Complex association patterns for inflammatory mediators in induced sputum from subjects with asthma.

BACKGROUND: The release of various inflammatory mediators into the bronchial lumen is thought to reflect both the type and degree of airway inflammation, eosinophilic Th2, and Th9, or neutrophilic Th1, and Th17, in patients with asthma. AIMS: We investigated whether cytokines and chemokines differed in sputum from subjects with more severe compared with milder asthma and whether unbiased factor analysis of cytokine and chemokine groupings indicates specific inflammatory pathways. METHODS: Cell-free supernatants from induced sputum were obtained from subjects with a broad range of asthma severity (n = 158) and assessed using Milliplex® Cytokines/Chemokine kits I, II and III, measuring 75 individual proteins. Each cytokine, chemokine or growth factor concentration was examined for differences between asthma severity groups, for association with leucocyte counts, and by factor analysis. RESULTS: Severe asthma subjects had 9 increased and 4 decreased proteins compared to mild asthma subjects and fewer differences compared to moderate asthma. Twenty-six mediators were significantly associated with an increasing single leucocyte type: 16 with neutrophils (3 interleukins [IL], 3 CC chemokines, 4 CXC chemokines, 4 growth factors, TNF-α and CX3CL1/Fractalkine); 5 with lymphocytes (IL-7, IL-16, IL-23, IFN-α2 and CCL4/MIP1ß); IL-15 and CCL15/MIP1δ with macrophages; IL-5 with eosinophils; and IL-4 and TNFSF10/TRAIL with airway epithelial cells. Factor analysis grouped 43 cytokines, chemokines and growth factors which had no missing data onto the first 10 factors, containing mixes of Th1, Th2, Th9 and Th17 inflammatory and anti-inflammatory proteins. CONCLUSIONS: Sputum cytokines, chemokines and growth factors were increased in severe asthma, primarily with increased neutrophils. Factor analysis identified complex inflammatory protein interactions, suggesting airway inflammation in asthma is characterized by overlapping immune pathways. Thus, focus on a single specific inflammatory mediator or pathway may limit understanding the complexity of inflammation underlying airway changes in asthma and selection of appropriate therapy.

Responsiveness to oral prednisolone in severe asthma is related to the degree of eosinophilic airway inflammation.

BACKGROUND: Patients with severe asthma appear relatively corticosteroid resistant. Corticosteroid responsiveness is closely related to the degree of eosinophilic airway inflammation. The extent to which eosinophilic airway inflammation in severe asthma responds to treatment with systemic corticosteroids is not clear. OBJECTIVE: To relate the physiological and inflammatory response to systemic corticosteroids in asthma to disease severity and the baseline extent of eosinophilic inflammation. METHODS: Patients with mild/moderate and severe asthma were investigated before and after 2 weeks of oral prednisolone (Clintrials.gov NCT00331058 and NCT00327197). We pooled the results from two studies with common protocols. The US study contained two independent centres and the UK one independent centre. The effect of oral corticosteroids on FEV1 , Pc20, airway inflammation and serum cytokines was investigated. Baseline measurements were compared with healthy subjects. RESULTS: Thirty-two mild/moderate asthmatics, 50 severe asthmatics and 35 healthy subjects took part. At baseline, both groups of asthmatics had a lower FEV1 and Pc20 and increased eosinophilic inflammation compared to healthy subjects. The severe group had a lower FEV1 and more eosinophilic inflammation compared to mild/moderate asthmatics. Oral prednisolone caused a similar degree of suppression of eosinophilic inflammation in all compartments in both groups of asthmatics. There were small improvements in FEV1 and Pc20 for both mild/ moderate and severe asthmatics with a correlation between the baseline eosinophilic inflammation and the change in FEV1 . There was a ~50% reduction in the serum concentration of CXCL10 (IP-10), CCL22 (MDC), CCL17 (TARC), CCL-2 (MCP-1) and CCL-13 (MCP-4) in both asthma groups after oral corticosteroids. CONCLUSIONS AND CLINICAL RELEVANCE: Disease severity does not influence the response to systemic corticosteroids. The study does not therefore support the concept that severe asthma is associated with corticosteroid resistance. Only baseline eosinophilic inflammation was associated with the physiological response to corticosteroids, confirming the importance of measuring eosinophilic inflammation to guide corticosteroid use.

eQTL of bronchial epithelial cells and bronchial alveolar lavage deciphers GWAS-identified asthma genes.

