Asthma Prevention And Management Guidelines: 2003, Japan (Jgl 2003), English Summary

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Author: Sohei Makino | K. Ohta | A. Morikawa

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DOI: 10.1159/000084008

Asthma Prevention and Management Guidelines 2003, Japan (JGL 2003): English summary Report of the Research Group for Asthma Prevention and Management Guidelines, supported by the Immunology & Allergy Research Study Project Ministry of Health, Labour and Welfare, Japan

Guest Editors

Sohei Makino Ken Ohta Sankei Nishima Akihiro Morikawa

12 figures and 20 tables, 2005

Basel • Freiburg • Paris • London • New York • Bangalore • Bangkok • Singapore • Tokyo • Sydney

S. Karger Medical and Scientific Publishers Basel • Freiburg • Paris • London New York • Bangalore • Bangkok Singapore • Tokyo • Sydney

Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com

Drug Dosage The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.

All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center (see ‘General Information’). © Copyright 2005 by S. Karger AG, P.O. Box, CH–4009 Basel (Switzerland) Printed in Switzerland on acid-free paper by Reinhardt Druck, Basel ISBN 3–8055–7943–8

Vol. 136, Suppl. 1, 2005

Contents

1

Foreword

Chapter 1 Definition, Diagnosis, Disease Types, and Classification of Asthma Definitions Definition of Adult Asthma 3 Definition of Childhood Asthma 3 Asthma Classification Based on Severity and Frequency of Asthma Attacks 3 3

Chapter 2 Epidemiology of Asthma 5 5 5 5 5 6 7 7 8 8 8 10 12 13 13 13

Epidemiology of Asthma Survey Methods Survey Results Current Prevalence of Asthma Symptoms Changes over Time in Asthma Symptom Prevalence Regional Differences in Asthma Prevalence Male-Female Ratio Age at Onset Family History of Asthma Number and Percentage of Patients Diagnosed with Asthma Asthma Deaths Asthma Deaths in Adults Asthma Deaths in Children Countermeasures to and Prevention of Asthma Deaths References Further Reading

© 2005 S. Karger AG, Basel Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com

Access to full text and tables of contents, including tentative ones for forthcoming issues: www.karger.com/iaa_issues

Chapter 3 Pharmacologic Control of Asthma 14 14 14 15 17 17 17 19 19 19 20 20 20 20 20 21 21 22 22 22 22 22 22 23 23 25 25 25 25 26 26 26 26 27 27 29 29 29

IV

Pharmacologic Treatment for Long-Term Management of Asthma Drugs Controller Medications Corticosteroids Sustained-Release Theophylline ␤2-Agonists Anti-Allergic Agents Reliever Medications Corticosteroids ␤2-Agonists Subcutaneous Epinephrine Injection Aminophylline/Theophylline Inhaled Anti-Cholinergic Drugs Other Drugs and Therapy Traditional Chinese Herbal Medicines (Kampo) Hyposensitization Therapy Nonspecific Therapy A Stepwise Plan of Pharmacologic Therapy in Adults Goal of Asthma Control Implementation of Asthma Therapy Four Steps in Long-Term Management of Asthma Step 1: Mild Intermittent Asthma Step 2: Mild Persistent Asthma Step 3: Moderate Persistent Asthma Step 4: Severe Persistent Asthma Supplement: Intractable Asthma Follow-Up Evaluation and Testing Management of Acute Exacerbation (Attacks) in Adults Management of Patients at Home Standard Drugs Used for the Treatment of Asthma Attacks (Reliever Medications) Inhaled ␤2-Agonists Subcutaneous Epinephrine Theophylline Factors Which Affect Serum Theophylline Level Corticosteroids Oxygen Other Therapy Procedures for Emergency Outpatient Treatment

Int Arch Allergy Immunol Vol. 136, Suppl. 1, 2005

Contents

29 29 29 31 31 31 34 35 36 36 37 37 37 40 40 41 41 41 41 42 42 42 42 42 43 43 43 44 44 45 49

Contents

Management and Treatment of Childhood Asthma Management of Acute Attacks in Childhood Asthma Home Management of Patients Treatment in a Medical Facility Treatment of Mild Attacks Treatment of Moderate Attacks Treatment of Severe Attacks Treatment for Acute Respiratory Failure Indications for Hospitalization Medication Plans for Long-Term Management of Childhood Asthma Controller Medications Anti-Allergic Drugs Inhaled Corticosteroids Sustained-Release Theophylline ␤2-Agonists Stages in Long-Term Asthma Management (Treatment Steps) Important Considerations when Treatment Is Stepped up or Stepped down Assessing Treatment Step-Down Sustaining Asthma Control Assessing Treatment Step-Up Discontinuing Long-Term Asthma Medication Steps in Asthma Treatment Mild Intermittent Asthma (Step 1) Mild Persistent Asthma (Step 2) Moderate Persistent Asthma (Step 3) Severe Persistent Asthma (Step 4) Early Intervention Primary Prevention Secondary Prevention References Further Reading


V

The following groups participated in the preparation of the ‘Asthma Prevention and Management Guidelines 2003, Japan (Update from: JGL1998).’ 1995/1996 Research Group of Bronchial Asthma (Research group director S. Makino and 40 members), Allergy Division, Long-Term Chronic Disease Research Projects, supported by Ministry of Health, Labour and Welfare, Japan. 1998 Research Group for Asthma Prevention and Management Guidelines (Research group director S. Makino and 44 members), Division of Effective Approaches for Treatment of Immunological and Allergic Disorders, Immunology and Allergy Research Study Project, supported by Ministry of Health, Labour and Welfare, Japan.

© 2005 S. Karger AG, Basel Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/iaa

Members of the research groups are as follows:

Director: Dr. Sohei Makino

Prof. Emeritus, Dokkyo University School of Medicine; Tokyo Allergic Disease Research Institute/Jobu Hospital of Pulmonary Medicine

Members (alphabetical order): Dr. Mitsuru Adachi

First Department of Internal Medicine, Showa University School of Medicine

Dr. Yukihiro Ago

National Center of Neurology and Psychiatry (Present Bunkyo Gakuin University)

Dr. Kazuo Akiyama

Research Center for Allergy and Rheumatology, National Sagamihara Hospital (Present Clinical Research Center for Allergy and Rheumatology, National Hospital Organization, Sagamihara National Hospital)

Dr. Minoru Baba

Doai Memorial Hospital

Dr. Yosuke Egashira

Tamana Central Hospital (Present Kyushu University of Nursing and Social Welfare)

Dr. Masaki Fujimura

Third Department of Internal Medicine, Kanazawa University School of Medicine

Dr. Takeshi Fukuda

Department of Pulmonary Medicine and Clinical Immunology, Dokkyo University School of Medicine

Dr. Kenshi Furusho

Kishiwada City Hospital (Present Kokura Allergy Clinics)

Dr. Yoji Iikura

Department of Pediatrics, Showa University School of Medicine

Dr. Hiroshi Inoue

Third Department of Internal Medicine, Iwate Medical University

Dr. Koji Ito

Department of Allergy and Respiratory Disease, Doai Memorial Hospital (Present Yugawara Kosei-Nenkin Hospital)

Dr. Itsuo Iwamoto

Clinical Cell Biology, Graduate School of Medicine, Chiba University

Dr. Junzaburo Kabe

Yugawara Kosei-Nenkin Hospital (Present Taiheiyo Cement Corp. Clinics)

Dr. Yuichiro Kamikawa

Department of Pharmacology, Dokkyo University School of Medicine

Dr. Yoshikazu Kawakami

First Department of Medicine, Hokkaido University School of Medicine (Present Kohnan Hospital)

Dr. Norio Kihara

Kihara Hospital

Dr. Satoshi Kitamura

Department of Pulmonary Medicine, Jichi Medical School (Present Minami-Tochigi Hospital)

Dr. Koichiro Kudo

International Medical Center of Japan

Dr. Kenji Mano

Department of Internal Medicine, Teikyo University School of Medicine (Present Taikyo College of Medical Technology)

Dr. Takehiko Matsui

Department of Pediatrics, Tokyo Metropolitan Ebara General Hospital


VII

Dr. Haruki Mikawa

Prof. Emeritus, University of Kyoto, Kansaidenryoku Hospital

Dr. Seishiro Miyagi

Okinawa Chubu Hospital (Present ‘Muribushi-Okinawa’, Muribushi Project for Okinawa Residency Program)

Dr. Terumasa Miyamoto

Prof. Emeritus, University of Tokyo; Japan Clinical Allergy Research Institute

Dr. Yutaka Morita

Department of Respiratory Medicine, Graduate School of Medicine, University of Tokyo (Present Ochanomizu University)

Dr. Yukio Nagasaka

Fourth Department of Internal Medical, Kinki University School of Medicine (Present Department of Medicine and Pulmonology, Kinki University Sakai Hospital)

Dr. Takemasa Nakagawa

Department of Internal Medicine, St. Marianna University School of Medicine

Dr. Shigenori Nakajima

Life Science Research Institute, Kinki University School of Medicine (Present Kinki University Nara Hospital)

Dr. Tsugio Nakazawa

Gunma University School of Health Sciences

Dr. Sankei Nishima

National Hospital Organization, Fukuoka National Hospital

Dr. Ken Ohta

Department of Medicine, Teikyo University School of Medicine

Dr. Takao Okubo

Prof. Emeritus, Yokohama City University; International University of Health and Welfare

Dr. Hiroki Sakakibara

Division of Pulmonology and Allergology, Fujita Health University School of Medicine

Dr. Yasuyuki Sano

Department of Allergy and Respiratory Medicine, Doai Memorial Hospital

Dr. Keisuke Shinomiya

Former Department of Pediatrics, National Himeji Hospital

Dr. Kenzo Takagi

Nagoya University School of Health Sciences

Dr. Kiyoshi Takahashi

National Hospital Organization, Minami-Okayama Medical Center

Dr. Gen Tamura

Department of Respiratory and Infectious Diseases, Tohoku University School of Medicine

Dr. Hisao Tomioka

Prof. Emeritus, Toho University

Dr. Kyoichiro Toyoshima

Osaka Prefectural Habikino Hospital (Present Toyoshima Pediatric Clinics)

Dr. Kazuharu Tsukioka

Niigata Allergic Disease Research Institute

Dr. Nobuo Ueda

Ehime Prefectural Central Hospital

Dr. Michio Yamakido

Second Department of Internal Medicine, Hiroshima University Faculty of Medicine (Present Kure Kyosai Hospital)

Collaborators: Dr. Susumu Hosoi

Department of Pediatrics, Graduate School of Medicine, Kyoto University (Present Ako City Hospital)

Dr. Hironori Sagara

Department of Pulmonary Medicine and Clinical Immunology, Dokkyo University School of Medicine

VIII


Int Arch Allergy Immunol 2005;136(suppl 1):1–2

Foreword

The 1990s are characterized as the time of the development of asthma prevention/management guidelines both internationally and within Japan. At the international level, the Global Initiative for Asthma (GINA) was issued with the support of the National Heart, Lung and Blood Institute of the United States (NHLBI) and the World Health Organization (WHO). The Japanese Society of Allergology provided a domestic version in Japanese in 1993, which was revised in 1995. This was followed in 1998 by the publication of Guidelines for the Prevention and Management of Asthma 1998 (JGL) elaborated by a research group of the Japanese Ministry of Health and Welfare. The JGL1998, which provides management guidelines based on the new understanding of the pathophysiology of asthma, has now come into widespread use in clinical practice throughout Japan. With the growing emphasis on evidence-based medicine (EBM), a revised edition of the JGL1998 treatment guidelines was issued in 2000, and a revised edition of GINA in 2002 (GINA2002). Meanwhile, the Japanese Society of Pediatric Allergy in Clinical Immunology published the Japanese Pediatric Guidelines for the Treatment and Management of Asthma 2000 (JPGL2000, revised in 2002). The most significant outcome of these guidelines has been a reduction in total asthma deaths since the guidelines first became available. Additionally, Japanese institutions adhering to these guidelines show a marked reduction in hospitalizations and emergency department visits from asthma exacerbation. With these encouraging trends, the increasing interest in EBM-based treatment guidelines, and the commercial availability of new pharmacotherapy options, the revised

© 2005 S. Karger AG, Basel 1018–2438/05/1365–0001$22.00/0 Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com


JGL1998 has now been further revised as Guidelines for the Prevention and Management of Asthma 2003 (JGL2003). Although based on the revised JGL1998, the JGL2003 also discusses new perspectives on the treatment of asthma, including GINA classifications of asthma severity and treatment guidelines from the Japanese Society of Pediatric Allergy and Clinical Immunology. These new guidelines target effective strategies for asthma prevention and management, based on a more comprehensive understanding of the fundamental pathophysiology of asthma. This English-language version of the JGL summarizes the major changes in the JGL2003, including the definition of asthma and changes in asthma epidemiology and pharmacotherapy. Methods for asthma management and pharmacotherapy naturally differ from country to country, depending on cultural factors and differences in medical systems. However, the increased emphasis on inhaled corticosteroids in these guidelines, as well as the changes in use of sustained-release theophylline, long-acting 2-agonists, and leukotriene antagonists will be of interest for an international audience. The new guidelines also state that aminophylline/theophylline therapy can be indicated in addition to rapid-acting 2-agonists and systemic corticosteroids in acute exacerbation attacks of asthma. Of additional interest, the JGL2003 recommends that the use of anti-inflammatory drugs should be considered whenever airway inflammation is present, even in cases of mild intermittent asthma. The effectiveness of this approach, which is intended to inhibit airway remodeling, will be determined by future assessment.

It is our hope that this English-language version of the JGL2003 will provide the international medical community with an introduction to asthma diagnosis and management in Japan, and will encourage the development of national guidelines which would provide the best treatment of asthma to each country. Finally, we would like to express our thanks to our colleagues who worked to develop these JGL. November 2004

Acknowledgments

We would like to express our thanks to Kyowa Kikaku Ltd. (Tokyo) and Biomedis International Ltd. (Tokyo) for providing the Japanese translations and for their support in the production of this supplement.

Guest Editors S. Makino K. Ohta S. Nishima A. Morikawa

2


Foreword

Chapter 1 Int Arch Allergy Immunol 2005;136(suppl 1):3–4

Definition, Diagnosis, Disease Types, and Classification of Asthma

Definitions

For these guidelines, we propose the following definitions of adult asthma and childhood asthma which require long-term treatment to control symptoms.

Definition of Adult Asthma Asthma is characterized by chronic airway inflammation and varying degrees of airflow limitation and airway hyperresponsiveness, accompanied by recurrent episodes of coughing, wheezing, and dyspnea. Airflow limitation is at least partially reversible, either spontaneously or with treatment. Many cells, including eosinophils, T cells, mast cells, airway epithelial cells and humoral factors contribute to airway inflammation. In patients with chronic disease, airflow limitation tends to become less reversible and it is common to see evidence of airway remodeling. Airway inflammation and airway remodeling are associated with airway hyperresponsiveness in sensitive patients.

