Search

Background: Many patients with severe asthma require chronic corticosteroid treatment to maintain asthma control.Research Question: Are the reduction in oral corticosteroid (OCS) use and the clinical efficacy observed with dupilumab treatment maintained long-term in patients with severe OCS-dependent asthma?Study Design and Methods: The LIBERTY ASTHMA TRAVERSE study (ClinicalTrials.gov identifier: NCT02134028) was a multinational, multicenter, single-arm, open-label extension study in patients ≥ 12 years of age with asthma who participated in previous dupilumab studies. Treatment consisted of dupilumab 300 mg every 2 weeks for up to 96 weeks. In this analysis, we present the data from patients who initially enrolled in the LIBERTY ASTHMA VENTURE study (ClinicalTrials.gov identifier: NCT02528214), a 24-week placebo-controlled study of dupilumab in patients with OCS-dependent severe asthma, and continued in the TRAVERSE study. The subgroups analyzed were: those who received dupilumab in both (dupilumab/dupilumab group) and those who received placebo in the VENTURE study and dupilumab in the TRAVERSE study (placebo/dupilumab group). Outcomes included OCS use, exacerbation rates, and measures of lung function and asthma control.Results: Ninety patients treated with dupilumab/dupilumab and 97 patients treated with placebo/dupilumab in the VENTURE study were enrolled and treated in the TRAVERSE study, with a mean OCS dosage of 11.0 mg/d (dupilumab) and 11.6 mg/d (placebo) at VENTURE study baseline. At TRAVERSE week 0, the mean daily OCS dosage was 3.1 mg/d and 6.4 mg/d (percentage decrease from the VENTURE study baseline, 68.8% and 41.3%) for the dupilumab/dupilumab group and placebo/dupilumab group, respectively, and decreased to 2.2 mg/d and 4.9 mg/d (78.3% and 53.4%) at week 48 and to 1.2 mg/d and 3.0 mg/d (89.3% and 74.4%) at week 96, respectively. Exacerbation rates were low during the TRAVERSE study. Further improvements from the VENTURE to TRAVERSE studies also were seen in FEV1 and 5-item Asthma Control Questionnaire scores. Safety findings were consistent with the known dupilumab safety profile.Interpretation: In the open-label TRAVERSE study, dupilumab demonstrated the ability to sustain the OCS dosage reduction from the parent OCS-sparing study, while maintaining a low exacerbation rate and improved lung function.Trial Registry: ClinicalTrials.gov; Nos.: NCT02134028 (TRAVERSE) and NCT02528214 (VENTURE); URL: www.Clinicaltrials: gov. [ABSTRACT FROM AUTHOR]

Background: Adipokines have inflammatory and fibrotic properties that may be critical in interstitial lung disease (ILD). We examined associations of serum adipokine levels with CT imaging-based measures of subclinical ILD and lung function among community-dwelling adults.Methods: A subset of the original Multi-Ethnic Study of Atherosclerosis cohort (n = 1,968) had adiponectin, leptin, and resistin measured during follow-up visits (2002-2005). We used regression models to examine associations of adiponectin, leptin, and resistin levels with (1) high-attenuation areas (HAAs) from CT scans (2004-2005, n = 1,144), (2) interstitial lung abnormalities (ILAs) from CT scans (2010-2012, n = 872), and (3) FVC from spirometry (2004-2006, n = 1,446). We used -(1/HAA2), which we denoted with H, to model HAA as our outcome to meet model assumptions.Results: Higher adiponectin was associated with lower HAA on CT imaging among adults with a BMI ≥ 25 kg/m2 (P for BMI interaction = .07). Leptin was more strongly associated with ILA among never smokers compared with ever smokers (P for smoking interaction = .004). For every 1-SD increment of log-transformed leptin, the percent predicted FVC was 3.8% lower (95% CI, -5.0 to -2.5). Higher serum resistin levels were associated with greater HAA on CT in a fully adjusted model. For every 1-SD increment of log-transformed resistin there was an increase in H of 14.8 (95% CI, 3.4-26.3).Conclusions: Higher adiponectin levels were associated with lower HAA on CT imaging among adults with a higher BMI. Higher leptin and resistin levels were associated with lower FVC and greater HAA, respectively. [ABSTRACT FROM AUTHOR]

