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BACKGROUND: Nebulized Hypertonic saline (HS) and positive expiratory pressure device (PEP) are often used in patients with bronchiectasis. We sought to describe the clinical characteristics in patients using HS and PEP, utilizing a large national database registry. METHODS: Data from the US Bronchiectasis and NTM Research Registry were used in this study. Patients with a diagnosis of bronchiectasis were included. Eligible patients were assigned to one of four mutually exclusive groups: HS only, PEP only, HS & PEP, or no airway clearance or mucoactive agent. Descriptive statistics were computed for the overall study population and stratified by the four groups. One-way ANOVA and chi-square tests were used to test the difference in the means in continuous variables and the association between categorical variables (respectively) across the four groups. RESULTS: A total of 2195 patients were included. Of those with bronchiectasis and a productive cough, a greater number of patients utilized HS only vs PEP only (17.5 % vs 9.1 %, p < 0.001). Similar association was found in those with Pseudomonas aeruginosa (22.3 % HS only vs 6.5 % PEP only, p < 0.001). There was a higher number of patients who used HS and PEP therapy in combination vs PEP therapy alone (25.0 % vs 9.1 %, p = 0.002), in those with a productive cough. CONCLUSIONS: In patients with bronchiectasis and a productive cough or Pseudomonas aeruginosa, HS is used more often than PEP alone. There is a need for further analysis to compare these two modalities and explore the factors influencing their utilization.
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Bronquiectasia , Infecções por Mycobacterium não Tuberculosas , Sistema de Registros , Fumar Tabaco , Humanos , Bronquiectasia/epidemiologia , Bronquiectasia/etiologia , Estados Unidos/epidemiologia , Masculino , Feminino , Pessoa de Meia-Idade , Infecções por Mycobacterium não Tuberculosas/epidemiologia , Idoso , Fumar Tabaco/efeitos adversos , Fumar Tabaco/epidemiologia , Adulto , Micobactérias não TuberculosasRESUMO
BACKGROUND: This study aimed to evaluate the association between the number of non-cystic fibrosis bronchiectasis (bronchiectasis) exacerbations during baseline and follow-up (objective 1) and to identify longitudinal changes in FEV1 associated with exacerbation frequency (objective 2). METHODS: This was a retrospective cohort study of adult patients enrolled in the US Bronchiectasis and Nontuberculous Mycobacteria Research Registry September 2008 to March 2020. Objective 1 outcome was association between exacerbations during baseline (24 months) and 0-to-24 month and 24-to-48 month follow-up windows. Objective 2 outcomes were change in FEV1 and FEV1 % predicted over 24 months stratified by baseline exacerbation frequency. RESULTS: Objective 1 cohort (N = 520) baseline frequency of any exacerbations was 59.2%. Overall, 71.4% and 75.0% of patients with ≥1 baseline exacerbations had ≥1 exacerbations during the 0-to-24 and 24-to-48 month follow-ups. Having ≥1 exacerbation during baseline was significantly associated with ≥1 exacerbation during the 0-to-24 month (P = 0.0085) and 24-to-48 month follow-ups (P=<0.0001). Objective 2 cohort (N = 431) baseline FEV1 was significantly lower in patients who had more exacerbations; however, decline in FEV1 from baseline was not significantly different between patients with 0, 1, and ≥2 exacerbations. In patients with more baseline exacerbations, FEV1 % predicted was significantly lower at baseline (P < 0.0001) and at 12 (P = 0.0002) and 24 month follow-ups (P < 0.0001). CONCLUSIONS: Patients with frequent bronchiectasis exacerbations may be more likely than those with less frequent exacerbations to experience disease progression based on future exacerbation frequency and lower FEV1 at baseline, although FEV1 decline may not differ by baseline exacerbation frequency.
