydroxyvitamin D level less than 30 ng/mL. They also had to have at least 1 severe asthma exacerbation in the last year (defined as systemic steroids for at least 3 days or an emergency department visit or hospitalization requiring systemic corticosteroids). All participants had to show bronchodilator responsiveness or airway responsiveness to methacholine inhalation. The mean age of the participants was 9.8 years (40% girls). A total of 219 subjects passed screening and entered run-in. A total of 192 subjects were randomly assigned to active drug or placebo capsules.This was a randomized, double-blind, parallel, placebo-controlled clinical trial. Participants initially all received placebo capsules and were maintained on inhaled fluticasone propionate, 176 μg per day (6–11 years) or 220 μg per day (12–16 years) during run-in. They continued the ICSs and then were randomly assigned to daily vitamin D3 4000 IU or continuing placebo for 48 weeks. After 24 weeks, participants dose of fluticasone was reduced by 50%, if asthma was well controlled and spirometry was normal. Serum vitamin D levels and parameters of asthma control were measured every 16 weeks. The primary outcome was the time to a severe asthma exacerbation. Secondary outcomes included the time to a viral-induced severe exacerbation, the proportion of participants in whom the dose of ICS was reduced halfway through the trial, and the cumulative fluticasone dose during the trial.A total of 94% of randomly assigned subjects completed the trial. A total of 36 participants (37.5%) in the vitamin D3 group and 33 (34.4%) in the placebo group had ≥1 severe exacerbations. Compared with the placebo, vitamin D3 supplementation did not significantly improve the time to a severe exacerbation. The mean time to exacerbation was 240 days in the vitamin D3 group versus 253 days in the placebo group (mean group difference: −13.1 days; adjusted hazard ratio: 1.13; P = .63). Vitamin D3 supplementation, compared with the placebo, did not significantly improve the time to a viral-induced severe exacerbation, the proportion of participants whose dose of ICSs was reduced, or the cumulative fluticasone dose during the trial. Serious adverse events were similar in both groups (vitamin D3 group: n = 11; placebo group: n = 9).In children 6 to 16 years old with persistent asthma and low vitamin D levels, vitamin D3 supplementation, compared with a placebo, did not significantly improve the time to a severe asthma exacerbation or ICS dosing.As the authors note, in several observational studies, researchers have linked low serum vitamin D levels to severe asthma exacerbations, lower lung function, and reduced response to corticosteroids. Yet meta-analyses and reviews of vitamin D3 supplementation for severe asthma exacerbations have found insufficient evidence to recommend vitamin D3 supplementation in children. In this study, the authors, looking at a high-risk population for asthma exacerbations, add to that negative body of literature.

Efficacy of intranasal fluticasone propionate and budesonide in management of allergic rhinitis\u2014a prospective comparative study

BackgroundAllergic rhinitis (AR) or Hay fever is a chronic inflammation of the nasal mucosa induced by IgE-mediated hypersensitivity due to exposure of various allergens. AR occurs as a response against these inhaled allergens that cause inflammation of nasal mucosal membranes. In this study, a reliable treatment for allergic rhinitis with maximum effectiveness and minimal side effects was assessed. This study compared the effectiveness of intranasal Fluticasone propionate (FUP) and intranasal Budesonide (BUD) in reducing the eosinophil count and in improving the nasal and ocular symptoms. This prospective study was conducted on 62 cases of allergic rhinitis and patients with mild-to-moderate allergic rhinitis were selected for the study. They were randomly divided into two groups; group I consists of 30 patients who received intranasal Fluticasone propionate aqueous spray, total daily dose of 200 μg (50 μg/spray) as 2 sprays in each nostril administered once daily, whereas the group II consists of 32 patients who received intranasal Budesonide aqueous spray, total daily dose of 400 μg/day (100 μg/spray) as 1 spray in each nostril administered twice daily.ResultsAnalysis on patient-based symptom scores revealed that both the groups showed statistically significant reduction in symptoms. Fluticasone propionate was found to be significantly more effective (P < 0.05) than Budesonide in reducing sneezing, nasal itching and majority of symptoms of individual symptom scores. Budesonide showed somewhat similar effect in reducing nasal blockage at 4 weeks of treatment.ConclusionClinically, both the drugs showed statistically significant improvement when compared to baseline, but Fluticasone propionate was superior at reducing nasal symptoms, ocular symptom and eosinophil count.

