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Mayo Clin Proc, December 2002, Vol 77 Managing Persistent Asthma 1333

Mayo Clin Proc. 2002;77:1333-1339 1333 2002 Mayo Foundation for Medical Education and Research

Concise Review for Clinicians

Management of Persistent Symptoms in Patients With Asthma

KAISER G. LIM, MD

From the Division of Pulmonary and Critical Care Medicine andInternal Medicine, Mayo Clinic, Rochester, Minn.

A question-and-answer section appears at the end of this article.

Address reprint requests and correspondence to Kaiser G. Lim, MD,Division of Pulmonary and Critical Care Medicine, Mayo Clinic, 200First St SW, Rochester, MN 55905.

The main goals of asthma therapy are to control symp-toms, prevent acute attacks, and maintain lung function asclose to normal as possible. Customizing the regimen torelieve the patients symptoms and control airway inflam-mation is important. If asthma is not well controlled, aninitial inhaled corticosteroid boost will treat the underly-ing heightened airway inflammation, and the addition of along-acting

2-adrenergic agonist or leukotriene receptor

antagonist will rapidly control symptoms. Most patientsdo not require prolonged treatment with expensive combi-nation or additive agents. Exercise-induced bronchocon-striction is a common source of symptoms. Treatments forscheduled and unscheduled exercises differ. Inhaled corti-costeroids prevent frequent and severe asthma exacerba-tions. When patients have persistent symptoms despite a

EIB = exercise-induced bronchoconstriction; FEV1 = forcedexpiratory volume in 1 second; HFA = hydrofluoroalkane;

ICS = inhaled corticosteroid; pMDI = pressurized metered-dose inhaler

pharmacological regimen, environmental factors andnonpharmacological interventions must be considered be-fore medication is increased. When an inhaled corticoste-roid is being considered, issues of compliance, drug deliv-ery device, and proper inhaler techniques are as importantas issues of potency, clinical efficacy, and adverse effects.The new hydrofluoroalkane preparations offer more lungdeposition and may be important in treating inflammationof the small airways in patients with asthma.

Mayo Clin Proc. 2002;77:1333-1339

Control of asthma symptoms is important since patientsexperience respiratory difficulty. Symptoms do notalways correlate strongly with objective measures of air-

way dysfunction, airway inflammation, or corticosteroid

requirement.1-3 As a therapeutic end point, resolution of

asthma symptoms is not always synonymous with resolu-

tion of the underlying airway obstruction and hyper-

responsiveness.4,5

Symptoms rather than underlying dis-ease severity reflect the level of asthma control.6 This fact

is important because symptom-based severity categoriza-

tion is often used to guide therapeutic decisions. Titrating

anti-inflammatory medication based on symptoms is an

imperfect science. High proportions of patients with

asthma do not reliably detect changes in their lung func-

tion.7-9 The perception of dyspnea associated with broncho-

constriction varies among patients.10 There is wide vari-

ability in bronchodilator use, even for similar degrees of

bronchoconstriction.

The initial choice of anti-inflammatory therapy is an

inhaled corticosteroid (ICS).11 The prescribed initial dose

often reflects the physicians clinical assessment of asthmaseverity.6 In the United States, specialists tend to pick

higher doses, whereas internists and pediatricians prescribe

lower doses of an ICS. Once the initial dose of ICS has

been determined, clinicians must choose an appropriate

strategy if the patient continues to be symptomatic. This is

the so-called step 3 option. However, several aspects of

anti-inflammatory therapy are unclear. For example, the

treatment regimen necessary to control asthma symptoms

may be insufficient for resolving inflammation, maximiz-

ing airway function, and preventing the accelerated longi-tudinal decline in lung function.12 Additionally, it is unclear

whether complete resolution of airway inflammation re-

sults in normalization of other features of asthma, ie, bron-

chial hyperresponsiveness and stabilization of airway func-

tion.13 A noninvasive, clinically convenient test to detect

and measure airway inflammation does not exist. There is

no equivalency of glycosylated hemoglobin to gauge ad-

equacy of anti-inflammatory therapy. With no objective

measure of inflammation, titration of therapy has been used

to achieve symptomatic control. A highly symptomatic

patient may require only a small dose of an ICS for symp-

tomatic control, whereas a patient with severe, persistent

asthma needs high doses of an ICS.14Itemizing the patients specific complaints, ie, symp-

toms, is important. By targeting symptoms with specific

pharmacological intervention, the clinician can monitor

treatment efficacy and determine the necessary therapeutic

duration. This approach is more logical than a generic

strategy of advocating additive or combination therapy for

the persistently symptomatic patient already using an ICS.

The following key questions should be addressed. Does the

patient have concurrent problems, such as sinusitis, rhini-


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Managing Persistent Asthma Mayo Clin Proc, December 2002, Vol 771334

Table 1. Five-Minute Assessment of Asthma Control

Nocturnal awakenings in the past 2 mo

Frequency of bronchodilator use/frequency of bronchodilator refill

Exercise or functional capacityExacerbation frequency and duration

Current peak flow and personal best peak flow

tis, or gastroesophageal reflux disease, that may affect

asthma control? When is the patient symptomatic? (Is it

exercise related, during exposure to cold air, nocturnal?) Is

the patient exposed to environmental triggers that need to

be eliminated? Is the patients dose of ICS adequate?