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Bronquiectasia , Progressão da Doença , Sistema de Registros , Bronquiectasia/fisiopatologia , Humanos , Masculino , Feminino , Volume Expiratório Forçado/fisiologia , Estudos Retrospectivos , Pessoa de Meia-Idade , Idoso , Estudos Longitudinais , Infecções por Mycobacterium não Tuberculosas/fisiopatologia , Infecções por Mycobacterium não Tuberculosas/complicações , Estados Unidos/epidemiologia , Adulto , SeguimentosRESUMO
Rationale: Nontuberculous mycobacteria (NTM) are prevalent among patients with bronchiectasis. However, the long-term natural history of patients with NTM and bronchiectasis is not well described. Objectives: To assess the impact of NTM on 5-year clinical outcomes and mortality in patients with bronchiectasis. Methods: Patients in the Bronchiectasis and NTM Research Registry with ⩾5 years of follow-up were eligible. Data were collected for all-cause mortality, lung function, exacerbations, hospitalizations, and disease severity. Outcomes were compared between patients with and without NTM at baseline. Mortality was assessed using Cox proportional hazards models and the log-rank test. Measurements and Main Results: In total, 2,634 patients were included: 1,549 (58.8%) with and 1,085 (41.2%) without NTM at baseline. All-cause mortality (95% confidence interval) at Year 5 was 12.1% (10.5%, 13.7%) overall, 12.6% (10.5%, 14.8%) in patients with NTM, and 11.5% (9.0%, 13.9%) in patients without NTM. Independent predictors of 5-year mortality were baseline FEV1 percent predicted, age, hospitalization within 2 years before baseline, body mass index, and sex (all P < 0.01). The probabilities of acquiring NTM or Pseudomonas aeruginosa were approximately 4% and 3% per year, respectively. Spirometry, exacerbations, and hospitalizations were similar, regardless of NTM status, except that annual exacerbations were lower in patients with NTM (P < 0.05). Conclusions: Outcomes, including exacerbations, hospitalizations, rate of loss of lung function, and mortality rate, were similar across 5 years in patients with bronchiectasis with or without NTM.
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Bronquiectasia , Infecções por Mycobacterium não Tuberculosas , Sistema de Registros , Humanos , Bronquiectasia/mortalidade , Bronquiectasia/fisiopatologia , Bronquiectasia/epidemiologia , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Infecções por Mycobacterium não Tuberculosas/mortalidade , Infecções por Mycobacterium não Tuberculosas/epidemiologia , Estados Unidos/epidemiologia , Hospitalização/estatística & dados numéricos , Modelos de Riscos Proporcionais , Micobactérias não Tuberculosas , Progressão da DoençaRESUMO
BACKGROUND: High frequency chest wall oscillation (HFCWO) is a form of airway clearance therapy that has been available since the mid-1990s and is routinely used by patients suffering from retained pulmonary secretions. Patients with cystic fibrosis (CF), neuromuscular disease (NMD), and other disorders, including bronchiectasis (BE) and COPD (without BE), are commonly prescribed this therapy. Limited evidence exists describing HFCWO use in the BE population, its impact on long-term management of disease, and the specific patient populations most likely to benefit from this therapy. This study sought to characterize the clinical characteristics of patients with BE who have documented use of HFCWO at baseline and 1-year follow-up. METHODS: An analysis from a large national database registry of patients with BE was performed. Demographic and clinical characteristics of all patients receiving HFCWO therapy at baseline are reported. Patients were stratified into two groups based on continued or discontinued use of HFCWO therapy at 1-year follow-up. RESULTS: Over half (54.8 %) of patients who reported using HFCWO therapy had a Modified Bronchiectasis Severity Index (m-BSI) classified as severe, and the majority (81.4 %) experienced an exacerbation in the prior two years. Of patients with 1-year follow-up data, 73 % reported continued use of HFCWO. Compared to patients who discontinued therapy, these patients were more severe at baseline and at follow-up suggesting that patients with more severe disease are more likely to continue HFCWO therapy. CONCLUSIONS: Patients who have more severe disease and continue to experience exacerbations and hospitalizations are more likely to continue HFCWO therapy. CLINICAL TRIAL REGISTRATION: NA.
