David J. Lederer

Delayed access and survival in idiopathic pulmonary fibrosis: a cohort study.

RATIONALE Idiopathic pulmonary fibrosis is often initially misdiagnosed. Delays in accessing subspecialty care could lead to worse outcomes among those with idiopathic pulmonary fibrosis. OBJECTIVES To examine the association between delayed access to subspecialty care and survival time in idiopathic pulmonary fibrosis. METHODS We performed a prospective cohort study of 129 adults who met American Thoracic Society criteria for idiopathic pulmonary fibrosis evaluated at a tertiary care center. Delay was defined as the time from the onset of dyspnea to the date of initial evaluation at a tertiary care center. We used competing risk survival methods to examine survival time and time to transplantation. MEASUREMENTS AND MAIN RESULTS The mean age was 63 years and 76% were men. The median delay was 2.2 years (interquartile range 1.0–3.8 yr), and the median follow-up time was 1.1 years. Age and lung function at the time of evaluation did not vary by delay. A longer delay was associated with an increased risk of death independent of age, sex, forced vital capacity, third-party payer, and educational attainment (adjusted hazard ratio per doubling of delay was 1.3, 95% confidence interval 1.03 to 1.6). Longer delay was not associated with a lower likelihood of undergoing lung transplantation. CONCLUSIONS Delayed access to a tertiary care center is associated with a higher mortality rate in idiopathic pulmonary fibrosis independent of disease severity. Early referral to a specialty center should be considered for those with known or suspected interstitial lung disease.

A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis.

BACKGROUND In two of three phase 3 trials, pirfenidone, an oral antifibrotic therapy, reduced disease progression, as measured by the decline in forced vital capacity (FVC) or vital capacity, in patients with idiopathic pulmonary fibrosis; in the third trial, this end point was not achieved. We sought to confirm the beneficial effect of pirfenidone on disease progression in such patients. METHODS In this phase 3 study, we randomly assigned 555 patients with idiopathic pulmonary fibrosis to receive either oral pirfenidone (2403 mg per day) or placebo for 52 weeks. The primary end point was the change in FVC or death at week 52. Secondary end points were the 6-minute walk distance, progression-free survival, dyspnea, and death from any cause or from idiopathic pulmonary fibrosis. RESULTS In the pirfenidone group, as compared with the placebo group, there was a relative reduction of 47.9% in the proportion of patients who had an absolute decline of 10 percentage points or more in the percentage of the predicted FVC or who died; there was also a relative increase of 132.5% in the proportion of patients with no decline in FVC (P<0.001). Pirfenidone reduced the decline in the 6-minute walk distance (P=0.04) and improved progression-free survival (P<0.001). There was no significant between-group difference in dyspnea scores (P=0.16) or in rates of death from any cause (P=0.10) or from idiopathic pulmonary fibrosis (P=0.23). However, in a prespecified pooled analysis incorporating results from two previous phase 3 trials, the between-group difference favoring pirfenidone was significant for death from any cause (P=0.01) and from idiopathic pulmonary fibrosis (P=0.006). Gastrointestinal and skin-related adverse events were more common in the pirfenidone group than in the placebo group but rarely led to treatment discontinuation. CONCLUSIONS Pirfenidone, as compared with placebo, reduced disease progression, as reflected by lung function, exercise tolerance, and progression-free survival, in patients with idiopathic pulmonary fibrosis. Treatment was associated with an acceptable side-effect profile and fewer deaths. (Funded by InterMune; ASCEND ClinicalTrials.gov number, NCT01366209.).

Racial and ethnic disparities in idiopathic pulmonary fibrosis: A UNOS/OPTN database analysis.

We previously reported poorer survival among non‐Hispanic blacks and Hispanics with idiopathic pulmonary fibrosis (IPF) compared to non‐Hispanic whites at our center. In the current study, we hypothesized that these disparities would exist in a nationwide cohort of wait‐listed patients with IPF. We performed a retrospective cohort study of 2635 patients with IPF listed for lung transplantation between 1995 and 2003 at 94 transplant centers in the United States. The age‐adjusted mortality rate was higher among non‐Hispanic blacks [hazard ratio (HR) = 1.24, 95% confidence interval (CI) 1.06–1.45, p = 0.009] and Hispanics (HR = 1.29, 95% CI 1.06–1.56, p = 0.01) compared to non‐Hispanic whites. These findings persisted after adjustment for transplantation, medical comorbidities and socioeconomic status. Worse lung function at the time of listing appeared to explain some of these differences (HR for non‐Hispanic blacks after adjustment for forced vital capacity percent predicted = 1.16, 95% CI 0.98–1.36, p = 0.09; HR for Hispanics = 1.21, 95% CI 0.99–1.48, p = 0.056). In summary, black and Hispanic patients with IPF have worse survival than whites after listing for lung transplant.