Trends in Nasal Spray Prescribing Patterns by Otolaryngologists in the US Medicare Population.

To quantify national and state-level prescribing and cost trends for the 3 most prescribed nasal sprays by otolaryngologists in the Medicare population. Through the Centers for Medicare and Medicaid Services (CMS) database and the Kaiser Family Foundation, we retrieved data on Medicare enrollment and on claims and costs of fluticasone propionate, azelastine HCl, and ipratropium bromide prescribed by otolaryngologists from January 1, 2013 to December 31, 2017. From 2013 to 2017, CMS reimbursed $128.8 million for 5.2 million claims of fluticasone propionate, azelastine HCl, and ipratropium bromide prescribed by otolaryngologists. The national claim rate for fluticasone propionate increased 6.5% per year from 2013 to 2015 and then decreased 4.3% per year from 2015 to 2017 while azelastine HCl and ipratropium bromide consistently increased annually (19.0% and 12.2% respectively) from 2013 to 2017. The cost for fluticasone propionate decreased 33.0% a year from 2013 to 2015 and then increased 5.4% annually to $13.60 per claim in 2017. Azelastine HCl decreased 14.8% annually from $91.30 to $50.23 per claim and ipratropium bromide increased 5.2% annually to $34.78 in 2017. Variations in the claim rate and cost for all 3 nasal sprays were observed in some states. Otolaryngologists are prescribing azelastine HCl and ipratropium at an increasingly higher rate in the Medicare population, while the rate for fluticasone propionate has been decreasing nationally. Utilization and costs of nasal sprays also vary geographically across the United States.

Nasal immune gene expression in response to azelastine and fluticasone propionate combination or monotherapy.

BackgroundThe combination of the antihistamine azelastine (AZE) with the corticosteroid fluticasone propionate (FP) in a single spray, has been reported to be significantly more effective at reducing allergic rhinitis (AR) symptoms than treatment with either corticosteroid or antihistamine monotherapy. However, the biological basis for enhanced symptom relief is not known. This study aimed to compare gene expression profiles (760 immune genes, performed with the NanoString nCounter) from peripheral blood and nasal brushing/lavage lysate samples in response to nasal spray treatment.MethodsModerate/severe persistent dust mite AR sufferers received either AZE (125 μg/spray) nasal spray (n = 16), FP (50 μg/spray) nasal spray (n = 14) or combination spray AZE/FP (125 μg AZE and 50 μg FP/spray) (n = 14) for 7 days, twice daily. Self‐reported symptom questionnaires were completed daily for the study duration. Gene expression analysis (760 immune genes) was performed with the NanoString nCounter on purified RNA from peripheral blood and nasal brushing/lavage lysate samples.ResultsIn nasal samples, 206 genes were significantly differentially expressed following FP treatment; 182 genes downregulated (−2.57 to −0.45 Log2 fold change [FC]), 24 genes upregulated (0.49–1.40 Log2 FC). In response to AZE/FP, only 16 genes were significantly differentially expressed; 10 genes downregulated (−1.53 to −0.58 Log2 FC), six genes upregulated (1.07–1.62 Log2 FC). Following AZE treatment only five genes were significantly differentially expressed; one gene downregulated (−1.68 Log2 FC), four genes upregulated (0.59–1.19 Log2 FC). Immune gene changes in peripheral blood samples following treatment were minimal. AR symptoms improved under all treatments, but improvements were less pronounced following AZE treatment.ConclusionAZE/FP, FP, and AZE had diverse effects on immune gene expression profiles in nasal mucosa samples. The moderate number of genes modulated by AZE/FP indicates alternative pathways in reducing AR symptoms whilst avoiding extensive local immune suppression.