Definition of Childhood Asthma Asthma in children is a disease involving repeated attacks of wheezing and dyspnea, which either resolve without treatment or can be relieved or ameliorated by treatment. The pathophysiology of this condition is attributed to reversible airway narrowing, mediated by the mucosal and muscular layers of the airway, along with histological changes due to chronic airway inflammation. The possibility of other respiratory or cardiovascular diseases that



may present with clinically similar symptoms must be ruled out before a diagnosis of asthma can be made. Note: Dyspnea is ordinarily defined as a subjective symptom. However, infants and babies cannot express their symptoms in words. Dyspnea is taken here to indicate labored breathing accompanied by evidence of discomfort or restlessness. In infants and babies who have asthma (hereafter termed ‘asthmatic infants’) and who are too young to describe their symptoms, signs of dyspnea include any indicators of discomfort or restlessness.

Asthma Classification Based on Severity and Frequency of Asthma Attacks

Effective asthma management and appropriately staged medical treatment must be based on an accurate determination of the severity and frequency of asthma symptoms. Quantitative parameters of respiratory function such as PEF and FEV1.0 can be used effectively in most patients 5 years of age or older. Asthma is classified as mild, moderate, or severe based on the frequency and severity of asthma symptoms (severity of attack), daily PEF and FEV1.0 values and diurnal variations, and types and dosages of drugs required to control daily symptoms. Several systems are available for classifying the severity of chronic asthma, including the criteria provided by the Japanese Society of Allergology and the criteria described in the International Consensus Report. Both of these classifications provide very similar definitions of mild asthma and severe asthma. Mild asthma is a condition limited to episodes of wheezing and mild symptoms (mild attack) which can be

controlled primarily by the use of bronchodilators as needed. Patients are considered to have severe asthma if their daily activities are severely restricted by frequent episodes of moderate to severe asthma symptoms (moderate to severe attack), controlled only by the regular use of high doses of inhaled corticosteroids (for example 800– 1,600 g/day of beclomethasone dipropionate; BDP), with the regular addition of oral corticosteroids in some cases. Moderate asthma includes a wide range of clinical findings between mild and severe asthma. Patients with moderate asthma show chronic mild to moderate symp-

4


toms which frequently interfere with daily activities and sleep and require the regular use of managers and antiinflammatory agents. A classification of asthma severity as described above would ideally be based on symptoms when the patient has not been treated. However, because most patients are already receiving some form of treatment when seen by the evaluating physician, clinical assessments regarding asthma severity should instead be based on the patient’s current symptoms and history of prior treatment. The physician should initiate treatment based on this clinical assessment, and then step up or step down this therapy until an appropriate treatment level is established.

Asthma Prevention and Management Guidelines


Epidemiology of Asthma

Epidemiology of Asthma

Both internationally and in Japan, most epidemiological findings are based on surveys and expressed as ‘prevalence of asthma symptoms’. In Japan, progression of symptoms is ordinarily expressed in terms of current symptoms and prior symptoms, while in some other countries statistics are divided into ‘current’ or ‘active asthma’ and ‘cumulative asthma’. Occasionally, figures are available for patients diagnosed on the basis of tests for airway hyperresponsiveness. Figures for ‘incidence’ are also sometimes cited with regard to the male/female ratio of asthma prevalence.

cording to ISAAC criteria is approximately 2- to 3-fold higher than reported by the ATS-DLD method. Symptoms are divided into ‘current’ and ‘prior’ at a point 1 year before the survey was performed. European Community Respiratory Health Survey (ECRHS) [3]: This report uses data collected in an international survey of adults 20–44 years of age who were living in Europe. The survey included six categories of questions on asthma symptoms, with totals collated by symptom. A diagnosis of asthma was assumed based on history of asthma attacks and physician’s diagnosis. Other reports include those from the British Medical Research Council (BMRC) and the International Union against Tuberculosis and Lung Disease (IULATLD), but these are rarely referenced in the current literature.

Survey Methods At present the following survey methods are widely used in Japan. American Thoracic Society – Division of Lung Diseases (ATS-DLD), Japanese version [1]: This survey primarily provides total of complaints of dyspnea, with symptoms divided into ‘current’ and ‘prior’ at a point 2 years before the survey was performed. Most epidemiological findings for asthma in Japan, both current and prior, are expressed in terms of the categories used in this survey. International Study of Asthma and Allergies in Childhood (ISAAC) [2]: This survey was used for an international asthma questionnaire for children 6–7 and 13–14 years of age. Because of consideration for varying levels of education, the survey was provided both in the form of written questionnaires and video questionnaires. The survey provides totals primarily for complaints of wheezing or whistling. The prevalence of asthma symptoms ac-



Survey Results Current Prevalence of Asthma Symptoms In Japan the cumulative prevalence of asthma according to ATS-DLD criteria is 5.1% in infants, 6.4% in children, and 3.2% in adults (6.2% among subjects 15–30 years of age). ISAAC findings showed asthma prevalence among children 13–14 years of age to be 13% in Fukuoka and 19% in Tochigi (table 1).

Changes over Time in Asthma Symptom Prevalence Asthma prevalence rates have increased substantially in recent years. Because asthma prevalence can vary so greatly from one region to another, comparison of an-

nual rates can be difficult. However, Japan-wide averages as calculated from earlier reports in the literature suggest that asthma prevalence among children in Japan was approximately 1% during the 1960s, rising to approximately 6% today. In that same time period, asthma prevalence among adults has risen from less than 1% to approximately 3%. Substantiating these findings, 7 long-term annual studies that were performed by the same physicians under identical protocols in patients from similar environmental backgrounds (table 2) have shown a 1.5- to 2fold increase in asthma prevalence during the last 10 years, both domestically and overseas.

Table 1. Asthma prevalence (mean prevalence throughout Japan)

Current Past Cumulative

Infants and babies, %

Children %

Adults %

4.2 0.9 5.1

4.0 2.4 6.4

1.7 1.3 3.0

Reprinted from 1996 survey results reported by the Coordinated Research Project on Long-Term Chronic Disease, MHLW. Number of subjects surveyed: 8,441 children, 11,495 adults; survey method: ATS-DLD.

Regional Differences in Asthma Prevalence Based on the results of surveys (in subjects 13–14 years of age) performed at 155 locations in 56 countries around the world, the ISAAC Steering Committee has reported regional findings for cumulative asthma prevalence ranging from 1.6% (Indonesia) to 36.8% (UK). Findings for Japan were 13% in Fukuoka and 19% in Tochigi, equivalent to or slightly lower than asthma prevalence rates in the developed countries of Europe and North America. Sears et al. [4] postulate that these regional differences reflect factors including (1) a lower prevalence of asthma in the developing nations than in the developed nations, and (2) a lower prevalence of asthma in colder climates than in warmer climates. Findings from ECRHS, based on minimum and maximum values from surveys at 49 locations in 22 countries (subjects 20–44 years of age), showed for example ‘wheeze’ ranging from 12.8% (Antwerp, Belgium) to 29.8% (Caerphilly, UK), ‘wheeze and breathless’ ranging from 5.0% (Erfurt, Germany) to 16.3% (Caerphilly, UK), and ‘diagnosed asthma’ from 2.1% (Erfurt, Germany) to 8.4% (Cambridge, UK). ‘Diagnosed asthma’ is taken to indicate subjects who have experienced asthma attacks and received treatment with asthma medication, and these figures are comparable to ATS-DLD figures for cu-

Table 2. Generational features in asthma prevalence

1960

1970

1980

1990

Survey target

Fukuoka

5.7% (81–83)

7.7% (93–95)

6–12 yearsa [4]

Oslo

2.2% (81) 3.4%

4.2% (93) 8.0%

Schoolchildrenb [5]

3.2% (82)

4.6% (92)

6–12 yearsa [6]

3.6% (81)

5.4% (91)

6–12 yearsa

Western Japan Kitakyushu Aberdeen Southern Wales

1.6% (71) 10% (64) 4.2%

7 yearsd [7]

20% (89) 10.4% 17% (73) 6%

Australia

e

7 yearsd, e [8]

22% (88) 12% 21.0% (87) 5.6% (87)

c

25.1% (90) 8.0% (90)

Adultsd, f

Figures in parentheses indicate year of survey. a Current asthma (ATS-DLD). b Current asthma (diagnosed asthma). c Cumulative asthma (diagnosed asthma). d Wheezing.e Cumulative asthma (diagnosed asthma). f Current asthma.

6



100

Cumulative asthma onset (% )

90 80 70 60 50 40 30 20 10

Fig. 1. Cumulative distribution of wheezing

and bronchial asthma stratified by age group. U = Wheezing (children); S = asthma (children); d = wheezing (adults); o = asthma (adults).

0 0

1

mulative prevalence. Thus, the cumulative asthma prevalence of 3.0% among Japanese adults is estimated to be equivalent to or slightly lower than the mean for the countries of Europe. The factor most closely correlated to asthma prevalence in Japan is population density (tables 3, 4).

2

3

4

5

6

7

8

9

10 11 12 13 14 15 20 30 40 50

Age (years)

Table 3. Asthma prevalence and population density (children)

Asthma-like symptoms, %

Remission of asthmalike symptoms, %

U S R

4.4 3.0 2.6

1.1 1.0 0.7

Total

3.0

1.0

Male-Female Ratio International statistics indicate that childhood asthma develops more often in boys, while asthma after puberty is more likely to develop in women. In Japan, infant asthma is 2.8 times more common in boys than in girls, while among school children this ratio is 1.5. After 10 years of age the ratio drops to 1.0. A study of regional differences in data shows that this difference between boys and girls tends to be greater in rural areas and less pronounced in urban centers.

Age at Onset Asthma in children develops most commonly during infancy or early childhood. Among adults, the rate of onset is similar across age groups, with a tendency to be slightly higher in subjects 20–30 years of age (fig. 1).

Chapter 2. Epidemiology of Asthma

Table 4. Asthma prevalence and population density (adults)

Asthma-like symptoms, %

Remission of asthmalike symptoms, %

U S R

1.0 0.8 0.4

0.7 0.5 0.5

Total

0.8

0.6

Information on children reprinted from 1981–1983 survey results and information on adults reprinted from 1982 survey results, published by the Environmental Health Division, Environment Agency. U = Regional population density >5,000 persons/km2; S = regional population density 1,000–5,000 persons/km2; R = regional population density female 615 years of age Intractable asthma Asthma attack of life-threatening severity (history of serious attacks) Tendency to overuse MDI/nebulizer At-home 2-agonist monotherapy by nebulizer Irregular clinic visits for treatment (poor compliance) Frequent attacks requiring emergency room treatment History of serious food or drug allergies Complications Air leak syndrome Lower respiratory infection in infants or younger children Right ventricular hypertrophy (in patients 610 years of age) Emergency surgery Loss, broken home, living alone Assertive, forceful personality Medical environment inadequate for dealing with pediatric patients

Asthma Deaths in Children In Japan the asthma death rate (per 100,000 population) among children 0–19 years of age dropped steadily in children 0–4 years of age (fig. 5) until about 1987, when it began to level off. More recently there has been a reduction in asthma death rate among the children 5 years of age and older, but this reduction has not been duplicated in the 0–4-year-olds. In the age group 5–19 years of age (fig. 6) the asthma death rate rose with each age group during the 1960s, and that change was particularly noticeable in the 10–14-yearolds. From 1980 through the 1990s, increases in asthma death rate were limited to the group of 10–19-year-olds, with the greatest increase among the 15–19-year-old patients. Asthma mortality decreased in all groups beginning in 1970. Trends in asthma symptom severity before death have shown an increase in the ratio of asthma deaths occurring in patients with mild and moderate asthma. The 2001 report by the Asthma Death Research Group of the Japanese Society of Pediatric Allergy and Clinical Immunology [14], after excluding cases for whom asthma severity was unknown, noted that for 106 cases of asthma death prior to 1997 asthma was found to be mild in 26.4%, moderate in 30.2%, and severe in 43.4%. Of 8 cases occurring since 1998, 12.5% have been mild, 62.5% have been moderate, and 25.0% have been severe. Consideration of the patients’ medical history prior to death [14] showed a history of hospital admission for

12


asthma attacks in 60.4%. Previous attacks severe enough to cause disturbance of consciousness were noted in only 19.1%, tracheal intubation in 7.6%, and continuous drip infusion and/or inhalation of isoproterenal or in the form of eyedrops in 17.6%. In children the direct cause of asthma death is most commonly asphyxia. Complications in infants and babies include lower respiratory infection, and in adolescents air leak syndrome, right heart hypertrophy, and adrenal dysfunction associated with corticosteroid dependence. Factors contributing to asthma death [14] most commonly include delays in receiving appropriate medical care and unexpectedly sudden exacerbation of the asthma attack. Causes of delay in receiving appropriate medical treatment include misjudgment on the severity of the attack by the patient and family members, and over-reliance on 2-agonist MDI. The latter is a particularly common factor in asthma death among adolescents and male patients [14, 15]. Missed doses and poor compliance are also problems among adolescents with asthma. In asthma death, the final attack often develops suddenly [16]. Approximately half of asthma death patients are dead on arrival at the hospital, and an increasing number develop cerebral anoxia and never regain consciousness. Further research is needed in responding to asthma attacks. Risk factors for asthma death in children are summarized in table 5.


Countermeasures to and Prevention of Asthma Deaths (1) Asthma education: The patient, the patient’s family, and educators and other persons who come into contact with the patient need to realize that asthma can be fatal, and to learn specific responses appropriate to the severity of the asthma attack. Peak flow monitoring should be recommended, and the importance of keeping an accurate record in the patient’s asthma diary should be stressed. If a 2-agonist is taken by MDI, a clear, complete, and understandable explanation must be provided regarding appropriate use, the limits of effectiveness, and

measures to be taken when the 2-agonist is insufficiently effective. (2) Measures in the event of an acute attack: Asthma cards should be widely distributed. It is very important during an asthma attack that the patient be kept quiet and given oxygen, and the usefulness of appropriate emergency measures must be understood. (3) The fundamental importance of preventative treatment: In order to prevent asthma death, it is essential to eliminate allergens regularly and often, to consistently follow a preventative drug regimen, and to adequately suppress asthma attacks.

References 1 Ferris BG: Epidemiology standardization project. 2. American Thoracic Society. Am Respir Dis 1978; 118: 1–120. 2 The International Study of Asthma and Allergies in Childhood (ISAAC) steering committee: Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: ISAAC. Lancet 1998;351:1225–1232. 3 European Community Respiratory Health Survey: Variations in the prevalence of respiratory symptoms, self-reported asthma attacks, and use of asthma medication in the European Community Respiratory Health Suvey (ECRHS). Eur Respir J 1996;9:667–695. 4 Sears MR, Taylor DR, Print CG, Lake DC, Li QQ, Flannery EM, et al: Transplantation. Lancet 1990; 336:1391–1396. 5 Matsui T: Asthma death and its background. Medical topics series: Asthma ’94. Tokyo: Med Rev 1994:12–21.

