contents inhaled anti-asthmatic drugs, particularly inhaled corticosteroids, in the treatment of...

Vol.45, No.9 September 2002

CONTENTS

Bronchial Asthma

● Inhaled Corticosteroids in the Management of Adult Asthma

Mitsuru ADACHI and Toshimichi IMAI . . . . . . . . . . . . . . . . . . . . . . . . 361

● Self-Management with Peak Expiratory Flow Monitoring—Treatment for Bronchial Asthma—

Kazuo AKIYAMA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369

● How to Use Anti-Allergy Drugs

Ken OHTA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 375

● Managing Exacerbation of Asthma: Pharmacologic Therapy

Koichiro KUDO . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 381

● Current Treatment of Childhood Bronchial Asthma Basedon the Guidelines

Toru AKASAKA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 388

Managed Care

● A Preliminary Study of the Impact of Managed Careon Psychotherapy in Massachusetts

Hiroto ITO . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396

Topics

● Treatment of Age-related Macular Degeneration

Kanjiro MASUDA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403

JMAJ, September 2002—Vol. 45, No. 9 361

Inhaled Corticosteroids in the Managementof Adult AsthmaJMAJ 45(9): 361–368, 2002

Mitsuru ADACHI* and Toshimichi IMAI**

Professor* and Assistant Professor**,First Department of Internal Medicine, School of Medicine, Showa University

Abstract: The basic condition underlying bronchial asthma is a chronic airwayinflammation that involves inflammatory cells and cells constituting the respiratorytract. Repeated inflammation elicits airway remodeling, leading to severer andmore intractable asthma. Airway inflammation causes airway hyperresponsive-ness, which results in air flow limitation. There is no marked difference in the statusof airway inflammation according to whether the condition is atopic or non-atopicor whether the patient is an adult or a child. The goal of treatment of asthma is tocontrol and resolve airway inflammation. Inhaled corticosteroids represent safe,effective anti-inflammatory therapy and occupy a central role in the long-termmanagement of asthma. The main elements in the application of inhaled cortico-steroids include an understanding of the importance of choosing a dose commen-surate with the severity of the condition, use of the step-down technique, and earlyintervention of therapy. Because it is not possible to control all cases of asthma withinhaled corticosteroids alone, it is important to appropriately combine long-acting�2 agonists, slow sustained theophylline, and leukotriene antagonists.

Key words: Inhaled corticosteroids; Airway inflammation;Anti-inflammatory drugs; Airway remodeling; Early intervention

This article is a revised English version of a paper originally published inthe Journal of the Japan Medical Association (Vol. 125, No. 10, 2001, pages 1548–1553).The Japanese text is a transcript of a lecture originally aired on February 12, 2001, by the Nihon ShortwaveBroadcasting Co., Ltd., in its regular program “Special Course in Medicine”.

Introduction

Bronchial asthma is basically a disease of theairways, regardless of whether it is atopic ornon-atopic and whether the patient is an adultor a child. The central picture of bronchialasthma is that of a chronic airway inflammationthat involves inflammatory cells such as eosi-

nophils, mast cells, T cells (Th2), basophils, andneutrophils, and airway component cells suchas airway epithelial cells and fibroblasts. Thisairway inflammation is worsened and pro-longed by the production and release of variousmediators and cytokines.

In addition, repeated airway inflammationinduces airway remodeling that includes thick-

�Bronchial Asthma

362 JMAJ, September 2002—Vol. 45, No. 9

M. ADACHI and T. IMAI

ening of the reticular layer under the basementmembrane, epithelial metaplasia, proliferationof the submucosal glands, and thickening ofthe smooth muscle, leading to severer andmore intractable asthma. Airway inflammationcauses increased airway responsiveness, whicheasily brings about contraction of the bronchialsmooth muscle, increased vascular permeabil-ity, and hypersecretion of the airways, resultingin air flow limitation (Fig. 1). Therefore, theinhalation of anti-asthmatic drugs for directapplication to the airway seems to be moreeffective at lower doses and to have fewersystemic effects.

Current anti-asthmatic drugs available forthis route include sodium cromoglycate(DSCG), �2 agonists, corticosteroids, andanticholinergic drugs. Inhaled �2 agonists andinhaled corticosteroids occupy central roles as

bronchodilators and anti-inflammatory drugs,respectively.1) This paper describes the useof inhaled anti-asthmatic drugs, particularlyinhaled corticosteroids, in the treatment ofasthma, and outlines their place in guidelinesfor the treatment of asthma.

Remedies for Asthma Attack(Relievers)

Asthma attacks vary in degree, ranging frommild wheezing that is barely perceivable by thepatient him- or herself to severe attacks thatrender the patient unable to walk or talk. Atany degree of severity, inhaled �2 agonists playa central role in the treatment of asthmaattacks through their potent bronchodilatoraction. In addition to �2 agonists, inhaled anti-cholinergic drugs are used for the treatment of

Fig. 1 Pathological condition of the asthmatic airway

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INHALED CORTICOSTEROIDS THERAPY IN ADULT ASTHMA

cholinergic drugs is weaker and slower thanthat of inhaled �2 agonists. However, inhaledanticholinergic drugs exert a greater broncho-dilator action than inhaled �2 agonists inpatients with emphysema and therefore areuseful in the treatment of patients with asthmacomplicated by emphysema.

Drugs for Long-term Management ofAsthma (Controllers)

Drugs used for improving and eliminatingthe symptoms of asthma, normalizing respira-tory function, and maintaining normalized res-piratory function are called controllers. Theyare divided into anti-inflammatory drugs andlong-acting bronchodilators.

1. Anti-inflammatory drugsAnti-inflammatory drugs used as inhaled

anti-asthma drugs include disodium cromo-glycate (DSCG) and corticosteroids. Cortico-steroids have the most potent anti-inflammatoryactivity and a wide spectrum of anti-asthmaactions (Table 1).2)

Inhaled corticosteroids are extremely effec-

Table 1 Anti-asthma Actions of Steroids2)

General effects related to asthma(A) Increase in �-receptors

Effects on adenylate cyclase and cyclic AMP(B) Effects on leukocytic migration

1. Decreased number of lymphocytes in blood2. Suppression of aggregation of monocytes and

macrophages to the site of inflammation3. Inhibition of increase in number of neutrophils

and their aggregation to the site of inflammation4. Decreased number of eosinophils in blood5. Inhibition of expression of adhesion molecules

(C) Effects on cytokinesInhibition of the production of IL-1, TNF�,GM-CSF, IL-3, IL-2, IL-4, IL-5, IL-6, IL-8, IL-11,IL-12, IL-13, INF-�, RANTES, MIP-1�, and SCFInhibition of expression of GM-CSF in airwayepithelial cells

(D) Enhancement of neutral endopeptidase(E) Activation of endonuclease(F) Increase in lipocortin-1 production

Specific effects related to asthma(A) Inhibition of IgE production(B) Effects on mediators

1. Inhibition of histamine production2. Inhibition of eicosanoid release

(C) Effects on the pathological condition of asthma1. Vasoconstriction2. Suppression of vascular permeability3. Inhibition of late asthmatic response4. Inhibition of mucous secretion

asthma attacks.For the treatment of mild symptoms of

wheezing or chest tightness to those of moder-ate asthma, one or two puffs of a �2 agonistshould be administered using a pressurizedmetered-dose inhaler (pMDI), followed byadditional doses at 20-min intervals for onehour and then at one-hour intervals thereafter.At the same time, oral therapy including a �2

agonist and theophylline should be given. Ifsymptoms are eliminated [as indicated by 70%or greater of predicted peak expiratory flow(PEF)] or if the medication has been successfulfor 3–4 hours, the patient can remain at home.If symptoms fail to respond to the medicationand repeated inhaled �2 agonist therapy isnecessary, the patient will need to make anemergency visit.

The bronchodilator effect of inhaled anti-

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Fig. 2 Changes in morning PEF on inhaled DBP(400�g/day) or FP (200�g/day) therapy3)


tive for relieving the symptoms of asthma,reducing the frequency of acute exacerbation,and improving pulmonary function and sup-pressing its circadian variation. Since they areinhaled, they act directly at the site of the lesionand are thus effective at a lower dose than thatused for systemic administration. In addition,more than 90% of the drug that is swallowedwill be metabolized and inactivated by first-pass metabolism in the liver, providing a highlevel of safety. Therefore, inhaled corticoster-oids occupy a central position in long-termdrug treatment.

Unlike other drugs, the use of inhaled corti-costeroids permits a great deal of flexibility indose depending on the severity of the disease.In Japan, fluticasone propionate (FP) as well asthe conventional beclomethasone dipropio-nate (BDP) are available as dry powder inhala-tion. FP, which is equivalent to a half dose ofBDP (Fig. 2),3) seems likely to acquire a centralrole in anti-inflammatory therapy in the future.

Although the inhalation of DSCG is com-monly used in children and is effective in them,its efficacy is limited in adults. However, it hasbeen reported that combination therapy withan inhaled �2 agonist and inhaled DSCG liquidis effective for severe adult cases.

2. Long-acting bronchodilatorsAll bronchodilators currently used in Japan

are of the short-acting type. Since they aresuperior in immediate action and effectiveness,they are often used on an as-needed. Althoughsome reports suggest that they have anti-inflammatory action, not much can be expectedfrom them in this regard in the actual clinicalsetting. Although long-acting inhaled �2 ago-nists such as formoterol and salmeterol are notyet available in Japan, these drugs combinedwith low-dose inhaled corticosteroid therapyhave shown to be superior to high-dose inhaledcorticosteroid therapy in improving respiratoryfunction.4)

Inhaled Anti-asthma DrugsRecommended for Long-termManagement in Guidelinesfor the Prevention andManagement of Asthma

In severity-matched stepwise drug treatmentprescribed for the long-term management ofasthma in the Guidelines for the Preventionand Management of Asthma (Ministry of Healthand Welfare Immunity/Allergy Study Group)(see appendix, page 368),5) inhalation of DSCGis considered suitable for mild intermittenttype (Step 1) and moderate persistent type(Step 3), while serial usage is recommended formild persistent type (Step 2) (DSCG is catego-rized as a mediator antireleaser in the afore-mentioned table). Single use before exercise orexposure to the allergen is considered particu-larly effective in Step 1.

Combined use of inhaled anticholinergicdrugs is considered useful for Step 3. This classof drugs is relatively safe for elderly patientsand is expected to be useful for patients whohave concomitant chronic obstructive pulmo-nary disease (COPD) or severe shortness ofbreath. Serial use of inhaled �2 agonists forStep 2 cases is prescribed in the Guidelines.However, due caution is necessary with theserial use of these drugs because there is a riskof aggravating the symptoms of asthma if serialtreatment is prolonged.

Inhaled corticosteroids play a central role inthe long-term management of asthma. The useof BDP 200�g/day or FP 100�g/day is con-sidered useful for Step 1; BDP 200–400�g/dayor FP 100–200�g/day is prescribed for Step 2;BDP 400–800(up to 1,200)�g/day or FP 200–400�g/day is recommended for Step 3; andBDP 800–1,200(up to 1,600)�g/day or FP400–800�g/day is suggested for Step 4. Mostimportant techniques are the accurate assess-ment of the severity of disease on the basis ofclinical signs, symptoms and PEF values andthe use of the necessary and sufficient dose ofinhaled corticosteroids.



Practical Aspects of Drug Treatmentin the Long-term Management ofAsthma

1. Initial dose setting for inhaled corticosteroidtherapy: the step-down technique

The former guidelines direct that, in prin-ciple, the dose should be increased if responseto the current dose is insufficient. However,asthma is a paroxysmal disease, and it is impor-tant in the actual clinical setting to providerapid relief of symptoms and improve the qual-ity of the patient’s life. Currently, it is morecommon to adopt a step-down technique toachieve an adequate anti-asthma effect withina short period of time. In this technique,inhaled corticosteroid therapy is begun with ahigh dose, followed by dose reduction as clini-cal symptoms improve.

The initial dose of BDP is 600–800�g/dayfor Step 2 cases and 1,200–1,600�g/day forStep 3 cases, while the initial doses of FP arehalf the respective BDP doses. It is desirablethat these doses be reduced to appropriatemaintenance doses after a certain period oftime. In the introductory phase of inhaled cor-ticosteroid therapy or under the condition ofsustained asthma attack, oral corticosteroidtherapy with prednisolone 0.5 mg/kg given for4–7 days in parallel with the initiation of inhaledcorticosteroid therapy provides rapid elimina-tion of symptoms and smooth introduction ofinhaled corticosteroid therapy. This method isalso a kind of step-down corticosteroid therapy.

2. Early intervention with inhaledcorticosteroids and its clinical efficacy6)

Asthma is associated with varying degrees ofairway remodeling depending on the severityand duration of illness. The possibility that thisremodeling is involved in the aggravation andintractability of asthma has begun to drawmore attention.

Inhaled corticosteroids are considered effec-tive in preventing and improving airway

remodeling by inhibiting the production ofinflammatory cytokines in the airway. In actu-ality, however, it has become apparent thatthere is a significant difference in the degree ofimprovement in respiratory function and air-way hyperresponsiveness in terms of PEF andFEV1.0 according to when inhaled corticoster-oid therapy is introduced (Fig. 3).7)

More specifically, the anti-asthma activity ofdelayed inhaled corticosteroid therapy is lessthan that of early therapy, and improvement inrespiratory function and airway hyperrespon-siveness are delayed in comparison with thoseafter early therapy over the course of illness.This may be explained as follows: Airwayremodeling progresses to cause irreversibleorganic change in the airway when the intro-duction of inhaled corticosteroid therapy isdelayed, and this organic change results inreduced responsiveness to inhaled corticoster-oids. If symptoms persist in mild (Step 2) orseverer cases, inhaled corticosteroids play thecentral role in treatment. However, no definiteconsensus has been reached as to the proprietyor timing of their introduction in milder cases.


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Less than 6 months6–12 months1–2 years2–5 years5–10 years10 years or more

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Fig. 3 Changes in PEF after inhaled steroid therapy in 105asthma patients in relation to the timing of initiationof therapy7)

The longer the time until inhaled steroid therapy isintroduced, the worse the improvement in PEF.


If there are relatively constant symptomseven in mild cases or airway inflammation isapparent from eosinophilia in sputum, earlyintervention with inhaled corticosteroid therapyis considered to prevent future aggravation andintractability of the disease. Cough variantasthma (CVA), which proceeds to bronchialasthma in some cases, is considered to be a pre-cursor to asthma. Introduction of inhaled corti-costeroid therapy lasting for a certain periodmay prevent the onset of asthma in such cases.This issue deserves further consideration.