A consensus document for the selection of lung transplant candidates: 2014--an update from the Pulmonary Transplantation Council of the International Society for Heart and Lung Transplantation.

The appropriate selection of lung transplant recipients is an important determinant of outcomes. This consensus document is an update of the recipient selection guidelines published in 2006. The Pulmonary Council of the International Society for Heart and Lung Transplantation (ISHLT) organized a Writing Committee of international experts to provide consensus opinion regarding the appropriate timing of referral and listing of candidates for lung transplantation. A comprehensive search of the medical literature was conducted with the assistance of a medical librarian. Writing Committee members were assigned specific topics to research and discuss. The Chairs of the Writing Committee were responsible for evaluating the completeness of the literature search, providing editorial support for the manuscript, and organizing group discussions regarding its content. The consensus document makes specific recommendations regarding the timing of referral and of listing for lung transplantation. These recommendations include discussions not present in previous ISHLT guidelines, including lung allocation scores, bridging to transplant with mechanical circulatory and ventilator support, and expanded indications for lung transplantation. In the absence of high-grade evidence to support decision making, these consensus guidelines remain part of a continuum of expert opinion based on available studies and personal experience. Some positions are immutable. Although transplant is rightly a treatment of last resort for end-stage lung disease, early referral allows proper evaluation and thorough patient education. Subsequent waiting list activation implies a tacit agreement that transplant offers a significant individual survival advantage. It is both the challenge and the responsibility of the transplant community globally to ensure organ allocation maximizes the potential benefits of a scarce resource, thereby achieving that advantage.

Vascular Inflammation in Obesity and Sleep Apnea

Background— Unrecognized obstructive sleep apnea (OSA) is highly prevalent in obesity. Both obesity and OSA are associated with vascular endothelial inflammation and increased risk for cardiovascular diseases. We investigated directly whether the endothelial alterations that are attributed commonly to obesity are in fact related to OSA. Methods and Results— Seventy-one subjects with a body mass index ranging from normal to obese underwent attended polysomnography. To assess vascular inflammation and oxidative stress directly, we quantified the expression of nuclear factor-&kgr;B and nitrotyrosine by immunofluorescence in freshly harvested venous endothelial cells. To evaluate basal endothelial nitric oxide (NO) production and activity, we quantified the expression of endothelial NO synthase (eNOS) and phosphorylated eNOS. Vascular reactivity was measured by brachial artery flow-mediated dilation. Expression of eNOS and phosphorylated eNOS and flow-mediated dilation were significantly lower, whereas expression of nitrotyrosine was significantly greater in OSA patients (n=38) than in OSA-free subjects (n=33) regardless of central adiposity. Expression of nuclear factor-&kgr;B was greater in obese OSA patients than in obese OSA-free subjects (P=0.004). Protein expression and flow-mediated dilation were not significantly affected by increasing body mass index or central obesity in OSA patients and in OSA-free subjects. After 4 weeks of continuous positive airway pressure therapy, flow-mediated dilation and expression of eNOS and phosphorylated eNOS significantly increased whereas expression of nitrotyrosine and nuclear factor-&kgr;B significantly decreased in OSA patients who adhered to continuous positive airway pressure ≥4 hours daily. Conclusions— Untreated OSA rather than obesity is a major determinant of vascular endothelial dysfunction, inflammation, and elevated oxidative stress in obese patients.

Treatment of idiopathic pulmonary fibrosis with Ambrisentan: A parallel, randomized trial