Background: Angiotensin peptides have been implicated in idiopathic pulmonary fibrosis (IPF) pathogenesis. Angiotensin modulators are used to treat arterial hypertension, a frequent comorbidity of IPF. This post hoc analysis evaluated associations of antihypertensive treatments with disease-related outcomes in IPF.Methods: All patients randomized to placebo (n = 624) in the CAPACITY and ASCEND studies were categorized by antihypertensive treatment at baseline. Outcomes of disease progression (first occurrence of ≥ 10% absolute decline in % predicted FVC, ≥ 50-m decline in 6-min walk distance, or death) and all-cause mortality were assessed over 52 weeks.Results: At baseline, 111 and 121 patients were receiving an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin II receptor blocker (ARB), respectively; 392 were receiving neither. In multivariable analyses adjusted for differences in baseline characteristics compared with the non-ACEi/ARB group, ACEi treatment (hazard ratio [HR], 0.6 [95% CI, 0.4-0.9]; P = .026), but not ARB (HR, 0.9 [95% CI, 0.6-1.2]; P = .413), was associated with slower disease progression. Furthermore, the increase in all-cause mortality associated with cardiovascular disease was not observed in the ACEi group (HR, 1.1 [95% CI, 0.5-2.9]; P = .782), which presented a similar percentage of IPF-related mortality as the non-ACEi/ARB group (3.6% vs 3.6%). In contrast, patients in the ARB group had greater risk of all-cause mortality (HR, 2.5 [95% CI, 1.2-5.2]). These observations were validated in a pooled analysis that included patients from the INSPIRE trial.Conclusions: Prospective clinical trials are needed to evaluate whether angiotensin modulators may be beneficial to clinical outcomes in IPF.Trial Registry: ClinicalTrials.gov; Nos.: NCT01366209, NCT00287716, NCT00287729, NCT00075998; URL: www.clinicaltrials.gov). [ABSTRACT FROM AUTHOR]

Background: Declines in percent predicted FVC (% predicted FVC), declines in 6-min walk distance (6MWD), and respiratory hospitalizations are events associated with disease progression and mortality in idiopathic pulmonary fibrosis. The incidence of multiple events in the same patient over 12 months of pirfenidone treatment is unknown.Methods: Patients who received pirfenidone 2,403 mg/d (n = 623) or placebo (n = 624) in the ASCEND (study 016; NCT01366209) and CAPACITY (studies 004 and 006; NCT00287716 and NCT00287729) phase III trials were included in this post hoc analysis. Disease progression events were defined as relative decline in % predicted FVC ≥ 10%, absolute decline in 6MWD ≥ 50 m, respiratory hospitalization, or death from any cause. The incidence of disease progression events over 12 months was assessed.Results: The most frequent disease progression events were declines in % predicted FVC (pirfenidone vs placebo; 202 vs 304 events) and declines in 6MWD (pirfenidone vs placebo; 265 vs 348 events). Fewer patients who received pirfenidone had more than one progression event compared with placebo (17.0% vs 30.1%; P < .0001). Death following one or more progression event occurred less frequently in the pirfenidone group than in the placebo group (2.1% vs 6.3%; P = .0002).Conclusions: Pirfenidone significantly reduced the incidence of multiple progression events and death after a progression event over 12 months of treatment compared with placebo. These findings suggest that continued treatment with pirfenidone confers a benefit despite the occurrence of any single disease progression event.Trial Registry: ClinicalTrials.gov; Nos. NCT01366209, NCT00287716, and NCT00287729; URL: www.clinicaltrials.gov. [ABSTRACT FROM AUTHOR]

