step-care management of asthma

DOI 10.1378/chest.109.4.1056 1996;109;1056-1065Chest

Roger C. Bone Goals of Asthma Management

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reviewsGoals of Asthma ManagementA Step-Care ApproachRoger C. Bone, MD, FCCP

The past 15 years have seen a rise in mortality andmorbidity resulting from asthma, despite a concurrentrise in general knowledge about the disease. Thestep-care strategy recognized these changes in its ap¬proach to asthma management; however, this ap¬proach should be used only with attempts to controlenvironmental allergens. Step-care therapy requiresthat patients be categorized by the severity of illness.Step-one therapy is used for mild, infrequent symp¬toms and involves treatment based primarily on in¬haled bronchodilators. Step-two therapy is institutedin all asthmatics except the mildest cases; it involvestreatment by inhaled corticosteroids, cromolyn, or

nedocromil. Step-three treatment targets cases of se¬

vere asthma through the use of oral corticosteroids. In

all phases of treatment, however, it should be remem¬bered that patient education is of critical importance.Education improves patient compliance and is criticalto the successful treatment of asthma.

(CHEST 1996; 109:1056-65)

AHR=airway hyperresponsiveness; EIB=exereise-inducedbronchoconstriction; MDI=metered-dose inhaler; PEF=peak expiratory flow

Key words: airway hyperresponsiveness; bronchodilator;circadian rhythm; cytokines; inflammatory response; medi¬ators

r|^he past 15 years have seen a rapid expansion of our-"- knowledge regarding the pathophysiology ofasthma. Ironically, however, this advance has beenparalleled by an increase in both the frequency ofasthma and in the mortality and morbidity resultingfrom asthma. Although this may seem to be a conun¬

drum, it is probable that part of the reason for theseworsening asthma statistics is that physicians are notaware of these advances and their implications. Re¬search has now made clear that asthma is an inflam¬matory disease. This replaces the older and simplerconcept that the roots of this disease are based in

bronchospasm and resultant airways obstruction, whichdefine the essential physiologic abnormalities ofasthma. This physiologic basis for the disease is so

radically different from earlier explanations ofasthma s

pathogenesis that one researcher has felt justified in

renaming asthma a "chronic desquamative eosino-

philie bronchitis."1This new description ofasthma s pathogenesis makes

necessary alternative clinical approaches to the disease.Although the treatment of bronchospasm associatedwith asthma is essential, it is also important to consider

*From the Medical College of Ohio, Toledo.Manuscript received May 30, 1995; revision accepted November 7.Reprint requests: Dr. Bone, President and ChiefExecutive Officer,Professor of Medicine, Medical College of Ohio, 3000 ArlingtonAvenue, Toledo, OH 43614

the inflammatory aspect of the disease. Such an

approach to asthma has been described as step-caretreatment of asthma.2,3 This approach is algorithmic innature and promotes a graded response during treat¬ment, depending on the severity of disease. It alsoconforms to the guidelines offered by the NationalInstitutes of Health, British Thoracic Society, and theInternational Consensus Report on the Diagnosis andManagement of Asthma.4"6

PathophysiologyAsthma occurs in phases because the inflammatory

response is composed of a multitude of mediated in¬teractions, each with its own time frame. The acuteasthmatic response is characterized by wheezing andcoughing. The corresponding response in terms of in¬flammation consists of interactions between an aller¬gen and a mast-cell-bound IgE molecule. This acti¬vates the mast cell, which then releases histamine andother mediators of inflammation resulting in smoothmuscle contraction, increased vascular permeability,and vasodilation. This early response is rapid, occurringwithin minutes, and attracts other inflammatory cellsthat join in the response. Glandular activity is alsostimulated by this inflammatory cascade, resulting inthe secretion of mucus into the airways. The mucus

causes coughing and may result in dyspnea if the ob-

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Table 1.How Step-Care Affects the Early-Phase and Late-Phase Pulmonary Response*

Therapy Candidates Drug TherapyEarly-PhaseResponse

Late-PhaseResponse

Mechanismof Action

Step-one: Relieveacute symptoms

Patients with mildintermittentasthma

Step-two: Protectagainst andmanageinflammation withagents that havefew toxic effects

Patients with otherthan the mildestcase of asthma;step-two therapyshould probably beused in all patientswith asthma

Step-three: Controlsevere

exacerbations

Patients with asthmarefractory to

step-one andstep-two agents

p2-Adrenergic agents,albuterol,bitolterol,mesylate,metaproterenolsulfate, pirbuterolacetate, terbutalinesulfate

Anticholinergic agent:ipratropiumbromide

Aerosolcorticosteroids:Beclamethasonedipropionate,flunisolide,triamcinoloneacetonide

Other: Cromolynsodium,nedocromil

Oral corticosteroids:Methylprednisolone,prednisolone,prednisone

Rapid reversal ofacute symptoms;relax smoothmuscle

Producesbronchodilation byinhibiting vagallymediatedbronchoconstriction

Effective therapy

Prophylactically blockinflammation

Ineffective

Do not preventinflammation; donot reduce or

reverse airwayhyperresponsiveness

Unknown

Prevent andeffectively manageinflammation;inhibit mucusrelease; reduce or

reverse AHR

Blockprophylactically;reduce AHR

Prevent and manageinflammation;inhibit edemaformation andmucus release;reduce or reverse

increased AHR

Reversemediator-inducedbronchospasm

Unknown

Inhibitinflammatory cellinflux; stimulateproduction oflipocortin, therebypreventingformation ofprostaglandins andleukotrienes

Stabilize and preventmast celldegranulation

Inhibit inflammatorycell influx;stimulateproduction oflipocortin, therebypreventingformation ofprostaglandins andleukotrienes

*Theophylline can be used as an adjunct to step-one or step-two therapy. Salmeterol can be added as an adjunct to step-two therapy. Adapted withpermission from Bone RC. Step care for Asthma. Journal of Challenges in Asthma 1992; 1:1-8.