6 Beasley R, Nishima S, Pearce N, Crane J: Betaagonist therapy and asthma mortality in Japan. Lancet 1998;351:1406–1407. 7 Tanihara S, Nakamura Y, Matsui T, Nishima S: A case-control study of asthma and lifethreatening attack: Their possible relationship with prescribed drug therapy in Japan. J Epidemiol 2002;12:223–228. 8 Matsui T, et al: Study of the scientific basis for treatment of acute bronchial asthma: Research on eye and ear sciences, immunology, allergy and organ. Ministry of Health, Labour and Welfare, Japan 2002. 9 Suissa S, Ernst P, Benayoun S, Baltzan M, Cai B: Low-dose inhaled corticosteroids and the prevention of death from asthma. N Engl J Med 2000; 343:332–336. 10 Matsui T: Death from childhood asthma in comparison with adult asthma. Jpn J Allergol 2001;42: 814–824. 11 Nakazawa T, Iizuka K, Kobayashi S, Kawakami Y, Sudo M: Epidemiologic and clinical aspects of bronchial asthma death, from a medical perspective. Allergy Pract 1990; 10: 792– 795.

12 Matsui T: Epidemiology of asthma death. Arerugi-ka 1997;3:8–16. 13 Nakazawa T, Kawakami Y, Sudo M, Kobayashi S, Suetsugu S, Nakajima S, et al: Asthma death among adults in Japan 1995–1997: Analysis of 295 cases reported questionnaires sent to hospitals with more than 100 beds. Arerugi 2000; 34:505–511. 14 Japanese Society of Pediatric Allergy and Clinical Immunology: The committee report on asthma death in Japanese children in 2001. Jpn J Pediatr Allergy Clin Immunol 2002;16: 248–260. 15 Japanese Society of Pediatric Allergy and Clinical Immunology: The committee report on asthma death in Japanese children in 1994. Jpn J Pediatr Allergy Clin Immunol 1995; 9: 54–66. 16 Matsui T: Asthma deaths and their topics. Jpn J Pediatr Med 1996; 28:249–254.

Japanese Society of Pediatric Allergy and Clinical Immunology: The committee report on asthma death in Japanese children in 1999. Jpn J Pediatr Allergy Clin Immunol 2000;14:219–231. Matsumoto I, Odajima H, Nishima S, Kano S, Araki H, Umeno E, et al: Change in prevalence of allergic diseases in primary school children in Fukuoka city for the last fifteen years. Arerugi 1999;48:435–442. Ninan TK: Respiratory symptoms and atopy in Aberdeen schoolchildren: Evidence from two surveys 25 years apart. BMJ 1992;304:873– 875.

Nishima S: A study on the prevalence of bronchial asthma in school children in western districts of Japan: Comparison between the studies in 1982 and in 1992 with the same methods and same districts. Arerugi 1993;42:192–204. Skjonsberg OH, Clench-Aas J, Leegard J, Skarpaas R, Giaever P, Bartonova A, et al: Prevalence of bronchial asthma in schoolchildren in Oslo Norway. Comparison of data obtained in 1993 and 1981. Allergy 1995;50:806–810. Sudo M: Risk factors for death in patients and management of the patient at risk of asthma death: Adult. Arerugi-ka 1997;3:17–23.

Further Reading Burr ML, et al: Changes in asthma prevalence: Two surveys 15 years apart. Arch Dis Child 1989;64:1452–1456. Champbell DA, et al: South Australian asthma symptom prevalence survey. Aust NZ J Med 1991;21:658. Japanese Society of Pediatric Allergy and Clinical Immunology: The committee report on asthma death in Japanese children in 1994. Jpn J Pediatr Allergy Clin Immunol 1995;9:54–68.

Chapter 2. Epidemiology of Asthma


13


Pharmacologic Control of Asthma

Pharmacologic Treatment for Long-Term Management of Asthma

Drugs In these guidelines, all medications required for treatment of asthma are referred to as anti-asthma drugs. Antiasthma drugs can be divided into two broad classifications: controller medications (drugs used for long-term management of asthma) and reliever medications (drugs used to relieve acute asthma attacks). In some cases, depending on specific drug action and route of administration, the same drugs may be used both as controller and reliever medications. Asthma is a disease that develops as a result of widespread airway inflammation and constriction [1]. Drug therapy administered by inhalation directly into the airways can produce better effects at lower doses than other methods of administration, and with fewer systemic adverse effects. Disodium cromoglycate (DSCG), 2-agonists, corticosteroids, and anti-cholinergic agents can all be administered by inhalation. Inhaled drugs distribute widely through the airways when there is no or very little airway constriction. However, when airway constriction is present, inhaled drugs may distribute to well-ventilated areas of the lungs, but may have little effect in areas of poor ventilation. Further investigation of the long-term influence of inhaled drugs on the airway epithelium and cilia is needed. Anti-asthma drugs include oral corticosteroids, theophyllines, 2-agonists, and anti-allergic drugs. Anti-aller-



gic oral agents include chemical mediator release inhibitors, H1-antihistamines, thromboxane A2 antagonists/ synthase inhibitors, leukotriene antagonists, and Th2 cytokine inhibitors. In Japan, drug compliance among patients tends to be very good with oral agents. Such oral drugs distribute well from the blood stream to the bronchi, even to areas of poor ventilation. However, higher doses are required than when administering the same drug by inhalation, and there is a higher incidence of systemic adverse effects. The physician must therefore carefully consider the balance between desired effects and potential adverse reactions when selecting an appropriate combination of inhaled and oral drugs for each patient.

Controller Medications Controller medications (controllers) for asthma are drugs used on a long-term basis to reduce or eliminate asthma symptoms and to achieve and maintain normalization of respiratory function. Controllers can be broadly classified into anti-inflammatory drugs and long-acting bronchodilators. The most potent asthma controller medications are corticosteroid drugs, which can be administered by inhalation or orally. Other controller drugs are anti-allergic agents which include DSCG, mediator release inhibitors, H1-antihistamines, thromboxane A2 synthase inhibitor and receptor antagonists, leukotriene receptor antagonists, and Th2 cytokine inhibitors. Longacting 2 sympathetic agonists and sustained-release theophylline are used as long-acting bronchodilators. Sus-

Table 1. Types of asthma controller medications

A Corticosteroid agents 1 Inhaled corticosteroids (i) Beclomethasone dipropionate (ii) Fluticasone propionate (iii) Budesonide 2 Oral corticosteroids B Sustained-release theophylline C Long-acting 2-agonist 1 Inhaled Salmeterol xinafoate 2 Patch Tulobuterol 3 Oral Procaterol hydrochloride Clenbuterol hydrochloride Formoterol fumarate Tulobuterol hydrochloride Mabuterol hydrochloride D Anti-allergic agents 1 Mediator release inhibitors (i) Sodium cromoglycate (ii) Tranilast (iii) Amlexanox (iv) Repirinast (v) Ibudilast (vi) Tazanolast (vii)Pemirolast 2 H1-antihistamines (i) Ketotifen (ii) Azelastine (iii) Oxatomide* (iv) Mequitazine (v) Epinastine 3 Thromboxane inhibitors a. Thromboxane A2 synthase inhibitors (i) Ozagrel hydrochloride b. Thromboxane A2 antagonists (i) Seratrodast 4 Leukotriene antagonists (i) Pranlukast (ii) Zafirlukast (iii) Montelukast 5 Th2 cytokine inhibitors (i) Suplatast * Not indicated for asthma in adults. Indicated for pediatric asthma.

tained-release theophylline is thought to be useful also for the long-term management of asthma because it reduces airway inflammation. Controllers are classified on the basis of their mechanism of pharmacologic action (table 1).

Chapter 3. Pharmacologic Control of Asthma

Corticosteroids Corticosteroids are the most effective anti-inflammatory medications currently available for the treatment of asthma, although the mechanisms by which these drugs act to relieve asthma symptoms are not completely understood [1]. The major pharmacological effects of corticosteroids include: (1) suppression of inflammatory cell infiltration into the airways and lungs [2] and inhibition of inflammatory cell migration and activation; (2) reduction in vascular permeability [3]; (3) suppression of airway mucosal cell secretions [4]; (4) reduction in airway hyperresponsiveness [5]; (5) inhibition of cytokine production [6]; (6) enhancement of the effects of 2-agonists [7]; (7) inhibition of arachidonic acid metabolism in cells other than mast cells, with a consequent decrease in leukotriene and prostaglandin production in man [8]. Corticosteroid drugs can be administered intravenously, intramuscularly, orally, or by inhalation. Inhaled corticosteroids are associated with considerably fewer adverse effects than corticosteroids given by intravenous, intramuscular, or oral administration, so inhalation is the preferred route of corticosteroid administration for longterm maintenance (controller) therapy. In cases where asthma symptoms cannot be controlled with the maximum dose of inhaled corticosteroids, oral corticosteroids should be added as supplementary therapy. Early intervention with inhaled corticosteroids beginning soon after the onset of asthma has been reported to inhibit airway remodeling [9]. In patients with severe asthma (Step 4), long-term use of oral corticosteroids is indicated to supplement the effects of inhaled corticosteroid medication, to supplement adrenocortical function, and to suppress general proliferation and infiltration of inflammatory cells. Table 2 lists the three inhaled corticosteroids currently in clinical use in Japan: beclomethasone dipropionate (BDP), fluticasone propionate (FP), and budesonide (BUD). Types of aerosol delivery can be categorized as metered dose inhalers using pressurized gas (p-MDI) and breath-activated dry powder inhalers (DPI). For p-MDI units, further division can be made into those that use CFCs as the drug delivery vehicle and those that use the CFC substitute HFA. Since BDP-CFC was withdrawn from the market in April 2005, and since DPI and MDIHFA have become available they should be substituted for BDP-CFC except in a very few cases. Inhaled corticosteroids are the treatment of first choice for the long-term management of patients with persistent asthma (Step 2 or above). Numerous studies have compared the effectiveness of these drugs, either by comparing equivalent doses or by comparing dose multiples, but


15

Table 2. Inhaled corticosteroids available for clinical use in Japan

BDP (beclomethasone propionate) FP (fluticasone propionate) BUD (budesonide)

p-MDI (pressurized metered dose inhaler)

DPI (dry powder inhaler)

BDP-CFC (Aldesin®, Becotide®, etc.)* BDP-HFA (QVAR®) FP-HFA (Flutide® Air) None

None FP-DPI (Flutide® Diskus, Flutide® Diskhaler) BUD-DPI (Pulmicort®)

* BDP-CFC was withdrawn from the market in April 2005.

Table 3. Recommended dose of inhaled corticosteroid at each treatment step

Drug product

Step 1 (very low dose) g/day

Step 2 (low dose) g/day

Step 3 (moderate dose) g/day

Step 4 (high dose) g/day

BDP-CFC* BDP-HFA FP-HFA FP-DPI BUD-DPI

200* 100 100 100 200

200–400* 100–200 100–200 100–200 200–400

400–800* 200–400 200–400 200–400 400–800

800–1,600* 400–800 400–800 400–800 800–1,600

* BDP-CFC was withdrawn from the market in April 2005. For Step 2 and above, inhaled corticosteroids are the first choice for long-term asthma treatment. These recommended doses do not indicate the titer providing antiasthma effectiveness for each inhaled corticosteroid. Instead, the maximum dose approved by the MHLW, Japan, for each inhaled corticosteroid is given as the maximum dose for Step 4, half of that value is used as the maximum dose for Step 3, and half of the Step 3 value is used as the maximum dose for Step 2. The attending physician should select the safest and most effective drug for each patient.

the former method does not allow quantitative calculations, while the latter does not always show significant differences even when using dose multiples of the same drug [1, 10]. Thus, in order to quantitatively assess the relative effectiveness of these drugs, it is necessary to perform a comparative study of each drug at multiple dose levels, just as has been done in the comparative study of BDP-HFA and BDP-CFC [11]. However, such comparative studies are few [12, 13]. These guidelines set the maximum dosage for inhaled corticosteroids in the treatment of severe asthma, Step 4, in consideration of international guidelines and the recommendations of MHLW, Japan. The maximum dose for Step 3 has been set at half the maximum dose for Step 4, and the maximum dose for Step 2 has been set at half the maximum dose for Step 3 (table 3). Inhaled corticosteroids are associated with a significantly lower level of systemic adverse drug reactions than any other corticosteroid drug delivery method; however, their use is associated with local adverse drug reactions

16


such as oropharyngeal candidiasis and hoarseness. Inhaled corticosteroids can also affect the eyes (cataracts, glaucoma) and the skin (thinning of the skin, prone to bleeding), suppress hypothalamus, pituitary, and adrenal function, and affect the bones (osteoporosis) [14]. Therefore, the patient should be instructed to always gargle after inhaling the drug to reduce oropharyngeal symptoms and to minimize the amount of the drug that is absorbed systemically. Clinical research performed thus far has not yet provided sufficient data to support any uniformly accepted conclusion on the effects of inhaled corticosteroids on the adrenal cortex. A number of reports on ordinary dose levels suggest that these effects fall within a permissible range [15–19], but there have also been reports of acute adrenal failure in a few patients under treatment with very high doses [20], so particular caution should be used at high dose levels. There has also been some concern about the use of inhaled corticosteroids during pregnancy, but reports appear to indicate that the use of BUDDPI during the first trimester has no influence either on


congenital birth defects or on the pregnancy itself [21, 22], and the FDA has approved BUD-DPI for pregnancy category B, making it the first inhaled corticosteroid with this rating. Growth in children is reported to be unaffected by 1 year of treatment with FP-DPI [23] or by 4 years of BUD-DPI [24], and administration of BUD-DPI in adulthood also appears to have no effect on patient height [25]. Sustained-Release Theophylline Theophylline has been used for many years as a bronchodilating agent in the treatment of asthma. Long-acting sustained-release theophylline is often prescribed for long-term control of symptoms of asthma such as wheezing and dyspnea. The pharmacologic action of theophylline involves nonspecific inhibition of phosphodiesterase. Recent investigations have also confirmed several antiinflammatory effects of theophylline, including suppression of T cell and eosinophil infiltration into the airways [26–28], inhibition of T cell proliferation [29] and cytokine production [30], and induction of apoptosis of eosinophils [31]. Theophylline is metabolized in the liver, with a rate of metabolism that varies widely among individual patients. Elevated serum theophylline level may cause serious adverse reactions [32], although most of these adverse effects can be prevented by careful monitoring of serum drug levels. The required daily dosage of theophylline varies among patients, but averages approximately 400 mg/day. Serum theophylline level should generally be maintained between 5 and 15 g/ml. Adverse reactions associated with theophylline may include nausea and vomiting soon after initial oral administration. The initial manifestations of theophylline toxicity in patients with elevated serum concentration also include gastrointestinal symptoms such as nausea and vomiting. Further increases in serum concentration produce tachycardia and other cardiac arrhythmias. Severe theophylline toxicity can cause seizures and death.