BACKGROUND: Genome-wide association studies (GWASs) have identified various genes associated with asthma, yet, causal genes or single nucleotide polymorphisms (SNPs) remain elusive. We sought to dissect functional genes/SNPs for asthma by combining expression quantitative trait loci (eQTLs) and GWASs. METHODS: Cis-eQTL analyses of 34 asthma genes were performed in cells from human bronchial epithelial biopsy (BEC, n = 107) and from bronchial alveolar lavage (BAL, n = 94). RESULTS: For TSLP-WDR36 region, rs3806932 (G allele protective against eosinophilic esophagitis) and rs2416257 (A allele associated with lower eosinophil counts and protective against asthma) were correlated with decreased expression of TSLP in BAL (P = 7.9 × 10(-11) and 5.4 × 10(-4) , respectively) and BEC, but not WDR36. Surprisingly, rs1837253 (consistently associated with asthma) showed no correlation with TSLP expression levels. For ORMDL3-GSDMB region, rs8067378 (G allele protective against asthma) was correlated with decreased expression of GSDMB in BEC and BAL (P = 1.3 × 10(-4) and 0.04) but not ORMDL3. rs992969 in the promoter region of IL33 (A allele associated with higher eosinophil counts and risk for asthma) was correlated with increased expression of IL33 in BEC (P = 1.3 × 10(-6) ) but not in BAL. CONCLUSIONS: Our study illustrates cell-type-specific regulation of the expression of asthma-related genes documenting SNPs in TSLP, GSDMB, IL33, HLA-DQB1, C11orf30, DEXI, CDHR3, and ZBTB10 affect asthma risk through cis-regulation of its gene expression. Whenever possible, disease-relevant tissues should be used for transcription analysis. SNPs in TSLP may affect asthma risk through up-regulating TSLP mRNA expression or protein secretion. Further functional studies are warranted.

Severe chronic allergic (and related) diseases: a uniform approach--a MeDALL--GA2LEN--ARIA position paper.

Concepts of disease severity, activity, control and responsiveness to treatment are linked but different. Severity refers to the loss of function of the organs induced by the disease process or to the occurrence of severe acute exacerbations. Severity may vary over time and needs regular follow-up. Control is the degree to which therapy goals are currently met. These concepts have evolved over time for asthma in guidelines, task forces or consensus meetings. The aim of this paper is to generalize the approach of the uniform definition of severe asthma presented to WHO for chronic allergic and associated diseases (rhinitis, chronic rhinosinusitis, chronic urticaria and atopic dermatitis) in order to have a uniform definition of severity, control and risk, usable in most situations. It is based on the appropriate diagnosis, availability and accessibility of treatments, treatment responsiveness and associated factors such as comorbidities and risk factors. This uniform definition will allow a better definition of the phenotypes of severe allergic (and related) diseases for clinical practice, research (including epidemiology), public health purposes, education and the discovery of novel therapies.

Predicting worsening asthma control following the common cold.

The asthmatic response to the common cold is highly variable, and early characteristics that predict worsening of asthma control following a cold have not been identified. In this prospective multicentric cohort study of 413 adult subjects with asthma, the mini-Asthma Control Questionnaire (mini-ACQ) was used to quantify changes in asthma control and the Wisconsin Upper Respiratory Symptom Survey-21 (WURSS-21) to measure cold severity. Univariate and multivariable models were used to examine demographic, physiological, serological and cold-related characteristics for their relationship to changes in asthma control following a cold. Clinically significant worsening of asthma control was observed following a cold (mean+/-SD increase in mini-ACQ score of 0.69+/-0.93). Univariate analysis demonstrated that season, centre location, cold duration and cold severity measurements were all associated with a change in asthma control. Multivariable analysis of the covariates available within the first 2 days of cold onset revealed that the day 2 and cumulative sum of day 1 and 2 WURSS-21 scores were significant predictors of the subsequent changes in asthma control. In asthmatic subjects, cold severity within the first 2 days can be used to predict subsequent changes in asthma control. This information may help clinicians prevent deterioration in asthma control following a cold.

