The mouse trap: It still yields few answers in asthma.
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Animals↗
Biomedical subjects
Sally Wenzel
Publications and source records attributed to Sally Wenzel.
Physiologic and pathologic abnormalities in severe asthma.
Severe asthma remains poorly understood and frustrating to treat, partly because it is a heterogeneous disease. Recent improvements in the definition of severe asthma have allowed better characterization of the phenotypes of severe asthma and the related physiologic and pathologic abnormalities. Early-onset severe asthma is a more allergy-associated disease than late-onset asthma. Persistent eosinophilia is more commonly seen in patients who have late-onset disease but is associated with a more symptomatic disease in both early- and late-onset disease. Recent studies suggest that response to therapy in severe asthma may depend on the phenotype.
Asthma↗
The efficacy and safety of mometasone furoate delivered via a dry powder inhaler for the treatment of asthma.
Inhaled corticosteroids are the gold standard of daily therapy for effective control of all stages of persistent asthma. For this review of the new inhaled corticosteroid mometasone furoate, a MEDLINE/PubMed search using the terms "mometasone furoate AND asthma" found 57 articles, 17 of which presented data from efficacy and safety studies reviewed herein. In clinical trials, once-daily evening dosing of mometasone furoate delivered via dry powder inhaler (200 or 400 mu g/day) was effective in patients with mild to moderate asthma previously treated with short-acting beta2-agonists alone and in those previously maintained on inhaled corticosteroid therapy. In patients with severe asthma, mometasone furoate 400 mu g twice daily eliminated or reduced the need for oral prednisone while improving lung function, asthma symptoms, and quality of life. Clinical studies have shown that mometasone furoate is generally well tolerated and has minimal systemic activity at recommended doses. In conclusion, mometasone furoate provides primary care and specialty physicians with a safe, effective, and convenient option to meet the challenges of asthma management.
Anti-Asthmatic Agents↗
Toward optimal health: Sally Wenzel, M.D. Discusses the need for better asthma management in women. Interview by Jodi R. Godfrey.
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Asthma↗
Ciclesonide reduces the need for oral steroid use in adult patients with severe, persistent asthma.
STUDY OBJECTIVES: Oral corticosteroids (OCS) may be associated with systemic adverse events (AEs), which can be reduced by replacing OCS with inhaled corticosteroids (ICS). The potential of ciclesonide, a novel ICS, to reduce OCS use in patients with severe, persistent asthma was evaluated in this study. DESIGN: A phase III, 12-week, international, multicenter, double-blind, placebo-controlled, parallel-group study. PATIENTS: Adult and adolescent patients (> or = 12 years old; n = 141) with severe, persistent, oral steroid (prednisone)-dependent asthma. INTERVENTIONS: Patients were randomized to receive ciclesonide (640 mug/d or 1,280 microg/d [ex-actuator]) bid or placebo for 12 weeks. Weekly evaluations determined eligibility for prednisone dose reduction based on predetermined criteria. MEASUREMENTS AND RESULTS: The prednisone dose was significantly reduced by 47% and 63% in the groups receiving ciclesonide, 640 microg/d, and ciclesonide, 1,280 microg/d, respectively, vs an increase of 4% in the placebo group (both p < or = 0.0003) at week 12. By week 12, prednisone was discontinued by approximately 30% of patients in the ciclesonide-treated groups, vs 11% of patients in the placebo group (both p < or = 0.04). FEV1 improved significantly at week 12 in the ciclesonide treatment groups vs placebo (p < 0.03). The occurrence of local and systemic AEs was comparable between all treatment groups. CONCLUSION: Study results suggest that ciclesonide significantly reduces the need for OCS in patients with severe, persistent asthma, while maintaining asthma control.
Administration, Oral↗
Improvements in distal lung function correlate with asthma symptoms after treatment with oral montelukast.