2-Agonists 2-Agonists are bronchodilator drugs that relax smooth muscles in the airways and promote the removal of airway secretions by ciliary movement. These drugs can be administered as inhaled, patch, oral, and parenteral formulations. Long-acting formulations of 2-agonists are used as controller medications in asthma. In general, 2-agonist agents should be used in combination with anti-inflammatory drugs such as inhaled corticosteroids, for long-term control of asthma [33].


Conventional oral formulations include procaterol hydrochloride, clenbuterol hydrochloride, formoterol fumarate, tulobuterol hydrochloride, and mabuterol hydrochloride. The tulobuterol patch, developed in Japan, is another long-acting agent, but it is a poor choice for monotherapy. Salmeterol xinafoate is a long-acting inhaled drug at present used in Japan. Recent research indicates that salmeterol xinafoate is extremely effective in combination with inhaled corticosteroids [34, 35]. Although all of these formulations are quite safe, if the patient complains of adverse drug reactions such as tremor, palpitations, or tachycardia, which are most commonly seen with oral formulations, less common with patches, and least common with inhaled formulations, the dose should be reduced or treatment discontinued. Major adverse drug reactions include reports of serious serum hypokalemia. Particular caution should be observed in the presence of ischemic heart disease, hyperthyroidism, or diabetes. There is generally no attenuation of the bronchodilator effect of these drugs with continued use. With the exception of salmeterol xinafoate, all of the inhaled 2-agonists currently marketed in Japan are short-acting drugs, and are thus not recommended as controller medications. Anti-Allergic Agents ‘Anti-allergic agent’ is a general term for Th2 cytokine blockers and drugs that regulate the release and action of chemical mediators involved in type I allergic reactions. Advanced understanding of the mechanism of type I allergic reactions has led to the development of drugs that block the production of various chemical mediators and drugs that act as chemical receptor antagonists. These guidelines classify anti-allergic agents on the basis of their pharmacologic mechanism of action. Anti-allergic agents include mediator release inhibitors, H1-antihistamines, thromboxane A2 synthase inhibitors and receptor antagonists, leukotriene receptor antagonists, and Th2 cytokine inhibitors (table 1). All of these agents have been proven effective in double-blind clinical trials. Although most of the trials were against a control drug, placebo-controlled studies have been conducted for DSCG [36, 41], ketotifen fumarate [37, 42], azelastine hydrochloride [43, 44], ozagrel hydrochloride [38], seratrodast [39, 45], pranlukast hydrate [40, 46], zafirlucast, montelucast, and suplatast tosilate. Mediator Release Inhibitors These drugs inhibit the release of chemical mediators from mast cells during type I allergic reactions. They are


17

effective in about 30–40% of atopic asthma patients with mild to moderate symptoms [47–52]. These drugs must be administered for at least 4–6 weeks in order to accurately assess treatment efficacy in a specific patient [47– 52]. DSCG has been found to reduce eosinophil counts in bronchial washings following long-term use of inhaled anti-allergic agents [53], and also to suppress airway inflammation in patients with atopic asthma [54], leading to its use as a controller drug. Reported adverse effects of these drugs include hemorrhagic cystitis with tranilast and flushing with tazanolast. H1-Antihistamines Although each drug also acts specifically in other additional ways, the major pharmacologic action of these drugs is inhibition of the action of histamine on H1 receptors. The effectiveness of these agents is similar to that of the mediator release inhibitors, with some reports of 20– 30% efficacy rates in atopic asthma patients who have mild to moderate symptoms [55–59], while other researchers have found this efficacy rate to be as high as 50% in similar patient populations [60]. These drugs must also be administered for at least 4–6 weeks in order to accurately assess treatment efficacy [55–59]. In clinical trials conducted in Europe and the United States, azelastine effectively relieved asthma symptoms [61] and enabled reductions in corticosteroid dose [62]. Terfenadine is effective in the prevention of alcohol-induced asthma [63]. H1-antihistamines are also effective in patients with asthma related to cough receptor sensitivity [64] and in asthma patients with cough as a predominant symptom [65]. Drug treatment produces relatively rapid improvement in these patients, usually in about 2 weeks. Ketotifen fumarate can bring significant improvement in symptoms, pulmonary function, and airway hyperresponsiveness, as well as exhibiting anti-inflammatory effects on airway tissue [66], while azelastine hydrochloride appears to inhibit local infiltration of inflammatory cells into the airway [67]. These drugs are expected to prove useful in the treatment of asthma complicated by allergic rhinitis [68–70]. The H1-antihistamines are associated with adverse effects (e.g. drowsiness, malaise) similar to those of other anti-histamine drugs. Oxatomide should be administered with caution to children because of the possible development of extrapyramidal symptoms. The administration of azelastine has been associated with taste disturbances (bitter taste).

18


Thromboxane A2 Inhibitors and Antagonists This class of drugs includes the thromboxane A2 synthase inhibitors and thromboxane A2 receptor antagonists. The thromboxane A2 synthase inhibitors block the production of thromboxane A2 and stimulate production of prostacyclin (prostaglandin I2). The thromboxane A2 receptor antagonists inhibit the action of thromboxane A2 and also inhibit the actions of prostaglandin D2 and prostaglandin F2. Ozagrel hydrochloride (a thromboxane A2 synthase inhibitor) and seratrodast (a thromboxane A2 receptor antagonist) inhibit airway hyperresponsiveness in patients with asthma [71, 72], and act to suppress airway inflammation and to improve abnormal mucociliary transport in asthmatic patients [73, 74]. The thromboxane A2 inhibitors show about 40% efficacy in mildly to moderately symptomatic patients with atopic or mixed-type asthma [75, 76]. These drugs are generally effective within 2–4 weeks. The thromboxane A2 inhibitors are also moderately effective in elderly asthmatic patients and patients with nonatopic (intrinsic) asthma [77]. The major adverse reactions associated with ozagrel hydrochloride include itching, nausea, vomiting, abnormal liver function tests, and elevated serum potassium levels. Rare instances of hemorrhagic diathesis-related adverse effects such as positive urine occult blood, gingival bleeding, and prolonged prothrombin times have also been reported. Adverse reactions associated with seratrodast include liver function test abnormalities and gastrointestinal manifestations such as nausea, vomiting, anorexia, abdominal pain, and diarrhea, as well as drowsiness, anemia, skin rash, headaches, palpitations, malaise, eosinophilia, and positive urine occult blood. Clinicians should also be aware that there have been rare reports of severe hepatic function abnormalities, with elevated serum bilirubin levels. Both of these drugs should be given with caution if administered concomitantly with other platelet aggregation inhibitor agents. Leukotriene Antagonists Leukotriene (LT) C4, D4, and E4 are termed cysteinyl leukotrienes (CysLTs), and CysLT receptors are divided into CysLT1 and CysLT2 receptors [78]. The only currently available leukotriene antagonists are the CysLT1 receptor antagonists, pranlukast hydrate, zafirlucast, and montelucast. Oral leukotriene antagonists generally provide rapid improvement in respiratory function (1–3 h after ingestion) [79]. They also slightly inhibit airway hyperresponsiveness in asthma patients [80]. Leukotriene antagonists significantly inhibit early- and late-phase


bronchoconstriction on inhaled antigen challenge, bronchoconstriction induced by exercise or cold air, and bronchoconstriction provoked by aspirin or other antipyretic analgesics [81–83]. For long-term asthma management, leukotriene antagonists can improve asthma symptoms and respiratory function, reduce the use of inhaled 2agonists, decrease airway inflammation and airway hyperresponsiveness, and significantly reduce inhaled corticosteroid dose and the number of asthma exacerbation events while improving the patient’s quality of life [84]. Leukotriene antagonists are particularly useful as an additive drug in patients who have a suboptimal response at moderate to high doses of inhaled corticosteroids [85], and appear to have a corticosteroid-sparing effect when used in conjunction with inhaled corticosteroids [86, 87]. Leukotriene antagonists can also provide effective monotherapy in some cases of mild asthma [88]. Treatment is usually effective within 2–4 weeks after starting therapy [89]. Churg-Strauss syndrome was reported in asthma patients who were maintained on leukotriene antagonists, but it seems probable that such developments are actually due to reduced corticosteroid dose rather than to a direct effect of the leukotriene antagonist [90]. Cases of severe liver damage have been reported with zafirlucast [91], and liver enzyme levels should be regularly monitored in patients under treatment with this drug. Th2 Cytokine Inhibitors The only currently available drug in this category is suplatast tosilate. In vitro studies show that this drug inhibits production of interleukin-4 (IL-4) and IL-5 from Th2 cells, and animal studies show reduction in IgE antibody titer, suppression of airway hyperresponsiveness [92], inhibition of goblet cell production [93], and improvement in airway inflammation. Bronchial mucosal biopsies from asthma patients reveal inhibition of eosinophilic infiltration into the airway mucosa, and patients also experience a reduction in asthma symptom severity [94, 95]. Suplatast tosilate also appears to have a corticosteroid-sparing effect [96].

Reliever Medications Corticosteroids Intravenous corticosteroids and some oral corticosteroids are used as reliever medications in patients with asthma. Patients with acute asthma attacks are treated short-term with large doses of intravenous corticoste-


roids. A short course of treatment with oral corticosteroids may be given to prevent further development of asthma exacerbations. The short-term administration (usually 1 week or less) of moderate to high doses of oral corticosteroids (e.g. prednisolone 0.5 mg/kg) early during a period of worsening symptoms of asthma can prevent acute serious exacerbations, reduce the frequency of emergency room visits and hospital admissions, and decrease the negative impact of asthma attacks on normal daily activities. In patients who frequently require the addition of short-term courses of oral corticosteroids, the physician should carefully ascertain the extent of patient compliance with regularly prescribed medications, confirm that inhaled corticosteroids are being taken properly, and reassess the drug doses and concomitant medications that are being used. In patients with severe acute asthma exacerbations who receive a short course (usually 1 week or less) of intravenous corticosteroids, the dose of corticosteroids must be tapered as soon as possible after an adequate therapeutic response has been achieved. For patients who have received short-term acute treatment of 2 weeks or less, corticosteroid doses can be rapidly reduced and discontinued without the development of adrenaline insufficiency (corticosteroid withdrawal symptoms).

2-Agonists All of the inhaled 2-agonists except for salmeterol currently marketed in Japan are short-acting drugs used as relievers. The use of inhaled 2-agonist drugs by aerosol or nebulizer produces bronchodilator effects which are equivalent or superior to those obtained with oral administration, while reducing the incidence of adverse drug reactions such as cardiac stimulation, skeletal muscle tremors, and hypokalemia. An increase in the use of 2-agonist inhalation for the relief of asthma attacks often signifies overall deterioration of asthma symptom control. If inhaled 2-agonists must be administered 5 or more times daily, a step-up in therapy (intensified controller therapy) should be considered. Short-acting inhaled 2-agonists are appropriate for the prevention of asthma from allergen exposure and of exercise-induced asthma. These inhaled drugs are also appropriate for treating symptoms of seasonal asthma. The standard method of treatment with inhaled 2-agonists is 2 puffs per time (1 puff per time with fenoterol) from a portable MDI. Use of a spacer device improves treatment safety by reducing adverse effects. These doses may be repeated as necessary, but if usage exceeds 6 puffs Int Arch Allergy Immunol 2005;136(suppl 1):14–49

19

(3 puffs for fenoterol) in 1 h, the patient should be evaluated by a physician. Subcutaneous Epinephrine Injection Subcutaneous injection of 0.1–0.3 ml epinephrine (0.1% Bosmin®) relaxes bronchial smooth muscle by its 2-effects and reduces airway mucosal edema by its -effect to produce bronchodilation. This dose can be repeated every 20–30 min, but patients should be carefully monitored to ensure that the pulse rate remains below 130 per minute. The use of epinephrine is contraindicated in patients with ischemic cardiac disease, hyperthyroidism, or glaucoma (administration permitted in patients with open-angle – simple – glaucoma). Epinephrine should be administered with caution in patients with hypertension, while the patient is being monitored by electrocardiography. Particular care should be taken when administering this drug to children. Aminophylline/Theophylline Aminophylline is a solubilized form of theophylline that can be given intravenously. Aminophylline intravenous infusion and oral aminophylline powder are regarded as asthma reliever therapy. Recently, theophylline solution has become available in Japan. In patients with normal theophylline clearance who have not been using the drug prior to an asthma attack, treatment with aminophylline can be safely carried out by administering one half of the initial 6 mg/kg dose during the first 15 min and the remaining half over the next 45 min. The adverse effects associated with aminophylline are similar to those observed with theophylline. It is also possible to use theophylline itself, formulated for intravenous infusion, and in such cases target drug blood levels should be established based on those for aminophylline administration. It should be noted that theophylline content of choline theophylline is 64% and that of aminophylline is 80%. Inhaled Anti-Cholinergic Drugs The inhaled anti-cholinergic drugs used in the treatment of asthma provide less potent bronchodilator effects than inhaled 2-agonists, and take slightly longer to achieve these effects, requiring about 1–2 h after dosing to achieve their maximum effect. The duration of bronchodilator action is about the same as or slightly longer than with the 2-agonists, and there are no significant adverse effects. Inhaled anti-cholinergic drugs are particularly effective when airway constriction is present, and they have an additive effect when used in

20


conjunction with 2-agonists. Since anti-cholinergic drugs demonstrate a greater bronchodilator effect than 2-agonists in asthma complicated by pulmonary emphysema, these drugs are thus particularly effective in elderly asthmatic patients with underlying pulmonary emphysema.

Other Drugs and Therapy Traditional Chinese Herbal Medicines (Kampo) Kampo medications (Japanese formulations of traditional Chinese herbal medicines) have a long tradition of use in the treatment of asthma. Historically, kampo therapy has been considered highly appropriate for the treatment of asthma, and considerable clinical experience has been accumulated and made available for use in developing and evaluating specific treatment guidelines. Because kampo medications are used to treat the patient’s overall condition rather than a specific disease, a specific drug formulation is generally selected based on an evaluation of the patient’s constitution (robust or deficient), physical resilience, and resistance to disease. Kampo formulations consist of natural unrefined preparations, and therefore do not provide the powerful pharmacologic action of modern allopathic drugs, so the attending physician must have sufficient clinical experience to distinguish between likely ‘responder’ and ‘nonresponder’ patients before initiating kampo therapy. In general, asthma attacks during the acute stage should be treated with kampo formulations of the mao type (e.g. sho-seiryu-to), while treatment during the chronic stage should focus on saiko-type formulations (e.g. saiboku-to) which build up the patient’s constitution. Mao-type agents are formulations containing mao (including ephedrines). They provide bronchodilating and antitussive action, and take effect relatively rapidly. Saiko formulations provide anti-inflammatory action, and their long-term use can be helpful in stabilizing symptoms. ‘Hi-kyo’ shown in table 4 indicates generally impaired gastrointestinal function; administration of ho (supplementary restorative) preparations (e.g. hochu-ekito) can improve nutritional status and build up physical resilience in such patients. When treating elderly patients with asthma, the attending physician should observe carefully to determine whether ‘jin-kyo’ pathophysiology is present. If so, the appropriate use of hojin (supplementary restorative to jin-kyo) preparations (e.g. hachimi-jiogan) can be useful.