struction is significant. Wheezing results from thecontraction ofairway smooth muscle in bronchospasm.The longer-term result of this inflammation is a

cellular infiltrate consisting ofeosinophils, neutrophils,and basophils, all ofwhich release additional mediatorsof inflammation. The number of lymphocytes andmonocytes within the lung increase within 12 h. Thesecells may be particularly important in bringing aboutthe chronic form of inflammatory response in asthmathrough the release of cytokines and arachidonic acid-derived mediators.7 This activity takes place in a timeframe of from 2 h to several days and longer followingactivation ofthe mast cells by antigen. This is called thelate-phase response.One important effect of this inflammation is the

sensitization and disruption ofthe airway lining, whichcan, in turn, cause irritation with reflex coughing. Thisnonspecific bronchial reactivity may underlie suchforms of asthma as exercise- and cold-induced asthmaand other responses to environmental changes, inhaledirritants, and infectious stimuli. Additionally, this long-

term response leaves the tissues sensitized and anyfurther interaction with allergens may cause a dramaticresponse, termed hyperresponsiveness. The terms ex¬

trinsic and intrinsic have long been used to defineasthma, the former being associated with high circu¬lating IgE levels and a positive response to skin prickswith allergens. Although our current understanding ofasthma does not allow us to fully explain this difference,it could be that these two forms are actually differentphases of the same disease. Systemic responsivenessmay be lost with age, turning the extrinsic into the in¬trinsic form of the disease.8

Long-term inflammation is also associated with an¬

other detrimental response.that of fiber deposition.Inflammation mediators have powerful effects on a

variety of cell types, including that of inducing thegenes for various connective tissue fibers. Althoughthis may be appropriate in areas where severe tissuedestruction has occurred, it is not advantageous inchronic asthma. Fibrosis, together with smooth musclehypertrophy, thickens the airway walls and causes fur-

CHEST /109 / 4 / APRIL, 1996 1057



OH OH

OH-f VCH-CH2-NH-CH3

Adrenaline

9" OH CH2H5 CH30H"\I/CH~ CH2~NH~9H

CH3

OH OH

OH-^VCH-^ CH2~NH

Isoetharine

CH3-9HCH3

IsoproterenolFigure 1. First-generation (3-adrenergic agonists. These are theolder p-agonists that are generally shorter acting and less specificfor p2~adrenergic receptor. These are rarely used today.

ther obstruction.There is a strong circadian rhythmicity to the

severity of asthma that exhibits its worst symptomsbetween 3 and 5 am. A form of asthma termednocturnal asthma, in which the patient awakes duringthe night with breathing difficulties, is often seen.

Pulmonary function values in nocturnal asthma mayvary by as much as 50% between 4 pm and 4 am.9During the night, increased numbers of inflammatorycells can be found in the BAL of patients with noctur¬nal asthma.10 This form of disease may be responsiblefor half of all asthma deaths. Although the cause ofthese circadian swings in severity is not fully under¬stood, there is undoubtedly input from a variety ofdifferent factors. These swings may have direct andindirect effects on the airways.

Patients with asthma may have disease of widelyvarying seriousness; symptoms may range from mild,episodic wheezing to acute exacerbations with life-threatening dyspnea. The episodic and circadian na¬

ture of asthma s symptoms are important consider¬ations during the assessment of a patient. Wheezing,breathlessness, and cough occurring in an episodicfashion are the hallmarks of asthma. Because of thisepisodic nature, detailed pulmonary function testscannot be performed frequently enough to providemuch useful information. However, measures of thepeak expiratory flow will be useful because they can beobtained easily at any time with small peak expiratoryflow gauges that can be used at home. Drug therapyshould be preceded by an attempt to control thepatient's exposure to environmental allergens andirritants.

Environmental risk factors in the development ofasthma appear to be potentially preventable. It may besafe to assume that changes in lifestyle and exposure to

allergens and sometimes dietary factors may be re¬

sponsible in the development ofasthma. However, dietas a risk factor is circumstantial. Asthma has a multi-factorial etiology and several factors may play inde¬pendent roles in its development.11 The evidence that

9* OH

/r~VcH-CH2-NH-CHOH

CH3

CH3

MetaproterenolOHNCH,

OH

2 OH CH3CH-CH2-NH-C-CH3

-n-OH CH3OH-^ VCH-CH2-NH-C-CH3

CH3

/""VcH-CHg-NH-CoV .>

Albuterol

Terbutaline

H3C

oco

OH\

&\CH-CH2- NH-CHCH3

OH CH3

H3C-/JV0CO4> OH CH3 PirbuterolCH-CH2- NH-CH

CH3

BitolterolFigure 2. Second-generation P-adrenergic agonists. These aremore specific for the p2-adrenergic receptor and have a longer du¬ration of action than the first-generation drugs. These agents areused as step-one agents for acute exacerbations of asthma.

allergens play a major role in asthma is undisputable.The levels of allergen exposure clearly influence theprevalence of airway hyperresponsiveness (AHR) insensitized subjects. Sensitization to house dust-miteallergens and to mold spores in dry climate has beenreported. The house dust-mite allergens are more im¬

portant than cat and cockroach allergens in predispos¬ing children to increased sensitization and morbidi-

12,13

The prevalence of asthma appears to be more com¬

mon in some urbanized regions. Air pollution has beenimplicated in the increased prevalence of asthma.Studies have indicated that lifestyle factors associatedwith modern living conditions increase the symptoms.For example, children living in industrial regions mayhave more severe airway responsiveness than childrenliving in rural regions.14'15 Exposure to passive smok¬ing and its effects on lung function have been studied.Babies whose mothers smoke have increased hair co¬

tinine and nicotine levels. Cotinine levels in youngchildren are related to the number ofsmokers towhomthe child is exposed. Other factors such as socioeco-nomic class and inadequate home ventilation may in¬crease exposure and enhance its effects.16'17 Since it iswell documented that allergens increase the severity ofboth AHR and morbidity, it is important that new ap¬proaches to avoid allergen exposure be explored. Newmethods may help reduce the incidence of asthma inall situations. Reduction ofrisk in even a minority ofthechildren would lead to an important public health

