Management of asthma exacerbations.
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Adrenal Cortex Hormones↗
Biomedical subjects
R F Lemanske
Publications and source records attributed to R F Lemanske.
The clinical trials in the initial five-year award period of the Asthma Clinical Research Network.
During its first years of existence, the Asthma Clinical Research Network initiated four major clinical trials and one pilot clinical trial. The objective of this article is to describe briefly the specific aims, design, and conduct of those five trials.
Administration, Inhalation↗
Recruitment strategies in the Asthma Clinical Research Network.
In any clinical trial, recruitment of trial participants usually requires an intense effort to reach the target sample size. The Asthma Clinical Research Network (ACRN) was keenly aware of this issue at its inception and therefore initiated and emphasized recruitment strategies for each of its clinical trials. This article describes the recruitment strategies for the ACRN's first four major clinical trials. Particular attention is given to the strategies for the recruitment of women and minorities. Finally, the specific strategies of each of the six ACRN clinical centers are presented.
Adolescent↗
Safety and reproducibility of sputum induction in asthmatic subjects in a multicenter study.
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.
Aged↗
Reduced interferon-gamma secretion by natural killer cells from rats susceptible to postviral chronic airway dysfunction.
After parainfluenza type 1 (Sendai) virus infection as weanlings, Brown Norway (BN), unlike Fischer 344 (F344), rats develop an asthma-like phenotype. Reduced postinfection interferon (IFN)-gamma levels in bronchoalveolar lavage fluid from BN weanlings and the prevention of chronic airway sequelae in BN rats by IFN-gamma treatment led to the hypothesis that cells from BN weanlings have a reduced ability to secrete IFN-gamma. After stimulation with Sendai virus or interleukin (IL)-12, splenocytes from uninfected BN weanlings secreted significantly less IFN-gamma than did splenocytes from F344 weanlings (P < 0.005), as determined by enzyme-linked immunosorbent assay. Because levels of potential IFN-gamma-secreting cells in the spleen differed between the strains, natural killer (NK) cells, an important IFN-gamma source during early antiviral responses, were purified from spleens of uninfected weanlings. When stimulated with IL-12, BN NK cells secreted significantly less IFN-gamma than did F344 NK cells (P < 0.001). Incubation of NK cells from either strain with IL-12 and IL-18 resulted in synergistic increases in IFN-gamma production, but BN cells still secreted significantly less IFN-gamma than did F344 cells (P < 0.05). Similarly, after incubation with either IFN-alpha or IFN-alpha plus IL-18, BN NK cells secreted significantly less IFN-gamma than did F344 NK cells (P < 0.05). Therefore, reduced IFN-gamma secretion by NK cells in BN weanlings may play a role in the development of postviral chronic airway dysfunction.
Animals↗
The utility of peak flow, symptom scores, and beta-agonist use as outcome measures in asthma clinical research.
STUDY OBJECTIVES: Several methods of utilizing peak expiratory flow (PEF) and other markers of disease activity have been suggested as useful in the management of asthma. It remains unclear, however, as to which surrogate markers of disease status are discriminative indicators of treatment failure, suitable for use in clinical trials. DESIGN: We analyzed the operating characteristics of 66 surrogate markers of treatment failure using a receiver operating characteristic (ROC) curve analysis. PARTICIPANTS: Information regarding FEV(1), symptoms, beta(2)-agonist use, and PEF was available from 313 subjects previously enrolled in two Asthma Clinical Research Network trials, in which 71 treatment failures occurred (defined by a 20% fall in FEV(1) from baseline). INTERVENTIONS: None. MEASUREMENTS AND RESULTS: None of the measures had an acceptable ability to discriminate subjects with a > or % fall in FEV(1) from those without, regardless of the duration of the period of analysis or the criteria for test positivity employed. Areas under the ROC curves generated ranged from 0.51 to 0.79, but none were statistically superior. Sensitivity and specificity combinations were generally poor at all cutoff values; true-positive rates could not be raised without unacceptably elevating false-positive rates concurrently. CONCLUSIONS: Studies that seek to detect treatment failure defined by a significant fall in FEV(1) should not use such individual surrogate measures to estimate disease severity.
Adolescent↗
Choosing therapy for childhood asthma.
