Specialty: Allergy and Pulmonary Medicine
Brigham and Women’s Hospital
15 Francis Street
Boston, MA 02115
The following is a list of recent publications for which this Partners Asthma Center physician has been cited as an author in PubMed databases. Study abstracts have been provided for your convenience.
Richy, F., J. Bousquet, et al. (2003). "Inhaled corticosteroids effects on bone in asthmatic and COPD patients: a quantitative systematic review." Osteoporos Int 14(3): 179-190.
Deleterious effect of oral corticosteroids on bone has been well documented, whereas this remains debated for inhaled ones (ICS). Our objectives were to analyze the effects of ICS on bone mineral density, fracture risk and bone markers. We performed an exhaustive systematic research of all controlled trials potentially containing pertinent data, peer-reviewed by a dedicated WHO expert group, and comprehensive meta-analyses of the data. Inclusion criteria were ICS, and BMD/markers/fractures in asthma/chronic obstructive pulmonary diseases (COPD) and healthy patients. Analyses were performed in a conservative fashion using professional dedicated softwares and stratified by outcome, study design and ICS type. Results were expressed as standardized mean difference/effect size (ES), relative risk (RR) or odds ratio (OR), depending on study design and outcome units. Publication bias was investigated. Twenty-three trials were reviewed; 11 papers fit the inclusion criteria and were assessed for the main analysis. Quality scores for the randomized controlled trials (RCTs) were 80%, 71% for the prospective cohort studies, and 78% for the retrospective cohort and cross-sectional studies. We globally assessed ICS effects on BMD and found deleterious effects: ES=0.61 ( p=0.001) for healthy subjects, and ES=0.27 ( p<0.001) for asthma/COPD patients. For these patients, this effect was 0.21 ( p<0.01) at the lumbar spine, and 0.26 ( p<0.001) at the hip or femoral neck. A single study evaluated the impact of ICS on hip fracture and reported an increased OR of 1.6 (1.24; 2.03). Lumbar fracture rate differences did not reach the level of statistical significance: 1.87 (0.5; 6.94). Osteocalcin and PICP were decreased and ICTP, pyridinoline and deoxypyridinoline levels were not significantly affected. Budesonide (BUD) appeared to be the ICS inducing the less deleterious effects on bone, followed by beclomethasone dipropionate (BDP) and triamcinolone (TRI). Publication bias investigation provided non-significant results. In our meta-analyses, BUD at a mean daily dose (SD) of 686 &mgr;g (158 &mgr;g), BDP at 703 &mgr;g (123 &mgr;g) and TRI at 1000 &mgr;g (282 &mgr;g) were found to affect bone mineral density and markers in patients suffering from the two major respiratory diseases. These findings could have practical implication in the long-term management of asthmatic and COPD patients.
Kalayci, O., M. Wechsler, et al. (2003). "LTC4 production by eosinophils in asthmatic subjects with alternative forms of ALOX-5 core promoter." Adv Exp Med Biol 525: 11-4.
Henderson, A. C., E. P. Ingenito, et al. (2003). "How does airway inflammation modulate asthmatic airway constriction? An antigen challenge study." J Appl Physiol 95(2): 873-82; discussion 863.
During the late-phase (LP) response to inhaled allergen, mediators from neutrophils and eosinophils are released within the airways, resembling what occurs during an asthma attack. We compared the distribution of obstruction and degree of reversibility that follows a deep inspiration (DI) during early-phase (EP) and LP responses in nine asthmatic subjects challenged with allergen. Heterogeneity of constriction was assayed by determining frequency dependence of dynamic lung resistance and elastance, airway caliber by tracking airway resistance during a DI, and airway inflammation by measuring inflammatory cells in induced sputum postchallenge. Despite a paucity of eosinophils in the sputum at baseline (<1% of nonsquamous cells), asthmatic subjects showed a substantial EP response with highly heterogeneous constriction and reduced capacity to maximally dilate airways. The LP was associated with substantial airway inflammation in all subjects. However, five subjects showed only mild LP constriction, whereas four showed more marked LP constriction characterized by heterogeneous constriction similar to EP. Bronchoconstriction during LP was fully alleviated by administration of a bronchodilator. These findings, together with the impaired bronchodilatory response during a DI, indicate a physiological abnormality in asthma at the smooth muscle level and indicate that airway inflammation in asthma is associated with a highly nonuniform pattern of constriction. These data support the hypothesis that variability in responsiveness among asthmatic subjects derives from intrinsic differences in smooth muscle response to inflammation.
Black, L. D., R. Dellaca, et al. (2003). "Tracking variations in airway caliber by using total respiratory vs. airway resistance in healthy and asthmatic subjects." J Appl Physiol 95(2): 511-8.
An index of airway caliber can be tracked in near-real time by measuring airway resistance (Raw) as indicated by lung resistance at 8 Hz. These measurements require the placing of an esophageal balloon. The objective of this study was to establish whether total respiratory system resistance (Rrs) could be used rather than Raw to track airway caliber, thereby not requiring an esophageal balloon. Rrs includes the resistance of the chest wall (Rcw). We used a recursive least squares approach to track Raw and Rrs at 8 Hz in seven healthy and seven asthmatic subjects during tidal breathing and a deep inspiration (DI). In both subject groups, Rrs was significantly higher than Raw during tidal breathing at baseline and postchallenge. However, at total lung capacity, Raw and Rrs became equivalent. Measured with this approach, Rcw appears volume dependent, having a magnitude of 0.5-1.0 cmH2O. l-1. s during tidal breathing and decreasing to zero at total lung capacity. When resistances are converted to an effective diameter, Rrs data overestimate the increase in diameter during a DI. Simulation studies suggest that the decrease in apparent Rcw during a DI is a consequence of airway opening flow underestimating chest wall flow at increased lung volume. We conclude that the volume dependence of Rcw can bias the presumed net change in airway caliber during tidal breathing and a DI but would not distort assessment of maximum airway dilation.
Wechsler, M. E. and E. Israel (2002). "Pharmacogenetics of treatment with leukotriene modifiers." Curr Opin Allergy Clin Immunol 2(5): 395-401.
PURPOSE OF REVIEW Pharmacogenetics is emerging as a field with great potential to improve both our understanding and treatment options in asthma. This review highlights the importance of pharmacogenetic associations of an important class of asthma therapy, the leukotriene modifiers, and asthma. RECENT FINDINGS: Over the past decade, different leukotriene modifier therapies have emerged and have resulted in improvements in asthma parameters in individuals with this condition. However, there is substantial interindividual variability with respect to the response to this and other asthma therapies. Over the past few years, polymorphisms of two genes in the leukotriene pathway, the gene and the synthase gene, have been identified and have been demonstrated to have pharmacogenetic associations with asthma. However, currently identified genetic determinants explain the response to therapy in only a minority of patients. SUMMARY: As the field of pharmacogenetics advances, an increasing proportion of individual variation in response to pharmacotherapy will be predictable on the basis of associations with particular genetic polymorphisms or patterns of polymorphisms. The pharmacogenetic association of leukotriene modifiers and asthma is an excellent example of how these associations hold out the promise of being able to individualize pharmacotherapy, by providing specific medications to those most likely to respond while avoiding therapy in those most likely to suffer adverse effects.
Szefler, S. J., R. J. Martin, et al. (2002). "Significant variability in response to inhaled corticosteroids for persistent asthma." J Allergy Clin Immunol 109(3): 410-8.
BACKGROUND: A clinical model is needed to compare inhaled corticosteroids (ICSs) with respect to efficacy. OBJECTIVE: The purpose of this investigation was to compare the relative beneficial and systemic effects in a dose-response relationship for 2 ICSs. METHODS: A 24-week, parallel, open-label, multicenter trial examined the benefit-risk ratio of 2 ICSs in persistent asthma. Benefit was assessed by improvements in FEV(1) and PC(20); risk was assessed by overnight plasma cortisol suppression. Thirty subjects were randomized to either beclomethasone dipropionate (BDP) 168, 672, and 1344 microg/day (n = 15) or fluticasone propionate (FP) 88, 352, and 704 microg/day (n = 15), both administered by means of a metered dose inhaler (MDI) with chlorofluorocarbon propellant via a spacer, in 3 consecutive 6-week intervals; this was followed by 3 weeks of FP dry powder inhaler (DPI) 2000 microg/day. RESULTS: Maximum FEV(1) response occurred with the low dose for FP-MDI and the medium dose for BDP-MDI and was not further increased by treatment with FP-DPI. Near-maximum methacholine PC(20) improvement occurred with the low dose for FP-MDI and the medium dose for BDP-MDI. Both BDP-MDI and FP-MDI caused dose-dependent cortisol suppression. Responsiveness to ICS treatment was found to vary markedly among subjects. Good (>15%) FEV(1) response, in contrast to poor (<5%) response, was found to be associated with high exhaled nitric oxide (median, 17.6 vs 11.1 ppb), high bronchodilator reversibility (25.2% vs 8.8%), and a low FEV(1)/forced vital capacity ratio (0.63 vs 0.73) before treatment. Excellent (>3 doubling dilutions) improvement in PC(20), in contrast to poor (<1 doubling dilution) improvement, was found to be associated with high sputum eosinophil levels (3.4% vs 0.1%) and older age at onset of asthma (age, 20-29 years vs <10 years). CONCLUSIONS: Near-maximal FEV(1) and PC(20) effects occurred with low-medium dose for both ICSs in the subjects studied. High-dose ICS therapy did not significantly increase the efficacy measures that were evaluated, but it did increase the systemic effect measure, overnight cortisol secretion. Significant intersubject variability in response occurred with both ICSs. It is possible that higher doses of ICSs are necessary to manage more severe patients or to achieve goals of therapy not evaluated in this study, such as prevention of asthma exacerbations.
Martin, R. J., S. J. Szefler, et al. (2002). "Systemic effect comparisons of six inhaled corticosteroid preparations." Am J Respir Crit Care Med 165(10): 1377-83.
The goal of this study was to establish a reliable method to evaluate systemic bioavailability and to determine equisystemic effects (microgram dose producing equal systemic cortisol suppression) of inhaled corticosteroids (ICS). Steroid naive asthma subjects (n = 156) were enrolled at six centers. A 1-week doubling dose design was used for each of six ICS and matched placebos for a total of four doses. Systemic effect was evaluated by hourly plasma cortisol concentrations (8 P.M. to 8 A.M.), 12- and 24-hour urine cortisol concentrations, and a morning blood osteocalcin. The area under the concentration-time curve for hourly cortisol concentrations was the best outcome variable to assess systemic effect. For the six ICS and matching placebos (beclomethasone-chlorofluorocarbon [CFC], budesonide dry powder inhaler [DPI], fluticasone DPI, fluticasone-CFC metered dose inhaler [MDI], flunisolide-CFC, and triamcinolone-CFC), only the placebo group and fluticasone DPI did not demonstrate a significant dose-response effect. Thus microgram comparison of all ICS could only be performed at a 10% cortisol suppression: flunisolide-CFC - 936; triamcinolone-CFC - 787; beclomethasone-CFC - 548; fluticasone DPI - 445; budesonide DPI - 268; fluticasone-CFC MDI - 111. This study represents the first step in evaluation of ICS efficacy based on equisystemic (cortisol suppression) effects of a given ICS, rather than doses judged arbitrarily to be comparable on a microgram basis.
Israel, E., P. S. Chervinsky, et al. (2002). "Effects of montelukast and beclomethasone on airway function and asthma control." J Allergy Clin Immunol 110(6): 847-54.
BACKGROUND: Maintaining asthma control is a major objective of therapy. Traditionally, the effectiveness of asthma therapy has been judged primarily by its effect on airway function rather than on multiaspect asthma control. OBJECTIVE: An inhaled corticosteroid and a leukotriene receptor antagonist were compared to determine whether they provided equivalent effects, as judged by days of asthma control. METHODS: In a randomized, multicenter, double-blind, placebo-controlled, parallel-group study, asthmatic patients (n = 782) with FEV(1) percent predicted values of between 50% and 85% and a weekly average beta-agonist use of more than 2 puffs per day were randomized to receive montelukast (10 mg daily), beclomethasone (200 microg twice daily), or placebo treatment for 6 weeks in a double-dummy fashion. We examined the distribution of the primary end point: percentage of days of asthma control. Secondary end points included FEV(1), albuterol use, occurrence of an asthma attack, asthma flare-up, rescue corticosteroid use, sustained asthma control, and adverse experiences. RESULTS: The percentage of days of asthma control was almost identical between the montelukast and beclomethasone groups (98% overlap in the distribution). Montelukast was at least equal to beclomethasone, and both were greater than placebo on the basis of frequency of asthma attacks, asthma flare-ups, and rescue corticosteroid use. Beclomethasone had a greater effect than montelukast and both treatments were better than placebo at improving FEV(1). CONCLUSIONS: Montelukast was as effective as beclomethasone, as judged by indices of clinical control other than FEV(1). When evaluating the outcome of montelukast therapy, FEV(1) might underestimate clinical effectiveness.
Deykin, A., A. F. Massaro, et al. (2002). "Exhaled nitric oxide as a diagnostic test for asthma: online versus offline techniques and effect of flow rate." Am J Respir Crit Care Med 165(12): 1597-601.