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Table 2.Agents to Consider in Step-Two Care*

Agent Route DosageAerosol corticosteroids

Beclomethasone

Flunisolide

Triamcinolone

AntiallergicsCromolyn sodiumNedocrimil

MDI, 43 ug per puff

MDI, 800 ug per puffMDI, 1.75 mg per puff

8 puffs or 336 ug; reduce to 2 puffs twice

per day when asthma is stableTriamcinolone

4 puffs or 1,000 pg; reduce to 2 puffs twice

per day when asthma is stableAntiallergics

8 puffs or 800 ug; reduce to 2 puffs twice

per day when asthma is stableCromolyn sodium

2 puffs, 4 times per day2 puffs, 4 times per day

*TheophyIline can be used as an adjunct to step-two agents. Adapted with permission from Bone.2

benefit. Some basic examples that improve health andmarkedly reduced allergen exposure include use ofgreater allergen-free furniture and homes, mattresscovers, and improved ventilation.18"20

Allergen-specific immunotherapy has been used formany years in the treatment of asthma. Recent trialsindicated that immunotherapy reduces asthma symp¬toms caused by house dust mites, cat dander, Alter-naria and Cladosporium molds, and grass, birch tree,and ragweed pollen.21 Use ofimmunotherapy remainscontroversial because to my knowledge, no study hasdefined the amount of medication required that can

significantly control the symptoms. Immunotherapyfor at least 3 years is optimal in patients with seasonalallergic rhinitis.22 New forms of immunotherapy (sub-lingual and oral) have recently been tried in an attemptto improve on convenience, with beneficial results.23^4Treatment of allergic rhinitis may result in an improve¬ment in asthma symptoms. In the patient with allergicrhinitis, nasal corticosteroid therapy may prevent the

seasonal increase in bronchial responsiveness to meth¬acholine. Nasal corticosteroids may have a protectiveeffect in patients with airway reactivity, perennialrhinitis, and asthma. Thus, rhinitis should be treatedaggressively in all patients with allergic asthma.2526

Other factors that have been implicated in the de¬velopment of asthma are psychological factors. Theprevalence and importance of psychogenic factors inasthma have been debated but evidence suggests thatpsychological stressors can lead to clinically significantdeterioration in asthma control.27"29 It is known incertain asthma patients that psychological factors playan important role in the stability or instability of thedisease and the patients' ability to participate in cogentself-management planning. In a recent study, agora¬phobia and panic disorder were more frequendy seen

in patients with asthma in outpatient clinics than in thegeneral population.30 In that study, significant im¬

provement was observed in patients who had autoge-nic therapy. Autogenic therapy is a psychophysiologic

Table 3.Management Plan Based on Measurement ofPEF*PEF Measured Every Morning or More Frequently if Unstable

PEF >70% potential normal value, continue "maintenance regimen" of(a) Inhaled p-sympathomimetic, as required(b) Inhaled corticosteroid twice daily

PEF <70% potential normal value(a) Double dose of inhaled corticosteroid for number of days required to achieve previous baseline(b) Continue this increased dose for same number of days(c) Return to previous dose of maintenance regimen

PEF <50% potential normal value(a) Start oral prednisone therapy, 40 mg daily, and contact physician(b) Continue this dose for the number of days required to achieve previous baseline(c) Reduce oral prednisone therapy to 20 mg daily for same number of days(d) Stop prednisone therapy

PEF < 150-200 L/min(a) Start oral prednisone therapy as above(b) Contact physician urgently or, if he or she is unavailable(c) Contact ambulance service or, if it is unavailable(d) Go directly to hospital

*Adapted from Beasley et al.46

CHEST /109 / 4 / APRIL, 1996 1059



Table 4.Example ofManagement Plan*

Potential Normal PEFf 550 L/min

Routine treatmentCorticosteroid inhaler puff 2xdayInhaled P-sympathomimetic inhaler as required

PEF <400 L/min: Increase inhaled corticosteroid to 1 puff 4xday and inhaled P-sympathomimetic as requiredPEF <250 L/min: Prednisone, 40 mg/d until PEF >500 L/min, then prednisone, 20 mg/d for same number of daysPEF <150 L/min: Begin oral prednisone therapy as above and contact physician urgently or go to hospital emergency department

*Example of written management plan given to a male patient aged 39 years.^Predicted PEF=540; best consistent PEF 550 L/min. Adapted from Beasley et s\.4

technique consisting of concentration on anatomic lo¬cations and physiologic processes in improving respi¬ratory function.

Treatment

Treatment of asthma should be based on the sever¬

ity ofthe disease. With the recognition of asthma as an

inflammatory disease, the goal of the treatment shouldbe to reduce bronchospasm and the inflammatorychanges. Recently, the emphasis in the treatment hasmoved from treating the symptoms with bronchodila¬tors such as P-agonists to prophylactic inhaled corti¬costeroid treatment. Step-care therapy has been de¬signed with the goal of reducing or arresting theinflammatory processes underlying asthma.