3. Drugs combined with inhaled steroidsIf low- or moderate-dose inhaled corticoster-

oid therapy does not achieve sufficient controlin patients with Step-2 or Step-3 disease, twotreatment options are available. One is toincrease the dose of corticosteroid to high-doseinhaled corticosteroid therapy, and the other isto keep using the same dose of corticosteroidand combine a long-acting inhaled �2 agonist,slow sustained theophylline, or leukotrieneantagonist. The combined effect of inhaled cor-ticosteroids and long-acting inhaled �2 ago-nists4) has already been discussed. Combineduse of sustained-release theophylline is alsomore effective than increased doses of inhaledcorticosteroid therapy alone (Fig. 4),8) and theusefulness of combined leukotriene antago-nists has been reported.

Future Prospects of Inhaled DrugTherapy in the Treatment of Asthma

Inhaled �2 agonists and inhaled corticoster-oids represent two main axes in the treatmentof asthma. Inhaled �2 agonists are the mostpotent bronchodilators, and no effective anti-inflammatory agents are superior to inhaledcorticosteroids. Although long-acting inhaled�2 agonists are not yet available in Japan, theintroduction of a compound drug consisting ofan inhaled corticosteroid and �2 agonist is cur-rently under consideration, leading to expecta-tions of high efficacy (as of February 2001).

BDP is administered in the form of a pres-surized metered-dose inhaler (pMDI), withfluorocarbon gas acting as the propellant.However, the industrial use of regulated chlo-rofluorocarbons (CFC) has been prohibitedbecause of the issue of ozone depletion, andsuspension of the ban on their medical use soonmay be terminated. Since there are also con-cerns about the influence on the environmentof the CFC substitute HFA, medication via adry power inhaler (DPI), as in the case of FP,seems likely to become more common in thefuture.

Budesonide, available in the form of adry powder, is expected to be introduced inJapan. A highly efficient dry power inhaler(Turbuhaler) is used for the inhalation of thisproduct. Improvement in the quality of life ofasthma patients is likely to be attemptedthrough the development of safer, more effec-tive corticosteroids and better inhalers.

REFERENCES

1) Adachi, M.: Handbook of Inhaled SteroidTherapy for Asthma. Nankodo, Tokyo, 1998;pp.1–7. (in Japanese)

2) Imai, T. and Adachi, M.: Bronchial asthma inadults. Shonika Shinryo 1998; 61: 653–661. (inJapanese)

3) Miyamoto, A., Takijima, N., Makino, S. et al.:Clinical investigation of inhaled fluticasonepropionate (SN 411) powder (Report 4):

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Duration of therapy (weeks)

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Budesonide 800�g b.d.

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**

Fig. 4 Additive effect of low-dose theophylline8)




Comparison with beclomethasone dipro-pionate administered by inhaler in asthmapatients. Rinsho Iyaku 1997; 13: 1609–1633.(in Japanese)

4) Pauwels, R.A., Lofdahl, C.G., Postma, D.S.et al.: Effect of inhaled formoterol andbudesonide on exacerbations of asthma. NEngl J Med 1997; 337: 1405–1411.

5) Ministry of Health and Welfare Immunity/Allergy Study Group: Guidelines for Preven-tion and Management of Asthma (1998 edi-tion). (ed. Makino, S. et al.) Kyowa Kikaku,Tokyo, 2000. (in Japanese)

6) Imai, T. and Adachi, M.: Clinical efficacy ofinhaled corticosteroids (early intervention).Arerugi-Meneki 1999; 6: 440–447. (in Japanese)

7) Selroos, O., Pietinalho, A., Lofroos, A.B. et al.:Effect of early vs late intervention with inhaledcorticosteroids in asthma. Chest 1995; 110:1228–1234.

8) Evans, D.J., Taylor, D.A., Zetterstrom, O. et al.:A comparison of low-dose inhaled budesonideplus theophylline and high-dose inhaledbudesonide for moderate asthma. N Engl JMed 1997; 337: 1412–1418.


Severity-matched Stepwise Drug Treatment in the Long-term Management of Asthma

Severity of Step 1: Step 2: Step 3: Step 4:symptoms mild intermittent disease mild sustained disease moderate sustained disease severe sustained disease

Distinctivefeatures ofsymptoms

PEF, FEV1.0

Treatment

� Stridor, cough*, dyspnea;once or twice a week.

� Short-term intermittentsymptoms.

� Nocturnal symptomsoccurring at most one ortwo times a month.

� 80% of� the patient’s bestvalue/predicted value.

� 20%� variation.

● Single use of inhaled/oral �2 agonist andtheophylline.

● Inhaled �2 agonist orinhaled DSCG; singleuse before exercise orexposure to the allergen.

(Anti-allergic drugs)• Serial use of leukotriene

antagonist/thromboxaneA2 inhibitor-antagonistshould be considered.

• Serial use of mediatorrelease inhibitor/histamine H1-antagonist/Th2 cytokine inhibitorshould be considered.

• (Inhaled steroids)#

Serial use ofBDP 200�g/day orFP 100�g/dayshould be considered.

� Symptoms occurring 2or more times a week.

� Activities of daily livingor sleep disturbed 2 ormore times a month.

� Nocturnal symptomsoccurring at least twicea month.

� 70–80% of the patient’sbest value/predictedvalue.

� 20–30% variation.

● Inhaled steroids#: seriallow-dose therapy withBDP 200–400�g/day orFP 100–200�g/day.

● Serial use of sustained-release theophylline.

(Anti-allergic drugs)● Serial use of leukotriene

antagonist/thromboxaneA2 inhibitor-antagonist.

● Serial use of mediatorrelease inhibitor/histamine H1 antagonist/Th2 cytokine inhibitor.

● Serial use oftransdermal/oral/inhaled �2 agonist.

● Additional single use ofinhaled �2 agonist (up to3–4 times per day)

� Frequent aggravation(even on therapy).

� Persistent symptoms.� Activities of daily living

limited.� Frequent nocturnal

symptoms.(� Serial use of oral

steroids.)

� 60%� of the patient’s bestvalue/predicted value.


● Inhaled steroids#: serialhigh-dose therapy withBDP 800–1,500�g/dayor FP 400-800�g/day.

● Oral steroids: short-termmoderate- to high-dosetherapy. Maintenancedose should be as low aspossible and given oncea day or every other day.

● Serial use of sustained-relapse theophylline.


(Anti-allergic drugs)• Serial use of leukotriene

antagonist/thromboxaneA2 inhibitor-antagonistshould be considered.


� Chronic symptomspresent.

� Inhaled �2 agonisttherapy required almostevery day.

� Activities of daily livingor sleep disturbed atleast once a week.

� Nocturnal symptomsoccurring at least oncea week.

� 60–70% of the patient’sbest value/predictedvalue.


● Inhaled steroids#:serial moderate-dosetherapy withBDP 400–800�g/dayor FP 200–400�g/day.

● Serial use of sustained-release theophylline.


(Anti-allergic drugs)● Serial use of leukotriene

antagonist/thromboxaneA2 inhibitor-antagonist.

• Mediator releaseinhibitor/histamine H1

antagonist/Th2 cytokineinhibitor should beconsidered.

• Combined use of inhaledanticholinergic drugshould be considered.


# : A spacer generally is used when using BDP. The doses prescribed in the present guidelines are set after consideration of approved dosesand their safety, and they do not represent potency ratios.

� : If one of the given items is met, the patient is categorized in that step. If there is overlap with another step, the severer step is adopted.The specified symptoms and respiratory function test results provide an outline of each step. They may vary or overlap with adjoining steps.

* : If the patient has stridor and cough alone, he or she is categorized as having mild intermittent disease (step 1) even if the symptomsappear 3 times a week.

Step-up: Proceed to the next step if the current treatment fails to control the condition. (In cases of �PEF60%, short-term moderate-or high-dose oral steroid therapy should be given.)

Step-down: The intensity of treatment may be decreased if the patient’s condition has been stable for at least 3 months since thetreatment goal was achieved. Continue with the level of treatment needed to maintain control of the condition.

(From the Ministry of Health and Welfare Immunity/Allergy Study Group: Guidelines for Prevention and Management of Asthma (1998edition) (ed. Makino, S. et al.) Kyowa Kikaku, Tokyo, 2000.)

APPENDIX



Self-Management with Peak ExpiratoryFlow Monitoring—Treatment for Bronchial Asthma—JMAJ 45(9): 369–374, 2002

Kazuo AKIYAMA

Director, Department of Allergic Disease, Clinical Research Center forAllergy and Rheumatology, National Sagamihara Hosipital

Abstract: Peak expiratory flow (PEF) monitoring should be considered in patientswith moderate to severe asthma, who are older than 5 years of age, have measur-able PEF values, and receive medication on a daily basis. In the practical treatmentand management of asthma, the PEF monitoring is most effective in cases wherestep-wise therapy according to asthma severity is applied in long-term manage-ment. The guidelines recommend to determine asthma severity on the basis ofsymptoms and PEF, and subsequently to select a controller medication for eachpatient consistent with the severity of the disease. The following two basic strate-gies are useful for increasing or decreasing the medication dosage: One is thestep-up therapy in which treatment is moved to the next step if the disease is notcontrolled by the current treatment, and the other is the step-down therapy in whichthe dosage can be reduced if the target of each treatment is achieved and thedisease is controlled and confirmed to be stable for at least 3 months. In thesestrategies, PEF monitoring serves as an important indicator. The guidelines alsorecommend the ZONE SYSTEM to detect the earliest possible signs of asthmaexacerbation and start the use of a reliever medication as early as possible.

Key words: Peak expiratory flow; Controller; Reliever; Step up; Step down;Zone system

issued in Western countries from the second halfof the 1980’s to the first half of the 1990’s, fol-lowed by the International Consensus Report(ICR)1) in 1992 by the National Institute ofHealth in the U.S.A., and the subsequently

Introduction

The international standardization and unifi-cation of the treatment for bronchial asthmahave been roughly attained by the guidelines

�Bronchial Asthma


K. AKIYAMA

patient is possible. This must be emphasizedeven more strongly in Japan where physicianshave to examine a patient with the least expen-diture of time. As is often the case, what thephysician considers common sense may notappear as such to patients, and conversely, whata patient considers to be common sense maynot appear as such to the physician. In additionto written instructions to each patient preparedby each hospital, booklets distributed by theJapan Allergy Foundation or pharmaceuticalcompanies may be useful.

Secondly, the GINA emphasizes the thoroughconduct of self-management with peak expira-tory flow (PEF) monitoring. In Japan, a uniqueasthma diary has been employed as a tool forcommunication between a patient and a physi-cian and it has been considered very useful.However, the description of symptoms basedonly on the patient’s subjective perceptions dif-fers occasionally from the objective evaluationin the determination of asthma severity, becausea patient gets used to asthma symptoms andthe response to low concentrations of oxygendecreases gradually. In the GINA and JGL ’98,it is recommended that a patient should mea-sure PEF several times a day using a PEFmeter to evaluate asthma condition objectively.The zone system is set up as an asthma manage-ment tool using this PEF monitoring. In thissystem, PEF monitoring is likened to a trafficsignal light in a patient’s self-managementplan, and measured PEF values are separatedinto the green zone (safe zone), yellow zone(caution zone), and red zone (medical warningzone). For each zone, a written instruction abouthow to use drugs and manage symptoms is givento the individual patient. This is an unequivocalmethod and easy for patients to understand. Inthe practical applications of PEF monitoring,however, PEF does not necessarily decreasebefore the development of subjective symp-toms, and there is the problem of how to dealwith “patients with consistent low PEF values”,that is, those who have asymptomatic asthmawithout an increase in PEF.

issued Global Strategy for Asthma Manage-ment and Prevention (GINA)2) summarized asthe NHLBI/WHO Workshop report in 1995,and “Guidelines for Prevention and Manage-ment of Asthma, 1998 revised edition (JGL’98)3)”in Japan.

Although traditionally bronchial asthma hadbeen considered to be a functional disease dueto the reversible contraction of bronchial smoothmuscles, the concept that bronchial asthma is achronic inflammatory disease of the airwayscaused by inflammatory cells such as lympho-cytes and eosinophilic leukocytes is currentlywell established, and it has been demonstratedthat inhaled adrenocortical steroids, which arethe most potent anti-inflammatory drugs, arethe initial drugs of choice to treat the inflamma-tion of the airways in bronchial asthma.

Medications for bronchial asthma can be sub-divided broadly into long-term control medica-tions for prevention (controller medications)and medications used on demand in attacks(reliever medications).

Bronchial asthma is a chronic disease thatrequires the patient’s self-management, thesame as high blood pressure and diabetes.Patient education is essential for appropriateself-management.

Patient Education in the Guidelines

Although the Japanese guidelines specifypatient education and self-management meth-ods in accordance with the GINA and with theaddition of original Japan-oriented recommen-dations, the GINA presents more precise andconcrete guidelines on patient education andself-management methods, which are empha-sized in this guideline.

Firstly, it is emphasized that education andinstructions to patients should be given notonly verbally but also in writing. It is worthy ofnote that this point is emphasized repeatedlyeven in Western countries where physicians canafford to take enough time when examining apatient, and sufficient communication with the


SELF-MANAGEMENT WITH PEF MONITORING

Thirdly, the guidelines provide detailedinstructions about home treatment method formanaging exacerbation of asthma. Probably dueto the differences in medical care systems andmedical insurance systems between Westerncountries and Japan, physicians in Japan, at leastthe author, for one, direct patients to take aninhaled �2-agonist using a metered dose inhaler(MDI) and an oral �2-agonist immediately afteran attack occurs, and to come to the hospital assoon as possible, if a few inhalations of �2-agonistwith MDI did not improve the symptoms; thepatients are also instructed to simply come tothe hospital whenever they are worried.

In contrast, the instructions in the ICR andGINA place higher priority on the guidance tominimize the number of visits to the hospital. Itis also to be noted that these guidelines are in aposition to make patients aware of the impor-tance of self-management, probably in relationto their medical care systems. For example, theGINA says that it is important for the success-ful management of asthma exacerbation to startasthma therapy when a slight sign of a reduc-tion in asthma control is observed, and thatthe initiation of therapy at home by patientsmay avoid the delay of treatment and make thepatients aware that they can manage their ownasthma exacerbation. Furthermore, the straight-forward contents of the instructions to patients,including dosing frequencies and dosages statedin figures, is thought to facilitate the under-standing by patients.

Peak Expiratory Flow Monitoring4)

Also, the Japanese guidelines (JGL ’98) rec-ommend self-management methods appropri-ate to the medical circumstances in Japan, whileincorporating the points to be learned from theICR and GINA. This article mentions severalmatters related to self-management in the treat-ment for bronchial asthma that require atten-tion, particularly self-management with peakexpiratory flow monitoring.

1. Matters that require attention whenperforming peak expiratory flow monitoring

Peak expiratory flow monitoring should beconsidered in patients with moderate to severeasthma, who are older than 5 years of age, haveprecisely measurable PEF values, and receivemedication on a daily basis. Currently, variouspeak flow meters are available commercially,such as Mini-Wright®, Assess®, Personal Best®,and Vitarograph®. Although there are differ-ences in measurement values among thesedevices, any device can be used without prob-lems, as long as the same device is used con-tinuously. A patient may select a device easy touse (Fig. 1). Measurement is performed prefer-ably while sitting up or sitting on a chair, andmust be carried out in the same position everytime.