Treatment with Fluticasone Propionate Increases Antibiotic Efficacy during Treatment of Late-Stage Primary Pneumonic Plague.

ABSTRACTSevere and late-stage pneumonias are often difficult to treat with antibiotics alone due to overwhelming host inflammatory responses mounted to clear infection. These host responses contribute to pulmonary damage leading to acute lung injury, acute respiratory distress syndrome, and death. In order to effectively treat severe and late-stage pneumonias, use of adjunctive therapies must be considered to reduce pulmonary damage when antimicrobial agents can be administered. Pneumonic plague, a severe pneumonia caused by inhalation of Yersinia pestis, is a fatal disease that causes death within 6 days without antibiotic intervention. Late-stage pneumonic plague is difficult to treat, as antibiotics must be delivered within 24 h after onset of symptoms to be effective. Here, we use a murine model of primary pneumonic plague to examine how host inflammatory responses impact antibiotic treatment of late-stage pneumonic plague. We developed a murine infection model demonstrating the poor outcomes associated with delayed delivery of antibiotics. We show that pretreatment of mice with intranasal fluticasone propionate increased the efficacy of delayed antibiotic delivery and enhanced murine survival. Mice receiving fluticasone propionate also showed decreased bacterial burden and reduced inflammatory pathology in the lungs. Further, we show that treatment and survival correlated with decreased levels of interleukin-6 (IL-6) and reduced neutrophil infiltration to the lungs. This work demonstrates how host inflammatory responses complicate treatment of late-stage pneumonic plague and suggests that targeting of host inflammatory responses may improve treatment of severe, late-stage pneumonia.

Corticosteroid insensitivity persists in the absence of STAT1 signaling in severe allergic airway inflammation.

Corticosteroid insensitivity in asthma limits the ability to effectively manage severe asthma, which is characterized by persistent airway inflammation, airway hyperresponsiveness (AHR), and airflow obstruction despite corticosteroid treatment. Recent reports indicate that corticosteroid insensitivity is associated with increased interferon-γ (IFN-γ) levels and T-helper (Th) 1 lymphocyte infiltration in severe asthma. Signal transducer and activator of transcription 1 (STAT1) activation by IFN-γ is a key signaling pathway in Th1 inflammation; however, its role in the context of severe allergic airway inflammation and corticosteroid sensitivity remains unclear. In this study, we challenged wild-type (WT) and Stat1-/- mice with mixed allergens (MA) augmented with c-di-GMP [bis-(3'-5')-cyclic dimeric guanosine monophosphate], an inducer of Th1 cell infiltration with increased eosinophils, neutrophils, Th1, Th2, and Th17 cells. Compared with WT mice, Stat1-/- had reduced neutrophils, Th1, and Th17 cell infiltration. To evaluate corticosteroid sensitivity, mice were treated with either vehicle, 1 or 3 mg/kg fluticasone propionate (FP). Corticosteroids significantly reduced eosinophil infiltration and cytokine levels in both c-di-GMP + MA-challenged WT and Stat1-/- mice. However, histological and functional analyses show that corticosteroids did not reduce airway inflammation, epithelial mucous cell abundance, airway smooth muscle mass, and AHR in c-di-GMP + MA-challenged WT or Stat1-/- mice. Collectively, our data suggest that increased Th1 inflammation is associated with a decrease in corticosteroid sensitivity. However, increased airway pathology and AHR persist in the absence of STAT1 indicate corticosteroid insensitivity in structural airway cells is a STAT1 independent process.