Table 4. Guidelines for the use of kampo formulations in the treatment of asthma

Acute phase

Chronic phase

Mao

Netsu-sho

characterized by heat, patient perspires freely

Ma-kyo-kan-seki-to

formulations

Kan-sho

characterized by chilling, sneezing, and nasal discharge

Sho-seiryu-to

Saiko

Kugai

characterized by persistent cough and mucus

Bakumondo-to

formulations

Moderate physical resilience, diagnoses intermediate between Jitsu-sho (robust constitution) and Kyo-sho (deficient constitution)

Saiboku-to,* Shosaiko-to

Hi-kyo

characterized by weakness in the stomach and intestines

Hochu-eki-to

Jin-kyo

characterized by weakness and cold feet and lower back

Hachimi-jio-gan

* Saiboku-to has been found to reduce corticosteroid dosage and activate pituitary-adrenocortical function in patients receiving corticosteroid treatment.

(1) In severe cases and for serious asthma attacks, priority should of course be given to modern (Western) drug therapy. (2) Mild and moderate cases of asthma are good candidates for treatment with kampo formulations. In such cases it is unnecessary to be concerned with the type of asthma. (3) When possible, the selection of kampo formulations should be based on the traditional sho criteria which form the basis for diagnosis and treatment in Oriental medicine. (4) The effects of kampo therapy are not immediately apparent. Patients receiving kampo formulations should be checked approximately 3–4 weeks after the start of treatment to determine therapeutic efficacy. If no beneficial effects are noted at this point, the formulations should be reevaluated. Effective treatment should be continued for an extended period (6 months to 2 years). Traditional acupuncture and moxibustion therapies also have been widely used in the treatment of asthma in Japan. However, no specific guidelines have been established, since such treatment is in most cases highly individualized for each patient, based on the experience and intuition of the practitioner. Hyposensitization Therapy Hyposensitization therapy can be effective in some patients. It is indicated in patients who continue to experience poorly controlled symptoms despite other appropriate asthma treatment, and whose asthma symptoms are clearly related to exposure to one or more known allergens when avoidance of the offending allergen(s) is impractical or impossible.


The following points should be kept in mind in order to increase the effectiveness and reduce the risks of hyposensitization therapy. (1) Perform hyposensitization therapy only after identifying the positive allergen(s) by means of a detailed medical history and laboratory studies such as RAST. (2) Perform hyposensitization only in a medical facility equipped to deal with emergency treatment of possible anaphylaxis. Monitor all patients for at least 30 min after allergen injection. (3) Hyposensitization is generally more effective in younger patients. (4) To further ensure patient safety, carry out hyposensitization only when patients are not experiencing symptoms. (5) Hyposensitization is generally carried out for 3–5 years. Patients who are exposed to specific inhaled allergens on a perennial basis may experience recurrent symptoms if the therapy is stopped. (6) Hyposensitization to food allergens and molds is currently not recommended. (7) Patients scheduled to undergo rapid hyposensitization therapy should be hospitalized. (8) For symptoms due to house-dust mite allergens, several studies report that hyposensitization therapy with mites is more effective than with house dust. However, a house dust extract is generally used for hyposensitization due to health insurance regulations in Japan. Nonspecific Therapy Gold sodium thiomalate (injection) and auranofin (oral) may be effective in patients with asthma. However, because of their potential severe toxicity, these drugs should only be considered when other conventional therapy has not been clinically effective.


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A Stepwise Plan of Pharmacologic Therapy in Adults Goal of Asthma Control (1) To decrease (or eliminate) nocturnal and chronic symptoms of asthma. (2) To reduce (or eliminate) exacerbations of asthma. (3) To prevent deaths due to asthma attacks. (4) To diminish (or eliminate) the need for oral corticosteroids. (5) To avoid restriction of daily activities such as exercise. (6) To normalize respiratory function as much as possible. (7) To maintain diurnal variations in PEF to within 20%. (8) To increase PEF to near normal levels. (9) To minimize (or eliminate) the occurrence of adverse drug reactions.

Implementation of Asthma Therapy Pharmacologic asthma therapy is classified into 4 steps based on the severity of asthma symptoms. The goal of pharmacologic therapy is to produce the maximum effect while using the minimum number of drugs and the minimum drug dosage possible. The appropriate step of therapy should be selected based on a comprehensive assessment of the patient’s present asthma symptoms and past response to therapy. The physician-patient relationship, particularly the level of mutual trust and reliability between the doctor and the patient, greatly enhances the effectiveness of initial therapy. After the patient has shown a stable improvement in initial symptoms for at least 3 months, a step-down in drug therapy can be attempted. The treatment of asthma is not limited to the use of drug therapy. It is also important to avoid and eliminate triggering factors and to consider the use of hyposensitization therapy. Conversely, a step-up in drug therapy is appropriate if the patient experiences worsening symptoms or if the current treatment regimen is providing inadequate control of symptoms. Maintenance therapy for asthma should be based on asthma symptoms and PEF measurements. A step-down in therapy may provoke worsening symptoms or unexpected development of a severe asthma attack. During step-down therapy, patients should be carefully monitored and instructed in action plans for any symptoms of exacerbation as drug doses are reduced.

22


Four Steps in Long-Term Management of Asthma Step 1: Mild Intermittent Asthma Symptoms and Findings Patients with mild intermittent asthma experience attacks of coughing, wheezing, and dyspnea less than once per week, and nocturnal symptoms no more than once or twice per month. Symptoms are mild and of short duration. These patients are asymptomatic during disease remission and do not need to restrict their daily activities. In general, baseline pretreatment values for FEV1.0 are at least 80% of predicted values, diurnal PEF variation is less than 20%, and PEF is at least 80% of the patient’s best value. Treatment These patients generally do not need to use controller drugs. They can be treated with inhaled or oral 2-agonists as needed during active symptoms. Short-acting (reliever) theophylline may also be used. At times when asthma symptoms are relatively frequent (for example, occurring more than once every 2 weeks), or during periods of increased airway inflammation as suggested by the presence of increased numbers of blood and sputum eosinophils, the addition of low-dose inhaled corticosteroids, sustained-release theophylline, a leukotriene antagonist, or an anti-allergic agent may be considered. Patients with exercise-induced asthma will benefit from using inhaled DSCG, inhaled short-acting 2-agonists, or leukotriene antagonists. Step 2: Mild Persistent Asthma Symptoms and Findings These patients experience asthma exacerbations at least once a week, but not every day. They occasionally have difficulty sleeping and some limitation of their daily activities due to symptoms. They experience nocturnal asthma attacks at least twice a month. Generally their baseline pretreatment FEV1.0 and PEF are at least 80% of predicted values, diurnal variation is 20–30%, and PEF is at least 80% of their personal best value. Treatment These patients require sustained treatment with controller medications. They may use inhaled corticosteroids (low-dose) on a daily basis, or some combination of sustained-release theophylline, leukotriene antagonists, and/ or inhaled DSCG. A long-acting (controller) 2-agonist in inhaled, patch, or oral formulation can be used for nocturnal symptoms, in combination with some other drug


such as inhaled corticosteroids. Anti-allergic drugs (mediator release inhibitors, H1-antihistamines, Th2 cytokine inhibitors, and thromboxane A2 inhibitors/antagonists) are used in combination with the above drugs, primarily in the treatment of atopic asthma, and such treatment should be continued if effective. If administration of an anti-allergic agent, leukotriene antagonist, and/ or sustained-release theophylline without inhaled corticosteroids fails to adequately control symptoms, then inhaled corticosteroids should be added to the treatment regimen or the patient should be switched to inhaled corticosteroids. Step-Up Additional doses of inhaled or oral short-acting 2agonists can be used as needed to relieve symptoms. However, if the patient requires these additional medications more than 3 or 4 times daily on a regular basis, a step-up in therapy is warranted. Also, patients whose symptoms cannot be controlled by low-dose corticosteroid treatment should be advanced to step 3 therapies. Step 3: Moderate Persistent Asthma Symptoms and Findings Patients with moderate persistent asthma are symptomatic almost daily and experience nocturnal symptoms and some limitations in their daily activities at least once per week. Virtually all of these patients must use inhaled short-acting 2-agonists as needed to relieve symptoms on a daily basis. In general, FEV1.0 and PEF are 60–80% of predicted values, diurnal variations exceed 30%, and PEF is 60–80% of personal best value. Treatment These patients generally use moderate doses of inhaled corticosteroids, in combination with one or more of the following: sustained-release theophylline, controller long-acting 2-agonists (inhaled, patch, or oral formulation), and leukotriene antagonists. Long-acting 2-agonists (inhaled, patch, or oral formulation) can be useful for preventing frequent daytime or nocturnal symptoms, but should be used only in combination with inhaled corticosteroids. Serum theophylline level should be maintained in the range of 5–15 g/ml. If Th2 cytokine blocker therapy is found to be effective, it should be continued (table 5). Step-Up Additional doses of short-term inhaled or oral 2-agonist can be administered as needed. However, if the pa-


tient requires these additional medications more than 3 or 4 times daily on a regular basis, a step-up in therapy is warranted. Step 4: Severe Persistent Asthma Symptoms and Findings Symptoms in these patients usually occur daily and vary widely in severity. Nocturnal symptoms are frequent, and daily activities are limited. It is often difficult to achieve even moderate control of symptoms and exacerbations, despite the use of high levels of drug therapy. These patients generally have baseline pretreatment FEV1.0 and PEF less than 60% of predicted values, diurnal PEF variations greater than 30%, and PEF less than 60% of their personal best values. Treatment Inhaled High-Dose Corticosteroids. These patients receive ongoing treatment with inhaled corticosteroids (high-dose). The goal of treatment in severe persistent asthma is to minimize asthma symptoms and to help patients participate in normal daily activities with as few restrictions as possible. This requires multidrug therapy involving high doses of inhaled corticosteroids together with long-acting 2-agonists (inhaled, patch, or oral formulation), sustained-release theophylline, and leukotriene antagonists, with the addition of oral corticosteroids if necessary. Long-acting 2-agonists (inhaled, patch, or oral formulation) have proven highly useful in preventing frequent daytime and nocturnal symptoms. Oral Corticosteroids. Short courses of oral corticosteroids at moderate to high doses (approximately 0.5–1 mg/ kg prednisolone, or equivalent, usually administered for 1 week or less) will often be required at the time of initial treatment, during a step-up in therapy for exacerbations, and when inhaled corticosteroids fail to adequately control symptoms. Subsequent symptoms in some patients may be controlled by high-dose inhaled corticosteroids. In cases where inhaled corticosteroids provide insufficient control, and treatment with oral corticosteroids must be continued, use short-acting drugs to minimize the maintenance dose of oral corticosteroids, and administer that oral dose once daily or every other day. Patients who have received a prolonged course of oral corticosteroids should be carefully monitored for signs and symptoms of adrenal insufficiency when being switched over to high-dose inhaled corticosteroids. Bronchodilators. Controller bronchodilator therapy includes the administration of long-acting 2-agonists (inhaled, patch, or oral formulations) and sustained-release


23

Table 5. A stepwise plan of pharmacotherapy based on disease severity for long-term management of asthma Disease severity

Step 1a, b Mild intermittent asthma

Step 2a, b Mild persistent asthma

Step 3a, b Moderate persistent asthma

Step 4a, b Severe persistent asthma

Clinical features

Symptoms less than once a week Symptoms are brief and intermittent Nocturnal symptoms no more than 1 or 2 times per month

Symptoms at least once a week, but not daily Difficulty sleeping and limitation of daily activities at least once a month Nocturnal symptoms at least 2 times per month

Symptoms experienced daily Short-acting inhaled 2-agonist required almost daily Difficulty sleeping and limitation of daily activities at least once a week Nocturnal symptoms at least once a week

Frequent asthma exacerbations (despite treatment) Symptoms daily Limitation of daily activities Frequent nocturnal symptoms

PEF, FEV1.0 c

680% of predicted value or personal best (PEF only) Variation of 30%

90%)* To prevent relapse by means of regular treatment with oral or inhaled medication Severity of attack

Dyspnea

Movement

Type of treatment

Where performed b

Test valuesa

Mild

Can lie down

Somewhat difficult

Inhaled 2-agonist as neededc Oral theophylline as needed

At home

PEF 70–80%

Moderate

Cannot lie down (orthopneic)

Quite difficult Can walk with difficulty

Repeated inhalation of 2-agonist by nebulizerd Subcutaneous 2-agonist (Bosmine®)e Aminophylline dripf IV corticosteroidg Oxygenh Consider inhaled anticholinergics

Emergency medical facility of clinic or hospital Discharge from emergency facility to home if patient remains asymptomatic for 1 h Hospitalization and step-up if improvement is poor in 4 h or absent in 2 h

PEF 50–70% Pao2 > 60 mm Hg Paco2 < 45 mm Hg Spo2 > 90%

Severe

Cannot move

Cannot walk Difficulty in speaking

Subcutaneous 2-agonist (Bosmine®)e Aminophylline continuous dripi Repeated IV corticosteroid g Oxygeni Repeated 2-agonist inhalation by nebulizerd

Emergency room Admit to hospital if poor response to treatment within 1h Provide further immediate care if symptoms worsen

PEF < 50% Pao2 < 60 mm Hg Paco2 > 45 mm Hg Spo2 < 90%

Emergency (no response or aggravation of symptoms following treatment for severe attack)

Cyanosis Confusion Disturbance of consciousness Incontinence Respiratory arrest

Cannot speak Unable to move

Continue above treatment Intubate if symptoms or respiratory status deterioratek Initiate mechanical ventilation if Pao2 < 50 mm Hg even with oxygen administration, and/or in the event of sudden elevation of Paco2 with disturbance of consciousnessk Mechanical ventilationk Bronchial lavage Consider general anesthesia with isoflurane, sevoflurane, or enflurane

Immediately hospitalize and admit to ICU b

PEF cannot be measured Pao2 < 60 mm Hg Paco2 > 45 mm Hg Spo2 < 90%

a

Values measured after bronchodilation, to be used for reference. Intensive care unit (ICU) or equivalent facility where endotracheal intubation, assisted respiration, bronchial lavage, and continual monitoring of blood pressure, ECG, and oximetry are available. c 2-Agonist inhalation using MDI, 1–2 puffs every 20 min, repeated no more than twice. If symptoms do not respond to treatment, or appear to be aggravated, 1 tablet of oral 2-agonist and choline theophylline or aminophylline (200 mg) should be given as needed. d 2-Agonist inhaled by nebulizer, repeated every 20–30 min. The patient should be monitored to ensure that pulse rate remains below 130/min. e Bosmine® (epinephrine 0.1%) 0.1–0.3 ml injected subcutaneously, may be repeated at intervals of 20–30 min. Pulse rate should be maintained at below 130/min. Contraindicated in patients with ischemic heart disease, glaucoma (except open-angle (simple) glaucoma), or hyperthyroidism. Blood pressure and ECG should be monitored during treatment in hypertensive patients. f IV infusion of aminophylline (6 mg/kg) and isotonic IV solution (200– 250 ml), with 1/2 dose administered over 15 min and the remainder over 45 min. Treatment must be discontinued at the appearance of any toxic sympb

28


toms, including headache, nausea, palpitations, or extrasystole. In patients who are receiving regular treatment with theophylline, serum theophylline levels should be monitored if possible. g IV injection of hydrocortisone (200–500 mg) or methylprednisolone (40– 125 mg), with subsequent IV hydrocortisone (100–200 mg) or methylprednisolone (40–80 mg) every 4–6 h as required. h Oxygen 1–2 liters/min via nasal cannula. i Continuous infusion of aminophylline. After initial infusion as described above (footnote f), aminophylline (250 mg, 1 ampoule) is continuously infused for 5–7 h (approximately 0.6–0.8 mg/kg/h). Serum theophylline level should be monitored and maintained at 10–20 g/ml (up to 15–20 g/ml for maximum effect), with treatment discontinued immediately if toxic symptoms develop. j Oxygen to increase and maintain Pao2 at approximately 80 mm Hg. k Endotracheal intubation and mechanical ventilation: intubation and mechanical ventilation of a patient in severe respiratory failure can be a high-risk procedure, and should be performed by two or more experienced specialists except in an emergency.