Measurement of the fraction of exhaled nitric oxide (FENO) has been proposed as a noninvasive assessment of asthmatic airway inflammation. The influence of the expiratory flow rate during the collection maneuver on the ability of FENO to discriminate healthy subjects from those with asthma is unknown. We compared online and offline measurement of FENO at different flow rates. FENO was collected with expiratory flows of 50-500 ml/second in 34 patients with asthma (PC(20) of less than 8 mg/ml) and 28 healthy subjects (PC(20) of more than 10 mg/ml) using offline collection techniques. In a subgroup of 18 individuals with asthma and 17 healthy subjects, we additionally measured FENO at multiple expiratory flow rates (47-250 ml/second) using online methods. FENO fell with an increasing expiratory flow rate; FENO was higher in subjects with asthma as compared with healthy subjects at each flow rate studied with both techniques (p < 0.001). Receiver operating characteristic (ROC) curves for the diagnosis of asthma indicated that FENO is a robust discriminator between individuals with asthma and healthy subjects (area under the ROC curves 0.79 +/- 0.06 to 0.86 +/- 0.06, p for significant discrimination < 0.0001). Neither expiratory flow rate nor collection technique (online versus offline) significantly altered this discriminatory capacity (area under the ROC curves = 0.84 +/- 0.07 with the slowest online method versus 0.80 +/- 0.07 with the fastest offline method, p = 0.46). These data indicate that the choice of expiratory flow rate and collection method can be based on practicality and patient comfort without compromising the utility of this test for asthma.
Nakamura, H., A. D. Luster, et al. (2001). "Variant eotaxin: its effects on the asthma phenotype." J Allergy Clin Immunol 108(6): 946-53.
BACKGROUND: Eotaxin, a CC chemokine expressed in the asthmatic lung, has been associated with impaired lung function. The role of its variant form is unknown. OBJECTIVE: The purpose of this study was to detect the population frequency and effects of a known single-nucleotide polymorphism in the eotaxin gene in which a threonine residue (THR(23)) is substituted for the wild-type alanine (ALA(23)) at the 23rd amino acid at the terminus of the peptide leader sequence. METHODS: We measured eotaxin protein secretion in 293 cells transfected with expression vectors and in PBMCs obtained from individuals bearing the alternative forms of the gene. A case-control study of plasma eotaxin levels and eosinophil counts, a comparison of baseline lung function by genotype in a population of 806 subjects with asthma, and a comparison of the allele frequency with a nonasthmatic population were performed. RESULTS: Human 293 cells and PBMCs with THR(23) variant eotaxin secreted significantly less eotaxin protein than did ALA(23)-bearing cells. In the case-control study, THR(23)-THR(23) individuals had lower plasma levels of eotaxin (310 [240-350] vs 420 [270-700] pg/mL; P < .05) and eosinophil counts (120 [5-220] vs 190 [110-470] cells/microL; P < .05) than ALA(23)-ALA(23) subjects; heterozygous subjects had intermediate levels. Higher levels of lung function were associated with THR(23) eotaxin (percent of predicted FEV(1), 65% +/- 3.5% [THR(23)-THR(23)] vs 58% +/- 0.9% [THR(23)-ALA(23)] and 56% +/- 0.5% [ALA(23)-ALA(23)]; P < .05). CONCLUSION: The THR(23) variant is associated with both decreased eosinophil counts and higher levels of lung function in subjects with asthma.
Moy, M. L., E. Israel, et al. (2001). "Clinical predictors of health-related quality of life depend on asthma severity." Am J Respir Crit Care Med 163(4): 924-9.
The National Asthma Education and Prevention Program guidelines define asthma severity before treatment by lung function and symptoms. It has been assumed, but not demonstrated, that improvement in these measures would translate into improvement in health-related quality of life (HRQL). Because HRQL is an important outcome in asthma management, we asked what are the determinants of HRQL? To address this question, we retrospectively analyzed HRQL data, as measured by the Juniper Asthma Quality of Life Questionnaire, in subjects with mild versus moderate-severe asthma from two clinical trials. We examined whether these traditional clinical outcomes have different relationships to HRQL depending on asthma severity. We also assessed whether the relationship between clinical outcomes and HRQL in subjects with moderate-severe asthma would change when subjects improved to mild-moderate disease with controller medication treatment. Lung function was not an independent predictor or determinant of HRQL at any level of asthma severity, whereas intensity of shortness of breath predicted HRQL at all levels of asthma severity. Rescue beta-agonist use independently predicted HRQL in subjects with mild asthma, but not in those with moderate-severe asthma. In subjects with moderate-severe asthma who improved to mild-moderate disease with controller treatment, rescue beta-agonist use predicted HRQL. We conclude that the independent determinants of HRQL vary according to asthma severity and change with asthma treatment.
Mauger, E. A., D. T. Mauger, et al. (2001). "Summarizing methacholine challenges in clinical research." Control Clin Trials 22(6 Suppl): 244S-51S.
In clinical trials in asthma, airway reactivity is commonly assessed by performing a methacholine challenge. Airway reactivity is thought to vary in proportion to asthma severity, and methacholine causes the airways of asthma subjects to constrict, thus lowering forced expiratory volume in 1 second (FEV(1)). A dose-response curve is obtained for each subject who meets standardized eligibility requirements to proceed with a methacholine challenge. When data from a methacholine challenge are used as an outcome variable in analysis, a univariate measure called the PC(20), the concentration of methacholine needed to produce a 20% fall in FEV(1) from baseline, is typically used to summarize the dose-response curve. Questions that arise regarding data generated from the methacholine challenge include: how to express data that do not yield a PC(20) value; whether PC(20) actually represents the best way to capture airway activity as expressed in a methacholine challenge; and whether the baseline FEV(1) is defined appropriately in calculation of PC(20). The impact of these issues on the statistical analysis of methacholine challenge data is described in this article. Some adjustments to the usual estimates of PC(20) and parametric modeling of the entire dose-response curve are proposed as alternatives that address some of the shortcomings of PC(20).
Lutchen, K. R., A. Jensen, et al. (2001). "Airway constriction pattern is a central component of asthma severity: the role of deep inspirations." Am J Respir Crit Care Med 164(2): 207-15.
Measurements of lung resistance and elastance (RL and EL) from 0.1 to 8 Hz reflect both the mean level and pattern of lung constriction. The goal of this study was to establish a relation between a deep inspiration (DI) and the heterogeneity of constriction in healthy versus asthmatic subjects. Constriction pattern was assessed from measurements of the RL and EL from 0.1 to 8 Hz in seven healthy subjects and in 12 asthmatics. These data were acquired before and after a DI and before and after a standard methacholine challenge versus a modified challenge in which a DI is prohibited. Generally, avoidance of a DI increased responsiveness. In healthy subjects and in those with mild-to-moderate baseline asthma a bronchial challenge, especially during self-inhibited DI, produced a heterogenous pattern of constriction inclusive of randomly distributed airway closures or near closures. Nevertheless, such subjects were able to reopen their airways via a DI. In contrast, in subjects with severe baseline asthma, there is a more extreme heterogeneous constriction pattern with random airway closures even at baseline. Further, there is no residual bronchodilatory effect of a DI either before or after bronchial challenge. We conjecture that inflammation and wall-remodeling facilitate a dangerous degree of heterogeneous constriction inclusive of airway closures or near closures, and contribute to the prevention of a DI from having a residual bronchodilatory effect.
Lilly, C. M., H. Nakamura, et al. (2001). "Eotaxin expression after segmental allergen challenge in subjects with atopic asthma." Am J Respir Crit Care Med 163(7): 1669-75.
Expression of pulmonary eotaxin protein and mRNA was determined in six subjects with atopic asthma and five nonatopic normal subjects. Levels of eotaxin expression and eosinophil mobilization were compared before and after segmental allergen challenge in subjects with atopic asthma. In the absence of allergen challenge, we found significantly higher levels of eotaxin in the bronchoalveolar lavage (BAL) fluid of subjects with asthma than in that of normal subjects (25 +/- 3 versus 15 +/- 2 pg/ml, p < 0.05). BAL eotaxin levels increased after segmental allergen challenge in all six subjects with atopic asthma tested, with a mean increase from 22 +/- 4 to 53 +/- 10 pg/ml (p = 0.013). Segmental allergen challenge was associated with a significant increase in the percentage of BAL macrophages and eosinophils that were immunopositive for eotaxin. Eotaxin mRNA was detectable by northern analysis in BAL cells exclusively from allergen-challenged segments. Allergen- induced increases in eotaxin levels were strongly associated with increases in BAL eosinophil recovery (r(2) = 0.88, p = 0.0036). Segmental allergen challenge also increased eotaxin expression in airway epithelial and endothelial cells obtained by endobronchial biopsy. These findings demonstrate, for the first time, that the airways of subjects with allergic asthma respond to allergen by increasing eotaxin expression. The tissue loci of eotaxin expression, the levels of eotaxin recovered in BAL fluid, and the association of eotaxin levels with eosinophil mobilization suggest either that eotaxin plays a mechanistic role in allergen-induced airway eosinophilia or that it serves as a biomarker for the causal mechanisms.
Leone, F. T., E. A. Mauger, et al. (2001). "The utility of peak flow, symptom scores, and beta-agonist use as outcome measures in asthma clinical research." Chest 119(4): 1027-33.
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.
Lemanske, R. F., Jr., C. A. Sorkness, et al. (2001). "Inhaled corticosteroid reduction and elimination in patients with persistent asthma receiving salmeterol: a randomized controlled trial." Jama 285(20): 2594-603.
CONTEXT: Inhaled long-acting beta(2)-agonists improve asthma control when added to inhaled corticosteroid (ICS) therapy. OBJECTIVE: To determine whether ICS therapy can be reduced or eliminated in patients with persistent asthma after adding a long-acting beta(2)-agonist to their treatment regimen. DESIGN AND SETTING: A 24-week randomized, controlled, blinded, double-dummy, parallel-group trial conducted at 6 National Institutes of Health-sponsored, university-based ambulatory care centers from February 1997 through January 1999. PARTICIPANTS: One hundred seventy-five patients aged 12 through 65 years with persistent asthma that was suboptimally controlled during a 6-week run-in period of treatment with inhaled triamcinolone acetonide (400 microg twice per day). INTERVENTION: Patients continued triamcinolone therapy and were randomly assigned to receive add-on therapy with either placebo (placebo-minus group, n = 21) or salmeterol xinafoate, 42 microg twice per day (n = 154) for 2 weeks. The entire placebo-minus group was assigned and half of the salmeterol group (salmeterol-minus group) was randomly assigned to reduce by 50% (for 8 weeks) then eliminate (for 8 weeks) triamcinolone treatment. The other half of the salmeterol group (salmeterol-plus group) was randomly assigned to continue both salmeterol and triamcinolone for the remaining 16 weeks (active control group). MAIN OUTCOME MEASURE: Time to asthma treatment failure in patients receiving salmeterol. RESULTS: Treatment failure occurred in 8.3% (95% confidence interval [CI], 2%-15%) of the salmeterol-minus group 8 weeks after triamcinolone treatment was reduced compared with 2.8% (95% CI, 0%-7%) of the salmeterol-plus group during the same period. Treatment failure occurred in 46.3% (95% CI, 34%-59%) of the salmeterol-minus group 8 weeks after triamcinolone therapy was eliminated compared with 13.7% (95% CI, 5%-22%) of the salmeterol-plus group. The relative risk (95% CI) of treatment failure at the end of the triamcinolone elimination phase in the salmeterol-minus group was 4.3 (2.0-9.2) compared with the salmeterol-plus group (P<.001). CONCLUSIONS: Our results indicate that in patients with persistent asthma suboptimally controlled by triamcinolone therapy alone but whose asthma symptoms improve after addition of salmeterol, a substantial reduction (50%) in triamcinolone dose can occur without a significant loss of asthma control. However, total elimination of triamcinolone therapy results in a significant deterioration in asthma control and, therefore, cannot be recommended.
Lazarus, S. C., H. A. Boushey, et al. (2001). "Long-acting beta2-agonist monotherapy vs continued therapy with inhaled corticosteroids in patients with persistent asthma: a randomized controlled trial." Jama 285(20): 2583-93.
CONTEXT: Long-acting beta(2)-agonists are prescribed for patients with persistent asthma and are sometimes used without inhaled corticosteroids (ICSs). No evidence exists, however, to support their use as monotherapy in adults with persistent asthma. OBJECTIVE: To examine the effectiveness of salmeterol xinafoate, a long-acting beta(2)-agonist, as replacement therapy in patients whose asthma is well controlled by low-dose triamcinolone acetonide, an ICS. DESIGN AND SETTING: A 28-week, randomized, blinded, placebo-controlled, parallel group trial conducted at 6 National Institutes of Health-sponsored, university-based ambulatory care centers from February 1997 to January 1999. PARTICIPANTS: One hundred sixty-four patients aged 12 through 65 years with persistent asthma that was well controlled during a 6-week run-in period of treatment with inhaled triamcinolone (400 microg twice per day). INTERVENTIONS: Patients were randomly assigned to continue triamcinolone therapy (400 microg twice per day; n = 54) or switch to salmeterol (42 microg twice per day; n = 54) or to placebo (n = 56) for 16 weeks, after which all patients received placebo for an additional 6-week run-out period. MAIN OUTCOME MEASURES: Change in morning and evening peak expiratory flow (PEF), forced expiratory volume in 1 second (FEV(1)), self-assessed asthma symptom scores, rescue albuterol use, asthma-specific quality-of-life scores, treatment failure, asthma exacerbation, bronchial reactivity, and markers of airway inflammation, compared among the 3 treatment groups. RESULTS: During the 16-week randomized treatment period, no significant differences between the salmeterol and triamcinolone groups were observed for conventional outcomes of clinical studies of asthma therapy-morning PEF, evening PEF, asthma symptom scores, rescue albuterol sulfate use, or quality of life. Both active treatments were superior to placebo. However, the salmeterol group had more treatment failures than the triamcinolone group (13/54 [24%] vs 3/54 [6%]; P =.004), as well as more asthma exacerbations (11/54 [20%] vs 4/54 [7%]; P =.04), greater increases in median (interquartile range) sputum eosinophils (2.4% [0.0% to 10.6%] vs -0.1% [-0.7% to 0.3%]; P<.001), eosinophil cationic protein (71 [-2 to 430] U/L vs -4 [-31 to 56] U/L; P =.005), and tryptase (3.1 [2.1 to 7.6] ng/mL vs 0.0 [0.0 to 0.7] ng/mL; P<.001). The duration of benefit when patients were switched from active treatment to placebo after 22 weeks of randomized treatment was not significantly longer in the triamcinolone group than in the salmeterol group. CONCLUSIONS: Patients with persistent asthma well controlled by low doses of triamcinolone cannot be switched to salmeterol monotherapy without risk of clinically significant loss of asthma control.