Pharmacogenetic studies of long-acting beta agonist and inhaled corticosteroid responsiveness in randomised controlled trials of individuals of African descent with asthma

Pharmacogenetic studies in asthma cohorts, primarily made up of White people of European descent, have identified loci associated with response to inhaled beta agonists and corticosteroids (ICSs). Differences exist in how individuals from different ancestral backgrounds respond to long-acting beta agonist (LABA) and ICSs. Therefore, we sought to understand the pharmacogenetic mechanisms regulating therapeutic responsiveness in individuals of African descent. We did ancestry-based pharmacogenetic studies of children (aged 5-11 years) and adolescents and adults (aged 12-69 years) from the Best African Response to Drug (BARD) trials, in which participants with asthma uncontrolled with low-dose ICS (fluticasone propionate 50 μg in children, 100 μg in adolescents and adults) received different step-up combination therapies. The hierarchal composite outcome of pairwise superior responsiveness in BARD was based on asthma exacerbations, a 31-day difference in annualised asthma-control days, or a 5% difference in percentage predicted FEV1. We did whole-genome admixture mapping of 15 159 ancestral segments within 312 independent regions, stratified by the two age groups. The two co-primary outcome comparisons were the step up from low-dose ICS to the quintuple dose of ICS (5 × ICS: 250 μg twice daily in children and 500 μg twice daily in adolescents and adults) versus double dose (2-2·5 × ICS: 100 μg twice daily in children, 250 μg twice daily in adolescents and adults), and 5 × ICS versus 100 μg fluticasone plus a LABA (salmeterol 50 μg twice daily). We used a genome-wide significance threshold of p<1·6 × 10-4, and tested for replication using independent cohorts of individuals of African descent with asthma. We included 249 unrelated children and 267 unrelated adolescents and adults in the BARD pharmacogenetic analysis. In children, we identified a significant admixture mapping peak for superior responsiveness to 5 × ICS versus 100 μg fluticasone plus salmeterol on chromosome 12 (odds ratio [ORlocal African] 3·95, 95% CI 2·02-7·72, p=6·1 × 10-5) fine mapped to a locus adjacent to RNFT2 and NOS1 (rs73399224, ORallele dose 0·17, 95% CI 0·07-0·42, p=8·4 × 10-5). In adolescents and adults, we identified a peak for superior responsiveness to 5 × ICS versus 2·5 × ICS on chromosome 22 (ORlocal African 3·35, 1·98-5·67, p=6·8 × 10-6) containing a locus adjacent to TPST2 (rs5752429, ORallele dose 0·21, 0·09-0·52, p=5·7 × 10-4). We replicated rs5752429 and nominally replicated rs73399224 in independent African American cohorts. BARD is the first genome-wide pharmacogenetic study of LABA and ICS response in clinical trials of individuals of African descent to detect and replicate genome-wide significant loci. Admixture mapping of the composite BARD trial outcome enabled the identification of novel pharmacogenetic variation accounting for differential therapeutic responses in people of African descent with asthma. National Institutes of Health, National Heart, Lung, and Blood Institute.

Evaluation of the Clinical Effectiveness of the Salmeterol/Fluticasone Fixed-Dose Combination Delivered via the Elpenhaler® Device in Greek Patients with Chronic Obstructive Pulmonary Disease and Comorbidities: The AEOLOS Study.