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Bronquiectasia , Oscilação da Parede Torácica , Fibrose Cística , Humanos , Bronquiectasia/terapia , Fibrose Cística/complicações , Fibrose Cística/terapia , Bases de Dados Factuais , Sistema de RegistrosRESUMO
Two recent major guidelines on diagnosis and treatment of ventilator-associated pneumonia (VAP) recommend consideration of local antibiotic resistance patterns and individual patient risks for resistant pathogens when formulating an initial empiric antibiotic regimen. One recommends against invasive diagnostic techniques with quantitative cultures to determine the cause of VAP; the other recommends either invasive or noninvasive techniques. Both guidelines recommend short-course therapy be used for most patients with VAP. Although neither guideline recommends use of procalcitonin as an adjunct to clinical judgment when diagnosing VAP, they differ with respect to use of serial procalcitonin to shorten the length of antibiotic treatment.
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Pneumonia Associada à Ventilação Mecânica , Humanos , Pneumonia Associada à Ventilação Mecânica/diagnóstico , Pneumonia Associada à Ventilação Mecânica/tratamento farmacológico , Pró-Calcitonina/uso terapêutico , AntibacterianosRESUMO
INTRODUCTION: Many patients with interstitial lung diseases (ILDs), especially fibrotic ILDs, experience chronic cough. It negatively impacts both physical and psychological well-being. Effective treatment options are limited. AREAS COVERED: The pathophysiology of chronic cough in IPF is complex and involves multiple mechanisms, including mechanical distortion of airways, parenchyma, and nerve fibers. The pathophysiology of cough in other fibrosing ILDs is poorly understood and involves various pathways. The purpose of this review is to highlight mechanisms of chronic cough and to present therapeutic evidence for its management in the most commonly occurring diffuse fibrosing lung diseases including idiopathic pulmonary fibrosis (IPF), connective tissue disease-related interstitial lung disease (CTD-ILD), sarcoidosis-related ILD (Sc-ILD), chronic hypersensitivity pneumonitis-related ILD (CHP-ILD), and post-COVID-19-related interstitial lung disease (PC-ILD). EXPERT OPINION: This review guides the management of chronic cough in fibrosing ILDs. In this era of precision medicine, chronic cough management should be individualized in each interstitial lung disease.
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Alveolite Alérgica Extrínseca , Doenças do Tecido Conjuntivo , Fibrose Pulmonar Idiopática , Doenças Pulmonares Intersticiais , Humanos , Doenças Pulmonares Intersticiais/complicações , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/terapia , Fibrose Pulmonar Idiopática/tratamento farmacológico , Pulmão , Fibrose , Tosse/diagnóstico , Tosse/etiologia , Tosse/terapia , Tosse Crônica , Progressão da DoençaAssuntos
Bronquiectasia , Doença Pulmonar Obstrutiva Crônica , Humanos , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Bronquiectasia/complicações , Bronquiectasia/diagnóstico por imagem , Tomografia Computadorizada por Raios X , SíndromeRESUMO
Rationale: CFTR (cystic fibrosis transmembrane conductance regulator) modulator drugs restore function to mutant channels in patients with cystic fibrosis (CF) and lead to improvements in body mass index and lung function. Although it is anticipated that early childhood treatment with CFTR modulators will significantly delay or even prevent the onset of advanced lung disease, lung neutrophils and inflammatory cytokines remain high in patients with CF with established lung disease despite modulator therapy, underscoring the need to identify and ultimately target the sources of this inflammation in CF lungs. Objectives: To determine whether CF lungs, like chronic obstructive pulmonary disease (COPD) lungs, harbor potentially pathogenic stem cell "variants" distinct from the normal p63/Krt5 lung stem cells devoted to alveolar fates, to identify specific variants that might contribute to the inflammatory state of CF lungs, and to assess the impact of CFTR genetic complementation or CFTR modulators on the inflammatory variants identified herein. Methods: Stem cell cloning technology developed to resolve pathogenic stem cell heterogeneity in COPD and idiopathic pulmonary fibrosis lungs was applied to end-stage lungs of patients with CF (three homozygous CFTR:F508D, one CFTR F508D/L1254X; FEV1, 14-30%) undergoing therapeutic lung transplantation. Single-cell-derived clones corresponding to the six stem cell clusters resolved by single-cell RNA sequencing of these libraries were assessed by RNA sequencing and xenografting to monitor inflammation, fibrosis, and mucin secretion. The impact of CFTR activity on these variants after CFTR gene complementation or exposure to CFTR modulators was assessed by molecular and functional studies. Measurements and Main Results: End-stage CF lungs display a stem cell heterogeneity marked by five predominant variants in addition to the normal lung stem cell, of which three are proinflammatory both at the level of gene expression and their ability to drive neutrophilic inflammation in xenografts in immunodeficient mice. The proinflammatory functions of these three variants were unallayed by genetic or pharmacological restoration of CFTR activity. Conclusions: The emergence of three proinflammatory stem cell variants in CF lungs may contribute to the persistence of lung inflammation in patients with CF with advanced disease undergoing CFTR modulator therapy.