Lara-Marquez, M. L., M. J. Moan, et al. (2001). "Atopic asthma: differential activation phenotypes among memory T helper cells." Clin Exp Allergy 31(8): 1232-41.
BACKGROUND: T cells have been implicated in the pathogenesis of atopic asthma. We have previously shown that memory T helper cells (CD4+CD45RO+) are preferentially activated relative to naive T helper cells (CD4+CD45RA+) after bronchial allergen challenge. However, specific T helper subpopulations that are activated in atopy and/or asthma remain undefined. OBJECTIVE: To determine the T helper subpopulations and activation phenotypes relevant to acute and stable asthma that may be common with or distinct from atopy. METHODS: Two groups of atopic asthmatics (ten acute and nine stable asthmatics) and two non-asthmatic groups (14 non-asthmatic atopics and eight normal non-atopic controls) were analysed. Ten acute asthmatics were assessed in the emergency room during an acute episode (FEV1 43.6% +/- 18.4). Nine stable asthmatics were assessed during a symptom-free period (FEV1 85% +/- 6). Using multiple colour flow cytometry we analysed T cell subpopulations and the expression of IL-2-receptor (IL-2R) and MHC-class II antigens (MHC II) on naive and memory T helper cells in the peripheral blood of asthmatic and non-asthmatic groups. RESULTS: Atopic asthmatics (acute and stable) had an increased percentage of memory T helper cells expressing IL-2R compared with normal non-atopics (mean SD 16.1 +/- 6%, 12.4 +/- 2% and 7.7 +/- 1.8%, P < 0.05) but not compared with non-asthmatic atopics (10 +/- 3.5%). Naive T helper cells had low expression of IL-2R and MHC II in all four groups. MHC II antigen expression was increased in memory T helper cells of asthmatics (acute and stable) compared with normal non-atopics (13.9 +/- 7.5, 10.6 +/- 5 and 4.9 +/- 2.5, P < 0.05) but not compared with non-asthmatic atopics (7.92 4). A novel finding was that IL-2R and the MHC II molecules were mainly expressed in non-overlapping populations and coexpression was found predominantly on memory T helper cells. Asthmatics (acute and stable) had higher proportion of double positive memory T helper cells (IL-2R+MHC II+) compared with both non-asthmatic groups (P < 0.05). CONCLUSIONS: We demonstrate a differential expression of IL-2R+ and MCH II+ on CD45RO+ T helper cells that would suggest that there are three subsets of activated memory T helper cells in asthmatics. Two non-overlapping IL-2R+ or MHC II+ CD45RO+ T helper cells and a third subpopulation of activated cells that coexpress IL-2R and MHC II (double positives). This latter subpopulation is significantly higher in asthmatics (acute or stable) compared with both non-asthmatic groups, suggesting a specific T helper activation phenotype distinct to atopic asthmatics as compared with atopic non-asthmatics.
Kline, J. A., E. G. Israel, et al. (2001). "Diagnostic accuracy of a bedside D-dimer assay and alveolar dead-space measurement for rapid exclusion of pulmonary embolism: a multicenter study." Jama 285(6): 761-8.
CONTEXT: A previous study suggested that the combination of a normal D-dimer assay and normal alveolar dead-space fraction is a highly sensitive screening test for pulmonary embolism (PE). OBJECTIVE: To determine if the combination of a normal alveolar dead-space fraction (volume of alveolar dead space/tidal volume </=20%) and a normal whole-blood agglutination D-dimer assay can exclude PE in emergency department (ED) patients. DESIGN: Prospective, noninterventional study conducted in 1998-1999. Study data were obtained prior to standard testing for PE, consisting of radionuclide lung scanning or contrast-enhanced computed tomography and 6-month follow-up plus selective use of venous ultrasonography and pulmonary angiography. Imaging studies were interpreted by blinded observers. SETTING: Six urban teaching hospitals in the United States. PATIENTS: A total of 380 hemodynamically stable ED patients aged 18 years or older with suspected acute PE. MAIN OUTCOME MEASURES: Sensitivity and specificity for PE with a positive test defined as having either alveolar dead-space fraction or D-dimer assay results abnormal. Alveolar dead-space fraction was determined by subtracting airway dead space from physiological dead space (determined using the modified Bohr equation) and D-dimer assay, assayed at bedside using 20 microL of arterial blood. RESULTS: Pulmonary embolism was diagnosed in 64 patients (16.8%), of those 20 had an abnormal D-dimer assay result, 3 had an abnormal alveolar dead-space fraction, 40 had abnormal results in both, and 1 had normal results for both tests. The sensitivity for diagnosis of PE was 98.4% (95% confidence interval [CI], 91.6%-100.0%). Among the 316 patients without PE, both D-dimer and dead-space results were normal in 163, for a specificity of 51.6% (95% CI, 46.1%-57.1%). Posterior probability of PE with normal results on both tests was 0.75% (95% CI, 0%-3.4%). CONCLUSION: In this multicenter study of ED patients, a normal D-dimer assay result plus a normal alveolar dead-space fraction was associated with a low prevalence of PE.
Israel, E., J. M. Drazen, et al. (2001). "Effect of polymorphism of the beta(2)-adrenergic receptor on response to regular use of albuterol in asthma." Int Arch Allergy Immunol 124(1-3): 183-6.
BACKGROUND: Regular use of inhaled beta-adrenergic agonists may have adverse effects in some asthma patients. Polymorphisms of the beta(2)-adrenergic receptor (beta(2)-AR) can affect its regulation; however, results of smaller studies of the effects of such polymorphisms on response to beta-agonist therapy have been inconsistent. METHODS: We examined the possible effects of polymorphisms at codons 16 (beta(2)-AR-16) and 27 (beta(2)-AR-27) on response to albuterol by genotyping 190 asthmatics who had participated in a trial of regular versus as-needed albuterol use. RESULTS: During the 16-week treatment period, patients homozygous for arginine (Arg/Arg) at beta(2)-AR-16 who used albuterol regularly had a small decline in morning peak expiratory flow (AM PEF). This effect was magnified during a 4-week run-out period, when all patients returned to as-needed albuterol only. By the end of the study, Arg/Arg subjects who had used albuterol regularly had an AM PEF 30.5 +/- 12.1 liters/min lower (p = 0.012) than Arg/Arg patients who had used albuterol as needed only. Subjects homozygous for glycine at beta(2)-AR-16 showed no such decline. Evening PEF also declined in the Arg/Arg regular but not in as-need albuterol users. No significant differences between regular and as-needed treatment were associated with polymorphisms at beta(2)-AR-27. CONCLUSIONS: Polymorphisms of the beta(2)-AR may influence airway responses to regular inhaled beta-agonist treatment.
Israel, E., T. R. Banerjee, et al. (2001). "Effects of inhaled glucocorticoids on bone density in premenopausal women." N Engl J Med 345(13): 941-7.
BACKGROUND: Inhaled glucocorticoids are the most commonly used medications for the long-term treatment of patients with asthma. Whether long-term therapy with inhaled glucocorticoids reduces bone mass, as oral glucocorticoid therapy does, is controversial. In a three-year prospective study, we examined the relation between the dose of inhaled glucocorticoids and the rate of bone loss in premenopausal women with asthma. METHODS: We studied 109 premenopausal women, 18 to 45 years of age, who had asthma and no known conditions that cause bone loss and who were treated with inhaled triamcinolone acetonide (100 microg per puff). We measured bone density by dual-photon absorptiometry at base line, at six months, and at one, two, and three years. Serum osteocalcin and parathyroid hormone and urinary N-telopeptide, cortisol, and calcium excretion were measured serially. We measured inhaled glucocorticoid use by means of monthly diaries, supported by the use of an automated actuator-monitoring device. RESULTS: Inhaled glucocorticoid therapy was associated with a dose-related decline in bone density at both the total hip and the trochanter of 0.00044 g per square centimeter per puff per year of treatment (P= 0.01 and P=0.005, respectively). No dose-related effect was noted at the femoral neck or the spine. Even after the exclusion of all women who received oral or parenteral glucocorticoids at any time during the study, there was still an association between the decline in bone density and the number of puffs per year of use. Serum and urinary markers of bone turnover or adrenal function did not predict the degree of bone loss. CONCLUSIONS: Inhaled glucocorticoids lead to a dose-related loss of bone at the hip in premenopausal women.
Forand, P. E., S. J. Kunselman, et al. (2001). "Genetic analysis in the Asthma Clinical Research Network." Control Clin Trials 22(6 Suppl): 196S-206S.
Because there is reason to believe that genetic variants could account for different treatment responses in subjects with asthma, it is important to collect blood for genetic-analysis purposes when conducting clinical trials in asthma. This article describes issues related to maintaining subject confidentiality, tracking and shipping blood samples, quality control procedures at the laboratory performing the genotyping, and necessary data verification checks when implementing the genetic-analysis database for the Asthma Clinical Research Network.
Fish, J. E., E. Israel, et al. (2001). "Salmeterol powder provides significantly better benefit than montelukast in asthmatic patients receiving concomitant inhaled corticosteroid therapy." Chest 120(2): 423-30.
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.
Fahy, J. V., H. A. Boushey, et al. (2001). "Safety and reproducibility of sputum induction in asthmatic subjects in a multicenter study." Am J Respir Crit Care Med 163(6): 1470-5.
The safety of sputum induction and the reproducibility of measurements in induced sputum in multicenter studies is unknown. We examined the safety of sputum induction in a two-visit, six-center study in 79 subjects with moderate to severe asthma (mean +/- SD FEV(1) 71 +/- 12% predicted, 67% taking inhaled corticosteroids). In addition, we compared the reproducibility of markers of inflammation in induced sputum with the reproducibility of the FEV(1) and the methacholine PC(20). The FEV(1) decreased > or = 20% from the postbronchodilator baseline in 14% of all subjects and in 25% of subjects whose initial prebronchodilator baseline was 40 to 60% of predicted. All subjects responded promptly to additional albuterol treatment, and no subject developed refractory bronchoconstriction requiring treatment other than reversal of bronchospasm in the study laboratory. The reproducibility of measurements of the eosinophil percentage, eosinophil cationic protein, tryptase, and methacholine PC(20) were similar (concordance correlation coefficients of 0.74, 0.81, 0.79, and 0.74, respectively), without any significant among-center effect. We conclude that sputum induction can be performed safely in subjects with moderate to severe asthma in multicenter clinical trials when carried out under carefully monitored conditions. Importantly, we demonstrate that measurement of markers of inflammation in induced sputum is as reproducible as methacholine PC(20) and should prove useful in the assessment of airway inflammation in multicenter clinical trials.
Wechsler, M. E., H. Grasemann, et al. (2000). "Exhaled nitric oxide in patients with asthma: association with NOS1 genotype." Am J Respir Crit Care Med 162(6): 2043-7.
An increased concentration of nitric oxide (NO) in exhaled air (FENO) is now recognized as a critical component of the asthmatic phenotype. When we identified patients with asthma on the basis of a standard case definition alone, we found that they were remarkably heterogeneous with respect to their FENO. However, when we included genotype at a prominent asthma candidate gene (i.e., NOS1) in the case definition, and determined the number of AAT repeats in intron 20, we identified a remarkably homogeneous cohort of patients with respect to FENO. Both mean FENO (p = 0.00008) and variability around the mean (p = 0.000002) were significantly lower in asthmatic individuals with a high number (> or = 12) of AAT repeats at this locus than in those with fewer repeats. These data provide a biologically tenable link between genotype at a candidate gene in a region of linkage, NOS1, and an important component of the asthmatic phenotype, FENO. We show that addition of NOS1 genotype to the case definition of asthma allows the identification of a uniform cohort of patients, with respect to FENO, that would have been indistinguishable by other physiologic criteria. Our isolation of this homogeneous cohort of patients ties together the well-established associations among asthma, increased concentrations of NO in the exhaled air of asthmatic individuals, and variations of trinucleotide repeat sequences as identified in several neurologic conditions.
Moy, M. L., J. Woodrow Weiss, et al. (2000). "Quality of dyspnea in bronchoconstriction differs from external resistive loads." Am J Respir Crit Care Med 162(2 Pt 1): 451-5.