Peak expiratory flow is, so to speak, themarker of the maximum instantaneous windspeed, which is proportional to the degree ofairway occlusion, and is supposed to be corre-lated with forced expiratory volume in one sec-ond. However, quite a few patients who havenormal peak expiratory flow values complainof breathlessness as a subjective symptom, sincepeak expiratory flow indicates only the flowrate in the central airway. In the flow volumecurves of such patients, V50 and V25 are lower,and the constriction and occlusion of peripheralairways are observed occasionally. Thus, it mustbe understood that peak expiratory flow is notalways an all-purpose marker to indicate thestate of the airways. As the extent of diurnalvariation in peak expiratory flow would serveas a measure of the state of asthma control,measurement twice a day (morning and eve-ning), and before inhalation or oral administra-tion of antiasthmatic drugs is necessary.

To find the personal best value of peak expi-ratory flow for each patient, it is useful to addtwo measurements around 11 a.m. and 2 p.m.during the early stage of peak expiratory flowmonitoring, when ventilatory function worksbest in many patients. By making a comparisonbetween peak expiratory flow values before


and after the use of bronchodilators such as �2-agonists, its reversibility can be known. If peakexpiratory flow remains at low values withoutshowing reversibility, this indicates that thecurrent therapy is insufficient and another ther-apy should be selected. If peak expiratory flowincreases significantly, this indicates that thebronchodilator currently used is effective andthe long-term management method to maintainthe peak expiratory flow value after the use ofthe bronchodilator should be reconsidered.

2. Significance in long-term managementIn cases where step-wise therapy according

to asthma severity (see appendix, page 368) isapplied in long-term management, the effect ofpeak expiratory flow monitoring works effec-tively in the practical treatment and manage-ment of asthma. The guidelines recommendto determine asthma severity on the basis ofsymptoms and PEF, and subsequently to selecta long-term management medication (controller

medication) depending on the severity.When PEF is not less than 80% of the per-

sonal best value or the predicted value and thedaily variability is less than 20%, asthma sever-ity is classified as “Mild Intermittent in STEP1”; when PEF is 70–80% of the personal bestvalue or the predicted value and the daily vari-ability is 20–30%, it is classified as “Mild Persis-tent in STEP 2”; when PEF is 60–70% of thepersonal best value or the predicted value andthe daily variability is not less than 30%, it isclassified as “Moderate Persistent in STEP 3;and when PEF is not more than 60% of thepersonal best value or the predicted value andthe daily variability is not less than 30%, it isclassified as “Severe Persistent in STEP 4”, andthe type and dosage of the drug consistent withthe degree of severity are specified. The purposeis to allow a patient to perform self-managementwithout visiting on each occasion, by giving tothe patient the physician’s instructions on whatactions to take at each step.

K. AKIYAMA

Fig. 1 Commercially available peak flow meters4)

VitarographVitarograph (U.S.A.)product imported bySuzume Medical

Personal BestHealthScan (U.S.A.)product imported byPolytechs, Ltd.

Mini-WrightClement Clarke (England)product imported byMatsuyoshi & Co., Ltd.

AssessHealthScan (U.S.A.)product imported byChest MI


To increase or decrease the medication dos-age, the following two basic strategies are use-ful: one is the step-up therapy in which treat-ment is moved to the next step if the disease isnot controlled by the current treatment; theother is the step-down therapy in which thedosage is reduced if the target of each treat-ment can be achieved and the disease is con-trolled, and confirmed to be stable for at least 3months. For these strategies, PEF monitoringserves as an important indicator.

3. Zone system (Table 1)Asthma is a highly variable disease. As has

been mentioned, the purpose of the asthmamanagement zone system is to prevent theexacerbation of asthma by having the patientmonitor his own asthma state, in order to detectthe earliest possible signs of exacerbation andtake prompt actions at home.

The Green Zone with a peak expiratory flowvalue of 80–100% of the personal best valueindicates that asthma is controlled well. If thisstate continues for at least 3 months, a step downin long-term management will be warranted.

The Yellow Zone with a peak expiratory flowvalue of 50 to 80% of the personal best valuesignals the presence of an episode of asthma. Inthis case, it is advisable that an inhaled �2-agonist

SELF-MANAGEMENT WITH PEF MONITORING

be taken to relieve the attack quickly and, if theresponse to the medication is insufficient, anoral steroid previously designated by the physi-cian should be taken before seeing the physician.

The Red Zone with a peak expiratory flowvalue of less than 50% of the personal bestvalue signals a state in which the symptom ofasthma is observed even at resting and affectdaily life. In this case, the patient must take aninhaled �2-agonist right away and an oral ste-roid early, and must see the physician immedi-ately if the peak expiratory flow value is notimproved.

Conclusion

The results of the studies by the JapaneseSociety of Allergology and the Japanese Res-piratory Society have demonstrated that themajority of the causes of deaths due to asthmaattacks, numbering 6,000 yearly, are attributedto the delay of appropriate treatment. It is hopedthat the widespread use of the zone system,utilizing peak expiratory flow monitoring, wouldresult in prompt and appropriate treatmentand reduce deaths due to asthma attacks. Therecent significant advances in controller medi-cations and reliever medications have facili-tated the control of bronchial asthma markedly.

Table 1 Home Management for Asthma Exacerbation (Attack)3)

Therapy is performed according to the zone system. When the response to an inhaled �2-agonist used at the initiation ofasthma control is insufficient, medical examination by a physician is necessary even if the symptoms or the reduction inpeak expiratory flow is minor.● Green Zone (peak expiratory flow value: 80–100% of the personal best value)

Asthma is under control. The symptoms of asthma, if any, include wheezing.If any symptom is observed, an inhaled �2-agonist should be taken.

● Yellow Zone (peak expiratory flow value: 50–80% of the personal best value)Some symptoms of asthma (nighttime symptoms, disturbance in daily activity, cough, wheezing, feeling chest pressureat rest and on exercise) are observed. An inhaled �2-agonist should be taken up to 3 times per hour, and, if the responseto the inhaled �2-agonist is insufficient, an oral steroid should be taken at a dosage designated by the physician, and seethe physician. If peak expiratory flow returns to and stays in the green zone, progress may be observed without seeingthe physician.

● Red Zone (peak expiratory flow value: less than 50% of the personal best value)The symptoms of asthma are observed at rest and affect daily life. An inhaled �2-agonist should be taken right away,followed by early administration of an oral steroid. If a rapid improvement of peak expiratory flow cannot be obtained,the patient must see the physician immediately. Administration of oxygen should be initiated, if it is in readiness.


We, as clinical physicians, want to achievea better control of bronchial asthma and toimprove patient QOL in the clinical setting byproviding appropriate treatment and manage-ment utilizing various available tools.

REFERENCES

1) International Consensus Report on Diagnosisand Management of Asthma. Clin Exp Allergy1992; 22(supl. 1).

2) Global Initiative for Asthma. Global Strategyfor Asthma Management and Prevention.

K. AKIYAMA

NHLBI/ WHO WORKSHOP REPORTMARCH 1993, NIH NHLBI Publication 1995;95: 3659.

3) Immunology and Allergology Workshop ofthe Ministry of Health and Welfare: Guide-lines for Prevention and Management ofAsthma. 1998 revised edition under the super-vision of Makino, S., Kosho, M. and Miya-moto, A., Kyowa Kikaku Communication,Tokyo, 2000. (in Japanese)

4) Tsukioka, K.: Peak Expiratory Flow Values inthe Japanese. Kyowa Kikaku Communication,Tokyo, 1995. (in Japanese)


How to Use Anti-Allergy DrugsJMAJ 45(9): 375–380, 2002

Ken OHTA

Professor, Department of Medicine, Teikyo University School of Medicine

Abstract: Currently, anti-allergy drugs are classified, on the basis of their actionmechanism, into 5 types including mediator-release inhibitors, histamine H1

antagonists, thromboxane A2 inhibitors, leukotriene antagonists, and Th2 cytokineinhibitors. The asthma treatment guideline released in Japan stipulates treatmentwith one of these types of anti-allergy drugs, regardless of the severity of disease.There are no definite grounds for the choice of anti-allergy drugs. When the patienthas complications involving other allergic diseases, the physician chooses, in orderof preference, histamine H1 antagonists, mediator-release inhibitors, and Th2cytokine inhibitors, depending on the indications with the concomitant allergicdisease. When symptoms are severe, leukotriene antagonists and thromboxane A2

inhibitors are chosen. The physician may also consider increased doses of steroidinhalants and sustained release theophylline. At present, the use of two or moreanti-allergy drugs together is not acknowledged, but this will be the subject ofresearch in the future, because anti-allergy drugs with different mechanisms ofaction used at the same time will theoretically increase their effects.

Key words: Mediator-release inhibitors; Histamine H1 antagonists;Thromboxane A2 inhibitors; Leukotriene antagonists;Th2 cytokine inhibitors

Introduction

Bronchial asthma is an obstructive respira-tory disease characterized by reversible occlu-sion, hypersensitivity, and chronic inflamma-tion of the airway. Allergic reactions play animportant role as a factor in inducing airwayinflammation. When asthma patients are testedfor allergies, using a skin reaction test, about70% exhibit the presence of IgE antibodiesby showing positive reactions to house dust

and its major component, the house dustmite (dermatophagoides). About 70% of thesepatients had diseases involving atopic con-ditions. The test results revealed that allergicreactions can be considered an important tar-get of asthma treatment.

What Are Anti-allergy Drugs?

“Anti-allergy drug” is the general term fordrugs that regulate the release and action of


�Bronchial Asthma


chemical mediators involved in allergic reac-tion, mediated by IgE (immediate or type Iallergic reaction), or inflammatory mediators(Table 1).1) The many anti-allergy drugs cur-rently on the market are classified, on the basisof their action mechanism, into 5 types includ-ing mediator-release inhibitors, histamine H1

antagonists, thromboxane A2 inhibitors, leuko-triene antagonists, and Th2 cytokine inhibitors.

Types of Anti-allergy Drugs (Table 2)2)

1. Mediator-release inhibitorsMediator-release inhibitors include DSCG

(sodium cromoglicate), which was the first anti-

K. OHTA

allergy drug developed. These drugs are ex-pected to be effective in 30 to 40% of mild tomoderate cases with atopic asthma, but it takesthem 4 to 6 weeks to manifest any effect. Asthese drugs do not have anti-histamin action,they do not induce drowsiness in patients.

2. Histamine H1 antagonistsHistamine H1 antagonists more or less induce

drowsiness, which generally remits or disap-pears within several days after the start of treat-ment. Histamine H1 antagonists also inhibitmediator release and are effective in 20 to 30%of mild to moderate cases with atopic asthma,but it takes them 4 to 6 weeks to manifest

Table 1 Biological Activity of Inflammatory Mediators Considered to Be Involved in Asthma1)

Action Histamine PGD2 PGF2� TXA2 LTB4 LTC4, D4, E4 PAF

Bronchial smooth muscle contraction � ¤ ¤ ¤ � ¤ ¤

Airway hyperresponsiveness � � � � ? � ¤?

Capillary permeation enhancement � � � � ? ¤ ¤

Airway mucus secretion enhancement � � � ? � ¤ �

Leukocyte migration activity � � ? ? ¤ ? ¤

“�”, “¤”, “�” and “?” in the table refer to “action”, “strong action”, “no action” and “unknown or not definite,” respectively.

Table 2 Types and Names of Drugs for Long Term Asthma Control2)

1. Steroids1) Steroid inhalants

i ) Beclometasone propionateii ) Fluticasone propionate

2) Oral steroids2. Sustained release theophylline3. Long-acting �2 stimulants4. Anti-allergy drugs

1) Mediator-release inhibitorsi ) Sodium cromoglicateii ) Tranilastiii) Amlexanoxiv ) Repirinastv ) Ibudilastvi ) Tazanolastvii) Pemirolast potassium

* Contraindicated in pediatric asthma, not adult asthma.

2) Histamine H1 antagonistsi ) Ketotifen fumarateii ) Azelastin hydrochlorideiii) Oxatomide*iv ) Mequitazinev ) Terfenadinevi ) Epinastine hydrochloridevii) Astemizole

3) Thromboxane A2 inhibitors(1) Thromboxane A2 synthetase inhibitors

i ) Ozagrel hydrochloride(2) Thromboxane A2 antagonists

i ) Seratrodast4) Leukotriene antagonists

i ) Pranlukast hydrate5) Th2 cytokine inhibitors

i ) Suplatast tosilate


any effect.

3. Thromboxane A2 inhibitors and antagonistsThromboxane A2 inhibitors consist of 2 types

of agents, i.e., thromboxane A2 synthetase inhibi-tors and thromboxane A2 antagonists (receptorantagonists).

These drugs are effective in 40% of mild tomoderate atopic and mixed-type asthma. Sincetheir effects can be observed in only 2 to 4weeks of treatment, it is possible to assessresults at an earlier stage than with mediator-release inhibitors and histamine H1 antago-nists, which must be administered for 4 to 6weeks before any effect can be observed.3,4)

These drugs are also reported to be effectiveagainst infectious asthma. However, due to acase of severe hepatic disorder reported aftermarketing, physicians are recommended toadminister the thromboxane A2 antagonist,seratrodast, and conduct monthly hepatic func-tion tests.

4. Leukotriene antagonistsLTC4, D4 and E4 receptor antagonists are

available for use as leukotriene antagonists.Much attention has been focused on thesedrugs in Europe and the U.S., where two drugswere developed, but Japan took the lead anddeveloped pranlukast hydrate, which has beenvaluated highly since it went on the market.

These drugs are effective in 50 to 60% ofmild to moderate atopic and mixed-typeasthma. Since the effects of the drug appear inonly several days to 1 week, or 2 to 4 weeksat the latest, results can be assessed muchsooner than with mediator-release inhibitorsand histamine H1 antagonists, which must beadministered for 4 to 6 weeks before anyeffects can be observed.5) Another report6)

found that these drugs not only inhibited air-way inflammation but also inhibited airwayhypersensitivity in asthma patients. Moreover,aspirin- and exercise-induced asthma is expectedto be inhibited with these drugs since theyshowed inhibitory effects in both a sulpyrine

ANTI-ALLERGY DRUGS

inhalation and an exercise-induced asthma tests.Zafirlucast and Montelukast, developed in

the West, have recently been put on the marketin Japan.