BACKGROUND Idiopathic pulmonary fibrosis (IPF) is characterized by formation and proliferation of fibroblast foci. Endothelin-1 induces lung fibroblast proliferation and contractile activity via the endothelin A (ETA) receptor. OBJECTIVE To determine whether ambrisentan, an ETA receptor-selective antagonist, reduces the rate of IPF progression. DESIGN Randomized, double-blind, placebo-controlled, event-driven trial. (ClinicalTrials.gov: NCT00768300). SETTING Academic and private hospitals. PARTICIPANTS Patients with IPF aged 40 to 80 years with minimal or no honeycombing on high-resolution computed tomography scans. INTERVENTION Ambrisentan, 10 mg/d, or placebo. MEASUREMENTS Time to disease progression, defined as death, respiratory hospitalization, or a categorical decrease in lung function. RESULTS The study was terminated after enrollment of 492 patients (75% of intended enrollment; mean duration of exposure to study medication, 34.7 weeks) because an interim analysis indicated a low likelihood of showing efficacy for the end point by the scheduled end of the study. Ambrisentan-treated patients were more likely to meet the prespecified criteria for disease progression (90 [27.4%] vs. 28 [17.2%] patients; P = 0.010; hazard ratio, 1.74 [95% CI, 1.14 to 2.66]). Lung function decline was seen in 55 (16.7%) ambrisentan-treated patients and 19 (11.7%) placebo-treated patients (P = 0.109). Respiratory hospitalizations were seen in 44 (13.4%) and 9 (5.5%) patients in the ambrisentan and placebo groups, respectively (P = 0.007). Twenty-six (7.9%) patients who received ambrisentan and 6 (3.7%) who received placebo died (P = 0.100). Thirty-two (10%) ambrisentan-treated patients and 16 (10%) placebo-treated patients had pulmonary hypertension at baseline, and analysis stratified by the presence of pulmonary hypertension revealed similar results for the primary end point. LIMITATION The study was terminated early. CONCLUSION Ambrisentan was not effective in treating IPF and may be associated with an increased risk for disease progression and respiratory hospitalizations. PRIMARY FUNDING SOURCE Gilead Sciences.BACKGROUND Idiopathic pulmonary fibrosis (IPF) is characterized by formation and proliferation of fibroblast foci. Endothelin-1 induces lung fibroblast proliferation and contractile activity via the endothelin A (ETA) receptor. OBJECTIVE To determine whether ambrisentan, an ETA receptor-selective antagonist, reduces the rate of IPF progression. DESIGN Randomized, double-blind, placebo-controlled, event-driven trial. (ClinicalTrials.gov: NCT00768300). SETTING Academic and private hospitals. PARTICIPANTS Patients with IPF aged 40 to 80 years with minimal or no honeycombing on high-resolution computed tomography scans. INTERVENTION Ambrisentan, 10 mg/d, or placebo. MEASUREMENTS Time to disease progression, defined as death, respiratory hospitalization, or a categorical decrease in lung function. RESULTS The study was terminated after enrollment of 492 patients (75% of intended enrollment; mean duration of exposure to study medication, 34.7 weeks) because an interim analysis indicated a low likelihood of showing efficacy for the end point by the scheduled end of the study. Ambrisentan-treated patients were more likely to meet the prespecified criteria for disease progression (90 [27.4%] vs. 28 [17.2%] patients; P = 0.010; hazard ratio, 1.74 [95% CI, 1.14 to 2.66]). Lung function decline was seen in 55 (16.7%) ambrisentan-treated patients and 19 (11.7%) placebo-treated patients (P = 0.109). Respiratory hospitalizations were seen in 44 (13.4%) and 9 (5.5%) patients in the ambrisentan and placebo groups, respectively (P = 0.007). Twenty-six (7.9%) patients who received ambrisentan and 6 (3.7%) who received placebo died (P = 0.100). Thirty-two (10%) ambrisentan-treated patients and 16 (10%) placebo-treated patients had pulmonary hypertension at baseline, and analysis stratified by the presence of pulmonary hypertension revealed similar results for the primary end point. LIMITATION The study was terminated early. CONCLUSION Ambrisentan was not effective in treating IPF and may be associated with an increased risk for disease progression and respiratory hospitalizations. PRIMARY FUNDING SOURCE Gilead Sciences.

Pulmonary Capillary Wedge Pressure Augments Right Ventricular Pulsatile Loading

Background— Right ventricular failure from increased pulmonary vascular loading is a major cause of morbidity and mortality, yet its modulation by disease remains poorly understood. We tested the hypotheses that, unlike the systemic circulation, pulmonary vascular resistance (RPA) and compliance (CPA) are consistently and inversely related regardless of age, pulmonary hypertension, or interstitial fibrosis and that this relation may be changed by elevated pulmonary capillary wedge pressure, augmenting right ventricular pulsatile load. Methods and Results— Several large clinical databases with right heart/pulmonary catheterization data were analyzed to determine the RPA-CPA relationship with pulmonary hypertension, pulmonary fibrosis, patient age, and varying pulmonary capillary wedge pressure. Patients with suspected or documented pulmonary hypertension (n=1009) and normal pulmonary capillary wedge pressure displayed a consistent RPA-CPA hyperbolic (inverse) dependence, CPA=0.564/(0.047+RPA), with a near-constant resistance-compliance product (0.48±0.17 seconds). In the same patients, the systemic resistance-compliance product was highly variable. Severe pulmonary fibrosis (n=89) did not change the RPA-CPA relation. Increasing patient age led to a very small but statistically significant change in the relation. However, elevation of the pulmonary capillary wedge pressure (n=8142) had a larger impact, significantly lowering CPA for any RPA and negatively correlating with the resistance-compliance product (P<0.0001). Conclusions— Pulmonary hypertension and pulmonary fibrosis do not significantly change the hyperbolic dependence between RPA and CPA, and patient age has only minimal effects. This fixed relationship helps explain the difficulty of reducing total right ventricular afterload by therapies that have a modest impact on mean RPA. Higher pulmonary capillary wedge pressure appears to enhance net right ventricular afterload by elevating pulsatile, relative to resistive, load and may contribute to right ventricular dysfunction.