To test the hypothesis that patients perceive the same quality of dyspnea during mild bronchoconstriction and external resistive loads, we studied subjects with asthma under two conditions: (1) during methacholine bronchoprovocation to mimic the bronchospasm of mild asthma and (2) while breathing on a circuit to which was added a range of external resistors to mimic the mechanical load of mild asthma. During each of these stimuli, respiratory variables, overall dyspnea intensity on a modified Borg scale, and the qualitative descriptors of breathlessness from a 19-item questionnaire were assessed. The "chest tightness" and "constriction" responses were significantly more frequent in the methacholine trials as compared with the external load trials (p < 0.0001). The "chest tightness" or "constriction" response was chosen during 92% of the 26 trials of methacholine bronchoconstriction compared with 3% of the 72 trials of breathing against the external resistors. Changes in functional residual capacity were not significantly different between the two conditions. We conclude that in mild asthma, the sensation of chest tightness is distinct from the sensation of work and effort and is not attributable to the mechanical load imposed on the respiratory system.
Maslow, A. D., M. M. Regan, et al. (2000). "Inhaled albuterol, but not intravenous lidocaine, protects against intubation-induced bronchoconstriction in asthma." Anesthesiology 93(5): 1198-204.
BACKGROUND: The ability of intravenous lidocaine to prevent intubation-induced bronchospasm is unclear. The authors performed a prospective, randomized, double-blind, placebo-controlled trial to test the ability of intravenous lidocaine and inhaled albuterol to attenuate airway reactivity after tracheal intubation in asthmatic patients undergoing general anesthesia. METHODS: Sixty patients were randomized to receive either 1.5 mg/kg intravenous lidocaine or saline, 3 min before tracheal intubation. An additional 50 patients were randomized to receive 4 puffs of inhaled albuterol or placebo 15-20 min before tracheal intubation. Anesthesia was induced with propofol. Immediately after intubation and at 5-min intervals, transpulmonary pressure and airflow were recorded, and lower pulmonary resistance (RL) was calculated. Isoflurane was administered after the initial two measurements to assess reversibility of bronchoconstriction. A bronchoconstrictor response to intubation was defined as RL greater than or equal to 5 cm H2O. l-1. s-1 in the first two measurements after intubation and RL subsequently decreasing by 50% or more after isoflurane. RESULTS: The lidocaine and placebo groups were not different in the peak RL before administration of isoflurane (8.2 cm H2O. l-1. s-1 vs. 7.6 cm H2O. l-1. s-1) or frequency of airway response to intubation (lidocaine 6 of 30 vs. placebo 5 of 27). In contrast, the albuterol group had lower peak RL (5.3 cm H2O. l-1. s-1 vs. 8.9 cm H2O. l-1. s-1; P < 0.05) and a lower frequency of airway response (1 of 25 vs. 8 of 23; P < 0.05) than the placebo group. CONCLUSIONS: Inhaled albuterol blunted airway response to tracheal intubation in asthmatic patients, whereas intravenous lidocaine did not.
Kline, J. A., K. L. Johns, et al. (2000). "New diagnostic tests for pulmonary embolism." Ann Emerg Med 35(2): 168-80.
In 1990, the multicenter Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED), sponsored by the National Institutes of Health, compared the diagnostic value of the radioisotopic ventilation-perfusion lung scan (V/Q scan) with that of pulmonary angiography for the diagnosis of pulmonary embolism (PE). Despite the endurance of the radioisotopic V/Q scan as the most widely used test for evaluation of pulmonary embolism (PE), a better screening tool is clearly needed for use in the emergency department. During the past decade, several new modalities have emerged for evaluation of patients with suspected PE. We evaluate the diagnostic utility of the D-dimer test and the alveolar dead space determination as potential screening tests and of spiral computed tomography, magnetic resonance imaging, transthoracic echocardiography, and transesophageal echocardiography as potential confirmatory tests for PE. For comparison, recent data on the diagnostic utility of the alveolar-arterial oxygen gradient and the V/Q scan are included. The potential application of these new tests to a hypothetical ED population is described.
Israel, E., J. M. Drazen, et al. (2000). "The effect of polymorphisms of the beta(2)-adrenergic receptor on the response to regular use of albuterol in asthma." Am J Respir Crit Care Med 162(1): 75-80.
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.
Israel, E. (2000). "Assessment of therapeutic index of inhaled steroids." Lancet 356(9229): 527-8.
Humbles, A. A., B. Lu, et al. (2000). "A role for the C3a anaphylatoxin receptor in the effector phase of asthma." Nature 406(6799): 998-1001.
Asthma is a chronic inflammatory disease of the airways and lung mucosa with a strong correlation to atopy and acquired (IgE) immunity. However, many features of bronchial asthma, such as smooth muscle contraction, mucus secretion and recruitment of inflammatory cells, are consistent with the actions of complement anaphylatoxins, in particular C3a and C5a. Complement activation forms a central core of innate immune defence against mucosal bacteria, viruses, fungi, helminths and other pathogens. As a system of 'pattern-recognition molecules', foreign surface antigens and immune complexes lead to a proteolytic cascade culminating in a lytic membrane attack. The anaphylatoxins C3a and C5a are liberated as activation byproducts and are potent pro-inflammatory mediators that bind to specific cell surface receptors and cause leukocyte activation, smooth muscle contraction and vascular permeability. Here we show that in a murine model of allergic airway disease, genetic deletion of the C3a receptor protects against the changes in lung physiology seen after allergen challenge. Furthermore, human asthmatics develop significant levels of ligand C3a following intra-pulmonary deposition of allergen, but not saline. We propose that, in addition to acquired immune responses, the innate immune system and complement (C3a in particular) are involved in the pathogenesis of asthma.
Grasemann, H., C. N. Yandava, et al. (2000). "A neuronal NO synthase (NOS1) gene polymorphism is associated with asthma." Biochem Biophys Res Commun 272(2): 391-4.
Recent family-based studies have revealed evidence for linkage of chromosomal region 12q to both asthma and high total serum immunoglobulin E (IgE) levels. Among the candidate genes in this region for asthma is neuronal nitric oxide synthase (NOS1). We sought a genetic association between a polymorphism in the NOS1 gene and the diagnosis of asthma, using a case-control design. Frequencies for allele 17 and 18 of a CA repeat in exon 29 of the NOS1 gene were significantly different between 490 asthmatic and 350 control subjects. Allele 17 was more common in the asthmatics (0.83 vs 0.76, or 1.49 [95% CI 1.17-1.90], P = 0.013) while allele 18 was less common in the asthmatics (0.06 vs 0.12, or 0.49 [95% CI 0.34-0. 69], P = 0.0004). To confirm these results we genotyped an additional 1131 control subjects and found the frequencies of alleles 17 and 18 to be virtually identical to those ascertained in our original control subjects. Total serum IgE was not associated with any allele of the polymorphism. These findings provide support, from case-control association analysis, for NOS1 as a candidate gene for asthma.
Deykin, A., A. F. Massaro, et al. (2000). "Exhaled nitric oxide following repeated spirometry or repeated plethysmography in healthy individuals." Am J Respir Crit Care Med 161(4 Pt 1): 1237-40.
Subjects with asthma have higher concentrations of exhaled nitric oxide (NO) than normal individuals. It has been demonstrated that in asthmatics, repeated FVC maneuvers reduce NO. Although the cause of this phenomenon is not known, it has been hypothesized that deep breaths associated with FVC maneuvers reduce exhaled NO by affecting neural sources of NO, possibly via a mechanism related to the pathobiology of asthma. To establish whether FVC maneuvers influence NO concentrations in normal individuals, we measured exhaled NO at baseline values and after FVC maneuvers performed every 15 min for 1 h in subjects without asthma. To investigate the role of deep breaths in reducing exhaled NO, we compared these results with concentrations of exhaled NO after plethysmography. Repeated FVC maneuvers over 60 min produced a decrease in NO concentrations in mixed expired gas (F(E)NO; 24.6 +/- 5.1% decrease for F(E)NO, p < 0. 01 versus baseline). In contrast to the results after spirometry, repeated specific airway conductance (sGaw) maneuvers do not have a significant effect on F(E)NO (p = 0.16). These results, which demonstrate that in nonasthmatic subjects FVC maneuvers-but not panting maneuvers-produce a fall in NO, suggest that the mechanism responsible for the reduction in exhaled NO after FVC maneuvers is related to volume history of the lung rather than the pathobiology of asthma.
Deykin, A., O. Belostotsky, et al. (2000). "Exhaled nitric oxide following leukotriene E(4) and methacholine inhalation in patients with asthma." Am J Respir Crit Care Med 162(5): 1685-9.
Nitric oxide (NO) is a molecular gas that can be recovered in higher levels from the exhaled gas of subjects with asthma than from subjects without asthma. However, the precise mechanisms responsible of promoting increased fraction of expired nitric oxide (FE(NO)) in asthma are unknown. As leukotriene antagonism has been shown to reduce FE(NO) in patients with asthma, we hypothesized that leukotrienes mediate the increased FE(NO) encountered in this condition. Furthermore, because leukotriene antagonism stabilizes serum eosinophil markers during reductions in inhaled corticosteroid doses, and FE(NO) has been shown to correlate with sputum eosinophils in asthma, we reasoned that the effect of leukotrienes on FE(NO) might be mediated by eosinophils recruited to the airway by leukotrienes. To test this hypothesis, we performed methacholine and leukotriene (LT) E(4) bronchoprovocation challenges in 16 subjects with atopic asthma and measured FE(NO) and sputum differential counts before and after bronchoprovocation. We then compared FE(NO) in the seven subjects who developed increased sputum eosinophils following LTE(4) inhalation with values measured after methacholine inhalation in these seven subjects. Following LTE(4) inhalation, eosinophils rose from 4.01 +/- 0.89% pre-LTE(4) to 8.33 +/- 1.52% post-LTE(4). The mean change in sputum eosinophils from baseline after LTE(4) inhalation was larger than that after methacholine inhalation (+4.31 +/- 1.25% versus -1.14 +/- 0.93%). After LTE(4) inhalation, FE(NO) levels did not differ from prechallenge baseline or from levels following methacholine inhalation (ANOVA p > 0.05). These data indicate that neither LTE(4) nor recruitment of eosinophils into the airway by LTE(4) is a sufficient stimulus to acutely increase FE(NO) in subjects with asthma.
Nakamura, H., S. T. Weiss, et al. (1999). "Eotaxin and impaired lung function in asthma." Am J Respir Crit Care Med 160(6): 1952-6.
We performed an association study of plasma eotaxin levels, eosinophil counts, total IgE levels, asthma diagnosis, and lung function in an ethnically diverse and geographically dispersed population. We studied 515 asthmatic and 519 normal subjects, none of whom was taking inhaled or oral corticosteroids. Logistic regression analysis demonstrated a direct relationship between asthma diagnosis and eotaxin levels (p < 0.0001). The odds of an asthma diagnosis increased with eotaxin quartile, with the highest quartile having an odds ratio of 5.4 (95% CI 3.2 to 9.2, p < 0.001) compared with the lowest eotaxin quartile. Eotaxin levels were inversely related to lung function (p < 0.001), with the mean percent predicted FEV(1) in the highest eotaxin quartile being 13.5 percentage points (SEM 2.1, p < 0.001) less than that in the lowest quartile. Plasma eotaxin levels were associated with asthma and inversely related to lung function independent of age, race, sex, or smoking status. When combined with eosinophil counts and IgE levels, eotaxin levels contributed to the odds of an asthma diagnosis and of impaired lung function. Our results are the first to associate eotaxin levels with asthma diagnosis and compromised lung function in a large geographically and ethnically diverse population.
Lofdahl, C. G., T. F. Reiss, et al. (1999). "Randomised, placebo controlled trial of effect of a leukotriene receptor antagonist, montelukast, on tapering inhaled corticosteroids in asthmatic patients." Bmj 319(7202): 87-90.
OBJECTIVE: To determine the ability of montelukast, a leukotriene receptor antagonist, to allow tapering of inhaled corticosteroids in clinically stable asthmatic patients. DESIGN: Double blind, randomised, placebo controlled, parallel group study. After a single blind placebo run in period, during which (at most) two inhaled corticosteroids dose decreases occurred, qualifying, clinically stable patients were allocated randomly to receive montelukast (10 mg tablet) or matching placebo once daily at bedtime for up to 12 weeks. SETTING: 23 academic asthma centres in United States, Canada, and Europe. PARTICIPANTS: 226 clinically stable patients with chronic asthma receiving high doses of inhaled corticosteroids (113 randomised to montelukast and 113 to placebo). INTERVENTIONS: Every 2 weeks, the inhaled corticosteroids dose was tapered, maintained, or increased (rescue) based on a standardised clinical score. MAIN OUTCOME MEASURES: Last tolerated dose of inhaled corticosteroids. RESULTS: Compared with placebo, montelukast allowed significant (P=0. 046) reduction in the inhaled corticosteroid dose (montelukast 47% v placebo 30%; least square mean difference 17.6%, 95% confidence interval 0.3 to 34.8). Fewer patients on montelukast (18 (16%) v 34 (30%) placebo, P=0.01) required discontinuation because of failed rescue. CONCLUSIONS: Montelukast reduces the need for inhaled corticosteroids among patients requiring moderate to high doses of corticosteroid to maintain asthma control.
Kaczka, D. W., E. P. Ingenito, et al. (1999). "Airway and lung tissue mechanics in asthma. Effects of albuterol." Am J Respir Crit Care Med 159(1): 169-78.