5. Th2 cytokine inhibitorsTh2 cytokine inhibitors inhibit the produc-

tion of excessive production of Th2 cytokinesthat induce the IgE antibodies and allergicinflammation. Among Th2 cytokines (Table 3),IL-4, which is involved in the production of theIgE antibody, and IL-5, which is involved in theactivation of eosinophil, have been attractingparticular attention. Reports have also foundthat IL-5 production is enhanced in asthmapatients, regardless of any allergic conditions,suggesting that Th2 cells are generally pre-dominant in asthma.

Currently, the only drug available in this cat-egory is suplatast tosilate, which was developedin Japan. This drug inhibits the production ofIL-4 and IL-5 and is reported to inhibit botheosinophil infiltration in the airway mucosaand airway hypersensitivity.7) However, thedrug has to be administered for 6 to 8 weeks

Table 3 Cytokines Produced by Th1 and Th2 Cells

Cytokines Th1 cells Th2 cells

IL-2 � �

IFN-� � �

TNF-� � �

GM-CSF � �

TNF-� � �

IL-3 � �

IL-4 � �

IL-5 � �

IL-6 � �

IL-10* � �

IL-13 � �

* IL-10 is produced by both Th1 and Th2 cells in humans.


before any effect can be observed, and its effectsare manifested slowly. In view of the pathologyof asthma, more attention should be paid to thedevelopment of Th2 cytokine inhibitors.

Positioning Anti-allergy Drugs inAsthma Treatment Guidelines

This section describes how the above-mentioned anti-allergy drugs are positioned inasthma treatment guidelines, according to the“Asthma Prevention and Control Guidelines”(prepared in 1998 by the Immunity & AllergyResearch Group of Ministry of Health & Wel-fare in Japan; revised in 2000).2) Anti-asthmadrugs are classified into those that act againstasthma attacks, or relievers which removeasthma symptoms, and those for long-termcontrol, or controllers which alleviate inflam-mation and stabilize the patient’s condition.Obviously, anti-allergy drugs are classified asthe controllers (Table 2).

According to the guidelines, asthma is classi-fied into 4 steps of severity, i.e., mild intermit-tent, mild persistent, moderate persistent, andsevere persistent. The guidelines recommendthe continuous or persistent use of anti-allergydrugs in treating each of these steps (refer toappendix, page 368).

1. Step 1Step 1 severity consists of the onset of asth-

matic symptoms such as cough and respiratorydifficulty once or twice a week. At this stage,physicians may consider using any of theanti-allergy drugs, excluding DSCG (sodiumcromoglicate), and the positioning of anti-allergy drugs is similar to that of low-doseinhalant steroids. Use of �2 stimulants andtheophylline for controlling the symptoms aswell as DSCG inhalation before exercise andexposure to allergens is recommended at thisstep.

2. Step 2Step 2 severity consists of the onset of the

K. OHTA

above symptoms two or more times a week.At this step, the guidelines recommend thecontinuous use of any of the anti-allergy drugs,in addition to the continuous use of low-doseinhalant steroids (beclomethasone dipropio-nate; BDP 200–400�g/day, fluticasone pro-pionate; FP 100–200�g/day) and sustained-release theophylline.

3. Step 3Step 3 severity consists of the presence of

chronic symptoms. At this step, the guidelinesrecommend the continuous use of leukotrieneantagonists/thromboxane A2 inhibitors in ad-dition to the continuous use of middle-doseinhalant steroids (BDP 400–800�g/day, FP200–400�g/day), sustained-release theophyl-line, and patch/oral/inhalant �2 stimulants.

4. Step 4Step 4 severity consists of not only very

severe and persistent but also aggravatedsymptoms. At this step, the guidelines suggestthe intermittent use of oral steroids and thecontinuous use of leukotriene antagonists/thromboxane A2 inhibitors in addition to thecontinuous use of high dose inhalant steroids(BDP 800–1,600�g/day, FP 400–800�g/day),sustained-release theophylline, and patch/oral/inhalant �2 stimulants.

The continuous use of anti-allergy drugs issuggested rather than recommended in Step 1and Step 4 because their usefulness has not yetbeen fully proven. However, it has alreadybeen reported that these drugs could reducethe use of high-dose inhalant steroids.8)

Personal Views on the Administrationof Anti-allergy Drugs

As described above, anti-allergy drugs arepositioned for long-term control of asthma andare selected according to the severity of thepatient’s condition. This leads to various ques-tions about the administration methods ofthese drugs.


The usefulness of anti-allergy drugs at Step 1has yet to be established. In other words, theguidelines will recommend aggressive treat-ments with these drugs if they are proven tobe effective as a part of an early interventionagainst asthma. At this moment the author gen-erally starts administering anti-allergy drugs topatients at Step 2 or higher.

I will prescribe anti-allergy drugs with anti-histamin action if the patient has complicationsinvolving other allergic diseases such as allergicrhinitis and atopic dermatitis, even if theasthma itself is mild. Since leukotriene antago-nists have recently been demonstrated to beeffective on nasal occlusion attributable toallergic rhinitis, treatment with this type ofdrug should be taken into consideration,depending on the patient’s symptoms. Basedon their pharmacological action and thera-peutic effects, it is all together conceivable thatwe will include leukotriene antagonists amongthe first drugs of choice used at Step 1.

For the treatment of the patient at Step 2I start with a low-dose inhalant steroid andsustained-release theophylline.9) Additionalanti-allergy drugs will be administered if thepatient’s symptoms are not controlled withsatisfaction. There are no definite criteria forselection. When the patient has additionalallergic diseases, drugs are chosen accordingto the presence or absence of contraindica-tions against that disease. In such cases, physi-cians may choose from mediator-release inhibi-tors, histamine H1 antagonists or Th2 cytokineinhibitors.

Caution must be exercised and it is notalways possible to administer histamine H1

antagonists, as they may induce drowsinessin some patients. Since the efficacy rate ofmediator-release inhibitors is rather low, treat-ment with Th2 cytokine inhibitors should beattempted if no effect is observed in 4 to 6weeks with mediator-release inhibitors. If bothtypes of drugs are ineffective, I will consideradministration of leukotriene antagonists aswell as increase of doses of inhalant steroids

ANTI-ALLERGY DRUGS

and sustained release theophylline.When the condition of a patient corresponds

to Step 3 or 4, I administer a leukotriene antag-onist first. If ineffective, I will administerthromboxane A2 inhibitors. What is especiallyimportant in the treatment of patients at Steps3 and 4 is adding a concomitant drug while pre-scribing each drug at a satisfactory dose, withinthe safe range. This is expected to enhance theactions of leukotriene antagonists and throm-boxane A2 inhibitors.

Though leukotriene antagonists and throm-boxane A2 inhibitors are similarly classified asanti-allergy drugs, mechanisms of their actionare distinct. Concomitant administration ofthese drugs is not allowed at present, butconcomitant use of anti-allergy drugs withdifferent mechanisms of action is theoreticallyexpected to increase their effectiveness. In thisregard, we should investigate if the concomi-tant administration of these drugs is beneficial.

Future Prospects for Anti-allergyDrugs

Due to their slow action and rather lowefficacy rate, the development of anti-allergydrugs was criticized at the initial stage. Thanksto earnest support and efforts, researchers inJapan were able to develop the first leukotrieneantagonist and the first thromboxane A2 inhibi-tor and antagonist. I strongly hope that a highlyspecific anti-allergy drug will be developedto improve asthma treatment in the future.When it becomes possible to predict the effi-cacy of a drug at the genetic level,10) it willbecome possible to perform so-called “tailor-made medicine.”

REFERENCES

1) Ohta, K.: 2. Inflammatory mediators. J Jpn SocIntern Med 1996; 85: 178–183. (in Japanese)

2) Immunity & Allergy Study Group, Ministry ofHealth & Welfare: Guideline for Preventionand Control of Asthma, Revised in 1998.


K. OHTA

Edited by Makino, S., Furusho, M. and Miya-moto, T. Kyowa Kikaku Ltd., Tokyo, 2000,pp.66–83. (in Japanese)

3) Miyamoto, T., Itoh, K., Makino, S. et al.: Clini-cal investigation of OKY-046 in adult bron-chial asthma—Dose finding study by multi-center double blind method—. J Clin ExpMed 1990; 154: 385–406. (in Japanese)

4) Nakajima, S., Miyamoto, T., Takishima, M. et al.:Clinical investigation of a thromboxane A2

receptor antagonist AA-2414 in adult bron-chial asthma—Optimal dose setting study bymulti-center double blind method—. J ClinTherap Med 1993; 9(suppl 8): 101–137. (inJapanese)

5) Miyamoto, T., Takishima, M., Makino, S. et al.:Investigation of usefulness of a leukotrieneC4, D4, E4 antagonist ONO-1078 in adult bron-chial asthma—Double blind study usingazelastin hydrochloride as the control drug—.J Clin Therap Med 1993; 9(supple 1): 71–107.(in Japanese)

6) Nakamura, Y., Hoshino, M., Sim, J.J. et al.:Effect of the leukotriene receptor antagonistpranlukast on cellular infiltration in the bron-chial mucosa of patients with asthma. Thorax1998; 53: 835–841.

7) Sano, Y., Makino, S. and Miyamoto, T.: Anti-inflammatory effect of suplatast tosilate onmild asthma. Chest 1997; 112: 862–863.

8) Tamaoki, J., Kondo, M., Sakai, N. et al.:Leukotriene antagonist prevents exacerbationof asthma during reduction of high-doseinhaled corticosteroid. The Tokyo Joshi-IdaiAsthma Research Group. Am J Respir CritCare Med 1997; 155: 1235–1240.

9) Ohta, K. and Yamashita, N.: Apoptosis of eosi-nophils and lymphocytes in allergic inflam-mation. J Allergy Clin Immunol 1999; 104:14–21.

10) Drazen, J.M., Yandava, C.N., Dube, L. et al.:Pharmacogenetic association between ALOX5 promoter genotype and the response toanti-asthma treatment. Nat Genet 1999; 22:168–170.



Managing Exacerbation of Asthma:Pharmacologic TherapyJMAJ 45(9): 381–387, 2002

Koichiro KUDO

Vice Director, International Medical Center of Japan

Abstract: The deterioration of asthmatic conditions is divided into “symptom” andacute exacerbation. “Symptom” is a pathological state in which the contraction ofbronchial smooth muscles is observed predominantly, and acute exacerbation isconsidered to be a more serious condition in which a severe inflammation of theairways is observed. The basic drugs used for treatment of these pathologicalstates include bronchodilators, corticosteroids, and oxygen. For mild symptoms,bronchodilators such as inhaled �2-agonists are used as a quick reliever. When thesymptoms are relieved, treatment is considered successful. When the symptomscannot be relieved or deteriorate rapidly, the condition is judged as acute exacer-bation, and bronchodilators and systemic corticosteroids are used together, as wellas oxygen if necessary. It is essential to make the patients understand the differ-ence between these two pathological states and the difference between the treat-ments for each state, and the importance of a prompt judgment of the pathologicalstate. The short-term use of oral corticosteroids in acute exacerbation is possibleunder patient self-management and is highly useful.

Key words: Acute exacerbation; Symptom; Bronchodilators;Systemic corticosteroid; Oxygen therapy; Patient education

The term “acute attack” is used convention-ally; lately, “acute exacerbation” has also comeinto use. The two terms are nearly synonymous.

The international guidelines recommendthat distinction should be made between theacute exacerbation of asthma and the “symp-tom” of asthma. This means that the nature ofthe symptoms of asthma should be broadlyclassified and should be managed accordingly.

Definition of Terms

Asthma is both a chronic inflammatory dis-ease of the airway and a disease with acuteexacerbation. To treat asthma, either long-termcontrol or quick relief medication is selectedaccording to the pathological state. Promptjudgment and treatment are needed whenthere is deterioration of the disease.

�Bronchial Asthma


K. KUDO

the above-mentioned “symptom” is includedin the “mild” classification. When the patientexperiences difficulty in talking or shows agita-tion and cyanosis, the state is referred to as“severe”; if there is mental confusion, somno-lence, disturbed consciousness, incontinence,and respiratory arrest, the state is evaluatedas “serious”.

For a mild acute exacerbation, home treat-ment by self-management is possible. For mod-erate, severe and serious acute exacerbation,appropriate management such as treatmentin an emergency room or hospitalization isnecessary.

Pharmacologic Therapy

Pharmacologic therapy for asthma is basi-cally the combination of a corticosteroid and abronchodilator, and administration of oxygen(Table 2).

The following methods for corticosteroidstreatment are used: (1) Administration of aninhaled corticosteroid at a dose 2 or 3 timeshigher than the usual dose, (2) intensive use of

“Symptom”, as used here, refers to mild condi-tions which can be relieved by an inhaled �2-agonist within several hours, and thereforetransient. The peak expiratory flow value (PEF)is not less than 60% of the personal best one.

On the other hand, acute exacerbation refersto conditions that cannot be relieved easily byan inhaled �2-agonist and continue for morethan a day, and in which PEF is less than 60%of the personal best one. The severity of acuteexacerbation is classified as indicated belowand the treatment is proposed in accordancewith the severity of asthma.

Classification of Severity of AcuteExacerbation (Table 1)

In the Japanese guideline, the severity ofan acute exacerbation is classified into fourlevels according to clinical symptoms (mild,moderate, severe, serious). For example, whenthe patient experiences difficulty in lying downdue to breathlessness, the severity is regardedas “moderate”; a state milder than “moder-ate” is regarded as “mild”. In a narrow sense,

Table 1 Classification of Severity of Acute Exacerbation

Breathlessness/symptoms Activity Laboratory test values Treatment

PEF�70–80%Home treatmentMild Breathless, but can lie down Slightly difficult Pao2; normal Emergency treatment

Spo2�95%

Cannot lie down duePEF: 50–80%

Emergency orModerateto breathlessness

Considerably difficult Pao2�60 torrhospital treatment

Spo2; 91–95%

Cannot move due PEF�50%

Severeto breathlessness Difficult to walk Pao2�60 torr Emergency orAgitation and talk Paco2�45 torr hospital treatmentCyanosis Spo2�91%

Mental confusionand somnolence

Serious Disturbed consciousness Impossible to talk Hospital treatment

Incontinenceand move the body ICU

Respiratory arrest

(Guidelines for the Prevention and Management of Asthma, 1998 revised edition, excerpts from Table 4 in page 88)


THERAPY OF ASTHMA EXACERBATION

an oral corticosteroid, and (3) intravenous ad-ministration. For mild severity, method (1), andfor moderate or more severe severity, methods(2) and (3) are selected, respectively.

Treatment method with bronchodilatorsincludes �2-agonists, inhalation, subcutaneousinjection of �2-agonists, intravenous admin-istration of aminophylline and subcutaneousinjection of epinephrine. Epinephrine has bothpharmacological activity of a �-action inducingbronchodilation and an �-action suppressingbronchoedema.

Oxygen is administered using a nasal can-nula, face mask and respirator. Recently, it wasreported that the noninvasive BiPAP methodis also effective. Oxygen is administered whilemonitoring with a pulse oximeter to keep Spo2

at not less than 90% or Pao2 at not less than80 torr.

