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The efficacy of α1 proteinase inhibitor (A1PI) augmentation treatment for α1 antitrypsin deficiency has not been substantiated by a randomised, placebo-controlled trial. CT-measured lung density is a more sensitive measure of disease progression in α1 antitrypsin deficiency emphysema than spirometry is, so we aimed to assess the efficacy of augmentation treatment with this measure. The RAPID study was a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial of A1PI treatment in patients with α1 antitrypsin deficiency. We recruited eligible non-smokers (aged 18–65 years) in 28 international study centres in 13 countries if they had severe α1 antitrypsin deficiency (serum concentration <11 μM) with a forced expiratory volume in 1 s of 35–70% (predicted). We excluded patients if they had undergone, or were on the waiting list to undergo, lung transplantation, lobectomy, or lung volume-reduction surgery, or had selective IgA deficiency. We randomly assigned patients (1:1; done by Accovion) using a computerised pseudorandom number generator (block size of four) with centre stratification to receive A1PI intravenously 60 mg/kg per week or placebo for 24 months. All patients and study investigators (including those assessing outcomes) were unaware of treatment allocation throughout the study. Primary endpoints were CT lung density at total lung capacity (TLC) and functional residual capacity (FRC) combined, and the two separately, at 0, 3, 12, 21, and 24 months, analysed by modified intention to treat (patients needed at least one evaluable lung density measurement). This study is registered with ClinicalTrials.gov, number NCT00261833. A 2-year open-label extension study was also completed (NCT00670007). Between March 1, 2006, and Nov 3, 2010, we randomly allocated 93 (52%) patients A1PI and 87 (48%) placebo, analysing 92 in the A1PI group and 85 in the placebo group. The annual rate of lung density loss at TLC and FRC combined did not differ between groups (A1PI −1·50 g/L per year [SE 0·22]; placebo −2·12 g/L per year [0·24]; difference 0·62 g/L per year [95% CI −0·02 to 1·26], p=0·06). However, the annual rate of lung density loss at TLC alone was significantly less in patients in the A1PI group (−1·45 g/L per year [SE 0·23]) than in the placebo group (−2·19 g/L per year [0·25]; difference 0·74 g/L per year [95% CI 0·06–1·42], p=0·03), but was not at FRC alone (A1PI −1·54 g/L per year [0·24]; placebo −2·02 g/L per year [0·26]; difference 0·48 g/L per year [–0·22 to 1·18], p=0·18). Treatment-emergent adverse events were similar between groups, with 1298 occurring in 92 (99%) patients in the A1PI group and 1068 occuring in 86 (99%) in the placebo group. 71 severe treatment-emergent adverse events occurred in 25 (27%) patients in the A1PI group and 58 occurred in 27 (31%) in the placebo group. One treatment-emergent adverse event leading to withdrawal from the study occurred in one patient (1%) in the A1PI group and ten occurred in four (5%) in the placebo group. One death occurred in the A1PI group (respiratory failure) and three occurred in the placebo group (sepsis, pneumonia, and metastatic breast cancer). Measurement of lung density with CT at TLC alone provides evidence that purified A1PI augmentation slows progression of emphysema, a finding that could not be substantiated by lung density measurement at FRC alone or by the two measurements combined. These findings should prompt consideration of augmentation treatment to preserve lung parenchyma in individuals with emphysema secondary to severe α1 antitrypsin deficiency. CSL Behring.

Limited data exist describing risk factors for mortality in patients having predominantly emphysema. A total of 609 patients with severe emphysema (ages 40-83 yr; 64.2% male) randomized to the medical therapy arm of the National Emphysema Treatment Trial formed the study group. Cox proportional hazards regression analysis was used to investigate risk factors for all-cause mortality. Risk factors examined included demographics, body mass index, physiologic data, quality of life, dyspnea, oxygen utilization, hemoglobin, smoking history, quantitative emphysema markers on computed tomography, and a modification of a recently described multifunctional index (modified BODE). Overall, high mortality was seen in this cohort (12.7 deaths per 100 person-years; 292 total deaths). In multivariate analyses, increasing age (p=0.001), oxygen utilization (p=0.04), lower total lung capacity % predicted (p=0.05), higher residual volume % predicted (p=0.04), lower maximal cardiopulmonary exercise testing workload (p=0.002), greater proportion of emphysema in the lower lung zone versus the upper lung zone (p=0.005), and lower upper-to-lower-lung perfusion ratio (p=0.007), and modified BODE (p=0.02) were predictive of mortality. FEV1 was a significant predictor of mortality in univariate analysis (p=0.005), but not in multivariate analysis (p=0.21). Although patients with advanced emphysema experience significant mortality, subgroups based on age, oxygen utilization, physiologic measures, exercise capacity, and emphysema distribution identify those at increased risk of death.