We examined the partitioning of total lung resistance (RL) into airway resistance (Raw) and tissue resistance (Rti) in patients with mild to moderate asthma (baseline FEV1, 54 to 91% of predicted) before and after albuterol inhalation. An optimal ventilator waveform was used to measure RL and lung elastance (EL) in 21 asthmatics from approximately 0.1 to 8 Hz during tidal excursions. Analysis of the RL and EL provided separate estimates of airway and lung tissue properties. Eleven subjects, classified as Type A asthmatics, displayed slightly elevated RL but normal EL. Their data were well described with a model consisting of homogeneous airways leading to viscoelastic tissues before and after albuterol. The other 10 subjects, classified as Type B asthmatics, demonstrated highly elevated RL and an EL that became highly elevated at frequencies above 2 Hz. These subjects required the inclusion of an airway wall compliance in the model prealbuterol but not postalbuterol. This suggests that the Type B subjects were experiencing pronounced constriction in the periphery of the lung, resulting in shunting of flow into the airway walls. Spirometric data were consistent with higher constriction in Type B subjects. Both groups demonstrated significant (p < 0.05) decreases in Raw and tissue damping after albuterol, but tissue elastance decreased only in the Type B group. The percent contributions of Raw and Rti to RL were similar in both groups and did not change after albuterol. We conclude that in asthma, Raw comprises the majority (> 70%) of RL at breathing frequencies. The relative contributions of Raw and Rti to RL appear to be independent of the degree of smooth muscle constriction.
Grasemann, H., J. M. Drazen, et al. (1999). "Simple tandem repeat polymorphisms in the neuronal nitric oxide synthase gene in different ethnic populations." Hum Hered 49(3): 139-41.
Allelic frequencies of a CA dinucleotide repeat in exon 29 and an intronic AAT trinucleotide repeat in the neuronal nitric oxide synthase (NOS1) gene were determined by simple sequence length polymorphism (SSLP) in 305 American-Caucasian and 105 African-American healthy subjects. There were highly significant differences in allele frequencies between the two ethnically diverse study populations.
Drazen, J. M., E. Israel, et al. (1999). "Treatment of asthma with drugs modifying the leukotriene pathway." N Engl J Med 340(3): 197-206.
Drazen, J. M., C. N. Yandava, et al. (1999). "Pharmacogenetic association between ALOX5 promoter genotype and the response to anti-asthma treatment." Nat Genet 22(2): 168-70.
Clinically similar asthma patients may develop airway obstruction by different mechanisms. Asthma treatments that specifically interfere with the 5-lipoxygenase (ALOX5) pathway provide a method to identify those patients in whom the products of the ALOX5 pathway (that is, the leukotrienes) contribute to the expression of the asthma phenotype. Failure of an asthma patient to respond to treatment with ALOX5-pathway modifiers indicates that leukotrienes are not critical to the expression of the asthmatic phenotype in that patient. We previously defined a family of DNA sequence variants in the core promoter of the gene ALOX5 (on chromosome 10q11.2) associated with diminished promoter-reporter activity in tissue culture. Because expression of ALOX5 is in part transcriptionally regulated, we reasoned that patients with these sequence variants may have diminished gene transcription, and therefore decreased ALOX5 product production and a diminished clinical response to treatment with a drug targeting this pathway. Such an effect indicates an interaction between gene promoter sequence variants and drug-treatment responses, that is, a pharmacogenetic effect of a promoter sequence on treatment responses.
Deykin, A. and E. Israel (1999). "Newer therapeutic agents for asthma." Adv Intern Med 44: 209-37.
The past decade has seen significant advances in the available treatments for asthma. These include longer-acting bronchodilating agents, high topical potency inhaled corticosteroids, and agents that interfere with leukotriene production or action. Table 3 summarizes the clinical effects of the newer therapeutic agents reviewed. Experimental therapies for the steroid-dependent patient have also been discussed. Although clinical trials to date have established many of these as effective in asthma, the results of ongoing, large, multicenter studies investigating the relative merits of these therapies, alone and in combination, will further clarify how to maximize the utility of these agents in the treatment of asthma.
Deykin, A. and E. Israel (1999). "Newer therapeutic agents for asthma." Dis Mon 45(4): 117-44.
The past decade has seen significant advances in the available treatments for asthma. These include longer-acting bronchodilating agents, high topical potency inhaled corticosteroids, and agents that interfere with leukotriene production or action. Table 3 summarizes the clinical effects of the newer therapeutic agents reviewed. Experimental therapies for the steroid-dependent patient have also been discussed. Although clinical trials to date have established many of these as effective in asthma, the results of ongoing, large, multicenter studies investigating the relative merits of these therapies, alone and in combination, will further clarify how to maximize the utility of these agents in the treatment of asthma.
Lara-Marquez, M. L., A. Deykin, et al. (1998). "Analysis of T-cell activation after bronchial allergen challenge in patients with atopic asthma." J Allergy Clin Immunol 101(5): 699-708.
BACKGROUND: T helper cells are a heterogeneous group of cells that have phenotypic and functional differences. Activated T helper cells have been found in peripheral blood after allergen challenge of subjects with atopic asthma, but the phenotypes of specific T helper subpopulation involved remains to be identified. OBJECTIVE: To characterize the T cell activation markers that may be regulated by allergens, we analyzed peripheral blood lymphocytes obtained before and after allergen challenge from subjects with atopic asthma. METHODS: We analyzed the distribution of the cell surface activation markers, interleukin 2 receptor (IL-2R) and major histocompatibility complex class II antigens (MHC II) among T helper subpopulations classified as naive (CD45RA) or memory (CD45RO) phenotypes. Nine adult subjects with atopic asthma underwent bronchoprovacative allergen inhalation and isocapnic cold air hyperventilation (ISH) challenge followed by serial spirometry. Peripheral blood mononuclear cells (PBMC) were isolated at baseline and 2 and 24 hours after challenge. Four-color flow cytometry was used to analyze the expression and distribution in vivo of IL-2R and MHC II activation markers on naive and memory T cell subsets after challenge. RESULTS: At 2 and 24 hours after allergen challenge, there was a significant increase in the CD45RO+IL-2R+ T helper cells compared with baseline (mean +/- SE, baseline, 12.5% +/- 1% versus 2 hours, 18.1% +/- 1% and 24 hours, 17.8% +/- 2%, p < 0.025). MHC II expression was not significantly increased after challenge on naive and memory T helper cells and coexpression of IL-2R and MHC II was only found in a small proportion of CD45RO+ T helper cells (2.7% +/- 1%). No changes of IL-2R or MHC II expression on T helper subsets were observed after ISH challenge in the same patients. We also found that 31% to 46% of T helper cells coexpress CD45RA and CD45RO simultaneously, and upregulation of IL-2-R and MHC II expression occurs only on those T helper cells that express CD45RO. CONCLUSIONS: We have found that T helper cells express both CD45RA and CD45RO isoforms, which suggests the existence of a transitional phenotype among naive and memory T helper cells in peripheral blood. In subjects with atopic asthma, our in vivo analysis characterizes two populations of activated memory T helper cells based on the expression of IL-2R or MHC II surface molecules after allergen challenge.
Drazen, J. M. and E. Israel (1998). "Should antileukotriene therapies be used instead of inhaled corticosteroids in asthma? Yes." Am J Respir Crit Care Med 158(6): 1697-8.
Deykin, A., O. Halpern, et al. (1998). "Expired nitric oxide after bronchoprovocation and repeated spirometry in patients with asthma." Am J Respir Crit Care Med 157(3 Pt 1): 769-75.
Compared with normal individuals, subjects with asthma have elevated levels of expired nitric oxide (NO). These levels are hypothesized to reflect the degree of airway inflammation. Expired NO levels rise during the late phase of allergen challenge and decrease in asthmatics after steroid treatment. Isocapnic cold air hyperventilation (ISH) is believed to cause airway narrowing through noninflammatory mechanisms. We measured mixed expired NO in 10 individuals with atopic asthma who underwent both ISH challenge and allergen challenge, and compared these measurements with the change in expired NO that occurred after serial spirometry alone. We found that ambient NO levels affected mixed expired NO. Controlling for inspired NO, we found that repeated spirometry alone produced a significant fall in mixed expired NO (p < 0.01) that was maximal after 30 min (36.6 +/- 8.5% fall). After allergen and ISH challenges, expired NO was elevated relative to levels after repeated spirometry (p < 0.01 and p = 0.065, respectively). In addition, we found that prechallenge expired NO levels were significantly correlated with the magnitude of the late fall in FEV1 following allergen challenge (r = 0.80, p < 0.01). These data demonstrate that repeated spirometry results in reduced mixed expired NO and suggest that both ISH and allergen-induced bronchoconstriction share pathobiologic mechanisms that produce increases in mixed expired NO.
O'Byrne, P. M., E. Israel, et al. (1997). "Antileukotrienes in the treatment of asthma." Ann Intern Med 127(6): 472-80.
PURPOSE: To review the activity in clinical models, the efficacy, and the safety of antileukotrienes as a new class of antiasthma treatment. DATA SOURCES: English-language trials identified from the archival literature, including the MEDLINE database, through 1996; bibliographic references; and textbooks. STUDY SELECTION: Reports from placebo-controlled, double-blind, randomized trials were selected. DATA EXTRACTION: Study designs and results were extracted from the clinical trial reports. Statistical evaluation of combined results was not attempted. DATA SYNTHESIS: The various classes of antileukotrienes have shown activity in clinical models of asthma, including exercise-induced, cold air hyperventilation-induced, allergen-induced, and aspirin-induced bronchoconstriction. In addition, the antileukotrienes partially reverse spontaneous bronchoconstriction in asthmatic persons, an effect additive to that of inhaled beta 2-agonists. Clinical trials of the antileukotrienes have shown clinical benefit, as measured by reductions in asthma symptom scores, improvements in air flow obstruction, and reductions in the rescue use of inhaled beta 2-agonists. Some, but not all, of the antileukotrienes have been shown to cause liver microsomal activation with increases in hepatic aminotransferase levels. CONCLUSIONS: Antileukotrienes are an important new therapy for asthma. Inhibition of leukotriene synthesis or action has a beneficial effect in the treatment of both induced and spontaneous asthma. These results show that leukotrienes are important mediators of the asthmatic response. In addition, encouraging results have been obtained from clinical trials of antileukotrienes; however, these results do not yet provide guidelines for the optimal clinical use of antileukotrienes in asthma treatment. Such recommendations await the results of further studies.
In, K. H., K. Asano, et al. (1997). "Naturally occurring mutations in the human 5-lipoxygenase gene promoter that modify transcription factor binding and reporter gene transcription." J Clin Invest 99(5): 1130-7.
Five lipoxygenase (5-LO) is the first committed enzyme in the metabolic pathway leading to the synthesis of the leukotrienes. We examined genomic DNA isolated from 25 normal subjects and 31 patients with asthma (6 of whom had aspirin-sensitive asthma) for mutations in the known transcription factor binding regions and the protein encoding region of the 5-LO gene. A family of mutations in the G + C-rich transcription factor binding region was identified consisting of the deletion of one, deletion of two, or addition of one zinc finger (Sp1/Egr-1) binding sites in the region 176 to 147 bp upstream from the ATG translation start site where there are normally 5 Sp1 binding motifs in tandem. Reporter gene activity directed by any of the mutant forms of the transcription factor binding region was significantly (P < 0.05) less effective than the activity driven by the wild type transcription factor binding region. Electrophoretic mobility shift assays (EMSAs) demonstrated the capacity of wild type and mutant transcription factor binding regions to bind nuclear extracts from human umbilical vein endothelial cells (HUVECs). These data are consistent with a family of mutations in the 5-LO gene that can modify reporter gene transcription possibly through differences in Sp1 and Egr-1 transactivation.
Fish, J. E., S. P. Peters, et al. (1997). "An evaluation of colchicine as an alternative to inhaled corticosteriods in moderate asthma. National Heart, Lung, and Blood Institute's Asthma Clinical Research Network." Am J Respir Crit Care Med 156(4 Pt 1): 1165-71.
Colchicine demonstrates an array of anti-inflammatory properties of potential relevance to asthma. However, the efficacy of colchicine as an alternative to inhaled corticosteroid therapy for asthma is unknown. Five centers participated in a controlled trial testing the hypothesis that in patients with moderate asthma needing inhaled corticosteroids for control, colchicine provides therapeutic benefit as measured by maintenance of control when inhaled steroids are discontinued. Subjects were stabilized on triamcinolane acetonide (800 microg daily) and then enrolled in a 2-wk run-in during which all subjects took both colchicine (0.6 mg/twice a day) and triamcinolone. At the end of the run-in, all subjects discontinued triamcinolone and were randomized to continued colchicine (n = 35) or placebo (n = 36) for a 6-wk double-blind treatment period. The treatment groups were similar in terms of disease severity. After corticosteroid withdrawal, 60% of colchicine-treated and 56% of placebo-treated subjects were considered treatment failures as defined by preset criteria. No significant difference in survival curves was found between treatment groups (log rank = 0.38). Other measures, including changes in FEV1, peak expiratory flow, symptoms, rescue albuterol use, and quality of life scores, also did not differ between groups. Of note, subjects failing treatment had significantly greater methacholine responsiveness at baseline than did survivors (PC20, 0.81+/-1.38 versus 2.11+/-2.74 mg/ml; p = 0.01). An analysis of treatment failures suggested that the criteria selected for failure reflected a clinically meaningful but safe level of deterioration. We conclude that colchicine is no better than placebo as an alternative to inhaled corticosteroids in patients with moderate asthma. Additionally, we conclude that the use of treatment failure as the primary outcome variable in an asthma clinical trial where treatment is withdrawn is feasible and safe under carefully monitored conditions.
Fischer, A. R., M. A. Rosenberg, et al. (1997). "Effect of a novel 5-lipoxygenase activating protein inhibitor, BAYx 1005, on asthma induced by cold dry air." Thorax 52(12): 1074-7.