Table 7. Emergency pathophysiology and treatment

Clinical findings

Test values

Absent breath sounds Cyanosis Loss of consciousness Respiratory arrest, cardiac arrest Pao2 < 50 mm Hg, even with maximum oxygen Disturbance of consciousness accompanied by sudden elevation of Paco2 (e.g. Paco2 increase of more than 5 mm Hg/h)

Treatment Oxygen Respiratory management: intubation Mechanical ventilation (volume preset respirator) Inhalation of 2-agonist, subcutaneous injection of Bosmine® (0.1% epinephrine) (heart rate not to exceed 130/min) IV aminophylline IV corticosteroids Additional Bronchial lavage (by bronchoscopy) treatment General anesthesia (e.g. isoflurane, sevoflurane, or enflurane)

Other Therapy U

U

U

U

U

U

Antibiotics are indicated for the treatment of bacterial infections with fever and purulent sputum. Expectorants or liquefied expectorants are generally not useful. Analgesics are generally not indicated. Anti-histamines are not effective for the treatment of acute asthma. Anti-allergic drugs are not effective for the treatment of acute asthma. Beclomethasone inhalation is not effective for the treatment of acute asthma. Fluid supplementation is generally not required in large amounts, but the patient should be monitored carefully for dehydration, and fluid supplementation should be provided if needed.

Procedures for Emergency Outpatient Treatment (tables 6, 7) Management and Treatment of Childhood Asthma

in 40–60% of patients with aspirin-induced asthma. When patients receive corticosteroids intravenously for the first time, it is generally recommended that they be given by drip infusion over a period of approximately 1 h. Systemic administration of corticosteroids may be indicated in the following cases: Exacerbation of moderate or greater severity. A history of severe asthma attacks requiring treatment with systemic corticosteroids. A history of very severe asthma attacks requiring hospitalization. Other factors placing the patient at high risk. U

U

U

U

Oxygen Oxygen should be given if the patient develops severe dyspnea and Pao2 below 60 mm Hg or oxygen saturation measured by a pulse oximeter (Spo2) less than 90%. Since hypoxia can aggravate airway smooth muscle constriction, the goal of treatment should be a Pao2 of approximately 80 mm Hg and an Spo2 of approximately 95%. Higher values are unnecessary. If oxygen is needed, preparation should also be made to intubate the patient and provide mechanical ventilation if required.


Management of Acute Attacks in Childhood Asthma Home Management of Patients Asthma symptoms vary widely in severity, ranging from mild wheezing to severe dyspnea. The progression of symptoms also varies among individual patients. In addition, a variety of drugs are available for use, some of which are given on an ongoing basis while others are used as needed at the time of an asthma attack. Some families are able to smoothly assess symptoms and judge the appropriate time for use of medication as needed, even when it has been months or years since the last asthma attack. However, sometimes an unexpectedly severe asthma exacerbation develops, and families that have only limited experience with such severe attacks may have difficulty in judging the seriousness of the situation. Physicians should provide both an oral explanation and written instructions to each patient (and to the parent or guardian), clearly outlining appropriate treatment during an asthma attack. When the asthma patient is an infant or baby, it is difficult for the patient to precisely describe symptoms, and there is also an additional danger that respiratory infection may be associated with rapid exacerbation. In such cases it is particularly important


29

Initial assessment

Mild attack

Moderate attack

Severe attack

PEF >60% (before β2-agonist inhalation) PEF >80% (after β2-agonist inhalation)

PEF 30–60% (before β2-agonist inhalation) PEF 50–80% (after β2-agonist inhalation)

PEF 80%

Inhalation of 2-agonist

>30–60%

>50–80%

Repeated inhalation of 2-agonist Aminophylline (IV or drip infusion)

15

4–6 4–6

0.8–1.0 0.6–0.8

Previous oral administration of theophylline

> 2–15 >15

3–4 3–4

0.8–1.0 0.6–0.8

mately 2 h of such treatment, hospitalization should be considered. For patients who experience obvious improvement or relief of symptoms, the cause of the attack should be investigated, and the patient may be discharged to home with proper instructions for daily activities and a drug treatment plan. If necessary, the patient’s controller medication regimen should be adjusted. Poor Response to Treatment. These patients show no response to treatment and may instead experience a worsening of symptoms. Respiratory and pulse rates continue to rise, and dyspnea becomes more severe. Spo2 is 91% or less and PEF is less than 30% of predicted or personal best value. Physical examination may reveal pulsus para-

34


doxus and facial pallor, and the patient finds it difficult to move. Such patients develop orthopnea, and sometimes cyanosis. These patients must be immediately hospitalized and treated for severe attack. Treatment of Severe Attacks As a rule, patients experiencing severe asthma attacks should be hospitalized for treatment. In a severe asthma attack, improvement is generally obtained by following early treatment with a rapid combination of follow-up measures performed simultaneously. If too much time is expended in monitoring the effects of one treatment, the patient’s symptoms may progress so far that there is little response to the next treatment option. Treatment response varies greatly among individual patients with severe asthma attacks. Consequently, what constitutes effective treatment in some patients is often not effective in others. Treatment should be started at first, and the patient should be successively advanced to more intense treatment levels. However, some steps may be eliminated in favor of the decision to use specific therapy in an individual patient based on past response to therapy. The following steps, based on previously discussed treatment, can be used as a guideline to therapy, but specific treatment must be tailored to the individual patient in the case of poor response. Initial therapy consists of oxygen administration and an inhaled 2-agonist by nebulizer. Secure an appropriate blood vessel, and begin administration of aminophylline by drip infusion using the dosages in tables 10 and 11 as a guideline. Intravenous fluid replacement should also be started as shown in table 12. Because aminophylline metabolism is affected by many factors, including the presence of viral infections, the dose should preferably be adjusted on the basis of measured serum drug concentrations [128]. Serum theophylline levels in excess of 18 g/ ml are associated with the development of various concentration-dependent adverse effects, so the dose of aminophylline should be adjusted to maintain theophylline levels below 15 g/ml [129]. Satisfactory Response to Treatment. Patients whose symptoms improve should be monitored and reevaluated 30 and 60 min after the start of treatment. Patients who continue to show satisfactory improvement should be monitored on the same treatment (intermittent 2-agonist inhalation and aminophylline by infusion) until symptoms are completely relieved. Poor Response to Treatment. Patients who respond poorly to the treatment described above, and patients who despite some initial improvement continue to expe-


Table 12. Determination of intravenous fluid requirements

Rapid initial infusion Solita T1

Slow replacement infusion Solita T3

Maintenance infusion b Solita T3

Calculation based on body surface area

300 ml/m2/first 1 h 150 ml/m2/h Until urinary voiding

2,000 ml/m2/24 ha

1,500 ml/m2/24 h

Calculation based on body weight

Infants = 100–150 ml/h 610 kg = 200 ml/h Until urinary voiding

Maintenance volume (ml) + Infants = 100 ml/kg (volume deficit – initial loading 10–20 kg = 1,000 + (weight in kg – 10 kg) ! 50 ml/24 h volume)/2 ml/24 h 621 kg = 1500 + (weight in kg – 20 kg) ! 20 ml/24 h

Patients with severe exacerbations of asthma often have signs of circulatory failure such as dehydration and oliguria. In these patients, a primary consideration should be rapid fluid replacement until urinary voiding in order to improve peripheral circulation. Any remaining volume deficit and maintenance volume can then be given over the next 24 h as a slow replacement infusion, followed by a switch to maintenance fluids. If the patient is on oral intake, the IV infusion should be decreased to 1,000–1,500 ml/m2/day in order to prevent fluid overload. a Adjust as necessary based on clinical findings. b Decrease as necessary in patients on oral intake.

rience significant symptoms after 30 min, should be advanced to the next stage of treatment (Step 3). High doses of intravenous corticosteroids should be administered immediately to the following patients: patients who show an insufficient therapeutic response to inhaled 2-agonists and a drip infusion of aminophylline; patients whose condition is further deteriorating, as evidenced by grunting, disturbing of consciousness, increasingly severe dyspnea, and/or signs of circulatory failure; and patients who have required large doses of corticosteroids for previous asthma attacks. Hydrocortisone 5– 7 mg/kg [130], methylprednisolone 1–1.5 mg/kg [131], or prednisolone 1–1.5 mg/kg are given by slow intravenous administration every 4–6 h depending on the patient’s status. The mineralocorticoid effects of hydrocortisone cause edema due to sodium retention, so if treatment is continued for more than 3 days it is best to switch to another drug. Satisfactory Response to Treatment. Pediatric patients who show a satisfactory response to treatment as evidenced by clinical improvement should continue to be monitored. One objective of therapy should be to taper and discontinue corticosteroid treatment within 1 or 2 days if symptoms continue to improve. If the patient does not respond to treatment or shows further clinical deterioration while receiving corticosteroids, hospitalization for continuous low-dose isoproterenol inhalation therapy should be considered [132–134]. Add 2–10 ml of 0.5% Asthpul® (or Proternol-L® 20–

60 ml) to 500 ml of physiological saline, and administer continuously with an Inspiron® nebulizer together with oxygen 5–10 liters/min by face mask or oxygen tent. Blood pressure, heart rate, respiration rate, and Spo2 must be monitored during treatment. Patients whose pulse rates decrease during subsequent monitoring for 30 min often experience relief from asthma symptoms. Although there have been reports of adverse cardiovascular effects from this treatment [135, 136], and further clinical studies are needed to define specific indications and methods of administering such therapy, it may prove to be an extremely effective form of treatment [137].



Treatment for Acute Respiratory Failure Respiratory failure is characterized by breathing with intercostal retractions, prolonged exhalation, and pronounced cyanosis, sometimes accompanied by urinary incontinence, diminishing or elimination of breath sounds, and disturbances of consciousness. In patients whose condition fails to improve despite implementation of the standard treatment measures for severe asthma attacks as described above, arterial blood gases should be reanalyzed and the patient’s respiratory status should be assessed. At this point, endotracheal intubation and mechanical ventilation should be seriously considered after confirming that there are no complications (such as subcutaneous emphysema, pneumomediastinum, atelectasis, or pneumonia) that would limit the effectiveness of

35

such treatment. Additional medical intervention should be attempted, such as increasing the dose of corticosteroids or isoproterenol, and attempting to alleviate acidosis, while simultaneously preparations are also being made for endotracheal intubation and assisted respiration or mechanical ventilation [138]. If the patient continues to show no clinical improvement, endotracheal intubation and assisted respiration or mechanical ventilation are required. There are no absolute criteria for the appropriateness of mechanical ventilation, since each case must be decided individually based on that patient’s clinical history, but the following guidelines can be used for reference. Criteria for Mechanical Ventilation (1) Decreasing respiratory efforts, with no improvement in respiratory status. (2) Worsening disturbances of consciousness, in a drowsy state. (3) Pao2 remains below 60 mm Hg even when oxygen is provided. (4) Paco2 exceeds 65 mm Hg, or rises by at least 5 mm Hg in 1 h. Methods of Mechanical Ventilation Intubation is associated with some risk, and should be performed by an anesthesiologist or other physician highly experienced in this procedure. (1) Assisted ventilation with oxygen delivered through a mask. (2) Intubation after the administration of either atropine sulfate (0.01 mg/kg intramuscularly or intravenously) and diazepam (0.2–0.5 mg/kg intramuscularly or intravenously) or midazolam (0.08– 0.1 mg/kg intramuscularly), and the muscle relaxant suxamethonium (0.8– 1.0 mg/kg intravenously). (3) Endotracheal intubation followed by mechanical ventilation through a T piece. (4) Ventilator-delivered breaths in a pattern synchronized with respiratory motion of the patient’s chest.

Indications for Hospitalization (1) Severe asthma attack. (2) Moderate asthma attack that shows no improvement after approximately 2 h of outpatient treatment. (3) Moderate asthma attack in which symptoms have persisted from the previous day, including sleep disturbance.

36


(4) Since the breathing process is not thoroughly habituated in infants, and there may also be complications of infection, condition can deteriorate rapidly. Early hospitalization is advised. (5) Complications such as pneumonia, atelectasis, or air leak syndrome. (6) No clinical improvement even after stepping up the long-term treatment plan.

Medication Plans for Long-Term Management of Childhood Asthma Childhood asthma is characterized pathophysiologically as a chronic inflammatory disorder, even in the absence of clinical symptoms. Keys to successful management include long-term suppression of airway inflammation, including those times when the patient is asymptomatic, so that these asymptomatic periods can be sustained for as long as possible. The objective of long-term treatment should be to provide maximum improvement in respiratory function and quality of life for the patient with a minimum of adverse reactions to treatment. Such care can only be provided from a basic medical perspective that supports the patient’s ordinary life and enables the asthmatic child to grow and develop as a healthy person psychologically and socially as well as physically. Long-term treatment involves more than just medication. During drug treatment, and even before the start of that treatment, appropriate changes in the patient’s surroundings should be made based on a careful review of the patient’s medical history and the results of allergic tests. This is a fundamental step in reducing asthma exacerbation factors. Opportunities must also be made to provide education about asthma pathophysiology to the pediatric patient, the patient’s family, and daycare, kindergarten, and school personnel (person in charge, nurseteacher, etc.). It is particularly important to raise awareness about asthma prevention and self-management, and to encourage effective implementation. To this end, asthma therapy must not be limited to a narrow definition of medical treatment, but must instead be viewed as a community responsibility that requires cooperation from other fields such as education and social work. Table 13 shows treatment objectives for asthmatic children. Ideally the patient will have no daytime or nocturnal symptoms, and will be able to perform daily activities normally. Additional objectives are stabilization of pulmonary function and PEF values.