Step-Care Therapy

Step-care therapy is a systematic management ap¬proach for the control of asthma. Step-care therapyrequires that the patient first be categorized as to theseverity of disease (Table 1). Based on the severity ofthe disease, therapeutic approaches have been de¬signed (step-one, step-two, or step-three therapy).4Step-One Therapy

Step-one therapy is appropriate for patients whomanifest mild symptoms on rare occasions. The life¬style of these patients is not affected greatly by thedisease. The clinical goal of step-one therapy is to

provide prompt relief from the symptoms, which maybe achieved usually with short-acting inhaled bron¬chodilators. Inhalers containing epinephrine are stillavailable without prescription and provide moderatebut relatively brief bronchodilation.The adrenergic receptors important in the treat¬

ment of asthma are predominantly P-receptors. P-Re-ceptors are subclassified as Pi-, P2-, and p3-receptors.Although other receptors are present in the lungs,bronchodilation is achieved mainly by P£-receptors.These receptors are further divided based on the du¬ration of action. These are short acting at 3- to 6-hduration of action, and those that are long acting havea duration of action of more than 12 h. p-Adrenergicagonists achieve their effects by binding to P2-adren-

ergic receptors. These receptors belong to a largegroup of receptors whose effects are brought about bya cascade of events that include activation of a G-pro-tein which, in turn, activates adenylate cyclase to con¬

vert adenosine triphosphate to cyclic adenosine mono¬phosphate. In the smooth muscles ofthe airways, cyclicadenosine monophosphate has the effect of relaxation,thus increasing the diameter ofthe airway. P2-Agonistshave nonbronchodilator effects in addition to bron¬chodilation. The nonbronchodilator effects includeenhancement of mucocilliary clearance, inhibition ofcholinergic neurotransmission, enhancement of vascu¬lar integrity, and inhibition of mediator release frommast cells, basophil, and also other cells. For relief ofacute symptoms, and also for prevention of exercise-in¬duced bronchospasm, more specific P2-adrenergic ag¬onists are preferred. They act rapidly (with a rapid peakeffect) and locally with few side effects (Figs 1 and 2).The limitations of short-acting p-agonists are (1)

their inability to control the symptoms of nocturnalasthma and (2) their short duration of protectionagainst exercise-induced bronchospasm. Both limita¬tions are related to the short duration of action oftheseagents. These agents should be used as occasionrequires for asthma symptoms. They should not beused unless there is a deterioration in peak flow or

development of symptoms. Among the short-actingdrugs that are currently available in the United States,there is little reason to choose one drug over the oth¬ers.

Investigators continue to develop p-adrenergic ag¬onists with improved activity. These forms are now

more specific for the p2-adrenergic receptor subtypefound in the lung airways and have fewer cardiaceffects. The adrenergic receptors themselves have alsobeen the subject of intense interest, being almostubiquitously expressed by human cells. The cloning ofthis gene has helped researchers to find new subtypesof the gene, while space-filling models have helpedresearchers to understand the finer points of receptor-ligand interactions.31

P2-Adrenergic agonists are the most effective bron¬chodilators for the treatment of acute episodes ofasthma and for the prevention of exercise-induced

1060 Reviews



9 HH-C-N

OH

HOCH2

-{ V-CH(OH)CH NHCHC

Formoterol

CH, /=

/"0CH3

0H A yCH(°H)CH2NHCH2CH2CH2CH2CH2CH2OCH2CH2CH2CH"\ /

SalmeterolFigure 3. Third-generation P-adrenergic agonists. These are more

selective for the P£-adrenergic receptor and have a longer durationof action than the first- and second-generation agents. Salmeterolhas been recently approved for use in the United States. See textfor recommendations regarding use of these agents.

bronchoconstriction. The long-acting P2-adrenergicagonists prevent nocturnal asthma and provide pro¬longed protection against exercise-induced broncho¬constriction. The long-acting P2-adrenergic agonistsshould be administered only at regular, prescribed in¬tervals. Short-acting P2-agonists should be given in¬stead of additional doses to relieve symptoms. InhaledP2-adrenergic agonists remain the most important classof bronchodilators currently available. When used ap¬propriately, they provide safe and effective relief ofsymptoms of airflow obstruction.32An important hindrance to achieving the full bene¬

fits offered by P-agonists is the improper use ofmetered-dose inhalers (MDIs); as many as 50% ofpatients using MDIs do so incorrectly. These patientsare not appropriately treated. Misuse often continueseven after repeated rounds of instruction.33 The most

significant problem seems to be coordinating the acti¬vation of the canister with an appropriate inhalation.Although the use of spacer devices is recommended,patients often do not carry them or do not use them.A patient's MDI technique should be observed care¬

fully by the physician who prescribes it. Othercommonproblems with MDI use include failure to shake thecanister before the use, inadequate breath holding, andthe failure to wait between puffs. Correct use of MDIis a skill taught through patient education.To overcome this problem, an auto inhalation device

has been introduced. This device is triggered by thepatient's inhalation rather than by hand actuation.Pulmonary function in patients receiving pirbuterolacetate via a MAXAIR Autoinhaler (3M Pharmaceuti¬cals; St. Paul, Minn) and those patients using standardMDIs were compared. Both systems produced similarresults in spirometry. This may be due to the two puffsof perbuterol regardless of the delivery system. Auto-inhalers are as effective as correctly used MDIs and are

a viable alternative for patients who have coordinationproblems with the standard MDI. Children whosepeak inspiratory flow rate is less than 0.5 L/s may not

be able to use the Autoinhaler correctly. Correct use

of the Autoinhaler will depend on effectively educat¬ing patients.34'35

Anticholinergic agents, such as ipratropium bro¬mide, are another form of drug that can be used in thetreatment of mild, occasional asthma (step-one thera¬py), after inhaled P-agonists are used. Vagal tonereleases aeetylcholine at nerve endings on the airways,resulting in a tonic smooth muscle contraction. Al¬though the numbers of acetylcholinergic receptorswithin the airway walls may vary considerably on an

individual basis, treatment with anticholinergics can

have a positive effect by inducing smooth muscle re¬

laxation. Studies indicate that anticholinergics may beadditive with P-agonists in providing relief to patientswith asthma.36 Patients with nocturnal asthma mayderive additional benefits from treatment with anti¬cholinergics. Because of the increase in vagal tone thatoccurs during sleep, aeetylcholine release at the airwaysmooth muscle may be implicated as a cause ofnocturnal asthma, making anticholinergics an appro¬priate therapy in some patients. Inhaled ipratropiumon waking has been shown to be effective in this con¬