BACKGROUND: Leukotrienes have been implicated in the mediation of airway obstruction induced by hyperventilation of cold dry air in asthmatic subjects. The effect of a novel inhibitor of 5-lipoxygenase activating protein, BAYx 1005, on the bronchospastic response to cold dry air hyperventilation was investigated in asthmatic patients. METHODS: After a screening cold dry air hyperventilation challenge to document cold air responsiveness, 16 asthmatic subjects (baseline forced expiratory volume in one second (FEV1) > 60% of predicted) underwent cold air challenge three hours after receiving 750 mg of BAYx 1005 or placebo using a randomised, double blind, crossover design. Leukotriene synthesis inhibition was estimated by measuring the concentration of leukotriene B4 in whole blood stimulated with calcium ionophore A21387. RESULTS: Treatment with BAYx 1005 produced a 34% (95% CI 11 to 63) increase in the amount of cold air minute ventilation required for a 10% decrease in FEV1 (PD10VE) compared with placebo (mean (SE) 37.6 (1.12) 1/min compared with 28.0 (1.13) 1/min, p < 0.006). The PD20VE increased 19% (95% CI 8 to 31) after treatment with BAYx 1005 compared with placebo (57.3(1.10)1/min versus 48.1 (1.10) 1/min, p < 0.002). Treatment with BAYx 1005 produced a 15.4% decrease in ionophore-stimulated LTB4 production, while treatment with placebo produced a 7.1% increase in ex vivo LTB4 (p < 0.02). CONCLUSIONS: Treatment with BAYx 1005, a novel inhibitor of leukotriene synthesis, produced a significant blunting of cold dry air responsiveness consistent with the hypothesis that leukotrienes mediate part of the bronchoconstriction induced by hyperventilation of cold dry air.
Kamada, A. K., S. J. Szefler, et al. (1996). "Issues in the use of inhaled glucocorticoids. The Asthma Clinical Research Network." Am J Respir Crit Care Med 153(6 Pt 1): 1739-48.
Israel, E., J. Cohn, et al. (1996). "Effect of treatment with zileuton, a 5-lipoxygenase inhibitor, in patients with asthma. A randomized controlled trial. Zileuton Clinical Trial Group." Jama 275(12): 931-6.
OBJECTIVE: To study the effect of 3 months of treatment with zileuton, an inhibitor of the enzymatic pathway (5-lipoxygenase) leading to leukotriene formation, on disease control in patients with mild to moderate asthma. DESIGN: Randomized, double-blind, parallel-group study in 401 patients. A 10-day placebo lead-in was followed by a double-blind treatment period of 13 weeks. SETTING: Asthma study clinics in university hospitals and private practices. PATIENTS OR OTHER PARTICIPANTS: Patients with mild to moderate asthma (forced expiratory volume in the first second [FEV1], 40% to 80% of predicted) whose only treatment was inhaled beta-agonists. INTERVENTIONS: Treatment with 600 mg or 400 mg of zileuton or placebo (each taken four times daily.) MAIN OUTCOME MEASURES: Frequency of asthma exacerbation requiring treatment with corticosteroids, use of inhaled beta-agonists, pulmonary function tests, asthma symptom assessment, and quality-of-life evaluation. Safety was evaluated by monitoring adverse events. RESULTS: Only eight (6.1%) of 132 patients receiving 600 mg of zileuton four times a day required corticosteroid treatment for asthma vs 21 (15.6%) of 135 patients receiving placebo (P=.02), giving a relative risk of 2.6. At the time of expected peak drug concentration, the average FEV1 improved 15.7% in the 600-mg zileuton group vs 7.7% in the placebo group (P=.006). Quality-of-life assessments significantly improved in the 600-mg zileuton group and not in the placebo group (P=.007 for the overall score). Elevations in liver function tests (more than three times normal), all of which reversed with drug withdrawal, occurred in five patients (P=.03 vs placebo), three patients (P=.12 vs placebo), and no patients treated with 600 mg of zileuton, 400 mg of zileuton, or placebo, respectively. CONCLUSIONS: Three months of 5-lipoxygenase inhibition produced a significant improvement in asthma control. These data indicate that 5-lipoxygenase products of arachidonic acid metabolism are mediators of inflammation with an important role in the biology of asthma.
Fraser, J. L., C. Lilly, et al. (1996). "Diagnostic yield of bronchoalveolar lavage and bronchoscopic lung biopsy for detection of Pneumocystis carinii." Mayo Clin Proc 71(11): 1025-9.
OBJECTIVE: To assess the need to perform a bronchoscopic lung biopsy (BLB) in addition to bronchoalveolar lavage (BAL) to obtain a definitive diagnosis of Pneumocystis carinii pneumonia. DESIGN: We retrospectively reviewed the results of concurrently collected paired BAL and BLB specimens to determine the diagnostic yield of both methods for the detection of P. carinii organisms. MATERIAL AND METHODS: During a 3-year period, the BAL fluid specimens stained with a commercially available direct immunofluorescence monoclonal antibody (DFA) reagent and the BLB specimens stained with Grocott methenamine-silver nitrate (GMS) were assessed for the presence of P. carinii. BAL fluid was routinely collected from multiple sites and combined into a single specimen for testing. RESULTS: During the 3-year period of study, 119 patients were identified who had paired BAL fluid and BLB specimens tested for the presence of P. carinii. Of the 119 patients, 16 had either BAL fluid that could not be interpreted or BLB tissue that was inadequate. Of the other 103 patients, 21 had P. carinii pneumonia. The sensitivity of the DFA method on BAL fluid and of the GMS method on BLB was 95% and 43%, respectively. CONCLUSION: For detection of P. carinii, the diagnostic yield is significantly higher for DFA-stained BAL specimens than for GMS-stained BLB specimens.
Drazen, J. M., E. Israel, et al. (1996). "Comparison of regularly scheduled with as-needed use of albuterol in mild asthma. Asthma Clinical Research Network." N Engl J Med 335(12): 841-7.
BACKGROUND: Inhaled beta-agonists are the most commonly used treatment for asthma, but data suggest that regularly scheduled use of these agents may have deleterious effect on the control of asthma. We compared the effects of regularly scheduled use of inhaled albuterol with those of albuterol used only as needed in patients with mild chronic, stable asthma. METHODS: In a multicenter, double-blind study, we randomly assigned 255 patients with mild asthma to inhale albuterol either on a regular schedule (126 patients) or only as needed (129 patients). The patients were followed for 16 weeks. RESULTS: The primary outcome indicator, peak expiratory air flow measured in the morning, did not change significantly during the treatment period in the scheduled (416 liters per minute after the run-in period and 414 liters per minute after the treatment period) or the as-needed (424 liters per minute at both times) treatment groups (P=0.71). There were no significant differences between the two groups in peak flow variability, forced expiratory volume in one second, the number of puffs of supplemental albuterol needed, asthma symptoms, asthma quality-of-life score, or airway responsiveness to methacholine. The statistically significant differences between the groups in evening peak flow and in the short-term bronchodilator response to inhaled albuterol were small and judged to be clinically unimportant. CONCLUSIONS: In patients with mild asthma, neither deleterious nor beneficial effects derived from the regular use of inhaled albuterol beyond those derived from use of the drug as needed. Inhaled albuterol should be prescribed for patients with mild asthma on an as-needed basis.
Fischer, A. R., C. A. McFadden, et al. (1995). "Effect of chronic 5-lipoxygenase inhibition on airway hyperresponsiveness in asthmatic subjects." Am J Respir Crit Care Med 152(4 Pt 1): 1203-7.
The leukotrienes are known bronchoactive agonists with potential proinflammatory effects that may be involved in mediating airway hyperresponsiveness. We investigated the effects of zileuton, an inhibitor of 5-lipoxygenase (5-LO), on airway responsiveness to cold, dry air in patients with moderate asthma. A group of 10 asthmatic patients underwent cold, dry air hyperventilation challenge; challenges were performed before drug treatment and 1 to 10 d after the completion of treatment with study drugs. The cold air minute ventilation required to cause a 15% decrease in FEV1 (PD15 VE) increased by 58% compared with the response before treatment, 1 to 10 d after the completion of 13 wk of treatment with zileuton. The geometric mean (geometric mean/SEM and geometric mean x SEM) PD15 VE increased from 24.5 (20.4, 29.5) L/min to 38.8 (34.7, 43.7) L/min (p = 0.01). Zileuton treatment inhibited 5-LO as measured ex vivo by ionophore-stimulated LTB4 levels in whole blood. In four of seven subjects, LTB4 levels before zileuton ingestion fell from 110.88 +/- 25.42 to 5.40 +/- 1.95 ng/ml 2 h post-zileuton dosing (p = 0.02, pre- versus 2 h postzileuton ingestion). Consistent with the short half-life of zileuton, 6 h postzileuton dosing the ionophore-stimulated, LTB4 levels in whole blood had increased to 89.68 +/- 35.54 ng/ml (p = 0.41, pre- versus 6 h postzileuton ingestion). Based on the first-order kinetics of zileuton, its effect on 5-LO activity should have been dissipated less than 16 h postingestion. Thus, chronic zileuton treatment decreased airway hyperresponsiveness as determined by reactivity to cold, dry air.(ABSTRACT TRUNCATED AT 250 WORDS)
Drazen, J. M. and E. Israel (1995). "Treatment of chronic stable asthma with drugs active on the 5-lipoxygenase pathway." Int Arch Allergy Immunol 107(1-3): 319-20.
It is now established that 5-lipoxygenase products are synthesized and released in the airway during asthmatic reactions. The importance of these products in the asthmatic response has been established through study of the effects of 5-lipoxygenase inhibitors and leukotriene D4 receptor antagonists in patients with chronic stable asthma. In this study we review the data demonstrating that chronic administration of zileuton, an inhibitor of 5-lipoxygenase, is associated with improved airway function, decreased asthma symptoms and decreased need for asthma medication use in patients with mild to moderate asthma.
Asano, K., C. M. Lilly, et al. (1995). "Diurnal variation of urinary leukotriene E4 and histamine excretion rates in normal subjects and patients with mild-to-moderate asthma." J Allergy Clin Immunol 96(5 Pt 1): 643-51.
BACKGROUND: Leukotriene E4 (LTE4) and histamine excreted into the urine reflect the in vivo synthesis and release of cysteinyl leukotrienes and histamine, respectively. We examined the diurnal variation of the excretion rate of these mediators over 4 consecutive days in normal subjects (n = 5) and patients with stable mild-to-moderate asthma (n = 8). METHODS: Sixteen consecutive 6-hour urine samples were collected over 4 days. Urinary LTE4 concentrations were determined by reverse-phase high-pressure liquid chromatography, followed by ELISA. Urinary histamine concentrations were measured by ELISA. The excretion rates of these compounds were normalized relative to urinary creatinine content. RESULTS: The mean urinary LTE4 excretion rate was 83.8 +/- 38.2 pg/mg creatinine (mean +/- SD) in normal subjects; in patients with asthma, the urinary LTE4 excretion rate (110.0 +/- 59.2 pg/mg creatinine) was significantly higher than that in normal subjects (p < 0.05). The urinary histamine excretion rate was not different between normal subjects (24.0 +/- 12.5 ng/mg creatinine) and patients with asthma (31.5 +/- 25.8 ng/mg creatinine). A robust and systematic within-day variation (p < 0.01), but no day-to-day variation, was observed in histamine excretion rate. Although the magnitude of variation in LTE4 excretion within a day was significantly greater in patients with asthma than in normal subjects (p < 0.05), we could not identify any specific diurnal variation pattern in either the normal or the asthma group. No significant correlation was observed between urinary LTE4 and histamine excretion rate within any subject. CONCLUSIONS: Patients with asthma excrete LTE4 in the urine at a greater rate than normal subjects. Although no systematic variation in urinary LTE4 excretion rates over the course of a day was observed in either normal subjects or patients with stable asthma, the presence of a systematic diurnal variation of urinary histamine excretion exists in both groups.
O'Donnell, W. J. and E. Israel (1994). "Inhaled diuretics in asthma: the search for the mechanism of action." J Asthma 31(2): 79-83.
Lilly, C. M., G. Besson, et al. (1994). "Capsaicin-induced airway obstruction in tracheally perfused guinea pig lungs." Am J Respir Crit Care Med 149(5): 1175-9.
The neurokinin receptors responsible for transducing the airway obstruction resulting from capsaicin infusion were defined in the tracheally perfused guinea pig lung. In this lung preparation, buffer is perfused via the trachea and allowed to exit the lung through numerous small holes in the pleural surface; airway obstruction is monitored as the backpressure (Pao) generated at a constant perfusion flow rate. Infusion of the specific NK1 receptor agonist, Sar-9 Met02(11) substance P, resulted in an increase in Pao; this effect was prevented by the NK1 receptor antagonist CP 99,994 but not by the NK2 receptor antagonist SR 48,968. Infusion of the specific NK2 receptor agonist Nle10-neurokinin A 4-10 resulted in an increase in Pao; this effect was prevented by the NK2 receptor antagonist SR 48,968 but not by the NK1 receptor antagonist CP 99,994. In the absence of NK receptor antagonists, infusion of capsaicin resulted in a significant increase in Pao, 31 +/- 4 cm H2O. In the presence of the NK1 receptor antagonist, the capsaicin response was not diminished, but in the presence of the NK2 receptor antagonist, the Pao response diminished to only 10 +/- 2 cm H2O, p < 0.001. These data indicate that when capsaicin is presented to the epithelial surface of the lung the resulting airway obstruction is mediated predominantly by NK2 receptor stimulation.
Israel, E. (1994). "Moderating the inflammation of asthma: inhibiting the production or action of products of the 5-lipoxygenase pathway." Ann Allergy 72(3): 279-84.