STUDY OBJECTIVES: The distal airways are likely to contribute to asthma pathobiology and symptoms but have rarely been specifically evaluated in relation to systemic oral therapy. We hypothesized that treatment with montelukast, an oral cysteinyl-leukotriene receptor antagonist, would improve both proximal and distal lung physiology in patients with mild asthma. DESIGN: Randomized, double-blind, crossover design. SETTING: Academic referral center. PATIENTS: Subjects with mild asthma limited to using short-acting inhaled beta(2)-agonists. INTERVENTIONS: Nineteen subjects with mild asthma underwent a baseline assessment of lung function, lung mechanics, and symptoms, followed by randomization to therapy with montelukast, 10 mg taken in the evening, or placebo in a crossover, double-blind fashion. Each treatment phase lasted 4 weeks, with a 2-week washout period. A repeat evaluation was performed during the last week of each treatment phase. MEASUREMENTS AND RESULTS: Montelukast resulted in improvement in (mean +/- SD) proximal and distal lung function parameters (change in FEV(1): montelukast, 0.16 +/- 0.06 L; placebo, -0.05 +/- 0.05 L; p = 0.008); change in specific conductance: montelukast, 7.2 +/- 2.9% predicted; placebo, -17 +/- 8% predicted; p = 0.007; change in % predicted residual volume [RV]: montelukast, 18.4 +/- 8.3% predicted; placebo, 3.0 +/- 2.9% predicted; p = 0.05). Improvement in symptoms (ie, wheeze and chest tightness) correlated with improvements in RV while receiving montelukast, but not while receiving placebo (Pearson coefficients: 0.55 and 0.66, respectively; p < 0.008 and 0.04, respectively). CONCLUSIONS: The systemically acting oral agent montelukast improves proximal and distal lung physiology. Improvements in distal lung function correlate with improvements in asthma symptoms.
Acetates↗
Severe asthma in adults.
Severe asthma remains poorly understood and frustrating to care for, partly because it is a heterogeneous disease. Patients with severe asthma disproportionately consume health care resources related to asthma. Severe asthma may develop over time, or shortly after onset of the disease. The genetic and environmental elements that may be most important in the development of severe disease are poorly understood, but likely include both allergic and nonallergic elements. Physiologically, these patients often have air trapping, airway collapsibility, and a high degree of methacholine hyperresponsiveness. Specific phenotypes of severe asthma are only beginning to be defined. However, describing severe asthma by age at onset (early- vs. late-onset) appears to describe two phenotypes that differ at immunologic, physiologic, epidemiologic, and pathologic levels. In particular, early-onset severe asthma is a more allergic-associated disease than late-onset severe asthma. In addition, patients with severe asthma can be defined on the basis of presence and type of inflammation. Severe asthma with persistent eosinophilia (of either early or late onset) is more symptomatic and has more near-fatal events. However, at least 50% of patients with severe asthma have very little identifiable inflammation. Thus, "steroid resistance" may occur at numerous levels, not all of which are caused by a lack of effect of steroids on inflammation. Treatment remains problematic, with corticosteroids remaining the most effective therapy. However, 5-lipoxygenase inhibitors, anti-IgE, and immunomodulatory drugs are also likely to have a place in treatment. Improving therapy in this disease will require a better understanding of the phenotypes involved.
Asthma↗
Increased TGF-beta2 in severe asthma with eosinophilia.
BACKGROUND: Airway eosinophilia and thickened subepithelial basement membrane have previously been reported to increase with increases in TGF-beta expression. However, little is known regarding the expression of specific TGF-beta isoforms (TGF-beta1, TGF-beta2, and TGF-beta3) in asthma, despite recent evidence suggesting that isoforms may have differing biologic activities. OBJECTIVE: This study examined airway tissue expression of the 3 TGF-beta isoforms and several downstream pathway elements in 48 patients with severe asthma with or without persistent eosinophilia, 14 patients with mild asthma, and 21 normal subjects. METHODS: Immunochemistry/immunofluorescence, quantitative real-time PCR and enzyme immunoassay were used to evaluate the 3 TGF-beta isoforms, their receptors, collagen I deposition, connective tissue growth factor expression, and tissue inhibitor of metalloproteinases 1 levels. RESULTS: Of the isoforms, only TGF-beta2 was different among the groups and increased in severe asthma (overall P < .0001). The increase was due to severe asthma tissue eosinophils which, unlike eosinophils in other groups, expressed high amounts of TGF-beta2. Subjects with severe asthma also had the thickest subbasement membrane and highest tissue inhibitor of metalloproteinases 1 levels. In contrast, TGF-beta receptor 1 and connective tissue growth factor were both consistently downregulated in asthma, regardless of severity. CONCLUSION: TGF-beta2, expressed mainly by eosinophils, is the predominant isoform expressed in severe asthma, and is associated with increased profibrotic responses. Decreased expression of TGF-beta receptor 1 and connective tissue growth factor in all asthma severity groups suggests a degree of activation of the TGF-beta pathway in airway tissue of all asthmatic compared with normal airways.
Adult↗
The anti-inflammatory effects of omalizumab confirm the central role of IgE in allergic inflammation.