Physiologic manifestations of human anaphylaxis.

In the course of a controlled study to evaluate different forms of immunotherapy for subjects with insect-sting hypersensitivity, we observed 11 subjects who had systemic cutaneous urticarial reactions and 3 subjects who experienced systemic anaphylaxis. With the exception of tachycardia, there were no cardiopulmonary changes in the subjects with urticaria, whereas the major manifestation of anaphylactic shock in the other three subjects was severe hypotension that was probably secondary to peripheral vasodilation. Significant abnormalities in gas exchange developed in two subjects. In one, bronchospasm precipitated a respiratory arrest followed by endotracheal intubation with mechanical ventilation. Although plasma histamine levels were not related to the development of cutaneous reactions, the plasma histamine levels correlated with the severity and duration of the cardiopulmonary changes observed during anaphylactic shock. The two subjects with the most severe shock showed evidence of intravascular coagulation characterized by a diminution of Factor V, Factor VIII, fibrinogen, and high molecular weight kininogen, as well as changes in components of the complement system. Standard therapy with epinephrine and fluids, usually recommended for the treatment of systemic anaphylaxis, did not immediately reverse either the hemodynamic or the respiratory abnormalities in the two subjects with the most severe anaphylactic shock. Hemodynamic recovery was gradual and did not seem directly related to any specific therapeutic intervention.

Cholinergic and neurogenic mechanisms in obstructive airways disease.

Although primary neural control of airway function is through parasympathetic pathways, more recent evidence indicates that there are important adrenergic and non-adrenergic, non-cholinergic neural mechanisms that may also influence respiratory function. The parasympathetic nervous system component includes neural receptors in the airways as well as afferent and efferent pathways that travel in the vagus nerves. Afferent vagal sensory receptors mediate the response to irritant or rapidly adapting receptor activation, Hering-Breuer, and the unmyelinated "C" fibers or "J" receptor pathways. The motor component of the parasympathetic nervous system has several important functions that regulate tone in normal system has several important functions that regulate tone in normal and obstructed airways. These pathways affect the following respiratory structures: bronchial smooth muscle; the mucociliary system; the larynx; and the nose. Finally, the parasympathetic nervous system may play a role in some species in the control of breathing and in the hyperpneic responses associated with airflow obstruction. In addition to cholinergic neural mechanisms, bronchomotor tone may also be influenced by adrenergic mechanisms and non-adrenergic, non-cholinergic neural pathways. Although there is minimal innervation of the airways by the sympathetic nervous system, there is ample evidence that beta-adrenoreceptors are present on bronchial smooth muscle. Beta-receptor stimulation not only relaxes airway smooth muscle, but also inhibits mediator release from mast cells in the airways and may alter vascular permeability. Alpha-adrenoreceptors are found in human airways and stimulation of these receptors causes bronchoconstriction. Although the importance of alpha-adrenoreceptors has been questioned, recent evidence suggests that alpha stimulation may play a role in cold air- and exercise-induced asthma. Finally, non-adrenergic, non-cholinergic nerves have been shown to cause relaxation of human airways in in vivo studies. There is increasing evidence that vasoactive intestinal peptide and peptide histidine methanol are the mediators of these responses. More recently, other neuropeptides (substance P, neurokinin A, and calcitonin gene-related peptide) have been localized in nerves in airways. These cause bronchoconstriction in vitro and may be released from afferent nerve terminals by an axon reflex. Although the precise role of these substances in controlling airway tone and bronchial secretions in humans is not fully understood, they may have important modulatory effects on the neural control of airway function.

Acute bronchodilating effects of ipratropium bromide and theophylline in chronic obstructive pulmonary disease.

The bronchodilator effects of a single dose of ipratropium bromide aerosol (36 micrograms) and short-acting theophylline tablets (dose titrated to produce serum levels of 10-20 micrograms/mL) were compared in a double-blind, placebo-controlled crossover study in 21 patients with stable, chronic obstructive pulmonary disease. Mean peak forced expiratory volume in 1 second (FEV1) increases over baseline and the proportion of patients attaining at least a 15% increase in the FEV1 (responders) were 31% and 90%, respectively, for ipratropium and 17% and 50%, respectively, for theophylline. The average FEV1 increases during the 6-hour observation period were 18% for ipratropium and 8% for theophylline. The mean duration of action was 3.8 hours with ipratropium and 2.4 hours with theophylline. While side effects were rare, those experienced after theophylline use did involve the cardiovascular and gastrointestinal systems. These results show that ipratropium is a more potent bronchodilator than oral theophylline in patients with chronic airflow obstruction.