The products of the 5-lipoxygenase pathway of arachidonic acid metabolism, particularly the leukotrienes, can mediate bronchoconstriction, mucous secretion, airway mucosal edema, chemotaxis, and mobilization of cells into the airway in the inflammatory process of asthma. This paper will review the current data on the efficacy of available leukotriene antagonists or inhibitors that act on the 5-lipoxygenase pathway in induced bronchoconstriction in humans and in clinical studies in asthma. Studies of asthmatic responses to antigen and cold air hyperventilation and exercise will be discussed. Data will be reviewed from investigations regarding the effects of these pharmacological agents as they relate to increased airway tone in asthmatic patients and, finally, as they relate to clinical and physiological improvement in mild to moderate asthma. These studies suggest that the antagonists and inhibitors that affect the 5-lipoxygenase products of arachidonic acid may provide a new approach in the pharmacologic treatment of asthma. Further clinical studies will be required to define the precise role of these agents.
Israel, E. and J. M. Drazen (1994). "Treating mild asthma--when are inhaled steroids indicated?" N Engl J Med 331(11): 737-9.
Goodman, D. E., E. Israel, et al. (1994). "The influence of age, diagnosis, and gender on proper use of metered-dose inhalers." Am J Respir Crit Care Med 150(5 Pt 1): 1256-61.
Metered dose inhalers (MDIs) are widely used in clinical practice for administering pharmaceuticals targeted to the lung. It is well known that the inhalation technique used with MDIs can substantially influence the clinical response to inhaled medications. To determine the acceptability of MDI maneuvers, we studied 59 subjects (26 females and 33 males; age, 20 to 81 yr; mean age, 38 yr) to determine whether the MDI technique used by these individuals complied with published recommendations for acceptable inhalation technique. Measurements were made with an MDI adapter that contained an unobtrusive, lightweight, miniature sensing system. Inspiratory flow at the moment of MDI actuation (Va), the volume (integrated from airflow) at actuation as a fraction of total inspiratory volume (Va/VI), breath-holding time (tBH), and inspiratory volume as a fraction of FVC (VI/FVC) were determined from 59 uncoached inhalations. We defined an acceptable maneuver, based on published data, by four components: (1) inspiratory flow at actuation (Va) between 25 and 90 L/min; (2) actuation during early inspiration (0 < Va/VI < or = 0.20); (3) adequate breath-holding time (tBH > 4 s), and (4) a deep inhalation (VI/FVC > 0.50). For all subjects, only 25% of inhalation maneuvers met all four criteria for acceptability. We found that a significantly higher proportion of male than female subjects performed an acceptable MDI maneuver (43% versus 4%, p < 0.001). There were no significant differences in technique between younger and older subjects or between patients with a diagnosis of asthma or chronic obstructive pulmonary disease (COPD). We conclude that most patients use their MDIs incorrectly; females of all ages are much more likely to have improper MDI technique than are males.
Drazen, J. M., C. M. Lilly, et al. (1994). "Role of cysteinyl leukotrienes in spontaneous asthmatic responses." Adv Prostaglandin Thromboxane Leukot Res 22: 251-62.
Levy, B. D., S. Bertram, et al. (1993). "Agonist-induced lipoxin A4 generation: detection by a novel lipoxin A4-ELISA." Lipids 28(12): 1047-53.
Lipoxin A4 (LXA4) possesses potent bioactions. To facilitate its detection, an enzyme-linked immunosorbent assay (ELISA) was developed that proved sensitive and selective. Quantitation by ELISA of LXA4 generated from cellular sources strongly correlated (r = 0.99) with values obtained by high-pressure liquid chromatography (HPLC). We used this LXA4-ELISA to examine parameters influencing LXA4 generation from endogenous substrates during human platelet-neutrophil (PLT-PMN) interactions in vitro. Agonist-induced LXA4 production was clearly evident at a PLT-PMN ratio of 10:1, and recombinant human granulocyte/monocyte colony stimulating factor-priming of PMN augmented LXA4 generation 5-6 fold. The chemotactic peptide formylmethionyl-leucyl-phenylalanine, platelet-derived growth factor and arachidonic acid (20:4n-6) each stimulated formation of immunoreactive LXA4 (iLXA4) in these co-incubations. The presence of iLXA4 was also evaluated in vivo in aspirin-sensitive asthmatic patients who, in a randomized, double-blind crossover design, underwent nasal lavage after they each ingested a predetermined threshold dose of aspirin or placebo. Aspirin challenge provoked statistically significant increases in iLXA4 in each patient (P < 0.005). These results validate the use of a solid-phase ELISA for detection of LXA4. Furthermore, the use of this ELISA has allowed the first documentation of iLXA4 formation in human subjects with aspirin-sensitive asthma following specific antigenic challenge.
Israel, E. J., N. Simister, et al. (1993). "Immunoglobulin G binding sites on the human foetal intestine: a possible mechanism for the passive transfer of immunity from mother to infant." Immunology 79(1): 77-81.
In humans, the prenatal transfer of IgG from mother to foetus is facilitated by a receptor for IgG on the placenta. However, amniotic fluid contains IgG of maternal origin, and transfer of swallowed IgG into the circulation from the foetal intestine represents another potential pathway of passive immunization. In this study we assayed for a foetal intestinal IgG receptor to support the hypothesis of this alternate pathway of antibody transfer. Microvillous membrane (MVM) from small bowel of aborted foetuses (18 weeks gestation) were probed with [125I]IgG to detect specific IgG binding sites. Binding was pH dependent and was maximal at pH 6. Competitive inhibition of the binding of [125I]IgG was noted with the addition of increasing amounts of unlabelled IgG. Scatchard analysis showed one binding site with a dissociation constant of 1.58 x 10(-7), similar to that of the IgG receptor described on the suckling rat intestine. The binding of labelled IgG to the human MVM receptor was Fc mediated. These observations provide evidence for an Fc receptor on the human foetal intestine.
Israel, E., P. Rubin, et al. (1993). "The effect of inhibition of 5-lipoxygenase by zileuton in mild-to-moderate asthma." Ann Intern Med 119(11): 1059-66.
OBJECTIVE: To evaluate the effectiveness of inhibiting the formation of the 5-lipoxygenase products of arachidonic acid by the 5-lipoxygenase inhibitor zileuton in the treatment of mild-to-moderate asthma. DESIGN: Randomized, double-blind, placebo-controlled study. SETTING: University hospitals and private allergy and pulmonary practices. PATIENTS: A total of 139 persons with asthma who had a forced expiratory volume in 1 second (FEV1) of 40% to 75% of the predicted value and who were not being treated with inhaled or oral steroids. INTERVENTION: Zileuton, 2.4 g/d or 1.6 g/d, or placebo for 4 weeks. MEASUREMENTS: Airway function, beta-agonist use, and symptoms; inhibition of 5-lipoxygenase assessed by measurement of urinary leukotriene E4 (LTE4). RESULTS: Zileuton produced a 0.35-L (95% CI, 0.25 to 0.45 L) increase in the FEV1 within 1 hour of administration (P < 0.001 compared with placebo), equivalent to a 14.6% increase from baseline. After 4 weeks of zileuton therapy, airway function and symptoms improved, with the greatest improvements occurring in the 2.4 g/d group: This group’s FEV1 increased by 0.32 L (CI, 0.16 to 0.48 L), a 13.4% increase, compared with a 0.05-L (CI, -0.10 to 0.20 L) increase in patients taking placebo (P = 0.02). Symptoms and frequency of beta-agonist use also decreased with zileuton, 2.4 g/d. The mean urinary LTE4 level decreased by 39.2 pg/mg creatinine (CI, 18.1 to 60.4 pg/mg creatinine) and 26.5 pg/mg creatinine (CI, 6.6 to 46.5 pg/mg creatinine) in the 2.4 g/d and 1.6 g/d groups, respectively, compared with a slight increase in the placebo group (P = 0.007 and P = 0.05). No difference was noted in the number of adverse events among treatment groups. CONCLUSIONS: Inhibition of 5-lipoxygenase can improve airway function and decrease symptoms and medication use in patients with asthma, suggesting that this inhibition can be useful therapy for asthma. Also, 5-lipoxygenase products may mediate part of the baseline airway obstruction in patients with mild-to-moderate asthma.
Israel, E., A. R. Fischer, et al. (1993). "The pivotal role of 5-lipoxygenase products in the reaction of aspirin-sensitive asthmatics to aspirin." Am Rev Respir Dis 148(6 Pt 1): 1447-51.
A subset of persons with asthma develop bronchospasm, naso-ocular, gastrointestinal, and/or dermal reactions after ingesting aspirin (ASA) or agents with the capacity to inhibit cyclooxygenase. The bronchopulmonary reactions have been associated with a rise in urinary LTE4. We examined the effects of an inhibitor of 5-lipoxygenase, zileuton, in a group of eight asthmatic patients with known sensitivity to ASA accompanied by LTE4 hyperexcretion. We first confirmed ASA sensitivity and an increase in urinary LTE4 after ASA ingestion in these patients using a placebo-controlled ASA challenge. Subjects were then randomized to a double-blind, crossover trial to examine the effects of zileuton versus placebo on the response to ASA. Zileuton treatment decreased baseline urinary LTE4 excretion from a mean of 469 +/- 141 pg/mg creatinine to 137 +/- 69 pg/mg creatinine (p < 0.02) and blunted the maximum increase in urinary LTE4 after ingestion of ASA (3,539 +/- 826 pg/mg creatinine versus 1,120 +/- 316 pg/mg creatinine [p < 0.01]). The pre-ASA challenge FEV1 was unchanged by zileuton (3.41 +/- 0.15 L versus 3.35 +/- 0.17 L, zileuton versus placebo). Zileuton prevented the fall in FEV1 in response to ingestion of ASA; post-ASA ingestion the mean of the minimal FEV1 fell to 2.72 +/- 0.18 L on the placebo day while there was no significant fall on the zileuton day (3.26 +/- 0.17 L; p < 0.014). Zileuton also prevented the development of the nasal, gastrointestinal (p < 0.006 and p < 0.025, respectively), and dermal symptoms which developed after ASA ingestion.(ABSTRACT TRUNCATED AT 250 WORDS)
O'Donnell, W. J., M. Rosenberg, et al. (1992). "Acetazolamide and furosemide attenuate asthma induced by hyperventilation of cold, dry air." Am Rev Respir Dis 146(6): 1518-23.
We investigated the assumption that the efficacy of inhaled diuretics in asthma is dependent upon inhibition of the Na+/K+/2Cl- cotransporter. We compared the protective effect of acetazolamide, a diuretic without significant effect on the loop cotransporter, with the protection provided by inhaled furosemide in a cold, dry air hyperventilation model of asthma. Seven asthmatic subjects underwent a baseline bronchial challenge and then received a nebulized dose of 80 mg of furosemide or 500 mg of acetazolamide or saline placebo in a randomized, double-blind, placebo-controlled crossover design. Repeat challenges were performed immediately and at 2 and 4 h postnebulization. Acetazolamide caused a 47.2% increase in the amount of cold, dry air required to reduce the FEV1, by 20% (expressed in terms of respiratory heat loss as PD20RHL), from 0.79 multiplied or divided by (x/divided by) 1.13 kcal/min (geometric mean x/divided by geometric SEM) at baseline to 1.17 x/divided by 1.09 kcal/min postnebulization (p < 0.025). Furosemide increased the geometric mean PD20RHL by 53.9%, from 0.86 x/divided by 1.12 kcal/min to 1.33 x/divided by 1.12 kcal/min (p < 0.001). There was no significant change after placebo inhalation (0.81 x/divided by 1.15 kcal/min versus 0.87 x/divided by 1.10 kcal/min, NS). Airway responsiveness had returned to baseline by 2 h postnebulization on all 3 days. Furosemide also caused bronchodilatation, producing a 14.1% rise in the mean FEV1 (p < 0.005 versus prenebulization), whereas neither acetazolamide nor placebo altered airway tone significantly.(ABSTRACT TRUNCATED AT 250 WORDS)
Drazen, J. M., J. O'Brien, et al. (1992). "Recovery of leukotriene E4 from the urine of patients with airway obstruction." Am Rev Respir Dis 146(1): 104-8.
The urinary excretion of leukotriene E4 (LTE4) was measured in subjects presenting for emergency treatment of airway obstruction. A total of 72 subjects presenting with airway obstruction performed peak flow determinations before and after three treatments with nebulized albuterol given at 20-min intervals. Of these subjects, 22 more than doubled their peak flow rates, while 19 failed to increase their peak flow rates more than 25% during the treatment period. These groups were designated "responders" and "nonresponders," respectively. Urinary LTE4 excretion was determined in 16 of the 22 responders and 12 of the 19 nonresponders as well as 13 normal subjects by precolumn extraction, analytic reversed-phase high-performance liquid chromatography, and enzyme immunoassay. In the normal subjects the urinary LTE4 excretion was significantly (p less than 0.0001) less than the urinary LTE4 measured in the responder subjects, but not less than the urinary LTE4 excretion in the nonresponder group (p = 0.071). The enhanced recovery of LTE4 from the urine of subjects with acutely reversible airway narrowing is consistent with a bronchoconstrictor role for the cysteinyl leukotrienes in spontaneous acute asthma.
Drazen, J. M. and E. Israel (1991). "Asthma: a solution to half the puzzle?" Am Rev Respir Dis 144(4): 743-4.
Israel, E., R. Dermarkarian, et al. (1990). "The effects of a 5-lipoxygenase inhibitor on asthma induced by cold, dry air." N Engl J Med 323(25): 1740-4.
