Nasal challenge with cold, dry air results in release of inflammatory mediators. Possible mast cell involvement.

The purpose of our study was to assess the effect of cold, dry air (CDA) on the nasal mucosa of selected individuals in relation to the release of inflammatory mediators associated with mast cells. 12 subjects with a history of nasal symptoms of rhinorrhea and congestion upon cold or dry environmental exposure were challenged by nasal breathing of CDA and warm, moist air (WMA). Each subject was tested on two occasions with the order of the challenges reversed. Symptom scores were recorded, and the levels of histamine, prostaglandin (PG) D2, kinins, and [3H]-N-alpha-tosyl-L-arginine methyl ester (TAME)-esterase activity in nasal lavage fluids were measured. CDA caused a significant increase in mediator levels and in symptom scores as compared to baseline or to WMA. No significant increase in symptom scores or mediators was noted after WMA challenge, with the exception of a marginal increase in kinins. The response to CDA was similar, regardless of challenge order. Changes in mediators correlated with one another, and symptom scores correlated significantly with the levels of histamine, kinins, and PGD2. Five subjects without a history of nasal symptoms on cold air exposure had no change in mediators or symptom scores after CDA or WMA challenge. We conclude that CDA causes the release of inflammatory mediators possibly associated with mast cells and speculate that such a mechanism may be involved in the bronchospasm induced by CDA in asthmatics.

Recurrent noncardiac pulmonary edema accompanying pregnancy-induced hypertension.

Severe pulmonary edema occurred in a patient during the third trimester of two consecutive pregnancies, 17 months apart. Noncardiac origin of the pulmonary edema was demonstrated by normal pulmonary capillary wedge pressures, normal roentgenographic cardiac dimensions with absence of effusions, normal echocardiographic ejection fraction, and elevated thermodilution cardiac outputs; moderate reduction in serum albumin levels may have contributed. In the setting of pregnancy-induced hypertension, the development of ARDS on each occasion suggests a pathophysiologic link.

Effects of colchicine on IgE-mediated early and late airway reactions.

BACKGROUND: The pathogenesis of bronchial asthma is thought to involve elements of both acute and chronic inflammation. Hence, there is growing interest in the potential of immunomodulatory drugs in asthma therapy. This study examines the effects of the anti-inflammatory compound colchicine on early and late allergen-induced, IgE-mediated airway reactions. METHODS: Nine mildly allergic asthmatic subjects were evaluated in a single-blind, two-way crossover study designed to examine the effects of colchicine and placebo on early and late airway reactions to ragweed allergen and related changes in nonspecific responsiveness to methacholine. RESULTS: Compared with placebo, colchicine provided 19% (p = 0.036) and 40% (p = 0.004) inhibition of early and late airway reactions to allergen, respectively. Allergen-induced increases in methacholine responsiveness were observed with both types of treatment, although there was a trend toward a smaller increase after administration of colchicine (p = 0.13). We also found that methacholine responsiveness per se was not directly altered by colchicine (n = 7). In 6 subjects, we found suppression of neutrophil leukotriene B4 generation after colchicine treatment, suggesting that the colchicine dose (0.6 mg twice daily) was sufficient to produce an anti-inflammatory effect. Further in vitro studies using purified human lung tissue mast cells failed to demonstrate inhibition of mediator release at concentrations corresponding to achievable tissue or blood levels during the in vivo trial. CONCLUSION: Colchicine partially inhibits IgE-mediated early and late airway reactions at conventional clinical doses. This inhibitory effect may be mediated via suppression of some cell species other than the lung tissue mast cell. Controlled studies to examine the benefits of colchicine in clinically evidenced asthma are warranted.

Salmeterol powder provides significantly better benefit than montelukast in asthmatic patients receiving concomitant inhaled corticosteroid therapy.