Acute severe asthma remains a major economic and health burden. The natural history of acute decompensations is one of resolution and only about 0.4% of patients succumb overall. Mortality in medical intensive care units is higher but is less than 3% of hospital admissions. \"Near-fatal\" episodes may be more frequent, but precise figures are lacking. However, about 30% of medical intensive care unit admissions require intubation and mechanical ventilation with mortality of 8%. Morbidity and mortality increase with socioeconomic deprivation and ethnicity. Seventy to 80% of patients in emergency departments clear within 2 hours with standardized care. The relapse rate varies between 7 and 15%, depending on how aggressively the patient is treated. The airway obstruction in the 20-30% of people resistant to adrenergic agonists in the emergency department slowly reverses over 36-48 hours but requires intense treatment to do so. Current therapeutic options for this group consist of ipratropium and corticosteroids in combination with beta2 selective drugs. Even so, such regimens are not optimal and better approaches are needed. The long-term prognosis after a near-fatal episode is poor and mortality may approach 10%.

Background: Angiogenesis has been implicated in the pathogenesis of idiopathic interstitial pneumonia (IIP). The aim of this study was to examine the relationship between plasma concentrations of the angiogenic cytokines interleukin 8 (IL-8), vascular endothelial growth factor (VEGF), and endothelin-1 (ET-1) and clinical parameters of disease progression over a 6 month period to identify potential aetiological mediators and prognostic markers of disease activity in patients with IIP. Methods: Forty nine patients with IIP (40 men) were recruited to the study. Plasma cytokine measurements, pulmonary function tests, and high resolution computed tomography (HRCT) scans were performed on recruitment and after 6 months. Plasma cytokine measurements were also performed in 15 healthy volunteers for control purposes. Results: Patients with IIP had significantly higher median (IQR) baseline concentrations of IL-8 and ET-1 than controls (155 (77–303) pg/ml v 31 (0–100) pg/ml, p<0.001) and (1.21 (0.91–1.88) pg/ml v 0.84 (0.67–1.13) pg/ml, p<0.01), respectively. Baseline concentrations of IL-8, ET-1, and VEGF were significantly related to the baseline HRCT fibrosis score (r = 0.42, p<0.005; r = 0.39, p<0.01; and r = 0.42, p<0.005, respectively). Patients with IIP who developed progressive disease had significantly higher baseline levels of IL-8 (345 (270–497) pg/ml v 121 (73–266) pg/ml, p = 0.001) and VEGF (1048 (666–2149) pg/ml v 658 (438–837) pg/ml, p = 0.019). Over 6 months the change in VEGF was significantly related to the change in HRCT fibrosis score (r = 0.565, p = 0.035) and negatively related to the change in forced vital capacity (r = −0.353, p = 0.035).