BACKGROUND. The enzyme 5-lipoxygenase catalyzes the metabolism of arachidonic acid to form products that have been implicated in the airway obstruction of asthma. We hypothesized that if products of the 5-lipoxygenase pathway are important in mediating this obstruction, then prevention of their formation should decrease the severity of an induced asthmatic response. METHODS. In a randomized, double-blind, placebo-controlled, crossover study, we examined the effect of A-64077, a 5-lipoxygenase inhibitor, on the bronchoconstriction induced by hyperventilation of cold, dry air in 13 patients with asthma. The completeness of 5-lipoxygenase inhibition was confirmed by examining the profile of eicosanoids produced in whole blood ex vivo after activation with the calcium ionophore A-23187. RESULTS. A-64077 decreased the mean (+/- SEM) ionophore-induced synthesis of leukotriene B4, a 5-lipoxygenase product, by 74 percent (from 265.3 +/- 30.3 to 69.5 +/- 21.5 ng per milliliter, P less than 0.001), but it did not affect the ionophore-induced synthesis of thromboxane B2, a cyclooxygenase metabolite of arachidonic acid (80.0 +/- 17.1 ng per milliliter before A-64077 vs. 75.8 +/- 14.3 ng per milliliter after A-64077). In concert with the selective inhibition of 5-lipoxygenase by A-64077, the amount of cold, dry air (expressed as respiratory heat exchange) required to reduce the forced expiratory volume in one second by 10 percent was increased by 47 percent after A-64077 (3.0 kJ per minute for placebo vs. 4.4 kJ per minute for A-64077, P less than 0.002). Similar results were obtained when minute ventilation was used as an indicator of outcome (27.5 liters per minute for placebo vs. 39.8 liters per minute for A-64077, P less than 0.005). CONCLUSIONS. Selective inhibition of 5-lipoxygenase by A-64077 is associated with a significant amelioration of the asthmatic response to cold, dry air, suggesting that 5-lipoxygenase products are involved in this response. This approach may be useful in the treatment of asthma.
Yager, D., J. P. Butler, et al. (1989). "Amplification of airway constriction due to liquid filling of airway interstices." J Appl Physiol 66(6): 2873-84.
Luminal epithelial projections formed during bronchoconstriction define interstices in which liquid can collect. Liquid in these interstices could amplify the degree of luminal compromise due to muscular contraction in at least two distinct ways. First, the luminal cross-sectional area is reduced by simple filling of the interstices. Second, if the surface tension (gamma) of the air-liquid interface is positive, the pressure drop across the interface produces an additional inward force that can further constrict the airway. We present a theoretical treatment of these two mechanisms together with data which suggest that both may significantly amplify the luminal narrowing due to airway smooth muscle contraction, particularly in small airways when gamma is high. To qualitatively assess the effects of altered gamma, guinea pig lungs with normal and altered airway liquid lining layers were frozen and studied while fully hydrated by low-temperature scanning electron microscopy. Airway gamma was altered in these animals by intratracheal instillation of 0.5 mg lysoplatelet-activating factor (lyso-PAF). The interstices of normal airways were dry, whereas the interstices of airways with altered surface lining layers were liquid filled. In addition, the surfactant inhibitory properties of lyso-PAF, 2-arachidonyl-PAF, and dipalmitoyl phosphatidylcholine (DPPC) were measured with a pulsating bubble surfactometer, using surfactant TA as the model surfactant. Minimal gamma (gamma min) of surfactant TA alone was 4.0 +/- 0.2 dyn/cm; a 5% mixture of lyso-PAF with surfactant TA resulted in a significantly (P less than 0.02) greater gamma min of 8.8 +/- 1.8 dyn/cm. In contrast, 2-arachidonyl-PAF and DPPC had minimal effects on gamma min of surfactant TA.
Israel, E., E. F. Juniper, et al. (1989). "Effect of a leukotriene antagonist, LY171883, on cold air-induced bronchoconstriction in asthmatics." Am Rev Respir Dis 140(5): 1348-53.
Isocapnic hyperpnea (ISH) of cold air induces bronchoconstriction in many asthmatic subjects. Although this response is well described, it is unclear whether this bronchoconstriction is related to the release of bronchoactive mediators. We examined whether pretreatment with LY171883, a competitive antagonist of leukotriene D4 activity via LTD4 receptors, reduced the bronchospastic response to cold air ISH in asthmatics using a randomized, double-blind, two-phase crossover design. In 20 subjects, 2 wk of treatment with either LY171883 600 mg twice a day or placebo did not result in a change in FEV1 (3.45 +/- 0.21 L placebo versus 3.59 +/- 0.20 L LY171883; p greater than 0.05). Nineteen subjects underwent cold-air ISH; LY171883 increased the geometric mean respiratory heat loss required to reduce the FEV1 by 20% (PD20RHE) from 1.00 kcal/min with placebo to 1.24 kcal/min with LY171883 (p less than 0.05). A similar difference was noted when responses were expressed as a function of minute ventilation. LY171883 produced greater shifts in the PD20RHE in more reactive subjects (r = 0.69, p less than 0.002). Among 11 different symptom scores recorded by 18 subjects, there was a significant decrease in daytime chest tightness with LY171883 (p less than 0.03). The increase in PD20RHE while the subjects received LY171883 is consistent with the hypothesis that LTD4 becomes available during cold-air ISH and may mediate bronchoconstriction. The small magnitude of the effect on the PD20RHE may be due to the role of other mediators in cold-air-induced bronchoconstriction or, alternatively, to an inadequate blockade of LTD4 effects.
Hodges, M. K. and E. Israel (1988). "Tracheobronchopathia osteochondroplastica presenting as right middle lobe collapse. Diagnosis by bronchoscopy and computerized tomography." Chest 94(4): 842-4.
Tracheobronchopathia osteochondroplastica (TO) is a rarely described disorder which historically has not been frequently recognized antemortem. Studies by computerized tomography (CT) and bronchoscopy now permit a definitive antemortem diagnosis and can obviate a more invasive diagnostic evaluation. We describe two cases of TO presenting as right middle lobe collapse, discuss the clinical and pathologic features, and outline an approach to its evaluation using CT and bronchoscopic study.
Israel, E., J. L. Robin, et al. (1987). "Differential effects of calcium channel blockers on leukotriene C4- and D4-induced contractions in guinea pig pulmonary parenchymal strips." J Pharmacol Exp Ther 243(2): 424-9.
Leukotriene (LT)C4 and LTD4-induced contractile effects in guinea pig pulmonary parenchyma were distinguished by their sensitivity to calcium channel blockers. LTC4-induced contractions were inhibited in a noncompetitive manner in the presence of calcium channel blockers, whereas LTD4 contractions were unaffected. In the presence of diltiazem, maximum LTC4-induced (1 X 10(-7) M) contractions were reduced by 24% and the concentration-effect curve was shifted to the right in a nonparallel manner; diltiazem had no significant effect on the LTD4 response. We used this differential sensitivity to calcium channel blockade to permit pharmacological characterization in guinea pig pulmonary parenchyma of the interaction of the competitive LT blocker FPL55712 and the putative LTD4 receptor, LTRd. We showed, using [3H]LTC4, that at least 15% of LTC4 is converted to LTD4 under our experimental conditions. We performed a Schild analysis of the inhibition of LTD4-induced contractions by FPL55712 in the presence of the calcium channel blocker diltiazem (0.67 mM). The Kb derived from this analysis (3.2 X 10(-7) M) agrees closely with the Ki derived for the interaction of FPL55712 and specific LTD4 binding in lung membranes. A Schild analysis of the interaction of FPL55712 and LTC4 in the presence of diltiazem resulted in competitive inhibition with a Kb of 4.7 X 10(-7) M. This apparent competitive inhibition, combined with the similarity of these binding constants, suggests that diltiazem is effective in blocking LTC4-mediated responses and that when these effects are blocked, LTC4 induced contractions are mediated through LTRd. The differential effects of calcium blockade on these two agonists provides evidence for distinct coupling mechanisms for LT receptors in this tissue.
Lee, T. H., E. Israel, et al. (1986). "Enhancement of plasma levels of biologically active leukotriene B compounds during anaphylaxis in guinea pigs pretreated by indomethacin or by a fish oil-enriched diet." J Immunol 136(7): 2575-82.
The changes in arterial plasma concentrations of immunoreactive leukotriene B (LTB) were compared after antigen challenge of two groups of sensitized, mepyramine-treated, and mechanically ventilated guinea pigs, one fed a diet enriched with fish oil and the other a control diet enriched with beef tallow. The lung tissue of animals fed a fish oil-enriched diet (FFD) for 9 to 10 wk incorporated eicosapentaenoic acid (EPA) and docosahexaenoic acid to constitute 8 to 9% of total fatty acid content, whereas these alternative fatty acids constituted less than 1% of the total fatty acid content of the lung tissue of animals on a beef tallow-supplemented diet (BFD). The maximum increase after antigen challenge in immunoreactive LTB4 from 0.16 +/- 0.04 ng/ml to 0.84 +/- 0.25 ng/ml in BFD animals and from 0.47 +/- 0.11 to 5.1 +/- 1.4 ng/ml immunoreactive LTB (LTB4 and LTB5) in FFD animals was significant (p less than 0.02) for each. Furthermore, the increase in total immunoreactive LTB in mepyramine-treated FFD animals was significantly greater than the increase in LTB4 in mepyramine-treated BFD guinea pigs at 2 to 8 min after antigen challenge (p less than 0.05). Resolution of arterial plasma immunoreactive LTB from pooled samples by reverse-phase high-performance liquid chromatography demonstrated that the sum of LTB4 and LTB5 in FFD animals exceeded that of LTB4 in BFD animals and that the quantity of LTB4 in the FFD animals was at least as great as that in the BFD animals during anaphylaxis. The products eluting at the retention times of LTB4 and LTB5 exhibited the chemotactic activity of their respective synthetic standards. The combination of indomethacin and mepyramine markedly augmented the antigen-induced increase in arterial plasma immunoreactive LTB4 concentrations in BFD animals, but had no effect on immunoreactive LTB levels in FFD animals. Limited in vivo measurements showing a lesser increase of plasma immunoreactive thromboxane B2 in the FFD relative to the BFD animals during anaphylaxis and ex vivo measurements showing a decreased LTB4-stimulated (cyclooxygenase product-dependent) contractile response of pulmonary parenchymal strips from the FFD relative to the BFD animals provide evidence for blockade in the cyclooxygenase pathway in the FFD animals. The measurements of arterial plasma LTB indicate that indomethacin treatment alone, which inhibits cyclooxygenase activity, and FFD treatment each augment the metabolism of arachidonic acid by the 5-lipoxygenase pathway in animals pretreated with mepyramine.(ABSTRACT TRUNCATED AT 400 WORDS)
Gross, T. P., E. Israel, et al. (1986). "Low prevalence of the booster phenomenon in nursing-home employees in Maryland." Md Med J 35(2): 107-9.
Lee, T. H., K. F. Austen, et al. (1985). "The effects of a fish-oil-enriched diet on pulmonary mechanics during anaphylaxis." Am Rev Respir Dis 132(6): 1204-9.
The pulmonary mechanical responses observed after antigen challenge in 2 groups of sensitized, mepyramine-treated, mechanically ventilated guinea pigs were compared: one group was fed a diet rich in fish oil and the other a control diet enriched with beef tallow. The lung tissue of animals fed a fish-oil-enriched diet for 9 to 10 wk incorporated eicosapentaenoic acid (EPA) and docosahexaenoic acid, which constituted 8 to 9% of the total fatty acid content, whereas these alternative fatty acids constituted less than 1% of total fatty acid content of the lung tissue of animals receiving a diet supplemented with beef tallow. With mepyramine pretreatment, animals receiving a fish oil diet exhibited a significantly greater decrease in dynamic compliance from 1.5 through 4.5 min after antigen challenge than did animals receiving a beef fat diet, whereas the decrements in pulmonary conductance were comparable. The combination of indomethacin and mepyramine markedly augmented the antigen-induced decrease in pulmonary mechanics in animals receiving a beef fat diet but not in those receiving a fish oil diet, such that the overall responses of the 2 groups were similar. These findings indicate that the fish oil diet and the indomethacin pretreatment of animals receiving the beef fat diet each facilitates the nonhistamine-mediated bronchoconstrictor response in pulmonary anaphylaxis.
Smith, C. R., R. Ambinder, et al. (1984). "Cefotaxime compared with nafcillin plus tobramycin for serious bacterial infections. A randomized, double-blind trial." Ann Intern Med 101(4): 469-77.
In a prospective, randomized, double-blind study, we compared cefotaxime with nafcillin plus tobramycin in the treatment of serious bacterial infections. Of 195 patients with suspected or proven infections who were not neutropenic, definite bacterial infections were identified in 81; 34 of 38 patients given cefotaxime and 26 of 43 given nafcillin plus tobramycin (p less than 0.01) responded to treatment. The difference in response rates occurred primarily in patients with rapidly fatal underlying disease or with an infection outside the urinary tract. A logistic regression analysis showed that treatment with cefotaxime was still associated with a higher response rate after adjusting for several potential confounding factors. Among patients treated for 3 days or more, our criteria for nephrotoxicity were met in 2 of 68 (2.9%) given cefotaxime and 16 of 57 (28.1%) given nafcillin plus tobramycin (p less than 0.001). Prolongation of the prothrombin time and enterococcal colonization did not occur more frequently with cefotaxime. We conclude that cefotaxime may be more effective and less toxic than nafcillin plus tobramycin for patients with serious bacterial infections.