dition.37Theophylline and other methylxanthines improve

pulmonary function, although the mechanisms bywhich they work have not been described adequately.Theophylline has a narrow therapeutic index and maybe toxic at doses just above those effective for asthmatreatment. Various guidelines for asthma managementrecommend the use of theophylline or aminophyllinein cases that respond poorly to aerosol MDIs and forshort-term exacerbations. Theophylline is regarded as

a weak bronchodilator with a high toxicity potential andits use has been declining. Recently, however, theo-phylline's properties as an anti-inflammatory agent andan immunomodulator have been emphasized. Al¬though serious drug toxic reactions, including cognitiveand behavioral side effects, have been reported, theo¬phylline can add to and prolong the responses to

P-agonists because it is also a weak anti-inflammatoryagent. It should be considered for use in asthmaticpatients who require oral corticosteroids.

It has been reported that low-dose therapy attenu¬ates the late asthmatic inflammatory response to

allergen through modulating an effect on lymphocytes,demonstrating the immunomodulatory role of theo¬phylline. Long-acting theophylline in low doses, witha serum concentration of 5 to 10 mg/L, may have a

significant effect in patients with unstable asthma.Theophylline, therefore, may have a more significantrole in future guidelines for the management of asth¬ma.5'6'38 Theophylline should be reserved for use as an

adjunct in step-one or step-two therapy and if used,blood levels of the drug should be monitored fre¬quently to prevent toxic reactions.

CHEST /109 / 4 / APRIL, 1996 1061



Step-Two TherapyWhen a patient with mild asthma begins to use in¬

haled bronchodilators on a regular basis, it is a sign thatthe disease is worsening and that step-two therapyshould be instituted (Table 2). Step-two therapy con¬

sists of daily medication with anti-inflammatory agentssuch as inhaled corticosteroids nedocromil or cro¬

molyn plus bronchodilators (inhaled P2-agonist as oc¬

casion requires, oral theophylline, oral P2-agonist). Themainstay of this treatment level is an inhaled cortico¬steroid. Corticosteroids act by decreasing the inflam¬mation that underlies hyperresponsivity and broncho¬spasm. The goal oftheir use is to manage the late-phaseinflammatory response while minimizing treatmentside effects. Inhaled corticosteroids have been shownto provide a protective effect against the deteriorationin lung function seen with prolonged regular use ofinhaled bronchodilator therapy alone.39

Studies have shown that inhaled corticosteroids havelittle effect on exercise-induced bronchoconstriction(EIB), unless it is taken for several weeks.4041 Al¬though corticosteroids have the ability to attenuateEIB, inhaled corticosteroids will not replace inhaledP2-agonists or cromolyn as the best prophylactictreatment for EIB. Inhaled corticosteroids have theability to prevent or reduce airway inflammation andAHR. The anti-inflammatory effect of inhaled corti¬costeroids in the treatment of asthma has been dem¬onstrated in several studies. Inhaled corticosteroidshave been shown to decrease eosinophil number anddensity as well as improve epithelial quality and reduceinflammatory cell infiltrate.42"44

There are several mechanisms involved in theinflammatory response that may be influenced bycorticosteroid therapy. The two important areas thathave been investigated are the decreased production ofcysteinyl leukotrienes and interference with the actionof proinflammatory cytokines. Cysteinyl leukotrienesare known to be involved in both early and late aller¬gic asthmatic responses. Inhaled corticosteroid treat¬ment attenuates both early and late responses; the in¬crease in leukotriene E4 excretion following allergen isnot attenuated. It is known that corticosteroid treat¬ment in vitro will inhibit phospholipase A2 responsiblefor eicosanoid synthesis. The increase in leukotriene E4excretion following allergen challenge may reflect a

whole-body increase in leukotriene production. In¬haled corticosteroids acting preferentially on the air¬

way may thus decrease local leukotriene productionwithout influencing urinary leukotriene E4.45 Corti¬costeroids have been known to reduce airway levels ofproinflammatory cytokines in patients with asthma.A recently developed technique that should consid¬

erably improve treatment is the implementation ofpeak flowmeters. These small, easy-to-use gauges

allow patients to measure their own peak expiratoryflow rates at home. The difference between morningand evening peak flow rates provides an estimation ofthe airway reactivity. When the difference exceedsapproximately 20% of the peak flow rate, additionaltherapy should be considered. Education, again, is thekey word: properly instructed patients should be ableto increase their own treatment dosage with inhaledcorticosteroids at the first sign of an exacerbation.A self-management plan in the treatment of adult

asthma has been devised that is specifically designed totackle the factors that contribute to death from asthma(Tables 3 and 4). This is a management regimen basedon regular objective assessment of airflow obstructionin association with adequate inhaled corticosteroidtreatment. This method was used in a study46 and hasbeen shown to be effective for adults with chronic se¬

vere asthma. The management plan is incorporatedwith several different treatment guidelines. The com¬

bination of these guidelines may have contributed tothe beneficial effect. The aim of this regimen is to starttreatment with oral corticosteroids in sufficient dosagewhen required early in an attack, and to use the sub¬sequent therapeutic response to determine the dura¬tion of the treatment. A combination of routine mea¬

surement of peak expiratory flow and a self-management plan appears to be effective in reducingsymptoms ofasthma and also improving lung function.