STUDY OBJECTIVES: Comparison of inhaled salmeterol powder vs oral montelukast treatment in patients with persistent asthma who remained symptomatic while receiving inhaled corticosteroids. DESIGN: Randomized, double-blind, double-dummy, parallel-group, multicenter trials of 12-week duration. SETTING: Outpatients in private and university-affiliated clinics. PATIENTS: Male and female patients > or = 15 years of age with a diagnosis of asthma (baseline FEV(1) of 50 to 80% of predicted) and symptomatic despite receiving inhaled corticosteroids. INTERVENTIONS: Inhaled salmeterol xinafoate powder, 50 microg bid, or oral montelukast, 10 mg qd. MEASUREMENTS AND RESULTS: Treatment with salmeterol powder resulted in significantly greater improvements from baseline compared with montelukast for most efficacy measurements, including morning peak expiratory flow (35.0 L/min vs 21.7 L/min; p < 0.001), percentage of symptom-free days (24% vs 16%; p < 0.001), and the percentage of rescue-free days (27% vs 20%; p = 0.002). Total supplemental albuterol use was decreased significantly more in the salmeterol group compared with the montelukast group (- 1.90 puffs per day vs - 1.66 puffs per day; p = 0.004) and nighttime awakenings per week decreased significantly more with salmeterol than with montelukast (- 1.42 vs - 1.32; p = 0.015). Patients treated with inhaled salmeterol were significantly more satisfied with their treatment regimen and how well, how fast, and how long it worked than were patients who were treated with oral montelukast. The safety profiles for the two treatments were similar. CONCLUSION: In patients with persistent asthma who remain symptomatic while receiving inhaled corticosteroids, adding inhaled salmeterol powder provided significantly greater improvement in lung function and asthma symptoms and was preferred by patients over oral montelukast.

The utility of peak flow, symptom scores, and beta-agonist use as outcome measures in asthma clinical research.

STUDY OBJECTIVES: Several methods of utilizing peak expiratory flow (PEF) and other markers of disease activity have been suggested as useful in the management of asthma. It remains unclear, however, as to which surrogate markers of disease status are discriminative indicators of treatment failure, suitable for use in clinical trials. DESIGN: We analyzed the operating characteristics of 66 surrogate markers of treatment failure using a receiver operating characteristic (ROC) curve analysis. PARTICIPANTS: Information regarding FEV(1), symptoms, beta(2)-agonist use, and PEF was available from 313 subjects previously enrolled in two Asthma Clinical Research Network trials, in which 71 treatment failures occurred (defined by a 20% fall in FEV(1) from baseline). INTERVENTIONS: None. MEASUREMENTS AND RESULTS: None of the measures had an acceptable ability to discriminate subjects with a > or % fall in FEV(1) from those without, regardless of the duration of the period of analysis or the criteria for test positivity employed. Areas under the ROC curves generated ranged from 0.51 to 0.79, but none were statistically superior. Sensitivity and specificity combinations were generally poor at all cutoff values; true-positive rates could not be raised without unacceptably elevating false-positive rates concurrently. CONCLUSIONS: Studies that seek to detect treatment failure defined by a significant fall in FEV(1) should not use such individual surrogate measures to estimate disease severity.

Physiology of aging related to outcome in the adult respiratory distress syndrome.

Thirty-nine patients with adult respiratory distress syndrome (ARDS) were enrolled in a study to identify potential age-related changes in organ system function that may help explain the apparent association between age and poor outcome in these patients. Criteria for enrollment included an arterial PO2-to-inspired O2 concentration ratio less than or equal to 200 in a clinical setting consistent with ARDS. Patients were excluded if they were less than 18 yr old, had clinical manifestations of congestive heart failure, were seropositive for the human immunodeficiency virus, or had stage II metastatic lung cancer. Patients were divided into two groups: those less than 60 yr old (mean 42 +/- 3 yr, n = 17) and those greater than or equal to 60 yr old (73 +/- 2 yr, n = 16). A group of six patients was analyzed as a separate subset based on a body temperature less than or equal to 97.5 degrees F at enrollment (hypothermic patients, 73 +/- 4 yr old). Sepsis was present in 67% of the nonhypothermic patients and in all the hypothermic patients. Mortality rates were 12% in the patients less than 60 yr and 69% in the nonhypothermic patients greater than or equal to 60 yr. All the hypothermic patients died. Sequential data obtained over 6 days were compared within and between groups. The following results were obtained. 1) The ratio of arterial PO2 to inspired O2 fraction was greater and the positive end-expiratory pressure used was significantly less in the patients greater than or equal to 60 yr old compared with the younger group.(ABSTRACT TRUNCATED AT 250 WORDS)

Zafirlukast for symptomatic mild-to-moderate asthma: a 13-week multicenter study. The Zafirlukast Trialists Group.