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Fibrose Cística , Doença Pulmonar Obstrutiva Crônica , Humanos , Pré-Escolar , Animais , Camundongos , Fibrose Cística/tratamento farmacológico , Fibrose Cística/genética , Fibrose Cística/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Pulmão/patologia , Doença Pulmonar Obstrutiva Crônica/patologia , Inflamação/metabolismoRESUMO
Brensocatib is a novel anti-inflammatory therapy in development for bronchiectasis treatment. Phase 2 WILLOW trial data demonstrate a low number needed to treat and negative number needed to harm, suggesting a favourable benefit-risk profile. https://bit.ly/3SbisW3.
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Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible, and rapidly fatal interstitial lung disease marked by the replacement of lung alveoli with dense fibrotic matrices. Although the mechanisms initiating IPF remain unclear, rare and common alleles of genes expressed in lung epithelia, combined with aging, contribute to the risk for this condition. Consistently, single-cell RNA sequencing (scRNA-seq) studies have identified lung basal cell heterogeneity in IPF that might be pathogenic. We used single-cell cloning technologies to generate "libraries" of basal stem cells from the distal lungs of 16 patients with IPF and 10 controls. We identified a major stem cell variant that was distinguished from normal stem cells by its ability to transform normal lung fibroblasts into pathogenic myofibroblasts in vitro and to activate and recruit myofibroblasts in clonal xenografts. This profibrotic stem cell variant, which was shown to preexist in low quantities in normal and even fetal lungs, expressed a broad network of genes implicated in organ fibrosis and showed overlap in gene expression with abnormal epithelial signatures identified in previously published scRNA-seq studies of IPF. Drug screens highlighted specific vulnerabilities of this profibrotic variant to inhibitors of epidermal growth factor and mammalian target of rapamycin signaling as prospective therapeutic targets. This profibrotic stem cell variant in IPF was distinct from recently identified profibrotic stem cell variants in chronic obstructive pulmonary disease and may extend the notion that inappropriate accrual of minor and preexisting stem cell variants contributes to chronic lung conditions.
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Fibrose Pulmonar Idiopática , Humanos , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/patologia , Pulmão/patologia , Miofibroblastos/patologia , Fibroblastos/patologia , Células-Tronco/metabolismo , Clonagem MolecularRESUMO
Bronchiectasis is a condition defined by permanently dilated airways and characterized by chronic cough and sputum and in many patients, recurrent exacerbations. Bronchiectasis is a heterogeneous condition, with numerous underlying risk factors and initiating conditions. These factors share in common the ability to impair the mechanisms by which the airways are protected from inflammatory or infectious insults. These underlying factors result in chronic bacterial infection of the airways, inciting a host inflammatory response in which the airways are the collateral damage. The damaged airways are unable to clear the infection, leading to ongoing inflammation and progressive damage.