Cromolyn sodium and such related compounds as

nedocromil sodium are another form of therapeuticagent appropriate for step-two therapy. Although theirexact mechanisms of action are unknown, they appearto inhibit the release of inflammatory mediators bymast cells. By stopping the early-phase reaction inasthma, the tendency toward inflammation may bearrested before it starts. One of the most importantproblems with inhaled corticosteroids and cromolyn or

nedocromil is the failure of patients to follow theirtreatment regimens. To the patient conditioned to therapid and dramatic beneficial effects provided by theP-agonists, these drugs appear to be ineffective; addi¬tionally, they are relatively expensive. Failure to com¬

ply with the treatment regimen is common; patientsmust be instructed that these anti-inflammatory drugsalleviate the inflammatory response and that the ben¬efits are long term and aimed at preventing exacerba¬tions, rather than treating them. This approach alsoappears to inhibit both the late-phase reaction inasthma and the dramatic response usually obtainedfrom challenges with allergens.

Longer acting inhaled P2-adrenergic-agonist haveovercome many of the shortcomings of previouslyavailable drugs (Fig 3). Currently, long-acting agonistswith high specificity for the P2-receptor are being de¬veloped, such as salmeterol xinafoate and formoterol.Salmeterol is now available for use in the United States,

1062 Reviews



while the use of formoterol is still being considered.The longer-acting p-agonists are more selective for theP2-adrenergic receptor and their activity persists for a

longer period of time at the receptor site. Salmeterolis indicated for long-term, twice-daily administration inthe maintenance treatment of asthma and in the pre¬vention of bronchospasm in patients 12 years of ageand older with reversible obstructive airways disease,including patients with symptoms of nocturnal asthmawho require regular treatment with inhaled, short-term P2-agonists. It should not be used in patientswhen asthma can be managed with occasional use ofshort-acting p2-agonists.

Salmeterol should never be used more than twicedaily. Increasing its use in an acute attack is inappro¬priate and may be dangerous. Salmeterol should not beused to treat acute asthma symptoms because it has a

slower onset of action.47 Patients must be providedshort-acting, inhaled P2-agonist for treatment of acutesymptoms. Patients using salmeterol may feel wellenough and may discontinue the anti-inflammatorytherapy. This discontinuation could cause a seriousexacerbation of asthma because salmeterol is not a

substitute for oral or inhaled corticosteroid therapy. Itsuse maybe beneficial in patients with nocturnal asthmaand exercise-induced asthma as maintenance thera¬py48"51

Although salmeterol is a major advance in thetreatment of asthma based on the available data,salmeterol should be reserved for patients who are al¬ready receiving step-two anti-inflammatory therapy.48Longer-acting agents improve sleep quality, morningpeak-flow measurements, and nocturnal symptoms.49In one 12-month trial of salmeterol vs albuterol, therewas no deterioration with long-term administration.Salmeterol has also been shown to be effective forprotection against EIB for up to and including 12 h inpatients with mild to moderate asthma.52

Step-Three TherapyStep-three therapy is reserved for patients whose

asthma is not controlled by step-two treatment andconsists ofmore aggressive forms of anti-inflammatorytreatment, the mainstay ofwhich is oral corticosteroidsat doses high enough to stop the inflammation. Theincidence of side effects, which can be serious withhigh-dose corticosteroids, is decreased by the use ofagents with a short duration of action, such as pred¬nisone. It is critical that treatment with these be insti¬tuted at the first indication ofuncontrolled asthma. Toooften in fatal asthma, anti-inflammatory drugs were

administered too little and too late. Oral dosages ofprednisone as high as 40 to 60 mg/d may be used forup to 2 weeks to counter serious exacerbations ofasthma. Following such treatments, corticosteroid dos¬ages should be tapered to maintenance levels of aero¬

sol-administered drug. When a patient is particularlydifficult to wean from corticosteroid therapy, long-term, alternate-day therapy may be a reasonable route.This method is less likely to result in such serious sideeffects of corticosteroid use as suppression of the ad¬renal gland, hypertension, and aseptic necrosis. Other,less serious effects of this medication may include fluidretention, mood changes, and GI upset.From the point of view embraced by advocates of

step-care treatment for asthma, the occurrence of an

exacerbation requiring step-three therapy may be a

failure ofstep-two therapy. Through appropriate use ofthe peak flowmeter, patients should be able to antic¬ipate exacerbations and increase their dosage of corti¬costeroids accordingly. The goal ofthis form ofpatient-dispensed medication is to prevent the exacerbationsof asthma that may require hospitalization and more

radical forms of treatment.The above ideas are consistent with the guidelines

developed in 1991 by the National Asthma EducationProgram. The guidelines can be summarized in fourkey points: (1) pharmacologic therapy; (2) appropriatemonitoring; (3) patient education; and (4) control ofthe environmental allergens and irritants that cause

asthma. Recent studies have shown that inadequatepatient education remains an impediment to appro¬priate treatment.53 One study has obtained promisingresults with the use of small-group instruction, whichresulted in improved asthma control, even whencompared with a program ofindividualized instruction.Not only did the patients derive support from withinthe group, but educators seems more at ease and werebetter able to understand the problems associated withtreatment.54 To achieve adequate patient education,the patient-physician relationship must work well so

that the patient can be taught how benefits may bederived from treatment. They must understand thelong-term benefits as opposed to the short-term ben¬efits of these treatments, a task that should be seen to

by the physician. When patients understand theirtherapy, they are more likely to comply with thetreatment and their asthma will be better managed.

