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Does doubling the dose of inhaled corticosteroids prevent asthma exacerbations?
Articles of note. . . Does doubling the dose of inhaled corticosteroids prevent asthma exacerbations? Many asthma management guidelines stress the importance of self-management plans to be used by suitably instructed patients in the overall care of asthma. In asthmatic individuals treated chronically with inhaled corticosteroids (ICSs), some self-management plans recommend doubling the maintenance dose of ICS when there is evidence of significant worsening of asthma symptoms or peak expiratory flow rates. But is there convincing evidence that doubling the dose of ICS will prevent further worsening of the asthma to the point of an acute exacerbation? This study investigated a group of 390 asthmatic individuals receiving chronic ICS therapy who were at increased risk for acute asthma exacerbations on the basis of their past medical histories. In a randomized, blind, parallel, controlled protocol, each of the patients added either a doubling dose of ICS or placebo at signs of worsening asthma. The primary study outcome was the percentage of individuals requiring use of a ‘‘burst’’ treatment with oral corticosteroids for an acute exacerbation of asthma during the 12-month study period. During this period, 53% of the patients felt the need to add inhaler therapy (doubling dose of ICS or placebo). A course of oral corticosteroids was subsequently needed in 11% of those adding ICS and in 12% of those adding placebo. The authors concluded that these findings did not support a beneficial effect in preventing asthma exacerbations for the addition of a doubling dose of ICS when asthma worsened. However, it was not clear whether the asthma symptoms and/or quality of life improved faster in those adding the doubling dose of ICS. Moreover, it is unclear whether the effect of doubling the dose of ICS was related to the baseline ICS dose in individual patients. A number of studies have shown that the beneficial effects of most ICSs begin to plateau at doses above 800-1000 lg/day in asthmatic adults. (Harrison et al. Lancet 2004;59:21-5.)
Mast cells are required for experimental oral allergen–induced diarrhea Gastrointestinal (GI) allergic disorders represent a diverse spectrum of inflammatory diseases that are occurring with apparent increasing incidence and severity, including GI dysfunction resulting in vomiting and diarrhea. Although there is often an increased frequency of mast cells and eosinophils in the GI tissues of involved patients, the mechanisms underlying these food-induced reactions have not been clearly delineated. To further investigate possible cellular and humoral pathogenic mechanisms in these
J ALLERGY CLIN IMMUNOL
Beyond Our Pages Burton Zweiman, MD, & Marc E. Rothenberg, MD, PhD, Editors
disorders, the investigators developed a murine model of oral allergen–induced intestinal inflammation accompanied by strong TH2-associated humoral and cellular responses. Exposure of ovalbumin (OVA)/ alum-sensitized mice to repeated doses of intragastric OVA induced genetically restricted, dose-dependent, acute diarrhea associated with increased intestinal permeability, eosinophilia, and mastocytosis. There was only a modest degree of associated systemic anaphylaxis, even though there was marked degranulation in mast cells in the GI tract after the intragastric OVA challenge. There was decreased allergeninduced diarrhea in sensitized mice previously treated with antibodies to c-kit (to deplete mast cells) or with anti-IgE antibodies and in FceRI-deficient mice. These findings pointed to IgE-mediated mast cell activation in the pathogenesis of this allergic GI disorder. Further studies showed that the allergen-induced diarrhea was dependent on synergistic signaling induced by serotonin and platelet-activating factor. However, perhaps surprisingly, histamine release did not appear to play a significant role. If these findings in mice are found to occur in human beings as well, they have significant implications for therapeutic approaches to clinical allergic disorders involving the GI tract. (Brandt et al. J Clin Invest 2003;112:1666-77.)
Culpable role for eosinophils in asthma remodeling Eosinophilia in the blood and tissue is a hallmark feature of allergic disease, but the role of the eosinophil in disease pathogenesis remains in debate. Recent studies with humanized anti–IL-5 in patients with asthma have suggested a role for eosinophils in airway remodeling events but, surprisingly, not in the development of airway hyperresponsiveness. In a recent study, the role of eosinophils in the pathophysiology of a chronic asthma model in mice was assessed. The investigators developed a model involving repetitive airway exposure to the allergen ovalbumin (OVA) over a course of 3 months. IL-5–deficient mice exhibited reduced eosinophil numbers in bronchoalveolar lavage fluid and in the lung tissue. This was associated with decreased lung TGF-b1 levels, and evidence was
May 2004
Page 1009
Mast cells are required for experimental oral allergen–induced diarrhea Gastrointestinal (GI) allergic disorders represent a diverse spectrum of inflammatory diseases that are occurring with apparent increasing incidence and severity, including GI dysfunction resulting in vomiting and diarrhea. Although there is often an increased frequency of mast cells and eosinophils in the GI tissues of involved patients, the mechanisms underlying these food-induced reactions have not been clearly delineated. To further investigate possible cellular and humoral pathogenic mechanisms in these
J ALLERGY CLIN IMMUNOL
Beyond Our Pages Burton Zweiman, MD, & Marc E. Rothenberg, MD, PhD, Editors
disorders, the investigators developed a murine model of oral allergen–induced intestinal inflammation accompanied by strong TH2-associated humoral and cellular responses. Exposure of ovalbumin (OVA)/ alum-sensitized mice to repeated doses of intragastric OVA induced genetically restricted, dose-dependent, acute diarrhea associated with increased intestinal permeability, eosinophilia, and mastocytosis. There was only a modest degree of associated systemic anaphylaxis, even though there was marked degranulation in mast cells in the GI tract after the intragastric OVA challenge. There was decreased allergeninduced diarrhea in sensitized mice previously treated with antibodies to c-kit (to deplete mast cells) or with anti-IgE antibodies and in FceRI-deficient mice. These findings pointed to IgE-mediated mast cell activation in the pathogenesis of this allergic GI disorder. Further studies showed that the allergen-induced diarrhea was dependent on synergistic signaling induced by serotonin and platelet-activating factor. However, perhaps surprisingly, histamine release did not appear to play a significant role. If these findings in mice are found to occur in human beings as well, they have significant implications for therapeutic approaches to clinical allergic disorders involving the GI tract. (Brandt et al. J Clin Invest 2003;112:1666-77.)
Culpable role for eosinophils in asthma remodeling Eosinophilia in the blood and tissue is a hallmark feature of allergic disease, but the role of the eosinophil in disease pathogenesis remains in debate. Recent studies with humanized anti–IL-5 in patients with asthma have suggested a role for eosinophils in airway remodeling events but, surprisingly, not in the development of airway hyperresponsiveness. In a recent study, the role of eosinophils in the pathophysiology of a chronic asthma model in mice was assessed. The investigators developed a model involving repetitive airway exposure to the allergen ovalbumin (OVA) over a course of 3 months. IL-5–deficient mice exhibited reduced eosinophil numbers in bronchoalveolar lavage fluid and in the lung tissue. This was associated with decreased lung TGF-b1 levels, and evidence was
May 2004
Page 1009