Effects of blood transfusion on exercise capacity in patients with sickle-cell anemia.

Although sickle cells have increased intracellular viscosity, the viscosity of patient's blood is usually not increased, because of the low hematocrit typically found in such patients. When patients receive transfusions, their exercise capacity increases, but it is unclear whether the change is due primarily to increased hemoglobin concentration, or also reflects improved flow properties of the blood due to dilution of sickle cells with normal erythrocytes. To evaluate the relative importance of these two factors, submaximal exercise studies were performed before and after a series of transfusions. Exercise capacity improved and the patients were able to perform increased amounts of work at lower heart rates. Regression analyses indicated that the percent of sickle cells in patient's blood did not have a significant effect on exercise capacity after the transfusion-induced increase in hemoglobin concentration was taken into account. At the hematocrits typically found in patients, altered viscosity of blood due to the presence of sickle cells is much less important than hemoglobin concentration as a determinant of exercise capacity.

A comparison of short-term treatment with inhaled fluticasone propionate and zafirlukast for patients with persistent asthma.

PURPOSE: To compare the short-term efficacy and safety of low-dose fluticasone propionate with that of oral zafirlukast therapy for patients previously treated with beta-2-agonists alone, and to evaluate the potential therapeutic benefit of switching from zafirlukast to a low-dose inhaled corticosteroid. SUBJECTS AND METHODS: This study consisted of a 4-week randomized, double-blind treatment period followed by a 4-week open-label period. Two hundred ninety-four patients > or =12 years old with asthma previously uncontrolled with beta-2-agonists alone were randomly assigned to treatment with low-dose inhaled fluticasone (88 microg twice daily) or oral zafirlukast (20 mg twice daily). After 4 weeks, all patients discontinued their double-blind therapy and received open-label fluticasone (88 microg twice daily). Outcomes included pulmonary function, asthma symptoms, albuterol use, asthma exacerbations, and adverse events. RESULTS: During the double-blind treatment period, fluticasone patients had significantly greater improvements in morning peak flow (29.3 L/min vs. 18.3 L/min), percentage of symptom-free days (19.8% vs. 11.6%), and daily albuterol use (-1.8 puffs per day vs. -1.1 puffs per day) compared with zafirlukast patients (P < or =0.025, each comparison). During the open-label treatment period, patients switched from zafirlukast to fluticasone experienced additional improvements in morning peak flow (17.2 L/min), evening peak flow (13.6 L/min), and FEV(1) (0.11 liter) and daily albuterol use (-0.9 puffs daily) compared with values obtained at the end of the double-blind treatment period (P < or =0.001, each comparison). CONCLUSION: Low-dose fluticasone was more effective than zafirlukast in improving pulmonary function and symptoms in patients with persistent asthma. In addition, switching patients from zafirlukast to fluticasone further improved clinical outcomes.

Evaluation of sleep-disordered breathing. Is polysomnography necessary?

To determine whether polysomnography is necessary to assess the presence and severity of sleep-disordered breathing, bedside observations by physicians were compared with the results of polysomnography in 37 patients with clinically suspected obstructive sleep apnea. Physician observations correlated with objective findings from polysomnography in detecting the presence of obstructive apnea (p less than 0.01), and had a high specificity and positive predictive value. The 20 patients correctly identified by clinical observation had a longer duration of apneic episodes (p = 0.02), increased severity of snoring (p = 0.02), resuscitative snoring (p less than 0.02), and paradoxic thoracoabdominal movement (p less than 0.05). However, 11 other patients with sleep-disordered breathing were not identified clinically; therefore, the sensitivity (64.5 percent) and diagnostic accuracy (70.3 percent) of brief clinical observation were low. Furthermore, the physicians' determinations of the severity of the condition on the basis of bedside estimates of disordered breathing rate, duration of episodes, and the degree of associated hemoglobin oxygen desaturation did not correlate with objective measurements. These findings suggest that a single, brief clinical observation alone is an ineffective screening procedure for detecting obstructive sleep apnea.