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Bronquiectasia , Doença Enxerto-Hospedeiro , Bronquiectasia/etiologia , Tosse , Humanos , Inflamação , Infecção PersistenteRESUMO
INTRODUCTION: Little information is available about Stenotrophomonas maltophilia in patients with bronchiectasis. We analyzed data from the US Bronchiectasis and NTM Research Registry to determine its prevalence and association with patient characteristics and severity of disease. METHODS: Baseline and follow-up data were entered into a central web-based database. Patients were grouped into four cohorts based on their baseline cultures: 1) S. maltophilia, no Pseudomonas aeruginsosa, 2) P. aeruginosa, no S. maltophilia, 3) No pathogens, 4) Pathogens other than P. aeruginosa and S. maltophilia. The association between S. maltophilia, demographic characteristics, pulmonary function, exacerbations and hospitalizations was assessed at baseline and one year follow-up. RESULTS: Among 2659 patients, 134 (5.0%) had grown S. maltophilia at baseline. The prior exacerbation rate at baseline was similar in patients with S. maltophilia and P. aeruginosa, but significantly higher than the other two groups. Hospitalizations were more frequent in patients with S. maltophilia or P. aeruginosa. Pre-bronchodilator FEV1 among S. maltophilia patients was between that of Pseudomonas patients and patients without either organism, but was not significantly different from any of the other groups. For all risk-adjusted one-year outcomes, patients with S. maltophilia had a non-significant trend towards worse outcomes compared to patients without P. aeruginosa, but were more similar to patients with P aeruginosa. DISCUSSION: Bronchiectasis patients with S. maltophilia may have worse outcomes than patients without this organism or without P. aeruginosa; further study is needed to determine if the non-significant trends we note are clinically significant.
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Bronquiectasia , Stenotrophomonas maltophilia , Bronquiectasia/complicações , Humanos , Pulmão , Pseudomonas aeruginosa , Sistema de RegistrosRESUMO
BACKGROUND: Perioperative care for total knee arthroplasty (TKA) has improved over time. We present an analysis of inpatient safety after TKA. METHODS: 14,057 primary TKAs captured by the Medicare Patient Safety Monitoring System between 2010 and 2017 were retrospectively reviewed. We calculated changes in demographics, comorbidities, and adverse events (AEs) over time. Risk factors for AEs were also assessed. RESULTS: Between 2010 and 2017, there was an increased prevalence of obesity (35.1% to 57.6%), tobacco smoking (12.5% to 17.8%), and renal disease (5.2% to 8.9%). There were reductions in coronary artery disease (17.3% to 13.4%) and chronic warfarin use (6.7% to 3.1%). Inpatient AEs decreased from 4.9% to 2.5%, (P < .01), primarily driven by reductions in anticoagulant-associated AEs, including major bleeding and hematomas (from 2.8% to 1.0%, P < .001), catheter-associated urinary tract infections (1.1% to 0.2%, P < .001), pressure ulcers (0.8% to 0.2%, P < .001), and venous thromboembolism (0.3% to 0.1%, P = .04). The adjusted annual decline in the risk of developing any in-hospital AE was 14% (95% confidence interval [CI] 10%-17%). Factors associated with developing an AE were advanced age (odds ratio [OR] = 1.01, 95% CI 1.00-1.01), male sex (OR = 1.21, 95% CI 1.02-1.44), coronary artery disease (OR = 1.35, 95% CI 1.07-1.70), heart failure (OR = 1.70, 95% CI 1.20-2.41), and renal disease (OR = 1.71, 95% CI 1.23-2.37). CONCLUSIONS: Despite increasing prevalence of obesity, tobacco smoking, and renal disease, inpatient AEs after primary TKA have decreased over the past several years. This improvement is despite the increasing complexity of the inpatient TKA population over time.