Table 13. Treatment objectives in childhood asthma

Table 14. Oral anti-allergic agents for pediatric applications

1

Category

Generic name Trade name

Chemical mediator release inhibitors

tranilast pemirolast repirinast

Rizaben® Pemilaston®, Alegysal® Romet®

H1-antihistamines

ketotifen azelastine oxatomide mequitazine

Zaditen® Azeptin® Celtect® Zesulan®, Nipolazin®

Leukotriene receptor antagonists

pranlukast montelucast

Onon® Singulair®, Kipres®

Th2 cytokine inhibitors

suplatast

IPD®

2 3 4 5 6

Child is able to participate normally in daily activities, including sports No nocturnal symptoms Routine use of 2-agonist is reduced or eliminated No absences from school Near-normal pulmonary function Little daily variability in PEF

Long-term treatment requires a clear understanding of the severity of the patient’s condition, followed by the development of an age-appropriate treatment plan depending on whether the patient is a school-age child, infant, or baby. After asthma attacks are being successfully managed and satisfactory improvement has been obtained, treatment can be stepped down over a period of 3–6 months. Treatment step-down should start with reducing or discontinuing the least effective drugs. The aim is to achieve the simplest possible drug treatment protocol. If insufficient improvement is seen after 1–2 months, treatment should be stepped up (fig. 4–6).

Controller Medications Anti-Allergic Drugs Disodium Cromoglycate The pharmacological action of DSCG remains poorly understood, but appears to center on a dose-dependent inhibition of the release of chemical mediators from mast cells [139]. The drug has also been reported to suppress allergic inflammation [140]. Pretreatment with DSCG can inhibit not only immediate asthmatic response, but also delayed response [141]. The drug can thus provide improvement in airway hypersensitivity. This response is not specific to allergens, but also inhibits airway contractions due to cold air, exercise [142], and inhalation of sulfur dioxide gas. Inhaled DSCG is available in three forms: capsules (20 mg/capsule), MDI (1 mg/puff), and inhaled liquid (20 mg/2 ml). Clinically, DSCG has been found to reduce asthma attacks and improve pulmonary function. Use of this drug may also make it possible to reduce the treatment dose for concomitant drugs [143]. Best effects are obtained when DSCG is introduced early into the asthma treatment protocol [144]. When pediatric patients with moderate to severe asthma were treated with regular inhala-


tion of DSCG containing a small amount of inhaled 2agonist, a significant improvement in asthma score was noted in comparison to the control group treated with DSCG alone [145]. Oral Anti-Allergic Drugs Table 14 shows the anti-allergic drugs currently indicated for pediatric asthma in Japan. Anti-allergic drugs are generally indicated for the treatment of intermittent asthma, mild persistent asthma, and moderate persistent asthma. The leukotriene receptor antagonists are also used in the treatment of severe persistent asthma. Inhaled Corticosteroids Inhaled corticosteroids are delivered directly to the airways, and provide powerful inhibition of airway inflammation with relatively few systemic adverse effects. These drugs currently play an important role in prophylactic drug treatment for asthma patients. In addition to reducing airway inflammation, inhaled corticosteroids also reduce asthma symptoms, decrease airway hypersensitivity, improve pulmonary function [146, 147], and reduce the number of asthma-related hospitalizations and asthma deaths [148]. Inhaled corticosteroids are reported to improve patient quality of life and to reduce the socioeconomic loss associated with asthma. Also, the early use of inhaled corticosteroids may prevent airway remodeling and may help to prevent irreversible airway constriction, worsening of symptoms, and deterioration into intractable asthma. However, these drugs have not been found to improve the percentage of pediatric asthma patients who outgrow their asthma naturally. There


37

Long-term hospitalization and treatment with oral corticosteroids (alternate day) under the supervision of pediatric allergist

Fig. 4. Long-term management of child-

hood asthma (6–15 years of age). a Oral anti-allergic agents include chemical mediator release inhibitors, H1-antihistamines, leukotriene receptor antagonists, and Th2 cytokine inhibitors. b When using a combination of DSCG inhaled liquid and lowdose 2-agonist inhaled liquid, 2-agonist inhalation should be discontinued as soon as the child’s symptoms (coughing, wheezing, etc.) improve. c Inhaled corticosteroid titer is expressed as CFC-BDP equivalents.

Fig. 5. Long-term management of childhood asthma (2–5 years of age). a Oral antiallergic agents include chemical mediator release inhibitors, H1-antihistamines, leukotriene receptor antagonists, and Th2 cytokine inhibitors. b Caution is required when using sustained-release theophylline, as this drug has been associated with adverse drug reactions including convulsions. c Inhalation of BDP (beclomethasone propionate) is accomplished by using a mask with assisted inhalation. Inhaled corticosteroid titer is expressed in the form of BDPCFC equivalents. d 2-Agonists should be discontinued as soon as the child’s symptoms (coughing, wheezing, etc.) improve. e If the child’s symptoms cannot be controlled by the treatment described in Step 4, treatment including oral corticosteroid therapy should be initiated under the supervision of a pediatric allergist.

Pharmacotherapy in response to asthma attacks Consider anti-allergic agentsa

Inhaled corticosteroidsc (BDP equivalent 200–400 µg/day)

Inhaled corticosteroidsc (BDP equivalent approx. 200 µg/day) or any of the Consider concomitant following, alone or in treatment with any combination: of the following: Oral anti-allergic Oral anti-allergic agentsa agentsa DSCGb b DSCG Sustained-release Sustained-release theophylline theophylline

Step 1

Step 2

Step 3

Intermittent asthma

Mild persistent asthma

Moderate persistent asthma


Any of the following, alone or in combination: Oral anti-allergic agentsa DSCG + β2-agonist (inhaled twice daily) Sustained-release theophyllineb Consider inhaled corticosteroidsc (BDP equivalent approx. 200 µg/day)

Leukotriene receptor antagonists DSCGb Sustained-release theophylline Long-acting β2-agonist (inhaled or patch formulation) Step 4–1

Inhaled corticosteroidsc (BDP equivalent 200–300 µg/day) Consider concomitant treatment with any of the following:

Step 4–2

Step 4 Severe persistent asthma

Inhaled corticosteroidsc,e (BDP equivalent 300–600 µg/day) Concomitant treatment with any of the following: Leukotriene receptor antagonists DSCG + β2-agonist (inhaled twice daily)

Oral anti-allergic agentsa

Sustained-release theophyllineb

DSCG + β2-agonist (inhaled twice daily)

β2-agonist (patch or oral) before bedtimed

Sustained-release theophyllineb β2-agonist (patch or oral) before bedtimed

Step 1

Step 2

Step 3

Step 4

Intermittent asthma



Severe persistent asthma

have been frequent reports that the discontinuation of inhaled corticosteroids is associated with progression of airway hypersensitivity and recurrence of symptoms [149]. The inhaled corticosteroids currently available in Japan for the treatment of pediatric asthma are BDP by

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Inhaled corticosteroidsc (BDP equivalent 400–800 µg/day) Concomitant treatment with any of the following:


MDI and FP inhaled dry powder. The present BDP inhalers are aerosols using CFCs, although recently a product using a CFC substitute (HFA) has come on the market for use in adults. Inhalation efficiency is increased by the use of HFA, and it appears that the clinical effectiveness of this product is approximately double that of the BDP-


Fig. 6. Long-term management of childhood asthma (!2 years of age). a Oral antiallergic agents include chemical mediator release inhibitors, H1 -antihistamines, leukotriene receptor antagonists, and Th2 cytokine inhibitors. b Caution is required when using sustained-release theophylline, as this drug has been associated with adverse drug reactions including convulsions. c Inhalation of BDP (beclomethasone propionate) is accomplished by using a mask with assisted inhalation. Inhaled corticosteroid titer is expressed in the form of BDPCFC equivalents. d 2-Agonists should be discontinued as soon as the child’s symptoms (coughing, wheezing, etc.) improve. e If the child’s symptoms cannot be controlled by the treatment described in Step 4, treatment including oral corticosteroid therapy should be initiated under the supervision of a pediatric allergist.

Inhaled corticosteroidsc (BDP 200 µg/day)

Oral anti-allergic agentsa


Inhaled corticosteroids c,e (BDP 300–400 µg/day)

Consider any of the following, alone or in combination: d

DSCG + β2-agonist (inhaled twice daily) Sustained-release theophyllineb (serum level 5–10 µg/ml) Consider inhaled corticosteroidsc (BDP approx. 100 µg/day)

Concomitant treatment with any of the following, alone or in combination:

Consider concomitant treatment with any of the following, alone or in combination: Oral anti-allergic agents

Leukotriene receptor antagonists

a

DSCG + β2-agonistd (inhaled twice daily)

DSCG + β2-agonistd (inhaled twice daily)

Sustained-release theophyllineb (serum level 5–10 µg/ml)

Sustained-release theophyllineb (serum level 5–10 µg/ml)



Step 1

Step 2

Step 3

Step 4

Intermittent asthma



Severe persistent asthma

CFC preparation. In Europe and North America a suspended preparation of corticosteroid for inhalation is also available, delivered through a nebulizer. This formulation has been reported to be particularly effective in infants and babies. Pediatric clinical trials were scheduled to begin in Japan in 2003. It appears that FP may provide approximately twice the pharmacological effect of BDP [150]. It is important to consider the patient’s age and the proposed method of inhalation when selecting the drug to be used and devising an effective inhalation method. For BDP inhalation it is best to use inhalation-assisting devices that improve inhalation efficacy and reduce the incidence of adverse drug reactions. With adequate instruction, it is also possible to use assisted inhalation with a mask in order to administer this drug to infants and babies. The use of dry powder requires a strong inhalation force from the patient, and is generally not well suited for use in children under the age of 5. When starting treatment, two methods are available. One is to start at a low dose and gradually step up until the optimal dose is reached. The second is to start at a high dose, and after symptoms are controlled to step down to the required maintenance dose. In either case, it is important to make sure that the maintenance dose is as low as possible while still providing the desired effects. Even if the correlation between dose and effect indicates a dose-dependent relationship [151], the effects of

increasing dose may diminish at high dose levels [150]. Instead of increasing inhaled corticosteroids to a higher dose, the concomitant use of sustained-release theophylline [152], long-acting inhaled 2-agonists [153], and leukotriene receptor antagonists [154] have been reported to be clinically useful. Adverse drug reactions can be divided into two types: localized reactions associated with inhalation, and systemic reactions resulting from corticosteroid absorption through the airways and gastrointestinal tract. Higher doses are associated with increasing amounts of product deposited within the airways, which increases the risk of systemic adverse effects. To date, reports indicate almost no problems of this nature when BDP doses are limited to 400 g/day or less [146]. However, since individuals vary widely in their sensitivity to corticosteroids, the patient and family should be constantly cautioned about the possibility of adverse drug reactions, and should be repeatedly instructed in how to routinely achieve appropriate inhalation of the minimum required dose and how to avoid overuse. These instructions should be accompanied by appropriate testing as needed.



Localized Effects Symptoms include pharyngeal irritation, coughing, and hoarseness, and can sometimes be prevented by using devices to assist with inhalation and/or by changing drugs. There have been no specific reports of increased risk of respiratory infection associated with these symp-

39

toms. However, the bronchi and lungs are still in the process of development in children. Further research is needed on the effects of long-term inhaled corticosteroids in this young age group, both the localized effects within the airways and the long-term effects on respiratory system development. Systemic Effects Regular treatment (almost BDP-CFC 400 g/day) with inhaled corticosteroids may inhibit growth by approximately 1 cm during the first year of treatment. However, no major subsequent effects have been noted, and most reports indicate no significant reduction in final height [147, 155–157]. When extremely sensitive procedures are applied, results indicate that inhaled corticosteroids produce an inhibiting effect on the diencephalon, pituitary, and adrenal cortex, but no reports to date have shown clinically problematic findings at ordinary dose levels [158]. Although concerns have been expressed about possible negative effects on bone metabolism, the skin, and the eyes, there have been no verified reports of problems in these areas in pediatric populations. Sustained-Release Theophylline This product is formulated for sustained release. Since the long-acting sustained-release agent is not immediately effective, it is used as a controller medication with the objective of achieving sustained inhibition of asthma symptoms. At one time the mechanism of action was attributed to bronchodilation due to nonspecific blocking of phosphodiesterase and resulting elevation in cyclic AMP. However, that effect now appears to play only a minor role, and the overall mechanism of action of the drug remains poorly understood. Recent reports show that theophylline prevents airway constriction in histamine and methacholine inhalation tests, although this effect is weak, and that the drug also reduces exercise-induced airway hypersensitivity at lower concentrations than were previously considered necessary [159–161]. Recent investigations have also confirmed several anti-inflammatory effects of theophylline, including suppression of airway infiltration by T lymphocytes and eosinophils, inhibition of T lymphocyte proliferation and cytokine production, and induction of apoptosis in eosinophils and neutrophils [162– 165]. Theophylline is metabolized in the liver, with a rate of metabolism that varies widely among individual patients and age groups. This is significant, since an elevated se-

40


rum theophylline level may cause serious adverse reactions. It is necessary to consider that theophylline clearance is especially low in babies, particularly those under 6 months of age. When establishing dosage levels for theophylline round-the-clock treatment, it is important to consider factors that will affect theophylline metabolism, including individual differences and complications such as infectious disease, as well as diet and other drugs being used by the patient. During initial treatment with sustained-release theophylline, it is best to monitor serum drug levels for a time in order to learn how that specific patient responds to the drug. Such monitoring is particularly important if the ordinary dose is not providing satisfactory effectiveness or if adverse drug reactions are suspected. Ordinarily, treatment should be started at a dose of 10 mg/kg/day and increased gradually in increments of 20–30% while monitoring serum drug levels and clinical effects. Serum theophylline level should generally be maintained between 5 and 15 g/ml. The most commonly reported adverse reactions to theophylline in children are gastrointestinal symptoms such as nausea and vomiting, followed by agitation, anorexia, diarrhea, and insomnia. Elevated serum concentrations produce palpitation and other cardiac arrhythmias. Severe theophylline toxicity can cause seizures and death. Theophylline-induced seizures are particularly common in patients 5 years of age or younger [166, 167], and there have been reports of seizures even at low plasma drug levels (less than 5 g/ml) in patients with a history of CNS symptoms. Caution is advised.