Background: We aimed to examine short- and long-term mortality in a mixed population of patients with interstitial lung disease (ILD) with acute respiratory failure, and to identify those at lower vs higher risk of in-hospital death.Methods: We conducted a single-center retrospective cohort study of 126 consecutive adults with ILD admitted to an ICU for respiratory failure at a tertiary care hospital between 2010 and 2014 and who did not undergo lung transplantation during their hospitalization. We examined associations of ICU-day 1 characteristics with in-hospital and 1-year mortality, using Poisson regression, and examined survival using Kaplan-Meier curves. We created a risk score for in-hospital mortality, using a model developed with penalized regression.Results: In-hospital mortality was 66%, and 1-year mortality was 80%. Those with connective tissue disease-related ILD had better short-term and long-term mortality compared with unclassifiable ILD (adjusted relative risk, 0.6; 95% CI, 0.3-0.9; and relative risk, 0.6; 95% CI, 0.4-0.9, respectively). Our prediction model includes male sex, interstitial pulmonary fibrosis diagnosis, use of invasive mechanical ventilation and/or extracorporeal life support, no ambulation within 24 h of ICU admission, BMI, and Simplified Acute Physiology Score-II. The optimism-corrected C-statistic was 0.73, and model calibration was excellent (P = .99). In-hospital mortality rates for the low-, moderate-, and high-risk groups were 33%, 65%, and 96%, respectively.Conclusions: We created a risk score that classifies patients with ILD with acute respiratory failure from low to high risk for in-hospital mortality. The score could aid providers in counseling these patients and their families. [ABSTRACT FROM AUTHOR]

Background: Preclinical studies have demonstrated that low-dose carbon monoxide (CO) can abrogate experimental lung fibrosis. To test the therapeutic role of inhaled CO, we designed a clinical study in patients with idiopathic pulmonary fibrosis (IPF).Methods: We conducted a multicenter, phase IIa, double-blinded, sham-controlled, clinical trial. Patients with IPF were randomized to treatment with inhaled CO at 100 to 200 parts per million or to inhaled 21% oxygen for 2 h daily, twice weekly, for 12 weeks. The primary study end point was the difference in change in matrix metalloproteinase-7 (MMP7) serum concentration after 12 weeks of treatment. Secondary end points included pulmonary function test measures, 6-min walk distance, rates of adverse events, acute exacerbation, hospitalization and death, and quality of life measures.Results: Fifty-eight subjects were randomized to treatment with inhaled CO (n = 29) or placebo (n = 29). Despite modest increases in CO blood levels, the change in MMP7 concentrations after 12 weeks of treatment did not significantly differ between the study arms (MMP7 difference at week 12, -0.90 ng/mL; 95% CI, -4.18 to 2.38 ng/mL). No differences were observed in physiologic measures, incidence of acute exacerbations, hospitalization, death, or patient-reported outcomes. Importantly, no differences in distribution of adverse events were noted between the treatment arms.Conclusions: Inhaled CO is well tolerated and can be safely administered to patients with IPF in the ambulatory setting; however, inhaled CO did not result in significant changes in study end points. Our findings support testing the efficacy of inhaled therapies in future IPF clinical trials.Trial Registry: ClinicalTrials.gov; No.: NCT01214187; URL: www.clinicaltrials.gov. [ABSTRACT FROM AUTHOR]

The article discusses the findings of a series of sensitivity analyses conducted to assess the robustness of the statistical finding and stability of the treatment effect estimate in the Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis (ASCEND) study. Topics covered include the nonparametric rank analysis of covariance (ANCOVA) model used in the ASCEND study, the results of the forced vital capacity (FVC) assessment, and the implications of the findings.

The article discusses a study that identified distinct grade 3 primary graft dysfunction (PGD) phenotypes based on severity of lung dysfunction and patterns of resolution. Findings show that 361 of the 1,255 subjects had grade 3 PGD within the first 72 hours after transplantation. Distinct phenotypes identified include severe persistent dysfunction, complete resolution of dysfunction with 72 hours, and attenuation, without complete resolution within 72 hours.