Inhaled corticosteroids remain the primary long-term treatment for controlling childhood asthma. Sodium cromoglycate (cromolyn sodium) and nedocromil sodium are both well tolerated, but usually less effective, alternatives to corticosteroids. Long-acting beta(2)-agonists (beta(2)-adrenoceptor agonists) may be useful adjuncts in patients already receiving inhaled corticosteroids who require frequent use of short-acting bronchodilators or experience nocturnal exacerbations (i.e. overall asthma control suboptimal). Theophylline has bronchodilator and anti-inflammatory effects and may also be used as an adjunct to inhaled corticosteroids. Leukotriene receptor antagonists are now an alternative as monotherapy in young children with mild persistent asthma, or as adjunctive therapy with inhaled corticosteroids as well. Short-acting inhaled beta(2)-agonists or other short-acting bronchodilators should be used as needed for acute episodes. For inhaled delivery, metered-dose inhalers with spacer devices (holding chambers) may be used as the delivery system in many patients, but the choice of inhalation method must be individualised, based largely on patient acceptance and compliance. Systemic corticosteroids may be used to gain prompt control when initiating long-term therapy in patients with severe, persistent asthma that does not respond to inhaled medication or in patients who are unable to take inhaled medication. The anti-immunoglobulin E antibody, omalizumab, is a novel therapy that attacks a fundamental immunopathological process of asthma and has shown promising results in several clinical trials.
Adrenal Cortex Hormones↗
Origins and treatment of airway inflammation in childhood asthma.
Several early events and risk factors are associated with the development of childhood asthma. Two significant risk factors are viral lower respiratory tract infections and atopy. Studies suggest that imbalances in TH1/TH2 cytokine responses in relationship to viral infections may play a role in the development of the childhood asthmatic phenotype. Airway inflammation is now recognized to contribute to the inception, persistence, and severity of asthmatic symptoms. The majority of information pertaining to airway inflammation in asthma has been derived from adult studies, but recent evaluations have been done in children. Available data are inconclusive as to the right medication to be used at the inception and during the evolution of the asthmatic phenotype in children. Inhaled corticosteroids (ICS) are not consistently effective in young children for a variety of reasons, including underlying pathophysiologic mechanisms that are unresponsive to the pharmacologic properties of ICS. The leukotriene receptor antagonists (LTRAs), recently approved for children as young as 2 years of age, address the relationship between leukotriene production and airway inflammation or remodeling in asthma. Therapeutic trials using LTRAs in children should prove beneficial.
Adrenal Cortex Hormones↗
The role of respiratory viruses in acute and chronic asthma.
Respiratory infections can have dual effects related to asthma. First, there is increasing evidence that severe infections with RSV and PIV in infancy can alter lung development and physiology to increase the risks of subsequent wheezing and asthma. Second, infections with common cold viruses and influenza commonly precipitate wheezing symptoms in children and adults who already have established asthma, and RV appears to be the most important virus in producing exacerbations of the disease. The principal mechanisms by which this occurs appears to be viral replication in epithelial cells, triggering a cascade of inflammation involving granulocytes, macrophages, T cells, and secreted cytokines and mediators. The inflammatory process, although essential to clear the infection, augments pre-existing airway inflammation in asthma, leading to increased airway obstruction and lower respiratory tract symptoms. Greater understanding of virus-induced changes in inflammation and corresponding changes in airway physiology may lead to new therapeutic approaches to the treatment and prevention of virus-induced airway dysfunction.
Acute Disease↗
Inflammatory events in asthma: an expanding equation.
Asthma is a chronic inflammatory disorder that can lead to progressive, potentially irreversible declines in lung function in some patients. Asthmatic inflammation develops when the sequential interaction of inflammatory cells with resident cells generates a cascade of events that contribute to the chronic inflammation and clinical manifestations associated with the disease, including further inflammation, airway smooth muscle spasm (bronchospasm), airway mucus secretion, airway edema and narrowing, and bronchial epithelial damage. Because of the chronic, progressive nature of asthmatic inflammation and the early age of onset, the ability to evaluate inflammation in children would be useful. Several procedures that quantify inflammatory mediators (in peripheral blood, induced sputum, bronchoalveolar lavage fluid, and bronchial biopsies) have shown potential usefulness in the evaluation of and the monitoring of disease severity in children (and, by extension, adults) with asthma. Further research needs to be devoted to the elucidation of when the inflammatory process starts and how it changes over time, to the determination of whether the inflammatory process is the same in all patients with wheezing, regardless of the stimulus, to the definition of the relationship between atopy and asthma, and to the establishment of the usefulness of testing for inflammatory markers to help identify individual asthmatic phenotypes, to evaluate disease severity, to measure therapeutic response, and/or to predict potential outcomes.
Asthma↗
The effect of polymorphisms of the beta(2)-adrenergic receptor on the response to regular use of albuterol in asthma.
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.
Adolescent↗
Effect of ICAM-1 blockade on lung inflammation and physiology during acute viral bronchiolitis in rats.