Background: Chronic Obstructive Pulmonary Disease (COPD) is an inflammatory lung disease characterized by airflow limitation that is not completely reversible. The fixed-dose combination of salmeterol and fluticasone propionate (SFC) has been approved as a treatment for COPD patients with a history of recurrent exacerbations and significant symptoms despite regular bronchodilator therapy. In the present study, we evaluated the change in FEV1, mMRC dyspnea score and satisfaction in COPD patients with at least one comorbidity versus those without comorbidities treated with a fixed-dose SFC via the Elpenhaler® device for 12 months. Methods: A 12-month multicenter prospective, observational study (NCT02978703) was designed. Data were collected during the enrollment visit (V0) and six (V1) and twelve months (V2) after the initiation of treatment with Elpenhaler® SFC. The evaluation of the efficacy of the fixed-dose SFC was performed by assessing the change in lung function and dyspnea as expressed by FEV1 and the mMRC dyspnea scale score in COPD patients with and without comorbidities. Results: In total 1016 patients were enrolled, following usual daily clinical practice. A statistically significant improvement was observed in FEV1 in the total study population between visits V0, V1 and V2, with a change from the baseline at V1 0.15 ± 0.22 L and at V2 0.21 ± 0.25 L (p < 0.0001 for both comparisons). This improvement was exhibited regardless of the COPD severity at the baseline, being more noticeable in GOLD 2020 groups B and C. Similarly, a significant improvement was observed in mMRC dyspnea scale values between successive visits (p < 0.0001). In patients without comorbidities, there was a significant improvement in FEV1 of 0.19 ± 0.24 L at V1 and 0.28 ± 0.27 L at V2 (p < 0.0001 for both comparisons), as well as in the mMRC dyspnea score (p < 0.0001). In patients with at least one comorbidity, a corresponding but smaller improvement in FEV1 was observed (0.11 ± 0.34 L at V1 and 0.20 ± 0.42 L at V2; p < 0.0001 for both comparisons and in the mMRC score (p < 0.0001). In the multiple linear regression analysis BMI, GOLD 2020 groups, mMRC and the presence of comorbidities at the baseline were significant factors for the change of FEV1 between V0 and V2. Conclusions: COPD patients treated for twelve months with SFC via the Elpenhaler® device showed significant improvement in lung function and dyspnea at 6 and 12 months, irrespective of the presence of comorbidities.

In Vitro Performance of the Wixela Inhub Inhaler Using Severe Chronic Obstructive Pulmonary Disease Patient Inhalation Profiles.

Background: Wixela Inhub (trademarks of Viatris, Inc.) is a dry powder inhaler (DPI) that delivers a fixed-dose combination of fluticasone propionate and salmeterol and is approved as a generic equivalent to Advair Diskus (trademarks of GlaxoSmithKline plc) for the treatment of asthma and chronic obstructive pulmonary disease (COPD). The dosing performance of DPIs is dependent on the patient's inspiratory capability, which may be impacted in disease populations such as those with severe COPD. The objective of this study was to evaluate the in vitro dose delivery of fluticasone propionate and salmeterol from the Inhub inhaler with in vivo inhalation profiles of severe COPD patients, using two types of breathing simulator with different modes of operation. Materials and Methods: Two breathing simulators (Si-Plan and Copley BRS3100) were used with United States Pharmacopoeia (USP) <601> apparatus 5 (Next Generation Impactor and accessories) to measure the total emitted dose and fine particle mass of fluticasone propionate and salmeterol for Wixela Inhub (250/50 mcg) using 13 severe COPD patient inhalation profiles. Results: Wixela Inhub demonstrated low flow dependency across the range of COPD patient profiles tested (peak inspiratory flow rate 60.8-84.9 L minute-1), when assessed by total emitted dose and fine particle mass. The results were similar to literature results reported for fluticasone propionate from the Diskus inhaler, tested using a proprietary breathing simulator and Andersen Cascade Impactor. Comparison between the breathing simulators showed no significant difference in fluticasone propionate results, but a small difference was observed between the breathing simulators for salmeterol total emitted dose and fine particle mass. Conclusions: This study demonstrates that severe COPD patients are likely to achieve a consistent inhaled dose from Wixela Inhub, with low flow dependency observed within this patient population. In addition, both breathing simulators, which differ significantly in design, produced similar results for fluticasone propionate, but yielded slightly (but statistically significant) different results for salmeterol.