The article discusses a study that derived and validated a six-month post-discharge mortality prediction model for elderly intensive care unit survivors. The model was derived from medical record and claims data for 1,526 consecutive patients aged less than 65 years. It was said that six-month mortality was 27.3 and 30.2 percent in the derivation and validation cohorts respectively. It was concluded that clinical variables at hospital discharge can help predict six-month mortality.

The article discusses a study which examined plasma surfactant protein D (SP-D) SP-D levels in 104 subjects from a prospective, multicenter cohort study of lung allograft recipients. The researchers observed that subjects undergoing transplant for idiopathic pulmonary fibrosis (IPF) had higher baseline serum levels of SP-D levels. It was concluded that plasma SP-D could be a biomarker of the air-blood barrier integrity in the native IPF lung.

The article evaluates the relationship between mean pulmonary artery pressure (mPAP) and primary graft dysfunction (PGD) among patients with idiopathic pulmonary fibrosis (IPF). The role of secondary pulmonary arterial hypertension (PAH) in mediating PGD risk in IPF patients is also explored. A multicenter prospective cohort study of 126 lung transplant procedures performed for IPF was conducted. It was found that higher mPAP in patients with IPF is associated with the development of PGD.

The article discusses the result of a study conducted to evaluate the effectiveness of using an interferon-gamma release assay to diagnose latent tuberculosis infection (LTBI) in foreign-born patients. It was found that the T-SPOT.TB test is superior in routine clinical use to the tuberculin skin test in identifying high-risk individuals among foreign-born populations with high rates of bacilli Calmette-Guerin vaccination.

The article presents information on a case study related to osteoporosis in diffuse parenchymal lung disease (DPLD). Eighty six patient with DPLD referred for lung transplantation were included in the study. The experts used dual-energy X-ray absorptiometry to measure bone mineral density at the lumbar spine, femoral neck. It was found that reduced BMD was prevalent in patients with DPLD who were referred for lung transplantation. There was no association with other clinical factors in this study. The study reflected that hispanic patients with DPLD are at greater risk of osteoporosis than non-hispanic patients.

As seen in this CME online activity (available at http://courses.elseviercme.com/694), idiopathic pulmonary fibrosis (IPF) is a specific form of chronic, progressive, fibrotic lung disease of unknown cause that is associated with substantial health-care utilization and high rates of mortality. The clinical symptoms of IPF are nonspecific and overlap with many pulmonary and cardiac diseases making differential diagnosis challenging. The American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association (ATS/ERS/JRS/ALAT) guidelines strongly recommend a multidisciplinary approach to the diagnosis of interstitial lung diseases; however, there are several limitations to the feasibility of this approach in clinical practice. Although early diagnosis is relevant to any chronic, progressive, and irreversible disorder, it is crucially important that effective treatments for IPF are prescribed without delay. A window of opportunity may exist during which time treatment can have optimal outcomes. Evidence on the clinical management of IPF is rapidly evolving, and key updates were made to the most recent ATS/ERS/JRS/ALAT guidelines. The widely used combination of prednisone, azathioprine, and N-acetylcysteine has now been associated with increased risk of hospitalization and death compared with placebo in patients with IPF. These treatments and others for IPF have been mostly supportive, but recently pirfenidone and nintedanib have demonstrated efficacy in reducing functional decline and disease progression in IPF. A pooled analysis of three phase 3 studies of pirfenidone found a significant 48% reduction in all-cause mortality, and a pooled analysis of a phase 2 and two phase 3 studies of nintedanib found a significant 43% reduction in on-treatment mortality. As patient exposure to these two new drugs increases, data continue to emerge on how and when to use these medications and on how to manage their side effects. Finally, several medications targeting the fibrotic pathobiology of IPF are currently in development. Given the limited treatment options for IPF, enrollment in a clinical trial may be the best chance to delay or prevent progression of IPF. This CME-certified expert video roundtable from CHEST reviews the ATS/ERS/JRS/ALAT guidelines with a specific focus on accurate and timely diagnosis of IPF and the latest data on the treatment of IPF. [ABSTRACT FROM AUTHOR]