New Treatments

Leukotrienes, which are products of 5-lipoxygenasepathway of arachidonic acid metabolism, are thoughtto be important mediators in the pathogenesis ofasthma. Their biological activity produces changes thatare similar to those seen in asthma. It was demon¬strated that 5-lipoxygenase inhibitors or leukotrienereceptor antagonists give good protection to patientsundergoing acute allergen challenge in the laboratory.Recently, a new drug, Zileuton (Leutrol) was devel¬oped, which is an iron ligand inhibitor of 5-lipoxygen¬ase.55,56

CHEST /109 / 4 / APRIL, 1996 1063



Several other new anti-inflammatory drugs havebeen developed. These drugs, which are currentlybeing tested, may change the treatment strategy in thefuture. Although these dings show promise in preclin-ical and early clinical trials, their efficacy and safetyhave not been determined.57 One ofthe new drugs thathas reached phase 3 testing is Zafirlukast, a leukot-riene-receptor blocker shows great promise as an an¬

ti-inflammatory agent. This drug binds specificallywitha high degree of affinity to the leukotriene D and leu¬kotriene E receptors, whereas the steroids blockinflammation by inhibiting cytokine production.58 Zile¬uton acts by inhibiting the breakdown of arachidonicacid in the first biosynthetic step to forming leukot¬rienes.59 Vasoactive intestinal peptide and antagoniststo platelet activating factor are being developed forpossible use in the treatment of asthma.60 Specificmonoclonal or polyclonal antibodies, genetically mod¬ified or mass-produced endogenous molecules, andany other tools that can interfere with the pathogene¬sis of asthma and inflammation may become availablein the future.57Management ofasthma has become one ofthe most

important challenges to the medical profession be¬cause of its increasing occurrence and the conse¬

quently unexplained mortality. Increasingly poor airquality has been expressed as one ofthe reasons for therise in mortality. The multifactorial nature of the dis¬ease explains why some patients respond to some

treatments while others do not. The essential part ofthe diagnosis should be the determination of patient'sresponse to various treatments. The future lookspromising as several new drugs with various anti-inflammatory actions may become available for use inthe treatment of asthma.

References1 Reed CE. New therapeutic approaches in asthma. J Allergy ClinImmunol 1986; 77:537-43

2 Bone RC. A step care strategy for asthma management. J RespirDis 1988; 9:104-17

3 Bone RC. Step care for asthma. JAMA 1988; 260:5434 National Heart, Lung, and Blood Institute. National asthma ed¬

ucation program: expert panel on the management of asthma:guidelines for the diagnosis and management of asthma. Dept ofHealth and Human Services publication (NIH) 1991-3042

5 British Thoracic Society. Guidelines on the management ofasthma. Thorax 1993; 48:Sl-24

6 Pauwels R. The international consensus report on the diagnosisand management of asthma. Eur Respir Rev 1993; 3:483-89

7 Holgate ST. The role of mediators and inflammation in asthma.J Respir Dis 1987; 8:20-37

8 Burrows B, Bloom JW, Traver GA, et al. The course and prog¬nosis of different forms of chronic airways obstruction in a sam¬

ple of the general population. N Engl J Med 1987; 317:1309-129 Hetzel MR, Clark TJH. Comparison of normal and asthmatic

circadian rhythms in peak inspiratory flow rate. Thorax 1980;152:511-17

10 Martin RJ, Cicutto LC, Smith HR, et al. Airway inflammation in

nocturnal asthma. Am Rev Respir Dis 1991; 143:351-5711 Seaton A, Godden DJ, Brown K. Increases in asthma: a more toxic

environment or a more susceptible population? Thorax 1994;49:171-74

12 Call RS, Smith TF, Morris E, et al. Risk factors for asthma in in¬ner city children. J Pediatr 1992; 121:862-66

13 Peat JK, Tovey EJ, Mellis CM, et al. Importance of house dust-mite and Alternaria allergens in childhood asthma: an epidemi-ological study of Australia. Clin Exp Allergy 1993; 23:812-20

14 Magnussen H, Jorres R. Effect of air pollution on the prevalenceof asthma and allergy: lessons from the German reunification.Thorax 1993; 48:879-81

15 Forastiere F, Corbo GM, Pistelli R, et al. Bronchial responsive¬ness in children living in areas with different air pollution levels.Arch Environ Health 1994; 49:111-18

16 Eliopoulos C, Klein J, Phan MK, et al. Hair concentrations ofnicotine and cotinine in women and their newborn infants. JAMA1994; 271:621-23

17 Cook DG, Whincup PH, Jarvis MJ, et al. Passive exposure to to¬bacco smoke in children aged 5-7 years: individual, family andcommunity factors. BMJ 1994; 308:384-89

18 Peat JK, Woolcock AJ. Trackling asthma: new approaches to oldproblems: why not prevent asthma [editorial]? Med J Aust 1994;160:604-06

19 Tovey E. House dust control measures: are they worthwhile?Mod Med Aust 1993; 8:118-27

20 Warner JA. Creating optimal home conditions for the dust-mite.Clin Exp Allergy 1994; 24:207-09

21 Bousquet J, Francois MB. Immunotherapy in asthma: is it effec¬tive? J Allergy Clin Immunol 1994; 94:1-11

22 Mosbech H, Osterballe O. Does the effect ofimmunotherapy lastafter termination of treatment? Allergy 1988; 43:523-29

23 Nelson HS, Oppenheimer J, Vatsia GA, et al. A double-blind,placebo-controlled evaluation of sublingual immunotherapy withstandardized cat extract. J Allergy Clin Immunol 1993; 92:229-36

24 Oppenheimer J, Areson JG, Nelson HS. Safety efficacy of oralimmunotherapy with standardized cat extract. J Allergy Clin Im¬munol 1994; 93:61-7

25 Welsh PW, Strieker WE, Chu-pin C, et al. Efficacy of beclom¬ethasone nasal solutions, flunisolide, and cromolyn in relievingsymptoms of nasal allergy. Mayo Clin Proc 1987; 62:125-34

26 Watson WT, Becker AB, Simons FER. Treatment of allergicrhinitis with intranasal corticosteroids in patients with mildasthma: effect on lower airway responsiveness. J Allergy ClinImmunol 1993; 91:97-101

27 Snadden D, Brown JB. The experience of asthma. Soc Sci Med1992; 34:1351-61

28 Lehrer PM, Isenberg S, Hochron SM. Asthma and emotion: a

review. J Asthma 1993; 30:5-2129 Davis D. Asthma and the psyche [editorial]. Thorax 1993; 48:51130 Shavitt RG, Gentil V, Mandetta R. Association of panic/agora¬

phobia and asthma: contributing factors and clinical implications.Gen Hosp Psychiatry 1992; 14:420-23