Comparison of Risk of Pneumonia Caused by Fluticasone Propionate versus Budesonide in Chronic Obstructive Pulmonary Disease: A Nationwide Retrospective Cohort Study

IntroductionInhaled corticosteroids (ICSs) play an important role in lowering the risk of acute exacerbation of chronic obstructive pulmonary disease (COPD). However, ICSs are known to increase the risk of pneumonia. Moreover, previous studies have shown that the incidence rate of pneumonia varies depending on the type of ICS. In this study, the risk of pneumonia according to the type of ICS was investigated in a population-based cohort.MethodsA retrospective cohort study was conducted using claims data of the entire population from the Korean National Health Insurance Service. Patients who were newly diagnosed with COPD and prescribed fluticasone propionate or budesonide were enrolled as study subjects. Cumulative doses of ICSs were classified into categorical variables to analyze the risk of pneumonia within identical ICS doses.ResultsA total of 47,473 subjects were identified and allocated as 14,518 fluticasone propionate and 14,518 budesonide users through 1:1 propensity score matching. Fluticasone propionate users were more likely to develop pneumonia than budesonide users (14.22% vs 10.66%, p<0.0001). The incidence rate per 100,000 person-years was 2,914.77 for fluticasone propionate users and 2,102.90 for budesonide users. The hazard ratio (HR) of pneumonia in fluticasone propionate compared to budesonide was 1.34 (95% CI 1.26–1.43, p<0.0001). The risk of pneumonia for fluticasone propionate compared to budesonide increased with higher ICS cumulative doses: 1.06 (0.93–1.21), 1.41 (1.19–1.66), 1.41 (1.23–1.63), and 1.49 (1.33–1.66) from the lowest to highest quartiles, respectively.ConclusionICS types and doses need to be carefully considered during treatment with ICSs in patients with COPD.

M052 MOTOR TICS, AN UNKNOWN SIDE EFFECT OF INTRANASAL FLUTICASONE

Intranasal corticosteroids are a first-line treatment for chronic allergic rhinitis. Adverse reactions to this drug are rare and include epistaxis, delayed linear growth, and immunosuppression and the drug is usually well tolerated. In this report, we describe a patient who developed motor tics and mood disturbances after initiating intranasal fluticasone propionate. This side effect is rarely described in the literature, however, is important to consider when initiating the medication in the pediatric population.

Review of efficacy of ciclesonide for the treatment of asthma in children.

Background: Ciclesonide (CIC) is an inhaled corticosteroid (ICS) approved for the maintenance treatment of asthma in patients ages ≥ 12 years. The prodrug aspect of CIC is associated with a safety profile that may make it ideal for children. Objective: The objective was to summarize efficacy results from the eight phase III, randomized, double-blind, controlled trials in children with asthma conducted during CIC clinical development. Methods: Four trials compared CIC 40, 80, or 160 µg/day with placebo. Two trials compared CIC 160 µg/day with fluticasone propionate 200 µg/day, one trial compared CIC 80 or 160 µg/day with fluticasone 200 µg/day, and one trial compared CIC 160 µg/day with budesonide 400 µg/day. Results: The primary end point was met by at least two CIC doses versus placebo in the trials in which the primary end point was the change from baseline in lung function outcome (forced expiratory volume in 1 second [FEV1] % predicted or morning peak expiratory flow [PEF]). A trial that compared CIC with placebo did not meet the primary end point of superiority in time-to-first severe wheeze exacerbation or lack of improvement. The primary end point of noninferiority to the active control (fluticasone or budesonide) in the change from baseline in a lung function outcome (FEV1, morning PEF, evening PEF) was met with the CIC 160-µg dose in all active control trials. CIC generally demonstrated statistically significant improvements in forced expiratory flow at 25%-75% of forced vital capacity, asthma symptoms, rescue medication use, and asthma control when compared with placebo and noninferiority for these outcomes compared with fluticasone or budesonide. Conclusion: In children with asthma, once-daily CIC significantly improved large and small airway function, asthma symptoms, and asthma control, and reduced rescue medication use compared with placebo. CIC was comparable with other ICS used to treat asthma in children, which demonstrated its worth for the pediatric population.