Anti-IgE therapy with omalizumab reduces serum levels of free IgE and downregulates expression of IgE receptors (Fc epsilonRI) on mast cells and basophils. In the airways of patients with mild allergic asthma, omalizumab reduces Fc epsilonRI+ and IgE+ cells and causes a profound reduction in tissue eosinophilia, together with reductions in submucosal T-cell and B-cell numbers. In patients with seasonal allergic rhinitis, omalizumab inhibits the allergen-induced seasonal increases in circulating and tissue eosinophils. Omalizumab decreases Fc epsilonRI expression on circulating dendritic cells, which might lead to a reduction in allergen presentation, T(H)2 cell activation, and proliferation. As a systemic anti-IgE agent, omalizumab has demonstrated clinical efficacy in patients with moderate and severe allergic asthma and in those with seasonal and perennial allergic rhinitis, as well as in patients with concomitant allergic asthma and allergic rhinitis. The anti-inflammatory effects of omalizumab at different sites of allergic inflammation and the clinical benefits of anti-IgE therapy in patients with allergic asthma and allergic rhinitis emphasize the fundamental importance of IgE in allergic inflammation.
Anti-Allergic Agents↗
Relationship of small airway chymase-positive mast cells and lung function in severe asthma.
Distal lung inflammation may be important in asthma pathophysiology. The goal of this study was to measure cellular inflammation in the large airway and four distal lung regions (small airway inner and outer wall, alveolar attachments, and peripheral alveolar tissue) and to correlate the specific inflammatory cells with several lung function parameters. Sections of concurrently obtained endobronchial and transbronchial/surgical biopsy tissue from 20 individuals with severe asthma were immunostained for T-lymphocyte, eosinophil, monocyte/macrophage, neutrophil, and two mast cell markers (tryptase and chymase). Specific cell distributions were determined and correlated with lung function measures. The number of inflammatory cells generally increased toward the periphery, but the percentage of T-lymphocytes, eosinophils, monocytes/macrophages, and neutrophils remained similar or decreased from large to small airways. In contrast, mast cell number, percentage, and the chymase-positive phenotype increased in small airway regions. After the analysis was adjusted for multiple comparisons, only chymase-positive mast cells significantly and positively correlated with lung function. Such a relationship was seen only in the small airway/alveolar attachments lung region (r(s) = 0.61-0.89; p </= 0.001 for all correlations). These data suggest that induction of chymase-positive mast cells, particularly in the small airway outer wall/alveolar attachments region, may be protective for lung function in severe asthma.
Adult↗
Design and baseline characteristics of the epidemiology and natural history of asthma: Outcomes and Treatment Regimens (TENOR) study: a large cohort of patients with severe or difficult-to-treat asthma.
BACKGROUND: Patients with severe and difficult-to-treat asthma represent a small percentage of asthma patients, yet they account for much of the morbidity, mortality, and cost of disease. The goal of The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study is to better understand the natural history of asthma in these patients. OBJECTIVE: To describe the methods and baseline characteristics of the TENOR study cohort. METHODS: The TENOR study is a 3-year, multicenter, observational study of patients with severe or difficult-to-treat asthma. From January through October 2001, more than 400 US pulmonologists and allergists enrolled patients. Patients 6 years or older who were considered to have severe or difficult-to-treat asthma by their physicians were eligible. Patients have been receiving care for 1 year or more, have a smoking history of 30 pack-years or less, and have current high medication or health care utilization in the past year. Data are collected semiannually. RESULTS: A total of 4,756 patients enrolled and completed a baseline visit. Overall, 73% of the TENOR study patients are adults, 10% are adolescents, and 16% are children. According to physician evaluation, 48% of patients have severe asthma, 48% have moderate asthma, 3% have mild asthma, and 96% have difficult-to-treat asthma. Severe asthmatic patients have the highest health care utilization in the past 3 months (P < .001). CONCLUSIONS: The TENOR study is the largest cohort of patients with severe or difficult-to-treat asthma. Although patients are equally divided into moderate or severe asthma categories, most are considered difficult-to-treat. The TENOR study highlights the lack of control in moderate-to-severe asthma and provides a unique opportunity to examine factors related to health outcomes in this understudied population.
Adolescent↗
Predicting response to omalizumab, an anti-IgE antibody, in patients with allergic asthma.