These drugs are combined, and the dosagesand administration frequency are determinedin accordance with the severity of symptoms.

The practical applications of pharmacologictherapy are described below.

1. Initial treatment(1) For mild symptoms

The use of an inhaled �2-agonist is the firstchoice. This method can relieve symptoms rap-idly and act quickly. A metered dose inhaler(MDI) is sprayed 2 to 4 times into a spacerwhich a patient is supposed to inhale. When asufficient response cannot be obtained, inhala-tion is repeated every 20 minutes for 1 hour.

A patient is allowed to go home when PEFreached at more than 60% of the personal bestvalue. In this case, short-term treatment with anoral corticosteroid is instructed, and if this medi-cation does not relieve symptoms, prompt visit-ing outpatient clinic should be recommended.

An oral corticosteroid should be continuedonce a day or twice a day in a daily dose equiva-lent to 20–30 mg of prednisolone until the peakexpiratory flow value returns to the personalbest value.(2) For moderate or more severe symptoms1) Inhalation of �2-agonist using a nebulizer:When inhalation of �2-agonist with the aid of aspacer is possible, it may be done in the samemanner described in the previous section, butwhen it is difficult due to severe conditions, theuse of a nebulizer is effective.

Dose: salbutamol 5 mg (ex. 1.0 ml of 0.5%Venetlin® solution)�10–15 ml of physiologicalsaline with ultrasonic nebulizer. When theresponse to a dose of inhaled �2-agonist isinsufficient, the same treatment is repeatedevery 20 minutes for 1 hour followed by repeti-tion every 60 minutes (Table 3). If any sideeffect due to an excessive dose is observed,treatment is interrupted temporarily. The fre-quent use of inhaled �2-agonists for chronicasthma generally causes fewer side effects.2) The switch to intravenous administration ofaminophylline may be effective. Although thereis a tendency to avoid the use of aminophyllinebecause of the narrow range of effective concen-trations (10–20�g/dl) and the possible occur-

Table 2 Pharmacologic Therapy for Acute Exacerbation of Asthma

Severity Inhaled �2-agonistSubcutaneous administration Intravenous administration

Steroids Oxygenof Bosmin® of aminophylline

Mild ��

Moderate ��

Severe ��

Serious ��

�� Definitively indicated, � Indicated, � Not definitively indicated, but can be used, � Not indicated


rence of serious side effects in high concentra-tions, treatment with aminophylline is less dif-ficult and useful method once it is learned howto use it safely. For safe administration, it isgiven over 20 to 30 minutes to obtain and thenmaintain the effective concentration of thedrug (Fig. 1). A relatively easy method isdescribed below.

The loading dose (LD) is 6 mg/kg, and thedrip infusion rate (DIR) is 0.6 to 0.8 mg/kg/hr,respectively (the average values derived statis-tically from a multitude of examples). If pos-sible, the blood concentration is monitored at afew points in time after administration, and theDIR is adjusted to gain the optimal concentra-tion of aminophylline. Again to ensure safetreatment, it is necessary to take 20 to 30 min-utes for the intravenous administration of LD.

With regard to theophylline, various factorsaffecting the blood concentration have beenreported. For example, the blood concentra-tion rises in heart failure, liver diseases, andviral infection, as well as in the concomitantuse with macrolides. It decreases in smokers.Since theophylline is metabolized by the drug-metabolizing enzyme P450 in the liver, it isinfluenced by concomitant used-drugs and thepathological state of patient. For more detailedinformation, see the established literature.3) Subcutaneous administration of epinephrineis used for moderate or more severe asthmaexacerbation. This drug is injected subcutane-ously at a dosage of 0.2 to 0.3 ml. As far as pulserate is less than 130/minute, repeated adminis-tration every 20–30 minutes is possible. For seri-ous or life-threatening conditions, it is admin-istered at a dosage of 0.3 to 0.5 ml. This drug,

K. KUDO

Table 3 How to Use �2-agonists and Epinephrine in the Acute Exacerbation of Asthma(From the Guideline 1988 by the Japanese Society of Allergology)

�2-agonists Treatment mode

Mild �2 MDIa) Home treatment is possible

Moderate �2 nebulizerb) Emergency/outpatient treatmentEpinephrine s.c.c) Hospital treatment

Severe Epinephrine s.c. Emergency/outpatient treatment�2 nebulizer Hospital treatment

Serious Epinephrine s.c. Hospital treatment�2 nebulizer ICU

a) 2 puffs/each dose, every 20 minutes for 1 hourb) Every 20–30 minutes, repeated administration is possible with condition

of HR�130/minutec) 0.1–0.3ml, every 20–30 minutes, repeated subcutaneous administration is possible

20�30min.

10

20

�g/dl

(1)

(2)�

(3)�

Fig. 1 Drip infusion method of aminophylline(indicated in moderate or more severe symptoms)

(1) The method described in the text.(2) An insufficient dose is administered over a long time

via drip infusion.(3) An excessive dose is administered rapidly via drip

infusion.Both cases of (2) and (3) lack the efficacy of aminophylline orcause side effects, respectively.


with both �-action and �-action, acts quickly.Its �-action reduces bronchoedema and its �-action induces bronchodilation. Epinephrine iscontraindicated in the presence of hyperthyroid-ism, ischemic heart disease, or glaucoma. The useof this drug is also contraindicated in dehydra-tion and should be avoided during pregnancy.4) Corticosteroid therapy: When corticoster-oids are used to treat acute exacerbation ofasthma, these drugs tend to be administered atinsufficient doses due to fear of the general sideeffects of steroids, or at excessive doses in orderto intend to improve the symptoms quickly. Thestandard method including appropriate dosageis recommended in the guidelines. Generally,the side effects of corticosteroids occur whenthey are administered systemically and for along term. The period during which steroidsare used for acute exacerbation would be rela-tively short.

It is important in acute exacerbation to usethe appropriate amounts of corticosteroidswithout concern about their side effects, butwith several cautions. That is because acuteexacerbation of asthma is a state in which theinflammation has progressed markedly, andbecause corticosteroids are the most potentdrugs in inflammation of asthma.

The guidelines recommend short term treat-ment with oral corticosteroids (Table 4). In

Japan, corticosteroids are administered at adose of 0.5 mg per kg of body weight in theform of prednisolone (PSL) for about 1–2weeks, until PEF returns to the personal bestvalue. Subsequently, the basic treatment forthe patient, that is, the use of a regular doseof an inhaled corticosteroid or a regular doseof an oral corticosteroid, is substituted withouttapering process.

The necessary corticosteroid amount shouldbe prescribed in advance, and the patientsshould be educated to take oral corticosteroidby their decision when they experience suchstates as listed in Table 4. In this way, thepatient will feel secure, will learn how to pre-vent serious acute exacerbation, and will ac-quire self-management skills.

With regard to intravenous administrationmethod: Administration of hydrocortisone ormethylprednisolone starting from 200–500 mgor 40–125 mg as a loading dose, respectively,followed by 200 mg or 40–80 mg, respectively, isadded every 4–5 hours for moderate or moresevere acute exacerbation.

With regard to the side effects of corticoster-oids to be kept in mind as mentioned below:

First, patients with diabetes complicatedwith asthma are in danger of increasing theirblood sugar level, occasionally resulting inketosis. For these patients, hospital treatment


Table 4 Indications, Timing and Cautions for the Use of Oral Steroids in the Acute Exacerbation of Asthma—Home Treatment and Hospital Treatment—

� BMJ 1993 S3: Rescue use of Cs tablets1. When symptoms or PEF deteriorates on a daily basis2. When PEF is 60% of the personal best value or lower3. Somnipathy4. When morning symptoms continue during daytime5. When the response to bronchodilators becomes weaker

Adult: equivalent to 30–60mg/day of PSL, for 2 days after the symptoms are controlled, then,administration is interrupted or the dosage is reduced

Children: equivalent to 1–2mg/kg of body weight of PSL, for 1–5 days, then, administration is interrupted� Japanese guidelines 1998 (by the Japanese Society of Allergology)

Equivalent to approximately 0.5mg/kg of body weight/day of PSL, for 1–2 weeks, then,administration is interrupted or the dosage is reduced

* Cautions in diabetes—an increase in blood sugar level or ketosis is caused.


using insulin should be determined, since treat-ment under self-management or on an outpa-tient basis is difficult. Luckily, treatment withinhaled corticosteroids never increases bloodsugar level.

Second, bolus intravenous administration oflarge doses of corticosteroids in patients withaspirin-induced asthma requires another cau-tion. Aspirin-induced asthma is a disease thatinvolves acute exacerbation occurring immedi-ately after administration of aspirin, pilin deriva-tives or acidic nonsteroidal anti-inflammatorydrugs, and it is said to account for approximately5% of adult asthma cases. Bolus intravenousadministration of large amounts of succinatecorticosteroids (for example, hydrocortisone,methylprednisolone, and prednisolone) or ster-oids containing paraben preservatives is con-sidered to induce asthma exacerbation.

When the presented case is aspirin-inducedasthma or when the presented ease is notcertain about complicity with aspirin-inducedasthma, the use of such steroids should beavoided. To be enough safer from serious sideeffects, phosphate corticosteroids (ex. beta-methasone, dexamethasone) should be usedinstead, or succinate corticosteroids, if used,should be given slowly (taking 1–2 hours) viadrip infusion, not via bolus intravenous injec-tion to prevent side effects.5) Hospital treatment: When hospitalization isrequired because initial treatment did not resultin satisfactory improvement, the same initialtreatment should be continued also in the hos-pital in principle. In serious conditions such asnear death, management with a respirator orsystemic management should be performedwith adequate pharmacologic therapy. If thesymptoms are still not improved and expecto-ration is caught extensively in the lumen ofbronchi, the use of inhalation anesthetics suchas isoflurane and enflurane followed by wash-ing of the bronchi may be effective. In suchcases, it is necessary to treat the patient incooperation with anesthesiologists.

K. KUDO

Treatment During Recovery Phasefrom Acute Exacerbation

The transition from acute phase to recoveryphase is evaluated on the basis of peak expira-tory flow value returned to at least 75% ofthe personal best value, or a daily variabilityin peak expiratory flow value of 25% or less.Reaching these values, therapy is switchedfrom drip infusion treatment to oral treatmentat reduced dosages, and finally returned to theregular treatment.

An example is given here: for steroids, dripinfusion is switched to oral administration at adosage equivalent to 20–30 mg/day of predni-solone, and then to inhalation of corticoster-oids; for theophyllines, drip infusion is switchedto oral administration; inhaled �2-agonists aregiven on an on-demand basis; administration ofoxygen is interrupted when Spo2 reaches 95%or Pao2 reaches 80 torr.

Various Questions ConcerningTreatment Methods

1. Inhalation of �2-agonists or drip infusionof Aminophylline

As discussed, there are several treatmentmethods aiming at bronchodilation. No conclu-sion has been determined yet as to which oneof these is best. Treatment with inhaled �2-ago-nists is easy to use and works quickly. To gainthe efficacy of drip infusion of aminophylline,theoretical calculations for optimal serum con-centration must be learned. The pharmaco-logical efficacy of aminophylline for asthmaare not only bronchodilating but also stimuluson respiratory muscles and respiratory center.Some reports have indicated that there is nodifference in efficacy between treatment withinhaled �2-agonists, treatment with amino-phylline, and a combination of both treatments,if each treatment is carried out correctly.

It should be said at this point that a physicianmay apply the treatment which is the physi-cian’s own forte after he or she has understood



the advantages and disadvantages of eachtreatment.

2. Other treatmentsThe use of antibiotics should be limited to

bacterial infection and is not necessary for viralinfection. Bacterial infection is differentiatedfrom viral infection by leukocytosis, an increasein CRP, pneumonic shadow in chest x-ray, andthe detection of bacteria in sputum. Generally,expectorants are not used because there is noexpectorant that is more effective than cortico-steroids. The use of sedatives in general is lim-ited to use only in ICU. Large amounts of fluidshould not be supplemented, which is hazard-ous. Supplementation of normal amounts offluid is appropriate.

3. Laboratory examinationsLaboratory examinations are generally per-

formed when hospitalization is needed. Forsuch examinations, blood sampling, chest x-raystudy, and expectoration test are carried out,giving particular attention to the bacterial infec-tion of the airways, cardiopulmonary complica-tions and blood sugar level.

Asthma Prevention

Once asthma exacerbation has developed, itis important to improve it quickly with appro-priate treatment. Prevention of the develop-ment of asthma exacerbation is also important.

Patient education under long-term managementis essential for this purpose. Patient educationincludes learning about long-term managementand therapies, how to recognize the early signsof asthma exacerbation using peak expiratoryflow monitoring, and how to step up in pharma-cologic therapy on the basis of objective indicesunder self-management. Detailed instructionon the use of oral corticosteroids is a criticalpoint for successful self-management.

In addition, the factors contributing to asthmaexacerbation should be pointed out and theremoval or avoidance of these risk factors isadvised to individual patient. It is recommended,for example, to avoid indoor pets, smoking,and drinking alcohol. It is very important toprevent acute exacerbation in this way and toavoid the development of severe exacerbation.

REFERENCES

1) Immunology and Allergology Workshop of theMinistry of Health and Welfare: Guidelinesfor Prevention and Management of Asthma,1998 revised edition under the supervision ofMakino, S., Kosho, M. and Miyamoto, A.,Kyowa Kikaku, Tokyo, 2000. (in Japanese)

2) Guidelines for the Diagnosis and Managementof Asthma, Expert Panel Report 2. NIH Pub-lication, July, 1997.

3) Makino, S.: Global Strategy for Asthma Man-agement and Prevention, NHLBI/WHO Work-shop Report. International Medical Publish-ers, Tokyo, 1995. (in Japanese)



Current Treatment of Childhood BronchialAsthma Based on the GuidelinesJMAJ 45(9): 388–395, 2002

Toru AKASAKA

Director, Division of Clinical Research, Department of Pediatrics,Morioka National Hospital

Abstract: According to “Guidelines for Treatment and Control of Childhood Bron-chial Asthma 2000,” guidance on daily living combined with pharmacotherapy isimportant in the treatment of bronchial asthma. Since atopic asthma is common inchildhood, environmental control may be effective if the antigens responsible areidentified. In the event of acute attacks, therapeutic drugs should be selectedaccording to the severity of the attack. For symptomatic relief, inhaled broncho-dilators should be administered repeatedly for mild attacks, followed by intravenousinjection of aminophylline for moderate attacks. In the case of severe attacks, intra-venous injection of steroids should be added to the above-described treatment. Forlong-term control (controllers), anti-inflammatory drugs, such as oral anti-allergicdrugs and inhaled steroids, as well as drugs providing symptomatic relief (reliev-ers), such as long-acting bronchodilators, should be administered according to theseverity of the disease. Patient education should aim at promotion of self care. Thepatients should be encouraged to objectively monitor their condition by maintainingdiaries and regularly monitoring their peak expiratory flows. It is also important topromote patients’ understanding of the content of the treatment, and to gain theircooperation. Group therapy by admission to camps or facilities may also be effec-tive. At school, where asthmatic children spend a large part of their daily lives,cooperation between the medical staff and educational staff is important.