Comparison of the anticholinergic bronchodilator ipratropium bromide with metaproterenol in chronic obstructive pulmonary disease. A 90-day multi-center study.

The short- and long-term efficacy and safety of an inhaled quaternary ammonium anticholinergic agent, ipratropium bromide, and a beta agonist aerosol, metaproterenol, were compared in 261 nonatopic patients with chronic obstructive pulmonary disease (COPD). The study was a randomized, double-blind, 90-day, parallel-group trial. On three test days-one, 45, and 90-mean peak responses for forced expiratory volume in one second and forced vital capacity and mean area under the time-response curve were higher for ipratropium than for metaproterenol. Clinical improvement was noted in both treatment groups, especially during the first treatment month, with persistence of improvement throughout the remainder of the study. Side effects were relatively infrequent and generally mild; tremor, a complication of beta agonists, was not reported by any subject receiving ipratropium. These results support the effectiveness and safety of long-term treatment with inhaled ipratropium in COPD.

Restricted T-cell antigen receptor repertoire in bronchoalveolar T cells from normal humans.

The repertoire of variable alpha (AV) and beta (BV) TCR genes was compared in the peripheral blood and BAL fluid of five healthy individuals. Rearranged TCR transcripts were amplified by a reverse transcription-polymerase chain reaction, using oligonucleotide primers specific for 22 AV and 24 BV gene families. Nearly all AV and BV gene families were expressed in BAL T cells at levels similar to those in blood T cells. The diversity of AV and BV gene repertoire was examined further, testing the distribution of nucleotide lengths of TCR junctional regions. Most V gene families had a normal distribution of junctional region lengths in both blood and BAL T cells. Some gene families, particularly AV21 and BV9 in BAL samples, had a skewed banding pattern, with fewer bands or predominance of several bands. The limited diversity in TCR junctional region lengths was more prominent in CD8+ T cells from BAL fluids than from blood. CD4+ T cells also contributed to the limited diversity in BAL T cells. The oligoclonal expansion of bronchoalveolar CD8+ T cells was confirmed by sequence analysis of AV21-constant alpha (AC) and BV9-BC junctional regions in the blood and BAL cells. The levels of V gene expression and the diversity of junctional region lengths were very similar in T cells obtained from three separate lobes of one donor. In general, skewed patterns of TCR junctional region lengths were not consistent over time two donors, over periods of 3 and 17 months. Together, these data show that the T-cell repertoire is diverse within the lungs of normal humans, except for an oligoclonal predominance of a few V gene families in both CD4+ and CD8+ T cells. The T-cell repertoire in the lungs changes over time, which may reflect environmental exposures.

Effects of carbon monoxide on myocardial ischemia.

The purpose of this study was to determine whether low doses of carbon monoxide (CO) exacerbate myocardial ischemia during a progressive exercise test. The effect of CO exposure was evaluated using the objective measure of time to development of electrocardiographic changes indicative of ischemia and the subjective measure of time to onset of angina. Sixty-three male subjects (41-75 years) with well-documented coronary artery disease, who had exertional angina pectoris and ischemic ST-segment changes in their electrocardiograms, were studied. Results from three randomized, double-blind test visits (room air, low and high CO) were compared. The effect of CO exposure was determined from the percent difference in the end points obtained on exercise tests performed before and after a 1-hr exposure to room air or CO. The exposures resulted in postexercise carboxyhemoglobin (COHb) levels of 0.6% +/- 0.3%, 2.0% +/- 0.1%, and 3.9% +/- 0.1%. The results obtained on the 2%-COHb day and 3.9%-COHb day were compared to those on the room air day. There were 5.1% (p = 0.01) and 12.1% (p less than or equal to 0.0001) decreases in the time to development of ischemic ST-segment changes after exposures producing 2.0 and 3.9% COHb, respectively, compared to the control day. In addition, there were 4.2% (p = 0.027) and 7.1% (p = 0.002) decreases in time to the onset of angina after exposures producing 2.0 and 3.9% COHb, respectively, compared to the control day. A significant dose-response relationship was found for the individual differences in the time to ST end point and angina for the pre- versus postexposure exercise tests at the three carboxyhemoglobin levels. These findings demonstrate that low doses of CO produce significant effects on cardiac function during exercise in subjects with coronary artery disease.