The efficacy of the oral leukotriene-receptor antagonist zafirlukast was assessed as maintenance therapy for patients with mild-to-moderate asthma. A total of 762 patients aged 12 to 76 years were enrolled in a 13-week, multicenter, double-masked, placebo-controlled, parallel-group trial and randomly assigned to receive either zafirlukast (20 mg twice daily) or placebo. Patients were maintained on as-needed beta-agonist therapy throughout the study and had to have a cumulative daytime asthma symptoms score > or = 8 (on a daily scale of 0 to 3) over 7 consecutive days before randomization. Efficacy was assessed by changes in symptoms, beta-agonist use, and pulmonary function. Safety was assessed by adverse experiences, laboratory test results, physical examination, and electrocardiography. Zafirlukast significantly decreased daytime asthma symptoms scores (-26.5%), nighttime awakenings (-19.8%), mornings with asthma (-29.0%), and beta-agonist use (-22.3%) and significantly increased morning peak expiratory flow rate (6.9%) and forced expiratory volume in 1 second (6.3%) compared with placebo. Changes in symptoms, beta-agonist use, and pulmonary function occurred within 2 days of zafirlukast treatment and continued throughout the trial. Zafirlukast was well tolerated. Pharyngitis and headache were the most common adverse events, occurring with similar frequency in both the zafirlukast and placebo groups. No clinically significant changes were observed in laboratory test results, findings on physical examination, or electrocardiographic findings. We conclude that zafirlukast produces early and sustained effects in the treatment of mild-to-moderate asthma.

Lung involvement in systemic sclerosis (scleroderma): relation to classification based on extent of skin involvement or autoantibody status.

Lung involvement accounts for significant morbidity and is a leading cause of mortality in patients with systemic sclerosis (SSc). It has been shown that different patterns of pulmonary involvement are seen in different subtypes of SSc. This paper reports a retrospective review of 72 patients with SSc to determine whether disease classification according to the extent of skin involvement alone (diffuse vs. limited) or autoantibody status was predictive of pulmonary parenchymal involvement. The diagnosis of interstitial lung disease was based on pulmonary function tests and chest radiographs. Restrictive lung disease was common in both limited SSc (lSSc) and diffuse SSc (dSSc), occurring in 30% and 50% of these patients respectively (P = 0.16). Radiographic evidence of significant interstitial disease was also comparable between the groups [nine of 32 lSSc patients (28%) vs. six of 17 dSSc patients (32%), P = n.s.]. No significant difference in mean lung function was found between patients with anti-Scl 70 antibody (n = 12) compared to those without (n = 60) (TLC 79.0 +/- SE 5.1% predicted vs. 82.8 +/- 2.2, P = n.s.; DLCO 63.0 +/- 5.1 vs. 59.7 +/- 2.5, P = n.s.). By contrast, statistically significant differences in mean lung function were found between patients with anticentromere antibody (ACA) (n = 24) and those without ACA (n = 48) (TLC 98.6 +/- SE 3.9% predicted vs. 79.7 +/- 3.1%, P < 0.001); and less frequent radiographic evidence of severe interstitial disease (0 of 17 with significant interstitial changes on chest radiograph vs. 15 of 32 (47%), P = 0.002). It is concluded that classification of SSc patients on the basis of the distribution of skin involvement poorly predicts the occurrence of interstitial lung disease. On the other hand, ACA is highly associated with the absence of interstitial lung disease.

Pharmaceutically-based severity stratification of an asthmatic population.