Lung volume reduction surgery (LVRS) is associated with weight gain in some patients, but the group that gains weight after LVRS and the mechanisms underlying this phenomenon have not been well characterized. To describe the weight change profiles of LVRS patients enrolled in the National Emphysema Treatment Trial (NETT) and to correlate alterations in lung physiological parameters with changes in weight. We divided 1,077 non-high-risk patients in the NETT into groups according to baseline body mass index (BMI): underweight (<21 kg/m(2)), normal weight (21-25 kg/m(2)), overweight (25-30 kg/m(2)), and obese (>30 kg/m(2)). We compared BMI groups and LVRS and medical groups within each BMI stratum with respect to baseline characteristics and percent change in BMI (%ΔBMI) from baseline. We examined patients with (ΔBMI ≥ 5%) and without (ΔBMI < 5%) significant weight gain at 6 months and assessed changes in lung function and ventilatory efficiency (Ve/Vco(2)). The percent change in BMI was greater in the LVRS arm than in the medical arm in the underweight and normal weight groups at all follow-up time points, and at 12 and 24 months in the overweight group. In the LVRS group, patients with ΔBMI ≥ 5% at 6 months had greater improvements in FEV(1) (11.53 ± 9.31 vs. 6.58 ± 8.68%; P < 0.0001), FVC (17.51 ± 15.20 vs. 7.55 ± 14.88%; P < 0.0001), residual volume (-66.20 ± 40.26 vs. -47.06 ± 39.87%; P < 0.0001), 6-minute walk distance (38.70 ± 69.57 vs. 7.57 ± 73.37 m; P < 0.0001), maximal expiratory pressures (12.73 ± 49.08 vs. 3.54 ± 32.22; P = 0.0205), and Ve/Vco(2) (-1.58 ± 6.20 vs. 0.22 ± 8.20; P = 0.0306) at 6 months than patients with ΔBMI < 5% at 6 months. LVRS leads to weight gain in nonobese patients, which is associated with improvement in lung function, exercise capacity, respiratory muscle strength, and ventilatory efficiency. These physiological changes may be partially responsible for weight gain in patients who undergo LVRS.

Idiopathic pulmonary fibrosis is characterized by a fibroproliferative response with only minor signs of inflammation, and it almost always causes rapid fibrotic destruction of the lung. 1 Regardless of treatment, the median survival is four to five years after the onset of symptoms. 2 The standard treatment for idiopathic pulmonary fibrosis is oral glucocorticoids. However, lung function improves in less than 30 percent of patients who receive this treatment. 2 The proliferation of fibroblasts and the accumulation of interstitial collagens are the hallmarks of progressive organ fibrosis. 3 In vitro studies have demonstrated that interferon-γ inhibits the proliferation of lung fibroblasts in a dose-dependent . . .

To determine the effect of medical treatment versus lung volume reduction surgery (LVRS) on pulmonary hemodynamics. Three clinical centers of the National Emphysema Treatment Trial (NETT) screened patients for additional inclusion into a cardiovascular (CV) substudy. Demographics were determined, and lung function testing, six-minute-walk distance, and maximum cardiopulmonary exercise testing were done at baseline and 6 months after medical therapy or LVRS. CV substudy patients underwent right heart catheterization at rest prerandomization (baseline) and 6 months after treatment. A total of 110 of the 163 patients evaluated for the CV substudy were randomized in NETT (53 were ineligible), 54 to medical treatment and 56 to LVRS. Fifty-five of these patients had both baseline and repeat right heart catheterization 6 months postrandomization. Baseline demographics and lung function data revealed CV substudy patients to be similar to the remaining 1,163 randomized NETT patients in terms of age, sex, FEV(1), residual volume, diffusion capacity of carbon monoxide, Pa(O(2)), Pa(CO(2)), and six-minute-walk distance. CV substudy patients had moderate pulmonary hypertension at rest (Ppa, 24.8 +/- 4.9 mm Hg); baseline hemodynamic measurements were similar across groups. Changes from baseline pressures to 6 months post-treatment were similar across treatment groups, except for a smaller change in pulmonary capillary wedge pressure at end-expiration post-LVRS compared with medical treatment (-1.8 vs. 3.5 mm Hg, p = 0.04). In comparison to medical therapy, LVRS was not associated with an increase in pulmonary artery pressures.