Relationship between airway obstruction and respiratory symptoms in adult asthmatics.

STUDY OBJECTIVES: To characterize the relationship between symptoms and the degree of airway obstruction as determined by the FEV1 and peak expiratory flow (PEF) in a cohort of adult patients attending a university-based urban asthma clinic. DESIGN: Each of six current asthma symptoms, including cough, dyspnea, wheeze, chest tightness, sputum production, and nocturnal awakening was rated by patients on a 0 (none) to 4 (constant) scale at initial and first follow-up clinic evaluations. Spirometry and PEF were measured at the initial clinic visit and PEF was measured at all follow-up visits. PATIENTS: Sixty-seven adult patients with chronic asthma. MEASUREMENTS AND RESULTS: Asthma symptoms did not correlate with the degree of airway obstruction as determined by the FEV1 (percent predicted FEV1 vs total symptoms: r=0.143; p=0.263; n=70) and only correlated poorly with PEF (percent predicted PEF vs total symptoms: r=0.384; p=0.0029; n=58). Subjective wheezing was the best individual predictor of the level of airway obstruction in this group of patients. When reassessed an average of 7.9 weeks later, patients reported significant improvement in several symptoms, including those of wheeze, chest tightness, dyspnea, and nocturnal awakening. However, this symptomatic improvement was not associated with improvement in the level of airway obstruction. CONCLUSIONS: Asthma symptoms correlate poorly with the level of airway obstruction as determined by the FEV1 and PEF. Following treatment, subjective improvement in asthma symptoms may occur without improvement in the level of airway obstruction. These results support the recommendation to measure airway obstruction objectively when assessing adult patients with chronic asthma.

Increased vascular pedicle width preceding burn-related pulmonary edema.

Widening of the vascular pedicle on the chest roentgenogram is a recently identified sign of increased circulating blood volume. To determine whether vascular pedicle enlargement can be detected during the initial day of burn resuscitation and whether this change correlates with the early development of pulmonary edema, we reviewed the serial chest roentgenograms of 42 patients with cutaneous burns and risk factors for inhalation injury. Although no patient had pulmonary edema at the time of vascular pedicle measurements, 18 (42.9 percent) developed this complication during the 3.3 +/- 1.5 days after injury. These patients were significantly older (p less than 0.025) and had received more resuscitative fluid (P less than 0.005) than those without pulmonary edema. Initial vascular pedicle width was similar in both groups (5.9 +/- 0.9 vs 6.0 +/- 1.0 cm) and did not change in patients without pulmonary edema (5.8 +/- 0.7 cm). Vascular pedicle width increased (6.9 +/- 1.2 cm, p less than 0.01) in patients who subsequently developed pulmonary edema, and 12 of the 13 patients who had changes exceeding +1.0 cm had this problem. Enlargement of the vascular pedicle is associated with early burn-related pulmonary edema and might provide a clinically useful predictor of this cardiopulmonary complication.

Radionuclide localization of massive pulmonary hemorrhage.

Lung scans with technetium sulfur colloid were performed in ten patients with life-threatening hemoptysis and nondiagnostic chest roentgenograms. Localized deposition of radionuclide was demonstrated in five of the six patients who were studied during active bleeding. These abnormalities were confirmed bronchoscopically in four patients, and lung scans provided clinically useful information regarding the bleeding site that had not been available from the medical history, physical examination, or chest roentgenogram. Evaluation with radionuclide scanning may complement bronchoscopic and roentgenographic studies in selected patients with massive pulmonary hemorrhage.

Computed chest tomography in the evaluation of hemoptysis. Impact on diagnosis and treatment.