Viral respiratory infections cause acute bronchiolitis and physiologic dysfunction in human infants and in animals. It is possible that the pulmonary dysfunction is a consequence of the inflammatory cells that are recruited during viral illness. We hypothesized that blockade of intercellular adhesion molecule-1 (ICAM-1), a major cell adhesion molecule, would impede the ingress of leukocytes during viral infection and attenuate virus-induced pulmonary dysfunction. Adult male rats were inoculated with parainfluenza type 1 (Sendai) virus or sterile vehicle, and treated with blocking or nonblocking MAb specific for rat ICAM-1. Respiratory system resistance, oxygenation (PaO2), methacholine responsiveness, and bronchoalveolar lavage (BAL) leukocyte counts were measured in anesthetized, paralyzed, ventilated rats. Treatment with the blocking ICAM-1 antibody reduced virus-induced increases in BAL neutrophils and lymphocytes by 70% (p < 0.001), but did not affect BAL monocytes/macrophages. Peripheral blood leukocyte counts were elevated in anti-ICAM-1 blocking antibody-treated rats (p = 0.0003). Although virus-induced increases in resistance and decreases in PaO2 were not affected by anti-ICAM-1 treatment, there was a small but significant attenuation of virus-induced methacholine hyperresponsiveness (p = 0.02). We conclude that ICAM-1 has an important role in neutrophil and lymphocyte infiltration during respiratory viral illness, and that virus-induced changes in pulmonary physiology are not related directly to the numbers of neutrophils and lymphocytes that migrate to the air spaces during infection.
Acute Disease↗
Serial segmental bronchoalveolar lavage in individual rats.
Bronchoalveolar lavage (BAL) is a well-characterized technique for analysis of cellular constituents of the airways and air spaces, but whole lung lavage requires that the animal be euthanized. We describe a technique of segmental BAL in rats that allows serial measurements of inflammation. A tracheal tube was placed, under direct visualization, in lightly anesthetized animals, and a catheter was passed through the tracheal tube and advanced to a wedge position. Five 0.1-ml volumes of buffer solution were instilled and then withdrawn with gentle suction. In normal rats, the percentages of neutrophils, eosinophils, and mononuclear cells had a high level of agreement in the segmental samples compared with those obtained subsequently by whole lung lavage. In rats with acute pulmonary inflammation, the differential leukocyte counts from segmental samples exhibited patterns of change that differed from those of whole lung lavage; however, most segmental samples were obtained from the left lung base so that regional variability could be minimized in serial studies. Lung mechanics and airway inflammation were not affected by repeated segmental BALs done 2 wk apart.
Aging↗
Prevention of chronic postbronchiolitis airway sequelae with IFN-gamma treatment in rats.
After viral bronchiolitis at an early age, Brown Norway (BN) rats develop chronic airway dysfunction consisting of inflammation, remodeling, episodic reversible obstruction, and hyperresponsiveness. We hypothesized that supplementation of interferon gamma (IFN-gamma) during viral illness would alter the inflammatory response and attenuate the postviral sequelae. Weanling rats were treated daily with aerosolized interferon gamma (IFN-gamma), from 2 d prior through 7 d after inoculation, and compared with saline-treated infected rats and with noninfected control rats. The IFN-gamma treatment had no significant effect on viral titers, growth retardation, or total bronchoalveolar leukocytes, but there was a slight decrease in lung interleukin-4 (IL-4) mRNA (p = 0.015) during the first week. Despite having minimal effects on the acute illness, the IFN-gamma had marked effects on postviral sequelae, the IFN-gamma group having less bronchiolar inflammation (p = 0.025) and fibrosis (p = 0.01), and lacking abnormalities in pulmonary resistance (p = 0.028) and dynamic compliance (p = 0.006) compared with the untreated postviral group. We conclude that IFN-gamma modulated the inflammatory response to viral illness, such that acute airway injury did not evolve into chronic airway dysfunction. If similar processes contribute to the development of human asthma, it may be possible to interrupt the progression of airway dysfunction with an early immunomodulatory intervention.
Airway Resistance↗
Early life origins of asthma.
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Air Pollution↗
Pharmacotherapy of chronic asthma.
The chronic treatment of asthma involves many considerations including the type of medication; the choice of delivery system; the appropriate timing for the initiation of therapy; the proper approaches for both step-up and step-down therapy; teaching patients the concepts of acute relief, preventive intervention and long-term control; avoidance of various factors which may cause acute exacerbations; and the recognition of the fatality-prone asthmatic to maximize drug efficacy and patient safety while minimizing morbidity and mortality. All of these factors need to be balanced in terms of short- and long-term risks versus benefits of therapy and the cost of care that various treatment interventions and regimens may entail.
Journal Article↗
A review of the current guidelines for allergic rhinitis and asthma.
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Asthma↗