Short-term exposure to ambient air pollution has been associated with lower lung function. Few studies have examined whether these associations are detectable at relatively low levels of pollution within current U.S. Environmental Protection Agency (EPA) standards. To examine exposure to ambient air pollutants within EPA standards and lung function in a large cohort study. We included 3,262 participants of the Framingham Offspring and Third Generation cohorts living within 40 km of the Harvard Supersite monitor in Boston, Massachusetts (5,358 examinations, 1995-2011) who were not current smokers, with previous-day pollutant levels in compliance with EPA standards. We compared lung function (FEV1 and FVC) after previous-day exposure to particulate matter less than 2.5 μm in diameter (PM2.5), nitrogen dioxide (NO2), and ozone (O3) in the \"moderate\" range of the EPA Air Quality Index to exposure in the \"good\" range. We also examined linear relationships between moving averages of pollutant concentrations 1, 2, 3, 5, and 7 days before spirometry and lung function. Exposure to pollutant concentrations in the \"moderate\" range of the EPA Air Quality Index was associated with a 20.1-ml lower FEV1 for PM2.5 (95% confidence interval [CI], -33.4, -6.9), a 30.6-ml lower FEV1 for NO2 (95% CI, -60.9, -0.2), and a 55.7-ml lower FEV1 for O3 (95% CI, -100.7, -10.8) compared with the \"good\" range. The 1- and 2-day moving averages of PM2.5, NO2, and O3 before testing were negatively associated with FEV1 and FVC. Short-term exposure to PM2.5, NO2, and O3 within current EPA standards was associated with lower lung function in this cohort of adults.

In healthy volunteers, the single-breath diffusing capacity of the lung for carbon monoxide (Dlco) decreases and Dlco normalized per liter alveolar volume (Va; Dlco/Va) increases if Va is decreased. We hypothesized that comparison of Dlco/Va with its predicted value at predicted total lung capacity (TLC) will result in an underestimation of the diffusion disorder in patients with a restrictive lung disease, if a similar relationship exists between Dlco/Va and lung volume as found in healthy volunteers. To test this hypothesis, we studied total gas transfer Dlco and Dlco/Va as functions of Va in patients who developed a restrictive lung disease and a diffusion disorder in a short period of time. An observational survey. Pulmonary function department. Thirteen patients without any initial pulmonary pathology who developed the mentioned pulmonary pathology due to bleomycin treatment. Bleomycin treatment. We performed the single-breath test at various Va levels before, during, and after bleomycin treatment. In the majority of the patients, the Dlco vs Va relationship remained parabolic, but shifted downwards during therapy. Therefore, the linear Dlco/Va vs Va relationship shifted downwards, while the negative slope was not changed, indicating the development of a decreased gas transfer. Six patients also developed a volume restriction. The agreement of the data with the hypothesis increased its probability. Consequently, to evaluate a diffusion disorder, Dlco/Va at a lower actual TLC of patients with a lung restriction should be compared to a reference Dlco/Va at a lung volume equal to the actual TLC.

Background: Not all patients with severe chronic obstructive pulmonary disease (COPD) progressively hyperinflate during symptom limited exercise. The pattern of change in chest wall volumes (Vcw) was investigated in patients with severe COPD who progressively hyperinflate during exercise and those who do not. Methods: Twenty patients with forced expiratory volume in 1 second (FEV1) 35 (2)% predicted were studied during a ramp incremental cycling test to the limit of tolerance (Wpeak). Changes in Vcw at the end of expiration (EEVcw), end of inspiration (EIVcw), and at total lung capacity (TLCVcw) were computed by optoelectronic plethysmography (OEP) during exercise and recovery. Results: Two significantly different patterns of change in EEVcw were observed during exercise. Twelve patients had a progressive significant increase in EEVcw during exercise (early hyperinflators, EH) amounting to 750 (90) ml at Wpeak. In contrast, in all eight remaining patients EEVcw remained unchanged up to 66% Wpeak but increased significantly by 210 (80) ml at Wpeak (late hyperinflators, LH). Although at the limit of tolerance the increase in EEVcw was significantly greater in EH, both groups reached similar Wpeak and breathed with a tidal EIVcw that closely approached TLCVcw (EIVcw/TLCVcw 93 (1)% and 93 (3)%, respectively). EEVcw was increased by 254 (130) ml above baseline 3 minutes after exercise only in EH. Conclusions: Patients with severe COPD exhibit two patterns during exercise: early and late hyperinflation. In those who hyperinflate early, it may take several minutes before the hyperinflation is fully reversed after termination of exercise.