The results of computed chest tomograms (CT) and chest roentgenograms (CR) were compared in 32 patients who presented with hemoptysis. The CT demonstrated roentgenographic abnormalities more often than CR (p less than 0.01), providing new diagnostic information in 15 patients (46.9 percent), and clarifying CR abnormalities in five (15.6 percent) others. In addition, CT correctly localized sources of bleeding in 23 (88.5 percent) of the 26 patients in whom a site was identified at bronchoscopy, while CR localization was correct in 17 (65.4 percent) (p less than 0.05). Despite this augmentation of roentgenographic yield, information derived from CT scans influenced the management of only six patients, did not obviate the need for bronchoscopy, and supplemented the combined diagnostic yield of CR and bronchoscopy in only two. Outcome was changed in one patient in whom CT had demonstrated an otherwise unrecognized malignant solitary pulmonary nodule. The chest roentgenogram and fiberoptic bronchoscopy provided all the information essential for diagnosis and therapeutic recommendations in 93.7 percent of these patients. Although the CT provided additional information in over one half of our patients, its overall impact on clinical management was small and does not support routine use of this imaging procedure in evaluation of hemoptysis. The possible role of chest CT in evaluating carefully selected patients with hemoptysis requires further study.

A screening test for airways reactivity. An abbreviated methacholine inhalation challenge.

A screening test to measure nonspecific airways reactivity was developed and compared to a standard methacholine inhalation challenge in 13 asthmatic patients and ten normal control subjects. The screening challenge consisted of one deep breath, then four breaths of a 5 mg/ml methacholine solution followed by one and four breaths of 25 mg/ml of methacholine. Subjects with a history of wheezing received the 5 mg/ml of methacholine first while those without a history of asthma began the challenge at the 25 mg/ml methacholine concentration. Spirometric test were employed and the challenge was terminated when FEV1 fell 20 percent from baseline. The standard methacholine challenge used a dosimeter and all subjects took five breaths of saline solution followed by seven increasing concentrations of methacholine. Dose response curves were constructed and the provocation dose of methacholine that caused a 20 percent fall in FEV1 was calculated for each protocol. Results of the screening methacholine challenge correlated with those obtained from the more lengthy standard protocol (r = 0.94), and correctly identified levels of airways reactivity in asthmatic patients and normal subjects. The abbreviated protocol was rapid (6-12 min), safe, and inexpensive. Since the equipment is readily available and easy to transport, it could be used at sites outside the hospital as a screening test for nonspecific airways reactivity.

Proventil HFA and ventolin have similar safety profiles during regular use.

OBJECTIVE: As a secondary objective to a long-term study evaluating the bronchodilator effectiveness of Proventil HFA (albuterol), to assess the safety of Proventil HFA, Ventolin, and hydrofluoroalkane 134a (HFA-134a) placebo over 12 weeks of regular dosing. DESIGN: Randomized, double-blind, double-dummy parallel group, placebo-controlled, multicenter trial of asthmatics requiring inhaled beta-adrenergic bronchodilators for symptom control. INTERVENTIONS: Treatment with Proventil HFA, Ventolin, or HFA-134a placebo, qid, for 12 weeks. MEASUREMENTS: Adverse events were reviewed at biweekly clinic visits. Between clinic visits, patients recorded morning and evening peak expiratory flow (PEF), asthma symptom and nighttime asthma sleep disturbance scores, and use of rescue beta-adrenergic bronchodilator on diary cards daily. Investigators provided a global assessment of asthma control at weeks 0, 4, 8, and 12. Vital signs were recorded over 6 h after dosing with study drug at weeks 0, 4, 8, and 12. Standard laboratory tests, CBC count, serum chemistries, and urinalysis were obtained at study start and end. RESULTS: Adverse event reporting rates were similar for the three treatment groups. The morning PEF tended to be lower for the Proventil HFA and Ventolin groups than the HFA-134a placebo group, but the evening PEF tended to be higher for the active treatment groups. Daytime asthma symptom scores tended to be lower (better) with active treatment than placebo, but nighttime asthma sleep disturbance scores were similar for all three treatment groups. Use of Ventolin Rotacaps as rescue medication was significantly greater for the HFA-134a placebo group than the Proventil HFA and Ventolin groups. Diary card data did not change within groups over time. Investigator global assessments of asthma scores clustered between fair and good for all three treatment groups throughout the study. Changes in heart rate and BP were small after dosing with study drug and tended to be similar for the active treatments and HFA-134a placebo groups. No clinically meaningful changes in results of standard laboratory tests were found in any treatment group during this study. CONCLUSIONS: Proventil HFA had a similar safety profile as Ventolin during regular use. A dosage of 16 puffs per day of propellant HFA-134a was well tolerated by asthmatics. Regular use of either Proventil HFA or Ventolin did not cause asthma control to deteriorate.