Algorithms designed to precisely identify disease severity for a given patient within a managed care population are helpful in organizing targeted interventions. These algorithms are also attracting considerable attention within the medical research community. Several health risk screening instruments have been developed; however, these involve survey methodologies and have several shortcomings. We present a valid and efficient method for predicting healthcare resource utilization among asthmatics in an Health Maintenance Organization (HMO) population. First, various diagnosis, procedure and pharmacy billing codes were used to identify the asthmatics within the database. The screening algorithm awards points each time one of these codes is identified for an HMO member. By varying the number of points necessary to consider a patient asthmatic, the sensitivity, specificity, positive and negative predictive values of the algorithm can be adjusted. Once identified as asthmatic, subjects were then stratified into severity levels based on pharmacy data. Severity stratification was validated directly by measuring asthma-related bed days utilized during the 12 months following the date of stratification. Our identification algorithm estimated an asthma prevalence of 3.84% within the studied population, with age-specific prevalence estimates that closely mirrored previously published survey data. There was a monotonic relationship between pharmacy severity levels and inpatient resource utilization. For example, asthmatics in severity level 1 used only 92 hospital days per 1000 asthmatics in the year following characterization, while those in levels 2-5 used 133, 156, 277 and 1168 hospital days (P < 0.001), respectively. Results from this model can be used as adjusters in other predictive models or stand alone to represent a patient's severity of illness.

Endothelial nitric oxide synthase: insight into cell-specific gene regulation in the vascular endothelium.

The vascular endothelium plays a crucial role in regulating normal blood vessel physiology. The gene products responsible are commonly expressed exclusively, or preferentially, in this cell type. However, despite the importance of regulated gene expression in the vascular endothelium, relatively little is known about the mechanisms that restrict endothelial-specific gene expression to this cell type. While significant progress has been made towards understanding the regulation of endothelial genes through cis/trans paradigms, it has become apparent that additional mechanisms must also be operative. For example, chromatin-based mechanisms, including cell-specific DNA methylation patterns and post-translational histone modifications, have recently been demonstrated to play important roles in the cell-specific expression of endothelial nitric oxide synthase (eNOS). This review investigates the involvement of epigenetic regulatory mechanisms in vascular endothelial cell-specific gene expression using eNOS as a prototypical model, and will address the possible contributions of these pathways to diseases of the vasculature.

Calcium channel antagonists in the treatment of asthma.

The pathophysiologic processes that contribute to airway obstruction in asthma involve Ca2+-dependent excitation-contraction and stimulus-secretion coupling mechanisms. The emergence of new compounds that specifically inhibit Ca2+ flux across membrane ionic channels has stimulated widespread interest in the therapeutic potential of these agents in asthma. Studies with these agents in relevant in vitro test systems and animal models, however, have yielded conflicting results and have thus far failed to furnish strong support for a therapeutic role. In human studies, these agents have been found to inhibit exercise-induced bronchospasm, but their ability to inhibit the effects of other stimuli and to dilate airways is equivocal. In general, clinical trials with currently approved drugs--diltiazem, nifedipine, and verapamil--are limited by potency, formulation, and side effects of these agents. What future role, if any, Ca2+ channel antagonists will have in the treatment of asthma is likely to depend on the development of newer agents with greater tissue selectivity at the level of airway smooth muscle and mast cells.

Occupational asthma: a spectrum of acute respiratory disorders.

Occupational asthma is a general term applied to a variety of clinical disorders, each characterized by acute, reversible respiratory symptoms caused by exposure to environmental or work-related stimuli. The diverse pathologic basis for this group of disorders includes bronchoconstriction, airway inflammation and edema, toxic or inflammatory alveolitis/bronchiolitis, or noncardiogenic pulmonary edema. On the basis of the abnormalities and the mechanisms responsible for lung injury, occupational asthma may be classified as (1) toxic or inflammatory reactions: (2) immediate "allergic" hypersensitivity reactions; (3) hypersensitivity reactions of unknown origin; (4) irritant reactions; and (5) delayed hypersensitivity reactions. Physical and chemical properties of the causative agent, host factors, and intensity of exposure largely determine the type of reaction produced. At the practical level, different reactions may be distinguished on the basis of characteristic clinical features and laboratory findings. Therefore, an understanding of the different reaction categories is useful in the identification of specific causative agents, in successful patient management, and in the development of environmental safeguards.