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Bronquiectasia/tratamento farmacológico , Bronquiectasia/microbiologia , Macrolídeos/administração & dosagem , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Infecções por Mycobacterium não Tuberculosas/microbiologia , Bronquiectasia/diagnóstico por imagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infecções por Mycobacterium não Tuberculosas/diagnóstico por imagem , Micobactérias não Tuberculosas/isolamento & purificação , Tomografia Computadorizada por Raios X , Estados UnidosRESUMO
RATIONALE: Non-cystic fibrosis bronchiectasis (NCFB) is characterized by dilated bronchi, poor mucus clearance and susceptibility to bacterial infection. Pseudomonas aeruginosa (PA) is one of the most frequently isolated pathogens in patients with NCFB. The purpose of this study was to evaluate the association between presence of PA and disease severity in patients within the US Bronchiectasis and Nontuberculous mycobacteria (NTM) Research Registry (BRR). METHODS: Baseline US BRR data from adult patients with NCFB collected between 2008 and 2018 was used for this study. The presence of PA was defined as one or more positive PA cultures within two years prior to enrollment. Modified Bronchiectasis Severity Index (m-BSI) and modified FACED (m-FACED) were computed to evaluate severity of bronchiectasis. Unadjusted and multivariable multinomial regression models were used to assess the association between presence of PA and severity of bronchiectasis. RESULTS: Average age of the study participants (n = 1831) was 63.7 years (SD = 14.1), 91.5% white, and 78.8% female. Presence of PA was identified in 25.4% of the patients. Patients with presence of PA had significantly lower mean pre-bronchodilator FEV1% predicted compared to those without PA (62.8% vs. 73.7%, p < .0001). In multivariate analyses, patients with presence of PA had significantly greater odds for having high (ORadj = 6.15 (95%CI:3.98-9.50) and intermediate (ORadj = 2.06 (95%CI:1.37-3.09) severity vs. low severity on m-BSI. CONCLUSION: The presence of PA is common in patients with NCFB within the Bronchiectasis and NTM Research Registry. Severity of bronchiectasis is significantly greater in patients with PA which emphasizes high burden of the disease.
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BACKGROUND: Increasing numbers of patients are being diagnosed with bronchiectasis, yet much remains to be elucidated about this heterogeneous patient population. We sought to determine the relationship between nutrition and health outcomes in non-cystic fibrosis (non-CF) bronchiectasis, using data from the U.S. Bronchiectasis Nontuberculous Mycobacterial Research Registry (U.S. BRR). METHODS: This was a retrospective, observational, longitudinal study using 5-year follow-up data from the BRR. Bronchiectasis was confirmed on computed tomography (CT). We stratified patients into nutrition categories using body mass index (BMI), and correlated BMI to markers of disease severity. RESULTS: Overall, n = 496 patients (mean age 64.6- ± 13 years; 83.3% female) were included. At baseline 12.3% (n = 61) were underweight (BMI < 18.5kg/m2), 63.9% (n = 317) had normal weight (BMI ≥ 18.5kg/m2 and <25.0kg/m2), 17.3% (n = 86) were overweight (BMI ≥ 25.0kg/m2 and < 30.0kg/m2), and 6.5% (n= 32) were obese (BMI ≥ 30kg/m2). Men were overrepresented in the overweight and obese groups (25.6% and 43.8% respectively, p < 0.0001). Underweight patients had lower lung function (forced expiratory volume in 1 second [FEV1] % predicted) than the other weight groups (64.5 ± 22, versus 73.5 ± 21, 68.5 ± 20, and 76.5 ± 21 in normal, overweight, and obese groups respectively, p = 0.02). No significant differences were noted between BMI groups for other markers of disease severity at baseline, including exacerbation frequency or hospitalization rates. No significant differences were noted in BMI distribution between patients with and without Pseudomonas, non-tuberculous mycobacteria, or by cause of bronchiectasis. The majority of patients demonstrated stable BMI over 5 years. CONCLUSIONS: Although underweight patients with bronchiectasis have lower lung function, lower BMI does not appear to relate to other markers of disease severity in this patient population.
