Treatment for Bronchial Asthma— Kazuo AKIYAMA

Vol.45, No.9 September 2002 CONTENTS Bronchial Asthma ● Inhaled Corticosteroids in the Management of Adult Asthma Mitsuru ADACHI and Toshimichi IMAI . 361 ● Self-Management with Peak Expiratory Flow Monitoring —Treatment for Bronchial Asthma— Kazuo AKIYAMA . 369 ● How to Use Anti-Allergy Drugs Ken OHTA . 375 ● Managing Exacerbation of Asthma: Pharmacologic Therapy Koichiro KUDO . 381 ● Current Treatment of Childhood Bronchial Asthma Based on the Guidelines Toru AKASAKA . 388 Managed Care ● A Preliminary Study of the Impact of Managed Care on Psychotherapy in Massachusetts Hiroto ITO . 396 Topics ● Treatment of Age-related Macular Degeneration Kanjiro MASUDA . 403 ⅥBronchial Asthma Inhaled Corticosteroids in the Management of Adult Asthma JMAJ 45(9): 361–368, 2002 Mitsuru ADACHI* and Toshimichi IMAI** Professor* and Assistant Professor**, First Department of Internal Medicine, School of Medicine, Showa University Abstract: The basic condition underlying bronchial asthma is a chronic airway inflammation that involves inflammatory cells and cells constituting the respiratory tract. Repeated inflammation elicits airway remodeling, leading to severer and more intractable asthma. Airway inflammation causes airway hyperresponsive- ness, which results in air flow limitation. There is no marked difference in the status of airway inflammation according to whether the condition is atopic or non-atopic or whether the patient is an adult or a child. The goal of treatment of asthma is to control and resolve airway inflammation. Inhaled corticosteroids represent safe, effective anti-inflammatory therapy and occupy a central role in the long-term management of asthma. The main elements in the application of inhaled corticosteroids include an understanding of the importance of choosing a dose commen- surate with the severity of the condition, use of the step-down technique, and early intervention of therapy. Because it is not possible to control all cases of asthma with inhaled corticosteroids alone, it is important to appropriately combine long-acting ␤2 agonists, slow sustained theophylline, and leukotriene antagonists. Key words: Inhaled corticosteroids; Airway inflammation; Anti-inflammatory drugs; Airway remodeling; Early intervention Introduction nophils, mast cells, T cells (Th2), basophils, and neutrophils, and airway component cells such Bronchial asthma is basically a disease of the as airway epithelial cells and fibroblasts. This airways, regardless of whether it is atopic or airway inflammation is worsened and pro- non-atopic and whether the patient is an adult longed by the production and release of various or a child. The central picture of bronchial mediators and cytokines. asthma is that of a chronic airway inflammation In addition, repeated airway inflammation that involves inflammatory cells such as eosi- induces airway remodeling that includes thick- This article is a revised English version of a paper originally published in the Journal of the Japan Medical Association (Vol. 125, No. 10, 2001, pages 1548–1553). The Japanese text is a transcript of a lecture originally aired on February 12, 2001, by the Nihon Shortwave Broadcasting Co., Ltd., in its regular program “Special Course in Medicine”. JMAJ, September 2002—Vol. 45, No. 9 361 M. ADACHI and T. IMAI Antigen Dendritic cell DC1,DC2 IgE Mast cell Naive T cell Histamine IL-6,IL-12 Tr yptase DC-CK1-R MHC I/II IL-5 LT CXCR4 CD28 B7-1,2 CCR7 TCR-CD3 complex PAF MDC,TARC PAF,LTB LTB 4 RANTES 4 CD40 IL-4,IL-13 CCR3,CCR4 IL-3 Eosinophil Eotaxin Neutrophil B cell CD40L IL-5 MCP-2,3,4 IL-4,IL-13 Active oxygen GM-CSF CCR3 Elastase Th2 cell MBP ECP Epithelial detachment� Mucous plug LTC 4 IgE Neural stimulation Fibrosis of subepithelial tissue Plasma effusion Sensory nerve Mucous gland stimulation Edema Cholinergic Hypersecretion, hyperplasia Vasodilation nerve reflex Angiogenesis Contraction of bronchial smooth muscle, thickening/hyperplasia of smooth muscle Fig. 1 Pathological condition of the asthmatic airway ening of the reticular layer under the basement bronchodilators and anti-inflammatory drugs, membrane, epithelial metaplasia, proliferation respectively.1) This paper describes the use of the submucosal glands, and thickening of of inhaled anti-asthmatic drugs, particularly the smooth muscle, leading to severer and inhaled corticosteroids, in the treatment of more intractable asthma. Airway inflammation asthma, and outlines their place in guidelines causes increased airway responsiveness, which for the treatment of asthma. easily brings about contraction of the bronchial smooth muscle, increased vascular permeabil- Remedies for Asthma Attack ity, and hypersecretion of the airways, resulting (Relievers) in