Key words: Children; Bronchial asthma; Guidelines; Controllers; Relievers

after referred to as asthma), mainly based on“Guidelines for Treatment and Control of Child-hood Bronchial Asthma 2000,”1) published bythe Japanese Society of Pediatric Allergy &

Introduction

In this article, I shall discuss, in brief, the treat-ment of childhood bronchial asthma (herein-

�Bronchial Asthma


with that of adult asthma based on the degree ofdisturbance of daily living, mild attacks in adultsare equated to moderate attacks in children.

In childhood asthma, reversibility of airwayobstruction is preserved relatively well, and pul-monary functions are almost normal during theintervals between attacks. In contrast, in adults,pulmonary functions are often impaired evenin between the attacks, the airway obstructionis less reversible, and bronchodilators tend tobe relatively less effective.

Measures against AcuteAsthmatic Attacks

It is necessary to explain the measures takento handle acute asthmatic attacks, as describedbelow, to children who have the ability to under-stand, as well as to guardians, such as parents,under whose direct care they are placed.

Clinical Immunology in April 2000.

Characteristics of Childhood Asthma

Since atopic asthma, in which past and familyhistory reveal a history of allergy, is commonin childhood, the antigens responsible can beidentified, based on information collected fromdetailed history taking as well as the results ofspecific IgE antibody testing and skin tests.Elimination of the environmental antigens thusidentified often leads to symptomatic improve-ment. In this respect, childhood asthma differssignificantly from adult asthma, which is of thenon-atopic type in most cases.

The severity of asthmatic attacks is evaluatedby the degree of disturbance of daily living andthe pulmonary function status, and is classifiedas mild, moderate or severe (Table 1). Whenthe severity of childhood asthma is compared

Table 1 Criteria for Evaluation of the Severity of Attacks1)

PulmonaryActivities of daily life Matters for reference

function status Play Sleep Mood & Speech Appetite Spo2 PEFNOTE2)

Mild stridor orwheeze is present,

Mild attack associated with Normal Normal Talk Normal 96% 60%

mild intercostal normally or more or more

retraction.

Obvious stridor, Rather badModerate attack intercostal Rather Occasionally Can reply when Rather bad 92–95% 30–60%retraction and difficult wake up

talked todyspnea are noted.

Marked stridor,dyspnea and

Impossible Impossible BadSevere attack

orthopnea areor almost or almost Cannot reply

Bad or 91% 30%noted. Cyanosis impossible impossible when talked to almost bad or less or lessis occasionallyobserved.

Note) Signs of respiratory failure (marked dyspnea, cyanosis, diminished breath sounds, and neurological disorder, includingdiminished reaction to pain, irritability or consciousness disturbance) should be watched for.

Note 2) PEF is expressed as a percentage of the predicted value before inhalation of �2-agonist, or against the self-best value.Additional note) The severity of attacks is determined based on the above-described clinical symptoms. In children, the

pulmonary function status does not always corroborate the severity of the clinical symptoms. Nonetheless, pulmonaryfunctions are also determined to help in guiding the treatment in the “Guidelines”. At present, standard values for thepulmonary functions are not specified. Therefore, the values presented here are just for the sake of reference. Re-examination of this subject is necessary in the near future. It goes without saying that priority should be accorded toclinical symptoms when judging the severity of the attacks for the purpose of treatment.

CURRENT TREATMENT OF CHILDHOOD BRONCHIAL ASTHMA


1. Measures at homeWhen mild attacks occur at home, the patient

should be advised to relax and practice abdom-inal breathing, and simple physical therapy,such as encouraging water intake to facilitateexpectoration of sputum, should be instituted,before pharmacotherapy is started. Such a calmapproach to assess the severity of attacks canhelp avoid overuse of �2-agonists by metereddose inhalers (MDI). However, it should beensured that there is no delay in the start ofappropriate treatment. If oral bronchodilatorsand inhaled �2-agonists as prescribed by thephysician do not work, local medical facilitiesmust be consulted.

2. Measures at medical institutionsWhen mild attacks occurring at home do not

respond to the usual treatment, or progress to

moderately severe attacks, treatment should besought at a medical institution. If the conditiondoes not respond to the treatment institutedaccording to the severity of the attack, treat-ment recommended for the next higher gradeof severity should be commenced. If adequateresponse is observed, the treatment may bedowngraded again.

3. Drugs for treating acute attacks (drugsproviding symptomatic relief: relievers)(Table 2)

Bronchodilators that help in remitting oreliminating the symptoms of acute attacks arecalled relievers. Differences in the measuresadopted to treat acute attacks in children andadults are summarized by Hosoi as follows.2)

1) The severity of attacks in children is equatedto the next higher grade of severity in adults.

Table 2 Treatment of Acute Attacks of Childhood Asthma at Medical Institutions1)

Symptoms Spo2PEF (School

Treatmentchildren or older)

Mild stridor or wheeze,sometimes associated 96% Often 60% (Step 1)

Mild attack with mild intercostal or more or more • Inhaled �2-agonistsretraction.

(Step 1)Obvious stridor, with • Repeated �2-agonist inhalation

Moderate attack intercostal retraction 92–95% Often between (Step 2)and dyspnea. 30% and 60% • Intravenous infusion or bolus injection

of aminophylline

(Step 1)• �2-agonist inhalation with

Marked stridor, with supplemental oxygen

dyspnea and orthopnea. (Step 2)Severe attack

Cyanosis is occasionally91% or Often 30%

• Intravenous infusion of aminophylline

observed.less or less and fluid replacement

• Correction of acidosis(Step 3)• Intravenous injection of steroids

Marked dyspnea, cyanosis, Continuation of above-described treatmentdiminished breath sounds 90% or less (Step 3) Referenceand neurological disorder(With Impossible • Continuous isoproterenol inhalationRespiratory (irritability, disturbed

supplemental to determine (Step 4)failure consciousness, orO2) • Endotracheal intubationdiminished reaction

• Artificial ventilationto pain)

Note) PEF is expressed as a percentage of the predicted value before inhalation of �2-agonists, or against the self-best value.

T. AKASAKA


2) Oral �2-agonists play a greater role in mildcases of childhood asthma (mild intermittentand mild persistent cases), while MDIs areindicated carefully.

3) Oral steroids are used with prudence.4) Aminophylline infusion and fluid replace-

ment are commonly adopted for the treat-ment of moderate to severe attacks (Step 2).

5) Subcutaneous injection of Bosmin® (epine-phrine) is not adopted as standard therapy.

6) Continuous inhalation of isoproterenol isused in the treatment of very severe attacks.

In the treatment of acute attacks in children,�2-agonists are administered orally or by inha-lation, and epinephrine is injected subcutane-ously in emergent situations. Theophylline isadministered orally or aminophylline by intra-venous injection, and in some rare cases, inhaledanticholinergic drugs are used.

4. Treatment of acute attacks (Fig. 1)(1) Treatment of mild attacks

�2-agonists are administered by inhalation,and after monitoring the clinical course for 15

minutes, the severity of the attack is evaluatedagain. If there is some improvement, but theresponse is still inadequate, the inhalationshould be repeated. If the response is not satis-factory, the treatment should be upgraded tothat recommended for moderate attacks.(2) Treatment of moderate attacks

�2-agonists are administered first by inhala-tion. A venous line is secured, and an intrave-nous injection or drip infusion of 4 to 6 mg/kgbody weight of aminophylline, added to main-tenance fluid or 20% glucose solution, is admin-istered over 20 minutes or longer. If the responseobserved is not satisfactory, the �2-agonist inha-lation should be repeated, and continuousaminophylline infusion must be started. If thelatter becomes necessary, the patient should behospitalized first.(3) Treatment of severe attacks

In children, great individual differences arenoted in the response to treatment, and effec-tive treatment often varies among individuals.

�2-agonists are administered by inhalationwhile supplemental oxygen is started, and amino-

Fig. 1 Plan of pharmacotherapy for acute attacks of childhood asthma at medical institutions1)

Inhaled�2-agonists

Inhaled�2-agonists �2-agonist inhalation and supplemental oxygen

Mild attack Moderate attack Severe attack Respiratory failure

Step 4

Step 3

Step 2

Step 1

Intravenous infusion or bolus injection of aminophylline (therapeutic blood con-centration of aminophylline,15 �g/ml or less)

Intravenous infusion or bolus injection of aminophylline (therapeutic blood concentration of aminophylline, 5 to 15 �g/ml ),

appropriate fluid replacement, correction of acidosis

Intravenous injection of steroids (hydrocortisone) or oral prednisolone

Endotracheal intubation/artificial ventilation

Continuous isoproterenol inhalation



phylline is administered by continuous intra-venous infusion. Hydrocortisone at the dose of5 to 7 mg/kg body weight is administered byslow intravenous injection at intervals of 4 to 6hours, or prednisolone injection is started atthe dose of 1 to 1.5 mg/kg body weight. If noadequate response is noted, continuous isopro-terenol inhalation in an oxygen tent is employed.The heart rate, respiratory rate, and oxygensaturation should be closely monitored.(4) Treatment of respiratory failure

If the pulmonary functions do not improvedespite the above measures, endotracheal intu-bation, assisted ventilation, and artificial venti-lation may become necessary.(5) Indications for hospitalization

Children with acute asthma are hospitalizedmore frequently than adult patients with acuteasthma, so as to ensure that they are treatedas quickly and as safely as possible. The indica-tions for hospitalization can be summarized asfollows.1) Severe attacks2) Moderate attacks that do not respond even

after 2 hours of appropriate treatment atthe outpatient clinic

3) Moderate attacks lasting more than 24 hours4) Acute asthma in infants5) Complications, such as pneumonia, atelec-

tasis, and pneumothorax6) Inadequate response despite upgradation of

long-term control

Measures for Long-term Controlof Asthma

1. Drugs used for long-term control(controllers)

The drugs used for long-term control of bron-chial asthma are called controllers, because theystabilize respiratory functions and improve thequality of life (QOL) of the subjects. The phar-macotherapy for long-term control of child-hood asthma differs from that for adult-onsetasthma in the following ways.2)

1) Even if the same terms are used for classifi-

cation of the severity of symptoms, the sameclinical condition is assigned a higher levelof severity in children.

2) The intermittent type of adult asthma encom-passes the mild intermittent type, mild per-sistent type, and moderate persistent type ofchildhood asthma.

3) Basically, the timing of initiation of inhaledsteroids is the same in both groups.

4) Treatment from Step 1 to Step 3 is carriedout before starting inhaled steroids.

5) Specialist guidance is required for long-termadministration of oral steroids.

6) In the treatment of the severe persistent typeof asthma, psychosocial factors and long-termhospitalization (institutionalization) shouldbe considered.

(1) Anti-inflammatory drugs1) Inhaled steroids

Beclomethasone dipropionate is available intwo formulations, which deliver 50�g and 100�gper inhaled dose. Fluticasone propionate, whichis commonly used in adults, has begun to be usedin some older children, but the drug should beadministered with caution in children.2) Sodium cromoglycate (DSCG)

DSCG is available in capsule, liquid, andaerosol formulations. Inhaled DSCG in combi-nation with �2-agonists has been reported tobe effective in the treatment of moderate orsevere asthma in children.3) Oral anti-allergic drugs

Oral anti-allergic drugs include inhibitors ofthe release of chemical mediators, histamineH1-receptor antagonists, and leukotriene antago-nists. When administered systemically, they areknown to exert effects against allergic diseasesin general.(2) Long-acting bronchodilators1) Long-acting �2-agonists

In Japan, only short-acting �2-agonists arecommercially available, and sufficient informa-tion regarding long-acting �2-agonists is lacking.2) Sustained-release theophylline

The rate of metabolism of theophylline inthe liver differs among different individuals,

T. AKASAKA


and is also dependent on the age of the subject.Moreover, the influences of complications,such as infection, contents of meals, and con-comitantly administered drugs should also betaken into consideration. When adequate effectsare not obtained after administration of theusual dose, or adverse drug reactions are sus-

pected, the blood concentration of the drugshould be determined. Since the drug is knownto induce convulsions even at low concentra-tions in patients with a past history of centralnervous system disorder, caution must be exer-cised during administration of the drug.

� Anti-allergic drugs, oral/DSCG

Step 1

Intermittent type

� Anti-allergic drugs, oral/DSCG

Step 2

� Anti-allergic drugs, oral

� �2-agonists (repeated use), [oral/inhaled]

Step 3

� Anti-allergic drugs, oral

� �2-agonists (repeated use), [oral/inhaled]

Step 4 Step 5 Step 6 Step 7

Mild persistent type Moderate persistent type Severe persistent type

� Xanthine preparation (RTC)






Therapeutic blood concentration of aminophylline, 5 to 15 �g/ml




Therapeutic bloodconcentration of aminophylline, 5 to 15 �g/ml

� BDP inhalation, 100 �g to up to 600 �g/day

� DSCG�salbutamol,

twice daily

� BDP inhalation, 200 �g to up to 1,200 �g/day



three to four times daily



four times daily


twice to four times daily


twice daily

� Oral administration of prednisolone for a short period (Once daily administration in the early morning of 5 to 10 mg/day, up to one week)

� (Consider) treatment by long-term hospitalization

� Oral administration of prednisolone for a prolonged period (Once-daily administration in the early morning of 5 to 10 mg/day; alternate-day administration if long-term administration is required, under specialist supervision)

� Treatment by long-term hospitalization

� �2-agonists (single use), [oral/inhaled]

� �2-agonists (single use), [oral/inhaled]

� �2-agonists (long-acting), [oral]



Fig. 2 Pharmacotherapy plan for long-term control of childhood asthma1)

Note 1) BDP: beclomethasone dipropionate RTC: round the clock DSCG: disodium cromoglycateNote 2) When multiple drugs are used concomitantly, it is important to ensure that ineffective drugs are eliminated in each

patient, and that more than the required number of drugs are not administered.Note 3) The efficacy of oral anti-allergic drugs in combination with leukotriene antagonists in severe persistent asthma is

still unknown.



2. Pharmacotherapy for long-term control(Fig. 2)

(1) Intermittent asthmaDrugs are administered according to the

severity of the attacks. Administration of anti-allergic drugs should be started immediately,depending on the symptoms.