STUDY OBJECTIVE: To determine baseline characteristics predictive of response to omalizumab, an anti-IgE antibody, in patients with allergic asthma. DESIGN: Pooled analysis of two multicenter, double-blind, randomized, placebo-controlled phase III studies with omalizumab. PATIENTS: One thousand seventy allergic asthma patients symptomatic despite moderate-to-high doses (mean, 725 micro g/d) of inhaled beclomethasone dipropionate (BDP). INTERVENTIONS: Omalizumab (n = 542) or placebo (n = 528) were administered at a 4-weekly subcutaneous dose of at least 0.016 mg/kg/IgE (IU/mL) for 16 weeks in addition to stable BDP therapy. MEASUREMENTS AND RESULTS: Univariate logistic regression was performed to explore baseline variables predictive of best response. Various aspects of response (reduced symptom scores, reduced usage of rescue medication, improved lung function, improved quality of life [QoL]) were explored as well as a composite definition of response (response in at least one of these four aspects with no asthma exacerbation during 16 weeks of treatment). Time to onset of response as well as the ability to predict eventual response were also determined for the composite definition of response. A consistent pattern of predictive covariates was seen over all definitions of response (except for QoL). For the composite definition, a history of emergency asthma treatment in the past year was the factor most predictive (p = 0.015) of best response on active treatment (response rate for those with such history was 67% for omalizumab and 42% for placebo; for those without a history the response rates were 63% and 54%, respectively). Another factor predictive of best response on active treatment was high BDP dose (p = 0.037; response rate for those treated with >or= 800 micro g/d was 65% for omalizumab and 40% for placebo; for those treated with < 800 micro g/d, the response rates were 63% and 55%, respectively). A low FEV(1) was also predictive (p = 0.072; response rates for those with FEV(1) or= 65% predicted, the response rates were 67% and 53%, respectively). Seventy-six percent of patients had at least one of these factors. This subgroup showed odds of being a responder (composite definition) 2.25 times higher (95% confidence interval, 1.68 to 3.01) than placebo. Some 38% of patients treated with omalizumab showed a response (composite definition) at the first evaluation time point at 4 weeks, increasing to 64% at week 16 (vs 48% for placebo; p < 0.001). Among omalizumab responders at 16 weeks, only 61% had responded at 4 weeks whereas 87% had responded at 12 weeks. CONCLUSIONS: Patients who benefit most when omalizumab is administered as add-on therapy are those receiving high doses of BDP, those with a history of frequent emergency asthma treatment, and those with poor lung function. Patients should be treated with omalizumab for a minimum duration of 12 weeks.
Adolescent↗
Methods for the assessment of endobronchial biopsies in clinical research: application to studies of pathogenesis and the effects of treatment.
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Adolescent↗
Severe/fatal asthma.
Severe asthma is poorly understood clinically, physiologically, and pathologically. While milder forms of asthma are generally easily treated, more severe forms often remain refractory to the best current medical care. Although some patients with severe asthma have had severe disease for most of their lives, there appears to be a second group that develops severe disease in adulthood. Additionally, it is not clear which genetic and environmental elements may be the most important in the development of severe disease. Physiologically, these patients often have airtrapping and may have loss of elastic recoil, as well. The pathology demonstrates a heterogeneity of findings, including continued eosinophilic inflammation, structural changes, distal disease, and, in at least one third of patients, a different pathology. Treatment remains problematic and likely will remain so until a better understanding of this disease develops.
Asthma↗
The relationship of induced-sputum inflammatory cells to BAL and biopsy.
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Asthma↗
Severe asthma: epidemiology, pathophysiology and treatment.
Severe asthma is poorly understood clinically, physiologically and pathologically. Whereas milder forms of asthma are generally easily treated, more severe forms often remain refractory to the best current medical care. Although some asthmatics have been severely affected for most of their lives, there appears to be a second group that develops severe disease in adulthood. Additionally, it is not clear which genetic and environmental elements may be most important in the development of severe disease. Physiologically, these patients often have airtrapping and may have loss of elastic recoil, as well. The pathology demonstrates a heterogeneity of findings, including continued eosinophilic inflammation, structural changes, and distal disease. Treatment is problematic and will probably remain so until a better understanding of this disease develops.
Anti-Asthmatic Agents↗
Pathology of difficult asthma.
Severe asthma is poorly understood clinically, physiologically and pathologically. Although milder forms of asthma are generally easily treated, more severe forms remain refractory to the best current medical care. Both genetic and environmental elements are likely to play an important role in the development of severe disease. Physiologically, these patients often have air-trapping, airway collapsibility and loss of elastic recoil. The pathology demonstrates a heterogeneity of findings and is based mainly on adult studies. Some patients demonstrate continued eosinophilic inflammation despite the use of high doses of corticosteroids. At least one-third appear to have pathological changes inconsistent with classically described asthmatic pathology. Persistent inflammation can lead to structural changes involving the airways and perhaps the parenchyma as well. Finally, inflammation and structural changes appear to exist well into the lung periphery, out of reach of many inhaled medications. The importance of each of these factors in the development of severe disease probably varies from patient to patient. Understanding the commonalities of the pathology of severe asthma should, however, lead to the development of improved therapies.
Asthma↗