2-Agonists 2-Agonists are bronchodilator drugs that in general are used for short-term relief from asthma attacks. These drugs are also often used in combination with controller medications. As a rule, 2-agonist agents should be used together with anti-inflammatory drugs for long-term control of asthma [168]. Oral formulations, including procaterol hydrochloride, clenbuterol hydrochloride, formoterol fumarate, and tulobuterol hydrochloride, tend to provide relatively long-term action. The 2-agonists that are currently available in Japan for administration by MDI in pediatric applications are salbutamol and procaterol. It is vital that the patient and family be thoroughly educated regarding the limited effectiveness of relying extensively on MDI 2-agonists alone for asthma control. When these drugs must be used on a routine basis, no more than 2–4 doses per day should


be given. More frequent use indicates that the asthma treatment level is insufficient. The cause of asthma attacks should be analyzed, and treatment should be stepped up. In some instances, regular treatment with a combination of DSCG + salbutamol or procaterol inhaled liquid is justified. In such cases, a small dose of the 2-agonist should be given concomitantly until symptoms are stable, but after symptomatic improvement has been achieved, the patient should be returned to monotherapy with inhaled DSCG. If symptoms recur, concomitant use of the 2-agonist can be reinitiated. However, frequent use of the 2-agonist is an indicator of inadequate therapy, and treatment should be stepped up. The tulobuterol patch provides sustained serum drug levels for 24 h after application. Further research is required to determine whether this agent can be successfully used as a long-term controller drug. Also, it is necessary to determine and use the appropriate dose for each specific age group. The new long-acting inhaled 2-agonist salmeterol has also been recently approved in Japan, and Japanese research into pediatric applications is now required. Patients and their families should be clearly instructed that all of these drugs are to be used in combination with inhaled corticosteroids, and must not be used alone as controller medications.

Stages in Long-Term Asthma Management (Treatment Steps) Important Considerations when Treatment Is Stepped up or Stepped down When implementing a medication plan for long-term asthma management, two methods are available. The first is to assess asthma severity during a brief observation period, initiate a treatment regimen (step) appropriate to that level of severity, and if the asthma is not satisfactorily controlled, to then gradually step up treatment. The second is to start at a step higher than the apparent severity of the asthma, in order to control symptoms quickly, and after symptoms are controlled to then step down to the required maintenance dose. There are no reports currently available in the literature that provide a direct comparison of these two approaches. However, in terms of controlling airway inflammation and improving respiratory function and the patient’s quality of life, there is considerable support for aggressive initial therapy focusing on the use of anti-inflammatory agents. Also, in actual clinical practice, the


patient’s quality of life is improved by first controlling symptoms and then stepping down treatment to an appropriate maintenance level. Assessing Treatment Step-Down When symptoms have been controlled and there has been no evidence of asthma attacks after several weeks or months (depending on asthma severity), treatment can be stepped down. The patient should be monitored for symptoms such as wheezing, dyspnea, nocturnal coughing, and exercise-induced asthma. Morning and evening PEF values should be determined, and if possible, lung function tests should also be performed, with particular emphasis on spirometric findings and the flow volume curve. PEF should be daily within 20% or be within 80% of personal best value, and FEV1.0 should be within 80% of predicted values. Sustaining Asthma Control Monitoring of the patient’s condition must be continued in order to ensure that asthma symptoms remain controlled. The patient’s progress should be monitored regularly at intervals of 1–2 months. This monitoring can include records of asthma attacks from the patient’s asthma diary, PEF measurements, status of routine daily activities such as sleep, exercise, and school life, and records of the extent of 2-agonist use. Asthma symptoms are well controlled if the patient is experiencing no restrictions on activities, including nocturnal sleep, PEF values show variability within 20% or are within 80% of personal best value, and the patient has no need of 2-agonists. When asthma symptoms have been under control for several weeks or months, drug treatment should be stepped down appropriately in order to determine the minimum treatment level necessary for sustained control. Bronchodilators are generally the first drugs to be reduced or eliminated from the treatment regimen. If symptoms do not improve, treatment should be quickly stepped up until symptoms are stabilized, after which cautious step-down is appropriate. Depending on the level of asthma severity, ongoing therapy should be initiated using an anti-inflammatory agent such as an inhaled corticosteroid or an anti-allergic agent. Moderate persistent asthma and severe persistent asthma are treated with ongoing administration of inhaled corticosteroids at the minimum dosage required to maintain asthma control. In severe cases, the duration of this sustained treatment may be measured in years. Mild persistent asthma is typically treated with ongoing ad-


41

ministration of anti-allergic drugs, and among Japanese asthma patients, compliance tends to be best with the use of oral anti-allergic drugs. Regardless of the level of asthma severity, long-term asthma management should be continued well after the initial asthma attacks have subsided. Assessing Treatment Step-Up When asthma symptoms are not being adequately controlled, or when symptom control cannot be sustained (exacerbation of symptoms, disturbance of nocturnal sleep, increase in the number of emergency room visits, over-reliance on inhaled 2-agonists, etc.), a step-up in treatment is called for. The first step is to reconfirm that the patient’s medication is being used correctly, and to investigate environmental factors associated with exacerbation of asthma symptoms. After in-depth assessment of factors such as the patient’s exposure to allergens and irritants, as well as psychosocial considerations, the patient and family should be instructed in ways to avoid these exacerbating factors. In order to reestablish control of asthma symptoms, current symptoms must first be alleviated. This generally involves the use of stronger anti-inflammatory medication by stepping up to the next level of treatment. Specifically, the dose of inhaled corticosteroids is increased or another drug is added to the treatment protocol. Discontinuing Long-Term Asthma Medication There are no specific criteria at present for scheduling the discontinuation of drug therapy in pediatric patients who have been under long-term asthma management. Criteria for assessing prognosis in pediatric asthma specify that the patient is to be considered clinically cured if the asthma has been untreated and symptoms have been absent for at least 5 years. A functional cure is achieved if the asthma has been untreated and symptoms have been absent for at least 5 years, and if results from pulmonary function tests and airway hyperresponsiveness tests are similar to findings in normal healthy subjects. If the patient has remained clinically asymptomatic for a prolonged period (1–2 years), discontinuation of medication may be considered. Although a functional cure is defined as the state in which pulmonary function tests and airway hyperresponsiveness tests show recovery to the same level as seen in normal healthy subjects, in reality it is quite difficult to achieve this final level of equivalence to healthy subjects.

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At any stage of treatment, a patient may experience temporary symptomatic improvement followed by recurrence or exacerbation. Also, serious and even fatal asthma attacks can occur rarely even in patients with intermittent asthma who have been asymptomatic with normal pulmonary function for prolonged periods. When discontinuing long-term treatment, the patient and family must be thoroughly instructed on environmental maintenance and lifestyle management in order to prevent the recurrence of attacks, and instruction must also be provided on how to respond quickly when an asthma attack develops. At all treatment steps, it is necessary to continue educating the patient and at the same time to control factors that affect asthma severity.

Steps in Asthma Treatment Mild Intermittent Asthma (Step 1) Children with mild intermittent asthma are able to function normally in daily activities in the absence of an asthma attack, but they may experience coughing, wheezing, and mild dyspnea a few times each year, especially with hard exercise or during a change in seasons. These patients should use prescribed medications as needed during an asthma attack. The regular use of an anti-allergic agent is appropriate in some patients. Patients with exercise-induced asthma may benefit from inhaling DSCG or a 2-agonist before exercise. Mild Persistent Asthma (Step 2) Children with mild persistent asthma experience coughing or mild wheezing once or more per month, but less than once per week. Although occasionally accompanied by dyspnea, these attacks are brief and have little impact on the child’s daily activities. Older children (6–15 years of age) should use inhaled corticosteroids. The dose of BDP-CFC is not to exceed 200 g/day and that of FP-CFC is not to exceed 100 g/ day divided into 2 equal doses. Other anti-inflammatory drugs that may be used include DSCG, oral anti-allergic drugs, and sustained-release oral theophylline. The leukotriene receptor antagonists offer anti-inflammatory action while also inhibiting bronchospasm, and may prove to provide efficacious monotherapy when treating mild persistent asthma. Infants (2–5 years of age) can be treated with oral antiallergic agents and sustained-release theophylline, and can also be given regularly scheduled inhalation therapy using a mixture of DSCG inhaled liquid 2 ml and 0.5%


Table 15. Indications for long-term hospitalization U

U

U

U

Asthma is too severe to be controlled effectively by pharmacotherapy alone Asthma cannot be adequately controlled because of allergens clearly present in the home environment, and the removal of those allergens has proven difficult or unfeasible The patient and family have a poor record of treatment compliance, so the treatment is not sustained and attacks cannot be controlled, and long-term hospitalization is desirable to provide patient education Psychological problems stemming from the patient’s family, friends, or school environment are interfering with the control of asthma attacks, and it is difficult to achieve good control in the context of outpatient treatment

salbutamol inhaled liquid (or procaterol inhaled liquid) 0.05–0.1 ml, twice daily. If the child does not respond to regularly scheduled inhalation therapy, concomitant use of inhaled corticosteroids should be considered. A mask can be combined with assisted inhalation (using a device such as an Aerochamber®) to give a maximum of BDP-CFC 200 g/day divided into 2 equal daily doses. Moderate Persistent Asthma (Step 3) The patient experiences coughing and mild wheezing at least once weekly, but not every day. Occasional moderate or severe attacks occur, and daily activities and sleep are disrupted. Children with moderate persistent asthma should receive regularly scheduled treatment with inhaled corticosteroids. Older children are given BDP-CFC 200–400 g/ day or FP 100–200 g/day, divided into 2 equal doses. After inhalation, the child should gargle. Assisted inhalation should be used for BDP administration with spacer devices. Infants should inhale BDP-CFC 200–300 g/day, divided into 2 equal doses. This is accomplished by using assisted inhalation with an infant’s mask placed firmly over the mouth. Children who are unable to gargle should be given a drink of water after inhalation. Depending on symptoms, the child may also receive concomitant treatment with oral anti-allergic drugs, sustained-release oral theophylline, or regularly scheduled twice-daily inhalation of DSCG + low-dose 2-agonist. In infants who experience persistent attacks, beforebedtime treatment with a 2-agonist in oral or patch form may be indicated. However, such treatment should be discontinued after the child’s symptoms improve.


Severe Persistent Asthma (Step 4) The child experiences persistent coughing and mild wheezing on a daily basis, with 1–2 moderate or severe asthma attacks per week. Symptoms interfere with routine activities and sleep. Nighttime exacerbations occur frequently, to the extent that the patient is not only unable to sleep, but must seek emergency care. Repeated acute hospitalizations are required (table 15). Step 4.1 The inhaled corticosteroid dose is increased. Older children are treated with inhaled BDP-CFC 400–800 g/ day, or FP 200–400 g/day, divided into 2 doses. Infants receive inhaled BDP-CFC 300–600 g/day, divided into 2 doses. Depending on symptoms, the child may also be treated concomitantly with a leukotriene receptor antagonist, sustained-release theophylline, or regularly scheduled twice-daily inhalation of DSCG + 2-agonist. If the child does not respond to this treatment, a longacting 2-agonist should be used. When using a long-acting inhaled 2-agonist (salmeterol), the patient and family should fully understand that this treatment is not for acute symptoms, and that frequent administration should be avoided. When attacks persist in infants, an oral 2-agonist should be given twice daily (morning and evening), or a 2-agonist patch should be applied at bedtime. Step 4.2 If the patient remains unresponsive to this treatment and especially if no improvement is seen even when the dose of inhaled corticosteroids is increased, long-term hospitalization or the administration of oral corticosteroids under the care of a pediatric allergist should be considered. In such cases, 5–10 mg of oral prednisolone should be used on alternate days. In hospitalized pediatric patients it is important to be aware of the potential for development of psychosocial problems. Long-term hospitalization is only indicated in cases of chronic severe asthma unresponsive to outpatient drug therapy.

Early Intervention In pediatric asthma, early intervention occurs in two forms. The first (primary prevention) is performed to prevent the development of asthma symptoms in children who are considered to be at high risk for this disease. The


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second (secondary prevention) is implemented soon after the onset of asthma, in order to prevent the condition from worsening or becoming intractable [169]. Primary Prevention When asthma risk factors are clearly present and the child is considered to be at high risk, it would be useful to be able to implement highly effective asthma prevention countermeasures during the prenatal, neonatal, and nursing periods. At present, however, although numerous reports have been published, few actually offer effective evidence-based measures in this regard. A number of reports have proven the correlation between exacerbation of airway symptoms and maternal smoking during pregnancy or exposure to second-hand smoke after birth. It is vital to instruct parents on the importance of refraining from smoking during pregnancy and after birth [170]. Exposure to large amounts of inhaled antigen immediately after birth also increases the incidence of antigen sensitivity and respiratory symptoms, suggesting that it is best to attempt to remove or avoid antigens during this period of the child’s life. However, some reports suggest that the development of allergies is inhibited by exposure to dogs or cats soon after birth [171]. Further research is needed in this area. Although the removal or avoidance of food antigens has been found to prevent food allergies and skin allergies to some extent, there are reports that question the effectiveness of this technique in preventing airway allergies. Caution is advised in this regard, so that parents will not be encouraged to excessively restrict inhaled allergens and food allergens as a form of primary prevention. Another potential method of primary prevention is prophylactic drug treatment to avoid the development of asthma. Infants and babies with atopic dermatitis have a higher asthma incidence than the general population, and it has been reported that treatment with histamine H1 receptor antagonists reduces the incidence of asthma in these children [172, 173]. However, these studies involved only a limited period of observation. Further investigation of long-term results is needed.

In asthma patients, chronic airway inflammation can cause progressive airway remodeling, accelerate airway hyperresponsiveness, and produce irreversible airway lesions. Early intervention with inhaled corticosteroids, beginning soon after asthma onset, has been found useful in adults. However, no studies have yet been performed regarding the effects of early intervention with inhaled corticosteroids on the long-term remission rate in pediatric asthma patients. Pediatric asthma usually develops in infancy or early childhood. However, since asthma does not always show typical identifying characteristics in this age group, many questions remain to be answered by further study. Those questions include: How should children who are developing asthma be selected? What forms of intervention are useful? And what indicators can be used to assess therapeutic effectiveness? Additionally, some reports suggest the importance of appropriately controlling symptoms in the early stage of asthma, regardless of whether inhaled corticosteroids are used. Further research is needed, not only in the use of inhaled corticosteroids, but also to investigate a wide range of other therapies and therapeutic combinations for early asthma treatment [174].

Secondary Prevention In children who have already developed asthma, it is important to remove or avoid exacerbating factors. Patients and their parents should be instructed in countermeasures that will not adversely affect the patient’s quality of life.

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Further Reading Beasley R, Cushley M, Holgate ST: A self-management plan in the treatment of adult asthma. Thorax 1989;44:200–204. Bousquet J, Michel FB: Specific immunotherapy in asthma – Is it effective? J Allergy Clin Immunol 1994;94:1–11. Egashira Y, Nagano H: A multicenter clinical trial of TJ-96 in patients with steroid dependent asthma. Ann NY Acad Science 1993;685: 580–583. Egashira Y: Special issue: Chinese medicine treatment of allergic disease: Asthma. Allergy Prac 1993;13:937–940. Hargreave FE, Dolovich J, Newhouse MT: The assessment and treatment of asthma: A conference report. J Allergy Clin Immunol 1990;85: 1098–1111.



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