air flow limitation (Fig. 1). Therefore, the inhalation of anti-asthmatic drugs for direct Asthma attacks vary in degree, ranging from application to the airway seems to be more mild wheezing that is barely perceivable by the effective at lower doses and to have fewer patient him- or herself to severe attacks that systemic effects. render the patient unable to walk or talk. At Current anti-asthmatic drugs available for any degree of severity, inhaled ␤2 agonists play this route include sodium cromoglycate a central role in the treatment of asthma (DSCG), ␤2 agonists, corticosteroids, and attacks through their potent bronchodilator anticholinergic drugs. Inhaled ␤2 agonists and action. In addition to ␤2 agonists, inhaled anti- inhaled corticosteroids occupy central roles as cholinergic drugs are used for the treatment of 362 JMAJ, September 2002—Vol. 45, No. 9 INHALED CORTICOSTEROIDS THERAPY IN ADULT ASTHMA 2) l/min Table 1 Anti-asthma Actions of Steroids FP ** : pϽ0.01 100 BDP *** : pϽ0.01 SEעGeneral effects related to asthma ( ) No. of cases mean (A) Increase in ␤-receptors 80 Effects on adenylate cyclase and cyclic AMP *** (B) Effects on leukocytic migration (82) 1. Decreased number of lymphocytes in blood 60 *** 2. Suppression of aggregation of monocytes and (82) macrophages to the site of inflammation *** ** 3. Inhibition of increase in number of neutrophils 40 (82) PEF (76) and their aggregation to the site of inflammation (76) 4. Decreased number of eosinophils in blood *** (77) *** (83) *** 5. Inhibition of expression of adhesion molecules 20 *** (78) (C) Effects on cytokines ␣ (83) *** Inhibition of the production of IL-1, TNF , 0 GM-CSF, IL-3, IL-2, IL-4, IL-5, IL-6, IL-8, IL-11, Intragroup comparison (paired t-test) ␥ ␣ (79) IL-12, IL-13, INF- , RANTES, MIP-1 , and SCF Intergroup comparison (t-test) 20מ Inhibition of expression of GM-CSF in airway epithelial cells (D) Enhancement of neutral endopeptidase 01234 weeks (E) Activation of endonuclease Course (F) Increase in lipocortin-1 production Fig. 2 Changes in morning PEF on inhaled DBP Specific effects related to asthma (400␮g/day) or FP (200␮g/day) therapy3) (A) Inhibition of IgE production (B) Effects on mediators 1. Inhibition of histamine production 2. Inhibition of eicosanoid release (C) Effects on the pathological condition of asthma 1. Vasoconstriction cholinergic drugs is weaker and slower than 2. Suppression of vascular permeability that of inhaled ␤2 agonists. However, inhaled 3. Inhibition of late asthmatic response anticholinergic drugs exert a greater broncho- 4. Inhibition of mucous secretion dilator action than inhaled ␤2 agonists in patients with emphysema and therefore are useful in the treatment of patients with asthma complicated by emphysema. asthma attacks. For the treatment of mild symptoms of Drugs for Long-term Management of wheezing or chest tightness to those of moder- Asthma (Controllers) ate asthma, one or two puffs of a ␤2 agonist should be administered using a pressurized Drugs used for improving and eliminating metered-dose inhaler (pMDI), followed by the symptoms of asthma, normalizing respira- additional doses at 20-min intervals for one tory function, and maintaining normalized res- hour and then at one-hour intervals thereafter. piratory function are called controllers. They At the same time, oral therapy including a ␤2 are divided into anti-inflammatory drugs and agonist and theophylline should be given. If long-acting bronchodilators. symptoms are eliminated [as indicated by 70% or greater of predicted peak expiratory flow 1. Anti-inflammatory drugs (PEF)] or if the medication has been successful Anti-inflammatory drugs used as inhaled for 3–4 hours, the patient can remain at home. anti-asthma drugs include disodium cromo- If symptoms fail to respond to the medication glycate (DSCG) and corticosteroids. Cortico- and repeated inhaled ␤2 agonist therapy is steroids have the most potent anti-inflammatory necessary, the patient will need to make an activity and a wide spectrum of anti-asthma emergency visit. actions (Table 1).2) The bronchodilator effect of inhaled anti- Inhaled corticosteroids are extremely effec- JMAJ, September 2002—Vol. 45, No. 9 363 M. ADACHI and T. IMAI tive for relieving the symptoms of asthma, Inhaled Anti-asthma Drugs reducing the frequency of acute exacerbation, Recommended for Long-term and improving pulmonary function and sup- Management in Guidelines pressing its circadian variation. Since they are for the Prevention and inhaled, they act directly at the site of the lesion Management of Asthma and are thus effective at a lower dose than that used for systemic administration. In addition, In severity-matched stepwise drug

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