31 Hodgson SV, McPherson A, Friedman M. The effect of be-tamethasone valerate aerosol on exercise-induced asthma inchildren. Postgrad Med J 1974; 50:S69-72

32 Laitinen LA, Laitinen AL, Haahtela T. A comparative study oftheeffects of an inhaled corticosteroid, budesonide and p2-agonist,terbutaline on airway inflammation in newly diagnosed asthma:a randomized, double blind, parallel-group controlled trial. J Al¬lergy Clin Immunol 1992; 90:32-42

33 Robinson D, Hamid Q, Ying S, et al. Prednisolone treatment inasthma is associated with modulation of the bronchoalveolar la¬vage cell interleukin-4, interleukin-5, and interferon-gamma cy¬tokine gene expression. Am Rev Respir Dis 1993; 148:401-06

34 Henriksen JM. Effect ofinhalation ofcorticosteroids on exercise-induced asthma: randomized double blind crossover study of

1064 Reviews



budesonide in asthmatic children. BMJ 1985; 291:248-4935 Evans PM, O'Connor BJ, Fuller RW, et al. Effect of inhaled

corticosteroids on peripheral blood eosinophil counts and densityprofiles in asthma. J Allergy Clin Immunol 1993; 91:643-50

36 Rebuck AS, Chapman KR, Abbound R, et al. Nebulized anti¬cholinergic and sympathomimetic treatment of asthma andchronic obstructive airways disease in the emergency room. AmJ Med 1987; 82:59-64

37 Morrison JFJ, Pearson SB, Dean HG. Parasympathetic nervous

system in nocturnal asthma. BMJ 1988; 296:1427-2938 Milgrom H, Bender. Current issues in the use of theophylline.

Am Rev Respir Dis 1993; 147:533-3939 Dompeling E, van Schayck CP, van Grunsven PM, et al. Slow¬

ing the deterioration of asthma and chronic obstructive pulmo¬nary disease observed during bronchodilator therapy by addinginhaled corticosteroids. Ann Intern Med 1994; 118:770-78

40 Pederson S, Frost L, Arnfred T. Errors in inhalation techniqueand efficacy in inhaler use in asthmatic children. Allergy 1986;41:118-24

41 Schecker MH, Wilson AF, Mukai DS, et al. A device forovercoming discoordination with metered-dose inhalers. J AllergyClin Immunol 1993; 92:783-89

42 Kumana CR, So SY, Lauder IJ, et al. An audit of antiasthmaticdrug inhalation technique and understanding. J Asthma 1993;30:263-69

43 Green SA, Holt BD, Liggett SB. Betai and beta2-adrenergic re¬

ceptors display subtype-selective coupling to Gs. Mol Pharmacol1992; 41:889-93

44 Nelson HS. P2-Adrenergic bronchodilators. Drug Ther 1995;333:499-506

45 Bone RC. A word of caution regarding a new long-acting bron¬chodilator. JAMA 1994; 271:1448

46 Beasley R, Cushley M, Holgate ST. A self-management plan inthe treatment of adult asthma. Thorax 1989; 44:200-04

47 Bone RC. Another word of caution regarding a new long-actingbronchodilator. JAMA 1995; 273:967-68

48 Douglas NJ. Nocturnal asthma. Thorax 1993; 48:100-02

49 Kemp JP, Bierman CW, Cocchetto DM. Dose response study ofinhaled salmeterol in asthmatic patients with 24-hour spirometryand holter monitoring. Ann Allergy 1993; 70:316-22

50 Brambilla C, Chastang C, Georges D, et al. Salmeterol comparedwith slow-release terbutaline in nocturnal asthma: a multicenter,randomized, doubleblind, double dummy, sequential clinicaltrial: French multicenter study group. Allergy 1994; 49:421-26

51 Ramage L, Lipworth BJ, Ingram CG, et al. Reduced protectionagainst exercise induced bronchoconstriction after chronic dosingwith salmeterol. Respir Med 1994; 88:363-68

52 Interiano B, Guntupalli KK. Metered-dose inhalers: do healthcare providers know what to teach? Arch Intern Med 1993;153:81-5

53 Wilson SR, Scamagas P, German DF, et al. A controlled trial oftwo forms of self-management education for adults with asthma.Am J Med 1993; 94:564-76

54 O'Shaughnessy KM, Wellings R, Gillies B, et al. Differential ef¬fects of fluticasone proprionate on allergy-evoked bronchocon¬striction and increased urinary leukotriene E4 excretion. Am RevRespir Dis 1993; 147:1472-76

55 McMillan R, Walker E. Designing therapeutically effective 5-li¬poxygenase inhibitors. Trends Pharmacol Sci 1992; 13:323-30

56 Levine SJ. Bronchial epithelial cell-cytokine interactions in airwayinflammation. In: Shelhamer JH, moderator. Airway inflamma¬tion. Ann Intern Med 1995; 123:288-304

57 Bone RC. Asthma: new treatments will improve disease man¬

agement. Clin Pulm Med 1995; 2:1-958 Hui K, Taylor G, et al. Effect of a 5-lipoxygenase inhibitor on

leukotriene generation and airway responses after allergen chal¬lenge in asthmatic patients. Thorax 1991; 46:184-89

59 Israel E, Rubin P, Kemp J, et al. The effect of inhibition of 5-li¬poxygenase by zileuton in mild to moderate asthma. Ann InternMed 1993; 119:1059-66

60 Ford-Hutchinson A. Leukotriene antagonists and inhibitors as

modulators of IgE-mediated reactions. Springer Semin Immu-nopathol 1993; 15:37-50

CHEST /109 / 4 / APRIL, 1996 1065



DOI 10.1378/chest.109.4.1056 1996;109; 1056-1065ChestRoger C. Bone

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