Inhaled DSCG or �2-agonists should be usedfor the prevention of exercise-induced asthma.(2) Mild persistent asthma

Round-the-clock (RTC) administration oftheophylline is required. In addition, single useof oral or inhaled �2-agonists is recommended.(3) Moderate persistent asthma

Inhaled DSCG in combination with �2-agonistsis administered regularly. When oral or adhe-sive �2-agonists are used regularly, they shouldbe discontinued as the symptoms improve. Ifsatisfactory response is obtained, combined inha-lation of DSCG and �2-agonists and RTC theo-phylline should be continued. When the treat-ment is ineffective, or only partially effective,inhaled beclomethasone should be used concom-itantly. As to the standard dose, 100 to 150�gper dose should be administered two to fourtimes a day using a spacer, and the patientsshould be advised to gargle after the inhalation.(4) Severe persistent asthma

Beclomethasone dipropionate is administeredat the dose of 100 to 300�g per dose two tofour times a day, and the maximum daily doseshould not exceed 1,200�g. Regular combinedinhalation of a mixture of DSCG and �2-agonists, oral �2-agonists, and RTC theophyl-line is recommended.

When the condition does not respond to theabove-described treatment and the patient’sdaily life is disturbed, the patient is referred toa specialist, or on the basis of consultation witha specialist, the dose of inhaled beclomethasoneis increased, or 5 to 10 mg of prednisolone areadministered once daily in the morning for upto one week.

If the condition still does not respond tothese treatments, the patient should be admit-ted to a specialized medical institution for long-

term hospitalization, while arranging for thechildren to receive education, possibly at aschool for children with the disease.

Patient Education

Patient education regarding childhood asthmashould be provided to both patients and theirguardians, depending on the degree of under-standing. In the case of infants, in particular,guardian education is essential. On the otherhand, in the case of adolescents, the patientsgradually come to play the main role in treat-ment, but often they are not sure at this agewhether they should still be dependent on theirparents or can act independently, and maybecome somewhat confused about their treat-ment. Since patients in their adolescence donot visit the hospital very often, the physiciansshould actively engage themselves in the taskof educating this group of patients.

1. Promotion of self careWe have established the following goals

to promote objective understanding by thepatients of their condition.1) Maintenance of an asthmatic diary.2) Monitoring of peak flow rate.3) Acquire knowledge and skills regarding how

to use the drugs, the effects of the drugs, andadverse drug reactions.

2. TrainingDuring the growing stage, physical training,

while ensuring precautions to prevent exercise-induced asthma, is useful in improving thechildren’s QOL. Instructions are given so thatchildren will be able to enjoy swimming, whichis considered relatively less likely to induceattacks, as well as various other types of sports.

3. Group therapyGroup therapy plays an educational role by

providing opportunities for developing inter-personal skills, and asthmatic children can learnto help each other through such activities as

T. AKASAKA


summer camps.

4. Liaison between school andmedical institution

The communication between the medical staffand educational staff to exchange informationis expected to assume increasing importance,so that the children can play active roles inschool, where they lead a large part of theirdaily lives.

Conclusion

Thus, as is evident from the above, “Guide-lines for Treatment and Control of ChildhoodBronchial Asthma 2000” comprehensively cov-

ers not only pharmacotherapy for the controlof asthma, but also provides guidance on dailyliving. I would be greatly pleased if physiciansfound the “Guidelines” useful in their dailymedical practice.

REFERENCES

1) Japanese Society of Pediatric Allergy & Clini-cal Immunology: Guidelines for Treatment andControl of Childhood Bronchial Asthma 2000.Edited by Furusho, M. and Nishima, M.Kyowa Kikaku, Tokyo, 2000. (in Japanese)

2) Hosoi, S.: Differences between children andadults in the guidelines (especially the timingof the use of inhalant steroids). Asthma, 1998;11: 17–25. (in Japanese)



A Preliminary Study of the Impact ofManaged Care on Psychotherapyin MassachusettsJMAJ 45(9): 396–402, 2002

Hiroto ITO

Senior Researcher, Department of Health Care Economics,National Institute of Health Services Management

Abstract:Objectives: We conducted a questionnaire survey to assess the impact of man-aged care on psychotherapy in Massachusetts.Methods: The subjects of the study were 198 psychotherapists and psychiatristsaffiliated with McLean Hospital and Massachusetts General Hospital, Massachu-setts, USA. We asked all 772 professionals affiliated with those institutions tocomplete a questionnaire on the impact of managed care and socio-demographiccharacteristics between February 25 and April 25, 1999.Results: Of the 772 subjects targeted, 198 (25.6%) responded. Three fourths ofthe respondents reported that managed care increased administrative time forpaperwork, and 41.9% said that managed care decreased the average number ofsessions for patients/clients. The respondents sometimes (66.2%) or often(10.6%) had to terminate treatment because managed care did not pay for con-tinued care. They sometimes (45.5%) or often (32.3%) terminated contracts orrefused to sign contracts with “managed care” organizations or turned down refer-rals from “managed care.” Psychotherapists fell into two groups: those who spentmuch of their time with managed care patients and those who did not, whereasthere was no such difference between psychiatrists.Conclusions: Managed care has reduced the number of psychotherapy sessionsin Massachusetts and increased administrative work.

Key words: Managed care; Psychotherapy

This article is a revised English version of a paper originally published inthe Journal of the Japan Medical Association (Vol. 127, No. 7, 2002, pages 1083–1088).This work was supported by a research grant from the Mental Health Okamoto Memorial Foundation.

Introduction

In this article “managed care” refers anyform of external utilization review. Managed

care has recently provided a model for a futurehealth care system, and many articles on man-aged care have been published.1) In Japan, forexample, managed care as practiced in the

�Managed Care


IMPACT OF MANAGED CARE ON PSYCHOTHERAPY

United States has been introduced on varioushealth plans, because Japan is facing a turningpoint in its health care system and is searchingfor new models for the system of the future.Feasibility studies on a prospective paymentsystem based on diagnostic related groups(DRG/PPS) represents a new trend in Japan,and managed care is one of the subjects of thenew models.

Based on a recent survey, Simon et al. con-cluded that negative views of managed carewere widespread among medical students, resi-dents, faculty members, and medical schooldeans.2) State and local governments are alsomoving rapidly to contract with managed carecompanies for mental health and substance-abuse services covered by Medicaid, one ofthe major public programs funding services ofthis type.3) Massachusetts was the first stateto introduce a statewide managed-care planfor mental health services within its Medicaidprogram.4)

Psychiatry, especially psychotherapy, will bedeeply impacted by the introduction of man-aged care. Because psychiatry requires a certainperiod of time for treatment to be effective,limitations on mental health care resources bymanaged care changes the dynamic flow oftreatment for psychiatric patients. Managedcare has had a major impact on psychotherapyin the United States. Since managed care com-panies cover only medical necessities,5–7) thenumber of sessions is restricted. Bennet hasnoted that long-term psychotherapy is difficultin the managed care era.5)

In contrast to the United States, it is difficultfor psychotherapists to open private offices inJapan for financial reasons. Although the uni-versal insurance program has included psycho-therapy since 1964, the fee is 3,700 yen (aboutUS$31) in 2001. If the introduction of managedcare into the Japanese health care system reducesthe utilization of psychotherapy, the develop-ment of psychotherapy will fall even furtherbehind.

In this study, we examined the differences in

the impact of managed care on psychothera-pists and psychiatrists in Massachusetts, whichhas the longest history of statewide managedcare. We hypothesized that (1) managed carehas impacted paperwork, average number ofsessions, and the number of patients with severemental illness who are treated, (2) and thatpsychotherapists and psychiatrists have had toterminate treatment earlier.

Subjects and Method

We asked all 772 professionals affiliated withMcLean Hospital and Massachusetts GeneralHospital in Massachusetts, to complete a ques-tionnaire between February 25 and April 25,1999. Of them, 198 (25.6%) returned the ques-tionnaire. Since 2 were excluded because ofincompleteness of the “profession” item, ulti-mately the 196 professionals (86 psychothera-pists and 110 psychiatrists) were subjects of thestudy. Of the 86 psychotherapists, 73 (84.9%)had a Ph.D. degree.

The questionnaire inquired about the impactof managed care and about socio-demographiccharacteristics such as gender, age, profession,years in practice, hours of direct patient carea week, and percentage of managed carepatients/clients. The questions regarding theimpact of managed care were: (Q1) Do youthink that administrative time for managedcare paperwork has changed?; (Q2) Has theaverage number of your sessions for managedcare patients/clients changed?; (Q3) Must youterminate treatment because managed caredoes not pay for continued care?; (Q4) Do youthink that the number of your patients/clientswith severe mental illness has changed due tomanaged care?; and (Q5) Are you terminatingcontracts or refusing to sign contracts with“managed care” organizations or turning downreferrals from “managed care”? Participantsanswered each question on a 3 point-scale.

We performed the statistical analysis by usingthe chi-square test and analysis of variancewith a SPSS software package. Hours of man-


aged care a week were calculated based on thehours in direct care practice and percentages ofmanaged care patients.

Results

1. Characteristics of respondentsThe characteristics of the respondents are

shown in Table 1. Mean age was 48.5 years old,with a mean of 17.8 years in practice. The per-

Table 2 Results for Each Question (%)

Psychiatrist Psychotherapist Total

Q1. Do you think that a dministrative time for managed care Increased 86 (80.4) 61 (74.4) 147 (77.8)paperwork has changed? (n�189) Unchanged 15 (14.0) 17 (20.7) 32 (16.9)

Decreased 6 ( 5.6) 4 ( 4.9) 10 ( 5.3)

Q2. Has the average number of your sessions for managed Increased 11 (10.4) 7 ( 8.5) 18 ( 9.6)care patients/clients changed? (n�188) Unchanged 48 (45.3) 39 (47.6) 87 (46.3)

Decreased 47 (44.3) 36 (43.9) 83 (44.1)

Q3. Must you terminate your treatment because managed Never 26 (24.3) 11 (13.6) 37 (19.7)care does not pay for continued care? (n�188) Sometimes 71 (66.4) 59 (72.8) 130 (69.1)

Often 10 ( 9.3) 11 (13.6) 21 (11.2)

Q4. Do you think that the number of your patients/clients Increased 25 (23.8) 18 (23.1) 43 (23.5)with severe mental illness has changed due to managed Unchanged 71 (67.6) 55 (70.5) 126 (68.9)care? (n�183)

Decreased 9 ( 8.6) 5 ( 6.4) 14 ( 7.7)

Q5. Are you terminating contracts or refusing to sign contracts Never 20 (18.7) 13 (16.5) 33 (17.7)with “managed care” organizations or turning down Sometimes 49 (45.8) 41 (51.9) 90 (48.5)referrals from “managed care”? (n�186)

Often 38 (35.5) 25 (31.6) 63 (33.9)

There are no significant differences in items between psychotherapist and psychiatrists.Total numbers differ because of missing values.

Table 1 Demographic Characteristics of Respondents

Total Psychiatrist Psychotherapist Test

Mean age in years (SD) n�196 48.5 (10.5) 49.4 (11.4) 47.2 (9.1) ns

Gender Male 118 (59.6) 77 (70.0) 41 (47.7) �2 (df�1)�10.0**Female 79 (39.9) 33 (30.0) 45 (52.3)

Length of practice in years (SD) n�193 17.8 (10.5) 18.5 (11.5) 16.8 (9.1) ns

Length of direct care a week in hours (SD) n�192 26.7 (11.9) 28.2 (13.0) 24.7 (9.9) t (df�190)�2.0*

Percentage of managed care patients (SD) n�188 49.6 (30.6) 51.9 (30.9) 46.8 (30.2) ns

Hours of managed care patients a week �4 45 (24.1) 24 (22.9) 21 (25.6) �2 (df�2)�8.86*5–20 95 (50.8) 46 (43.8) 49 (59.8)21� 47 (25.1) 35 (33.3) 12 (14.6)

*p�0.05 **p�0.001ns: not significant

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centage of female psychotherapists was signifi-cantly higher than the percentage of femalepsychiatrists.

The average number of hours spent in directpatient care was 26.7, and 49.6% of the timewas spent with managed care patients. The pro-portions of respondents who spent less thanhalf day, between half day and 2.5 days, andmore than 2.5 days were 23%, 49%, and 24%,respectively. The time spent on managed carepatients by psychotherapists was significantlyshorter than the time spent by psychiatrists.

2. Responses to each questionAs shown in Table 2, 77.8% of the respon-

dents thought that managed care had increasedadministrative time for paperwork, and 44.1%thought that managed care had decreased theaverage number of sessions for patients/clients.The respondents sometimes (69.1%) or often

(11.2%) had to terminate treatment becausemanaged care did not pay for continued care.They thought that the number of patients/cli-ents with severe mental illness had increased(23.5%) or was unchanged (68.9%) as a resultof managed care. They sometimes (48.5%) oroften (33.9%) terminated contracts or refusedto sign contracts with “managed care” organi-zations or turned down referrals from “man-aged care.”

There were no significant differences betweenpsychotherapists and psychiatrists in any of theitem.

There were no significant relationships be-tween replies to individual items except (Q3)“terminating their treatment because of man-aged care.” The relationships between repliesto Q3 and other items are shown in Table 3. Themore psychiatrists and psychotherapists termi-nated treatment because of managed care, the

Table 3 Termination of Treatment and Other Responses

Must you terminate treatment because managed care does not pay for continued care? (Q3)

Psychiatrists�2 (4)

Psychotherapists�2 (4)

Never Sometimes Often Never Sometimes Often

Increased 18 (72.0) 59 (83.1) 8 (80.0) ns 5 (45.5) 45 (77.6) 10 (90.9) ns

Unchanged 4 (16.0) 10 (14.1) 1 (10.0) 5 (45.5) 10 (17.2) 1 ( 9.1)

Decreased 3 (12.0) 2 ( 2.8) 1 (10.0) 1 ( 9.1) 3 ( 5.2) 0 ( 0. )

Increased 3 (11.5) 8 (11.4) 0 ( 0. ) 13.7** 0 ( 0. ) 5 ( 8.6) 2 (18.2) 11.2*

Unchanged 17 (65.4) 30 (42.9) 1 (10.0) 10 (90.9) 23 (39.7) 5 (45.5)

Decreased 6 (23.1) 32 (45.7) 9 (90.0) 1 ( 9.1) 30 (51.7) 4 (36.4)

Increased 3 (12.0) 18 (26.1) 4 (40.0) ns 0 ( 0. ) 14 (25.5) 4 (36.4) ns

Unchanged 22 (88.0) 44 (63.8) 4 (40.0) 10 (100) 36 (65.5) 7 (63.6)

Decreased 0 ( 0. ) 7 (10.1) 2 (20.0) 0 ( 0. ) 5 ( 9.1) 0 ( 0. )

Never 6 (24.0) 14 (19.7) 0 ( 0. ) ns 4 (40.0) 9 (15.8) 0 ( 0. ) 10.6*

Sometimes 11 (44.0) 34 (47.9) 3 (30.0) 1 (10.0) 33 (57.9) 6 (60.0)

Often 8 (32.0) 23 (32.4) 7 (70.0) 5 (50.0) 15 (26.3) 4 (40.0)

Total 37 131 21 37 131 21


Do you think that administrativetime for managed care paperworkhas changed? (Q1)

Has the average number of yoursessions for managed carepatients/clients changed? (Q2)

Do you think that the number ofyour patients/clients with severemental illness has changed due tomanaged care? (Q4)

Are you terminating contracts orrefusing to sign contracts with“managed care” organizations orturning down referrals from“managed care”? (Q5)



more the average number of sessions decreased.Psychotherapists who had never terminatedtreatment were divided into two groups: thosewho had never terminated contracts or refusedto sign contracts with managed care and thosewho had often terminated or refused suchcontracts.