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BACKGROUND: Patients with bronchiectasis have frequent exacerbations that are thought to be related to neutrophilic inflammation. The activity and quantity of neutrophil serine proteases, including neutrophil elastase, are increased in the sputum of patients with bronchiectasis at baseline and increase further during exacerbations. Brensocatib (INS1007) is an oral reversible inhibitor of dipeptidyl peptidase 1 (DPP-1), an enzyme responsible for the activation of neutrophil serine proteases. METHODS: In a phase 2, randomized, double-blind, placebo-controlled trial, we randomly assigned, in a 1:1:1 ratio, patients with bronchiectasis who had had at least two exacerbations in the previous year to receive placebo, 10 mg of brensocatib, or 25 mg of brensocatib once daily for 24 weeks. The time to the first exacerbation (primary end point), the rate of exacerbations (secondary end point), sputum neutrophil elastase activity, and safety were assessed. RESULTS: Of 256 patients, 87 were assigned to receive placebo, 82 to receive 10 mg of brensocatib, and 87 to receive 25 mg of brensocatib. The 25th percentile of the time to the first exacerbation was 67 days in the placebo group, 134 days in the 10-mg brensocatib group, and 96 days in the 25-mg brensocatib group. Brensocatib treatment prolonged the time to the first exacerbation as compared with placebo (P = 0.03 for 10-mg brensocatib vs. placebo; P = 0.04 for 25-mg brensocatib vs. placebo). The adjusted hazard ratio for exacerbation in the comparison of brensocatib with placebo was 0.58 (95% confidence interval [CI], 0.35 to 0.95) in the 10-mg group (P = 0.03) and 0.62 (95% CI, 0.38 to 0.99) in the 25-mg group (P = 0.046). The incidence-rate ratio was 0.64 (95% CI, 0.42 to 0.98) in the 10-mg group, as compared with placebo (P = 0.04), and 0.75 (95% CI, 0.50 to 1.13) in the 25-mg group, as compared with placebo (P = 0.17). With both brensocatib doses, sputum neutrophil elastase activity was reduced from baseline over the 24-week treatment period. The incidence of dental and skin adverse events of special interest was higher with the 10-mg and 25-mg brensocatib doses, respectively, than with placebo. CONCLUSIONS: In this 24-week trial, reduction of neutrophil serine protease activity with brensocatib in patients with bronchiectasis was associated with improvements in bronchiectasis clinical outcomes. (Funded by Insmed; WILLOW ClinicalTrials.gov number, NCT03218917.).
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Benzoxazóis/administração & dosagem , Bronquiectasia/tratamento farmacológico , Dipeptidil Peptidases e Tripeptidil Peptidases/antagonistas & inibidores , Oxazepinas/administração & dosagem , Serina Proteases/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzoxazóis/efeitos adversos , Bronquiectasia/metabolismo , Progressão da Doença , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Volume Expiratório Forçado , Humanos , Elastase de Leucócito/metabolismo , Masculino , Pessoa de Meia-Idade , Oxazepinas/efeitos adversos , Escarro/metabolismoRESUMO
BACKGROUND: In patients with bronchiectasis, airway clearance techniques (ACTs) are important management strategies. RESEARCH QUESTION: What are the differences in patients with bronchiectasis and a productive cough who used ACTs and those who did not? What was the assessment of bronchiectasis exacerbation frequency and change in pulmonary function at 1-year follow up? STUDY DESIGN AND METHODS: Adult patients with bronchiectasis and a productive cough in the United States Bronchiectasis and NTM Research Registry were included in the analyses. ACTs included the use of instrumental devices and manual techniques. Stratified analyses of demographic and clinical characteristics were performed by use of ACTs at baseline and follow up. The association between ACT use and clinical outcomes was assessed with the use of unadjusted and adjusted multinomial logistic regression models. RESULTS: Of the overall study population (n = 905), 59% used ACTs at baseline. A greater proportion of patients who used ACTs at baseline and follow up continuously had Pseudomonas aeruginosa (47% vs 36%; P = .021) and experienced an exacerbation (81% vs 59%; P < .0001) or hospitalization for pulmonary illness (32% vs 22%; P = .001) in the prior two years, compared with those patients who did not use ACTs. Fifty-eight percent of patients who used ACTs at baseline did not use ACTs at 1-year follow up. There was no significant change in pulmonary function for those who used ACTs at follow up, compared with baseline. Patients who used ACTs at baseline and follow up had greater odds for experiencing exacerbations at follow up compared with those patients who did not use ACTs. INTERPRETATION: In patients with bronchiectasis and a productive cough, ACTs are used more often if the patients have experienced a prior exacerbation, hospitalization for pulmonary illness, or had P aeruginosa. There is a significant reduction in the use of ACTs at 1-year follow up. The odds of the development of a bronchiectasis exacerbation are higher in those patients who use ACTs continuously, which suggests more frequent use in an ill bronchiectasis population.