Our purpose was to identify clinical, radiological and physiological (CRP) determinants of survival and to develop a CRP scoring system that predicts survival in newly diagnosed cases of idiopathic pulmonary fibrosis (IPF). The study population consisted of 238 patients with biopsy confirmed usual interstitial pneumonia. For each patient, clinical manifestations, chest radiographs, and pulmonary physiology were prospectively assessed. We used Cox proportional-hazards models to assess the effect of these parameters on survival. The effects of age and smoking were included in the analysis. Survival was related to age, smoking status (longer in current smokers), clubbing, the extent of interstitial opacities and presence of pulmonary hypertension on the chest radiograph, reduced lung volume, and abnormal gas exchange during maximal exercise. A mathematical CRP score for predicting survival was derived from these parameters. We showed that this CRP score correlated with the extent and severity of the important histopathologic features of IPF, i.e., fibrosis, cellularity, the granulation/connective tissue deposition, and the total pathologic derangement. Using these models, clinicians are in a better position to provide prognostic information to patients with IPF and to improve the selection of the most appropriate patients for lung transplantation or other standard or novel therapeutic interventions.

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BACKGROUND Long-acting beta-agonist (LABA) therapy improves symptoms in patients whose asthma is poorly controlled by an inhaled glucocorticoid alone. Alternative treatments for adults with uncontrolled asthma are needed. METHODS In a three-way, double-blind, triple-dummy crossover trial involving 210 patients with asthma, we evaluated the addition of tiotropium bromide (a long-acting anticholinergic agent approved for the treatment of chronic obstructive pulmonary disease but not asthma) to an inhaled glucocorticoid, as compared with a doubling of the dose of the inhaled glucocorticoid (primary superiority comparison) or the addition of the LABA salmeterol (secondary noninferiority comparison). RESULTS The use of tiotropium resulted in a superior primary outcome, as compared with a doubling of the dose of an inhaled glucocorticoid, as assessed by measuring the morning peak expiratory flow (PEF), with a mean difference of 25.8 liters per minute (P<0.001) and superiority in most secondary outcomes, including evening PEF, with a difference of 35.3 liters per minute (P<0.001); the proportion of asthma-control days, with a difference of 0.079 (P = 0.01); the forced expiratory volume in 1 second (FEV1) before bronchodilation, with a difference of 0.10 liters (P = 0.004); and daily symptom scores, with a difference of −0.11 points (P<0.001). The addition of tiotropium was also noninferior to the addition of salmeterol for all assessed outcomes and increased the prebronchodilator FEV1 more than did salmeterol, with a difference of 0.11 liters (P = 0.003). CONCLUSIONS When added to an inhaled glucocorticoid, tiotropium improved symptoms and lung function in patients with inadequately controlled asthma. Its effects appeared to be equivalent to those with the addition of salmeterol. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00565266.)

Inhaled beta-adrenergic agonists are the most commonly used medications for the treatment of asthma although there is evidence that regular use may produce adverse effects in some patients. Polymorphisms of the beta(2)-adrenergic receptor (beta(2)-AR) can affect regulation of the receptor. Smaller studies examining the effects of such polymorphisms on the response to beta-agonist therapy have produced inconsistent results. We examined whether polymorphisms at codon 16 (beta(2)-AR-16) and codon 27 (beta(2)-AR-27) of the beta(2)-AR might affect the response to regular versus as-needed use of albuterol by genotyping the 190 asthmatics who had participated in a trial examining the effects of regular versus as needed albuterol use. During the 16-wk treatment period there was a small decline in morning peak expiratory flow in patients homozygous for arginine at B(2)-AR-16 (Arg/Arg) who used albuterol regularly. This effect was magnified during a 4-wk run out period, during which all patients returned to using as-needed albuterol, so that by the end of the study Arg Arg patients who had regularly used albuterol had a morning peak expiratory flow 30. 5 +/- 12.1 L/min lower (p = 0.012) than Arg/Arg patients who had used albuterol on an as needed basis. There was no decline in peak flow with regular use of albuterol in patients who were homozygous for glycine at beta(2)-AR-16. Evening peak expiratory flow also declined in the Arg/Arg patients who used albuterol regularly but not in those who used albuterol on an as-needed basis. No significant differences in outcomes between regular and as-needed treatment were associated with polymorphisms at position 27 of the beta(2)-AR. No other differences in asthma outcomes that we investigated occurred in relation to these beta(2)-AR polymorphisms. Polymorphisms of the beta(2)-AR may influence airway responses to regular inhaled beta-agonist treatment.

Rationale: One-quarter to one-third of individuals with asthma smoke, which may affect response to therapy and contribute to poor asthma control. Objectives: To determine if the response to an inhaled corticosteroid or a leukotriene receptor antagonist is attenuated in individuals with asthma who smoke. Methods: In a multicenter, placebo-controlled, double-blind, doubledummy, crossover trial, 44 nonsmokers and 39 light smokers with mild asthma were assigned randomly to treatment twice daily with inhaled beclomethasone and once daily with oral montelukast. Measurements and Main Results: Primary outcome was change in prebronchodilator FEV 1 in smokers versus nonsmokers. Secondary outcomes included peak flow, PC 20 methacholine, symptoms, quality of life, and markers of airway inflammation. Despite similar FEV 1 , bronchodilator response, and sensitivity to methacholine at baseline, subjects with asthma who smoked had significantly more symptoms, worse quality of life, and lower daily peak flow than nonsmokers. Adherence to therapy did not differ significantly between smokers and nonsmokers, or between treatment arms. Beclomethasone significantly reduced sputum eosinophils and eosinophil cationic protein (ECP) in both smokers and nonsmokers, but increased FEV 1 (170 ml, p ϭ 0.0003) only in nonsmokers. Montelukast significantly increased A.M. peak flow in smokers (12.6 L/min, p ϭ 0.002), but not in nonsmokers. Conclusions: In subjects with mild asthma who smoke, the response to inhaled corticosteroids is attenuated, suggesting that adjustments to standard therapy may be required to attain asthma control. The greater improvement seen in some outcomes in smokers treated with montelukast suggests that leukotrienes may be important in this setting. Larger prospective studies are required to determine whether leukotriene modifiers can be recommended for managing asthma in patients who smoke.

The compliance of the total respiratory system and its components was studied in 24 normal and 12 obese spontaneously breathing unanesthetized subjects. The mean compliance of the total respiratory system was .119 l/cm H2O in normal individuals, but was .052 l/cm H2O in obese subjects. The difference indicated an increased elastic resistance to distention. The compliance of the lung in obese individuals was not different from that of the normals. The compliance of the chest wall was .224 l/cm H2O in normal subjects and was .077 l/cm H2O in obese individuals. In contrast to normal subjects, total respiratory compliance was markedly reduced by recumbency in obese individuals. This was entirely due to a further increase in the resistance of the chest wall. A significant correlation was demonstrated between vital capacity and total respiratory compliance in normal and obese subjects. It has been estimated that of the increase in the mechanical work of breathing in obesity is due to elastic work done on the chest wall. Submitted on November 2, 1959

STHMA IS MANAGED BY CONsensus guidelines. 1,2 Disease activity varies daily, seasonally, and episodically, presumably related to airway inflammation. 3 Accordingly, asthma management requires periodic dose adjustments of controller medications, particularly inhaled corticosteroids. Adjustments have been based on (1) physician assessment of symp-For editorial comment see p 1036.