As shown in Table 4, the responses of psy-chotherapists differed according to the lengthof time spent with managed care patients aweek. Psychotherapists who spent more timewith managed care patients reported there wasan increase in time for managed care paper-work significantly greater than those who spentless than 4 hours a week. Psychotherapists whospent more time with managed care patientsterminated treatment more frequently than

Table 4 Each Item and Hours of Managed Care Patients a Week by Professional

Psychiatrists Psychotherapist

Hours spent with managed care Hours spent with managed carepatients per week patients per week

�4 5–20 21� �2 (4) �4 5–20 21� �2 (4)

Increased 16 (72.7) 35 (76.1) 32 (91.4) 9 (45.0) 42 (85.7) 8 (72.7)

Unchanged 6 (27.3) 7 (15.2) 1 ( 2.9) ns 10 (50.0) 6 (12.2) 1 ( 9.1) 18.3**

Decreased 0 ( 0. ) 4 ( 8.7) 2 ( 5.7) 1 ( 5.0) 1 ( 2.0) 2 (18.2)

Increased 2 ( 9.5) 4 ( 8.9) 5 (14.3) 0 ( 0. ) 6 (12.2) 1 ( 8.3)

Unchanged 13 (61.9) 20 (44.4) 12 (34.3) ns 14 (73.7) 19 (38.8) 6 (50.0) ns

Decreased 6 (28.6) 21 (46.7) 18 (51.4) 5 (26.3) 24 (49.0) 5 (41.7)

Never 7 (33.3) 12 (26.1) 6 (17.1) 6 (31.6) 2 ( 4.2) 2 (16.7)

Sometimes 13 (61.9) 31 (67.4) 24 (68.6) ns 12 (63.2) 37 (77.1) 9 (75.0) 10.7*

Often 1 ( 4.8) 3 ( 6.5) 5 (14.3) 1 ( 5.3) 9 (18.8) 1 ( 8.3)

Increased 5 (23.8) 6 (13.6) 12 (34.3) 1 ( 5.3) 14 (29.8) 3 (27.3)

Unchanged 15 (71.4) 33 (75.0) 20 (57.1) ns 16 (84.2) 31 (66.0) 7 (63.6) ns

Decreased 1 ( 4.8) 5 (11.4) 3 ( 8.6) 2 (10.5) 2 ( 4.3) 1 ( 9.1)

Never 4 (18.2) 8 (17.4) 7 (20.6) 1 ( 5.3) 8 (17.0) 3 (25.0)

Sometimes 7 (31.8) 21 (45.7) 18 (52.9) ns 7 (36.8) 26 (55.3) 8 (66.7) 9.8*

Often 11 (50.0) 17 (37.0) 9 (26.5) 11 (57.9) 13 (27.7) 1 ( 8.3)


Q1. Do you think that administra-tive time for managed carepaperwork has changed?

Q2. Has the average number ofyour sessions for managed carepatients/clients changed?

Q3. Must you terminate yourtreatment because managed caredoes not pay for continued care?

Q5. Are you terminating contractsor refusing to sign contracts with“managed care” organizations orturning down referrals from“managed care”?

Q4. Do you think that the numberof your patients/clients withsevere mental illness has changeddue to managed care?

those who spent less than 4 hours a week. How-ever, they less frequently terminated or refusedto sign contracts with “managed care” organi-zations or turned down referrals from “man-aged care” than those who spent less than 4hours a week.

There were no significant correlations be-tween any of the items and time spent withmanaged care patients.

Discussion

1. Methodological issues and characteristicsof respondentsThe response rate for mailed questionnaire

surveys is usually said to be much lower thanwith other methods in the United States, even

H. ITO


when the surveyor pays a fee to respondentsfor their cooperation.8) In this study, more thanone fourth of the psychotherapists and psychia-trists returned the questionnaire, and there wasno fee for their cooperation. The shortness ofthe questionnaire may have contributed to thehigher response rate than expected, althoughthe response rate was not high and not verysatisfactory.

The mean age of the respondents was 48years old and they had an average of 18 years ofclinical experience. They spent an average of 27hours on direct patient care, which meant thatthe respondents spent more than half of theirworking hours on direct care of the patients.These results suggest that the respondentswere clinical professionals spending most oftheir time on clinical services.

2. Impact of managed careRespondents generally recognized the three

changes in direct patient care: administrativetime for managed care had increased theadministrative time for paperwork; termina-tion of treatment by professionals because ofmanaged care had increased; and terminationof contracts or refusal to sign contracts with“managed care” organizations or turning downreferrals from “managed care” had increased.

Managed care organizations always requirethat direct care professionals precisely docu-ment their practice for review. Direct care pro-fessionals need to explain why and how theyprovide treatment, and the increases in admin-istrative time reflect these requirements bymanaged care. In addition, increases in termi-nation of treatment because of managed care’srefusal to pay for continued care represents aserious problem for direct care. Managed caregenerally limits the number of sessions per yearor per lifetime. From a clinical standpoint,however, such limitations seem inappropriatebecause long-term psychotherapy can not beprovided when needed (Bennett, 1996).

The increases in termination or refusal ofcontracts with “managed care” organizations

show another trend among direct care profes-sionals. The psychotherapists who respondedcould be divided into two groups: those whospent a great deal of time with managed carepatients but frequently terminated their treat-ment, and those who did not see any managedcare patients at all. These results suggest thatpsychotherapists decide whether or not to seemanaged care patients in their practice. Thispsychotherapists’ response suggests that directcare professionals themselves decide to con-tract with managed care organizations. Psycho-therapists seem to select clients with or withoutmanaged care.

By contrast, there was no such differenceamong psychiatrists, although they spent longertime in direct care to see managed care patientsthan psychotherapists. It seems difficult forpsychiatrists to decide not to spend time withmanaged care patients. This is partly becausemedical treatment by psychiatrists is moreclosely related to the managed care paymentsystem in reimbursement than psychotherapyby psychotherapists. This means that managedcare has a greater impact on psychotherapy bypsychiatrists than by psychotherapists.

Conclusion

Managed care has had a great impact on psy-chotherapy in Massachusetts. It has reducedthe number of sessions, and increased adminis-trative work. Some psychiatrists and psycho-therapists terminate their contract with man-aged care to maintain their clinical practiceunder their own control. Policy makers shouldcarefully review the impact of payment systemchanges on clinical services before hastening tointroduce a new system.

REFERENCES

1) Lee, K.: Health Care Services in US. Igaku-shoin, Tokyo, 1998. (in Japanese)

2) Simon, S.R. et al.: Views of managed care: Asurvey of students, residents, faculty, and



deans at medical schools in the United States.New England Journal of Medicine 1999; 340:928–936.

3) Iglehart, J.K.: Managed care and mentalhealth. New England Journal of Medicine1996; 334: 131–135.

4) Dickey, B. and Azeni, H.: Impact of managedcare on mental health services. Health Affaire(Millwood) 1992; 11: 197–204.

5) Bennett, M.J.: Is psychotherapy ever medi-cally necessary? Psychiatric Services 1996; 47:

966–970.6) Borenstein, D.B.: Does managed care permit

appropriate use of psychotherapy? PsychiatricServices 1996; 47: 966–970.

7) Chodoff, P.: Medical necessity and psycho-therapy. Psychiatric Services 1998; 49: 1481–1483.

8) Siemitatycki, J.: A comparison of mail, tele-phone, and home interview strategies forhousehold health surveys. Am J Public Health1979; 69: 238–245.

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Treatment of Age-related MacularDegenerationJMAJ 45(9): 403–405, 2002

Kanjiro MASUDA

Director, Kanto Rosai Hospital

Key words: Age-related macular degeneration (ARD);Photodynamic therapy; Radiation therapy; Thermal therapy

Introduction

Age-related macular degeneration (ARD) isa disease of the macula in the retina, the inci-dence of which increases with age. Since themacula is affected, patients with ARD acknowl-edge visual impairment from the onset of thedisease. ARD is the leading cause of blindnessamong adults in the U.S. and Europe, and itsincidence in Japan is also gradually increasing.

Epidemiological data from a study conductedin Rotterdam reported an incidence of ARD of1.1% of the residents aged 55 and older. In asimilar study conducted in Hisayama-machi,Fukuoka Pref., Japan, the incidence of ARD inresidents aged 50 and older was 0.67%.

The International Classification of Diseasesdefines two types of maculopathy: early age-related maculopathy (drusen and retinal pig-ment epithelium abnormalities) and late age-related maculopathy (hemorrhage due to cho-roidal and subretinal neovascularization; wetand dry forms). ARD generally refers to lateage-related maculopathy, and risk factors asso-ciated with it include genetic predisposition,hypertension, smoking, and exposure to sun-

This article is a revised English version of a paper originally published inthe Journal of the Japan Medical Association (Vol. 126, No. 1, 2001, pages 84–85).

light. Included in the genetic factors are ATP-binding cassette transporter retina and A2Eproteins.

Diagnosis

Funduscopy reveals subretinal neovascular-ization in the macular area, exudation from thenewly formed blood vessels, retinal edema, andhemorrhage in patients with ARD. Fluoresceinfundus angiography with indocyanine green isnow available to identify choroidal neovascu-larization, in addition to conventional angio-graphy with sodium fluorescein. Optical coher-ence tomography makes possible the cross-sectional examination of the retina, and playsa critical role in investigating the presenceof subretinal neovascularization, the extent ofretinal detachment, and in providing improvedimages after treatment.

These new techniques have allowed visual-ization of the detailed state of spread of sub-retinal neovascularization, which was previ-ously impossible with conventional funduscopicexamination or fluorescein fundus angiographyusing sodium fluorescein.

�Topics


Treatment

This section describes the pharmacotherapy,non-invasive and invasive treatments that arecurrently available for ARD.

1. PharmacotherapyAlthough there is no well established phar-

macotherapy for ARD, therapeutics includingperipheral vasodilating drugs, vitamin B12, or �and �- interferon have been used. In animalexperiments, tranilast, kinase inhibitors, andperoxisome proliferator activated receptor-�ligands have been found effective in suppress-ing neovascularization. Studies have also beenconducted on antagonists for vascular endo-thelial growth factors and their receptors.

2. Non-invasive treatmentLaser photocoagulation is performed when

the distance between the neovascular mem-brane and the center of the macula is over200�m, as measured by fluorescein fundusangiography with sodium fluorescein or indo-cyanine green. The entire neovascular mem-brane should be thoroughly photocoagulated,or recurrence may occur in areas not coagu-lated. However, photocoagulation cannot beperformed on bleeding areas. In addition,caution should be exercised when performingphotocoagulation, as neurons within the photo-coagulated areas die. Subsequently, the area ofcoagulation may enlarge in the healing processand reach the central portion of the macula,resulting in an unexpected deterioration ofvisual acuity.

Low dose radiation therapy is used to occludenewly formed vessels by irradiation of the pos-terior pole of the fundus with about 20 Gy.The therapy is highly effective in some cases,particularly when the hemorrhage has alreadyreached the macula, as photocoagulation ther-apy is not applicable in such cases.

Photodynamic therapy (PDT) is a treatmentmethod that has recently attracted attention.PDT is designed to selectively destroy only

K. MASUDA

neovascular membranes by intravenously inject-ing a photosensitive agent, followed by irradia-tion with a laser at a specific wavelength thatdoes not harm normal neurons. This method-ology makes possible the coagulation of newlyformed blood vessels in the fovea centralis ofthe macula, which should not be photocoagu-lated. Verteporfin (Visudyne) has been used asa photosensitive agent. Results of one- andtwo-year clinical studies have demonstratedthe effectiveness of PDT with verteporfin inthe wet form of ARD. Other photosensitiveagents have also been studied and PDT is likelyto become an important treatment option inthe future.

Transpupillary thermal therapy is designedto occlude newly formed blood vessels by heat-ing choroidal neovascular membranes with anear-infrared diode laser. Its effectiveness, how-ever, has not been established.

3. Invasive treatmentEvacuation of subretinal hematoma is a sur-

gical technique designed to remove hematoma,before accumulation of blood in the inferiorportion of the retinal macula results in irre-versible damage to retinal neurons. In thisprocedure, an incision is made in the retinaclose to the hematoma, and tissue plasminogenactivator is injected via the incision into thehematoma which is dissolved and is removed.Although this technique has yielded favorableresults, it must be performed before the pres-ence of a hematoma results in retinal neurondisorders.

Surgical removal of subretinal neovascularmembranes is designed to resect submacularneovascular membranes by insertion of a for-ceps via a retinal incision near the macula.However, the surgery results in inevitable dam-age to retinal pigment cells or their extractiontogether with resected neovascular membranesduring surgery. As a result, the retinal neuronsof the macula cease to function and the prog-nosis is by no means favorable.

Recently, a surgical procedure has been per-


AGE-RELATED MACULAR DEGENERATION

formed in which pigment cells from the patient’siris have been cultured and then transplantedto the area where retinal pigment cells werelost after surgical removal of vascular mem-branes. This procedure was shown to be success-ful and is likely to provide a promising treat-ment option in the future.

Macular translocation surgery is performedto preserve the function of photoreceptor cellsof the macula. In the procedure, the entireretina is cut around the periphery, and it isrotated around the optic nerve papilla andrepositioned to an area where the retinal pig-ment cells are healthier. Although the rotationof the retina leads to anomalous retinal corre-spondence, resulting in a distorted image (theextent of distortion corresponds to the degreeof rotation), the patients eventually becomeaccustomed to this new image.

Conclusion

The incidence of ARD is expected toincrease in Japan. Although there are no wellestablished treatments for ARD at present, anumber of promising pharmacotherapy, non-invasive and invasive treatment options arebeing investigated.

REFERENCES

1) Tamai, S.: Age-related macular degeneration:Clinical conditions and new development intreatment. Rinsho-ganka 2000; 54: 1664–1673.(in Japanese)

2) Treatment of age-related macular degenera-tion with photodynamic therapy (TAP) StudyGroup: Photodynamic therapy of subfovealchoroidal neovascularization in age-relatedmacular degeneration with verteporfin: oneyear results of 2 randomized clinical trials—TAP report 1. Arch Ophthalmol 1999; 117:1329–1345.

contents inhaled anti-asthmatic drugs, particularly inhaled corticosteroids, in the treatment of...

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