Acute Exacerbation of Idiopathic Pulmonary Fibrosis. An International Working Group Report

Acute exacerbation of idiopathic pulmonary fibrosis has been defined as an acute, clinically significant, respiratory deterioration of unidentifiable cause. The objective of this international working group report on acute exacerbation of idiopathic pulmonary fibrosis was to provide a comprehensive update on the topic. A literature review was conducted to identify all relevant English text publications and abstracts. Evidence-based updates on the epidemiology, etiology, risk factors, prognosis, and management of acute exacerbations of idiopathic pulmonary fibrosis are provided. Finally, to better reflect the current state of knowledge and improve the feasibility of future research into its etiology and treatment, the working group proposes a new conceptual framework for acute respiratory deterioration in idiopathic pulmonary fibrosis and a revised definition and diagnostic criteria for acute exacerbation of idiopathic pulmonary fibrosis.

Cigarette smoking is associated with subclinical parenchymal lung disease: the Multi-Ethnic Study of Atherosclerosis (MESA)-Lung Study.

RATIONALE Cigarette smoking is a risk factor for diffuse parenchymal lung disease. Risk factors for subclinical parenchymal lung disease have not been described. OBJECTIVES To determine if cigarette smoking is associated with subclinical parenchymal lung disease, as measured by spirometric restriction and regions of high attenuation on computed tomography (CT) imaging. METHODS We examined 2,563 adults without airflow obstruction or clinical cardiovascular disease in the Multi-Ethnic Study of Atherosclerosis, a population-based cohort sampled from six communities in the United States. Cumulative and current cigarette smoking were assessed by pack-years and urine cotinine, respectively. Spirometric restriction was defined as a forced vital capacity less than the lower limit of normal. High attenuation areas on the lung fields of cardiac CT scans were defined as regions having an attenuation between -600 and -250 Hounsfield units, reflecting ground-glass and reticular abnormalities. Generalized additive models were used to adjust for age, gender, race/ethnicity, smoking status, anthropometrics, center, and CT scan parameters. MEASUREMENTS AND MAIN RESULTS The prevalence of spirometric restriction was 10.0% (95% confidence interval [CI], 8.9-11.2%) and increased relatively by 8% (95% CI, 3-12%) for each 10 cigarette pack-years in multivariate analysis. The median volume of high attenuation areas was 119 cm(3) (interquartile range, 100-143 cm(3)). The volume of high attenuation areas increased by 1.6 cm(3) (95% CI, 0.9-2.4 cm(3)) for each 10 cigarette pack-years in multivariate analysis. CONCLUSIONS Smoking may cause subclinical parenchymal lung disease detectable by spirometry and CT imaging, even among a generally healthy cohort.

Pirfenidone for idiopathic pulmonary fibrosis: Analysis of pooled data from three multinational phase 3 trials

Pirfenidone is an antifibrotic agent that has been evaluated in three multinational phase 3 trials in patients with idiopathic pulmonary fibrosis (IPF). We analysed pooled data from the multinational trials to obtain the most precise estimates of the magnitude of treatment effect on measures of disease progression. All patients randomised to pirfenidone 2403 mg·day−1 or placebo in the CAPACITY or ASCEND studies were included in the analysis. Pooled analyses of outcomes at 1 year were based on the pre-specified end-points and analytic methods described in the ASCEND study protocol. A total of 1247 patients were included in the analysis. At 1 year, pirfenidone reduced the proportion of patients with a ≥10% decline in per cent predicted forced vital capacity or death by 43.8% (95% CI 29.3–55.4%) and increased the proportion of patients with no decline by 59.3% (95% CI 29.0–96.8%). A treatment benefit was also observed for progression-free survival, 6-min walk distance and dyspnoea. Gastrointestinal and skin-related adverse events were more common in the pirfenidone group, but rarely led to discontinuation. Analysis of data from three phase 3 trials demonstrated that treatment with pirfenidone for 1 year resulted in clinically meaningful reductions in disease progression in patients with IPF. Treatment with pirfenidone for 1 year results in clinically meaningful reductions in IPF disease progression http://ow.ly/StvBk