Asthma control can be assessed quickly (Table 1). Is-

sues of asthma control that influence the patients quality

of life include nocturnal symptoms, ability to exercise, and

frequency of breathlessness. Inquiring about the patients

current peak flow rate correlates current lung function and

symptoms. It will also be an opportunity to educate the

patient regarding home monitoring and other self-manage-

ment skills. This article reviews pharmacological interven-

tion, but nonpharmacological treatment options must not

be neglected. The clinician should quickly review triggers,

compliance with allergen avoidance, and other possible

environmental and/or nonpharmacological options in pa-

tients with asthma.

DOSAGE OF ICS

When an asthmatic patient receiving an ICS has persistent

or increased symptoms, adequacy of the anti-inflammatorytherapy is often an issue. The recommendation to increase

the ICS dose in a persistently symptomatic patient assumes

that the dose-response relationship is linear. However, dose

dependency has been shown only with prednisone discon-

tinuation in corticosteroid-dependent asthmatic patients

and in providing protection against exercise-induced

asthma.15,16 A dose-response improvement in forced expira-

tory volume in 1 second (FEV1) and in asthma symptoms

has been difficult to demonstrate in patients with mild to

moderate asthma.17 At low doses, inhaled glucocorticoids

profoundly improve the FEV1

until it is close to the plateau

portion of the curve. The dose-response relationship to

asthma symptoms, like daytime and evening symptoms anddaily bronchodilator use, is similarly flat.

Objective assessment of airway function in patients with

persistent asthma symptoms is important before the dose of

inhaled glucocorticoids is increased. A decrease in FEV1or

peak flow rate from baseline may indicate heightened air-

way inflammation or bronchial hyperresponsiveness, a

relative inadequacy of anti-inflammatory therapy, and a

requirement for a higher dose of the ICS. A stable or

unchanged FEV1

or peak flow rate from baseline may

indicate that the symptoms are due to other concurrent

illnesses like sinusitis, rhinitis, gastroesophageal reflux, or

heart failure. A decline in FEV1

from baseline in a patient

with increasing asthma symptoms is a helpful adjunct in

determining the need for increasing ICS therapy. If thepatients symptoms are related to exercise or cold exposure,

even if the lung function or FEV1

is stable, an empirical trial

of ICS boost may be necessary.18 A high sputum eosinophil

count (>5%) indicates the need for a higher dose of ICS.

In a symptomatic patient with mild to moderate asthma,

an initial boost of an ICS with higher doses of an ICS for 4

to 6 weeks will be effective for most cases of heightened

airway inflammation that may be causing more symptoms.

This would be equivalent to 4 to 6 weeks of 880 g of

fluticasone propionate or 800 to 1600 g of budesonide. Ofnote, airway inflammation takes time to resolve. The time

to peak FEV1

improvement with inhaled glucocorticoids is

generally 2 to 4 weeks. In the meantime, a second agent can

be added for rapid control of symptoms while airway in-

flammation and heightened bronchial hyperresponsiveness

respond to the higher dose of ICS. The addition of a long-

acting -adrenergic bronchodilator or a leukotriene recep-tor antagonist can lead to faster control of nocturnal symp-

toms and exercise- and cold-induced bronchoconstriction,

reducing the need for rescue albuterol usage.19 Long-acting

-adrenergic bronchodilators like salmeterol xinafoate and

formoterol fumarate are more potent that leukotriene re-

ceptor antagonists and theophylline.20 The longer duration

of bronchodilation is advantageous in blunting exercise-

and cold-induced bronchoconstriction and in providingnocturnal symptomatic relief. Leukotriene receptor antago-

nists like zafirlukast and montelukast sodium may have

additional anti-inflammatory action, whereas long-acting

-adrenergic bronchodilators do not have anti-inflamma-tory effects on the airways. There should be a set time limit

to the use of additive or combination therapy in light of the

expense. In patients with mild and moderate asthma, it is

unclear which patients should receive combination therapy

beyond 6 weeks.21,22 Once symptoms improve, a low to

medium dose of ICS alone is often sufficient. This is

termed steppingdown.23 Additive therapy should be con-

sidered an escalation of treatment intensity. No data are

available regarding the efficacy of combination treatmentin young children.

In patients with moderate to severe asthma who have

frequent exacerbations and severe symptoms, a longer du-

ration of combination therapy may be required. Once the

patients condition is stable and a reduction in the dose of

ICS is being considered, use of a long-acting -adrenergic

bronchodilator should be discontinued. This approach sim-

plifies the treatment regimen, avoids masking of symp-

toms, and allows optimal titration of the ICS.24 Conceptu-


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ally, the use of a long-acting bronchodilator is similar to

scheduled, regular use of a short-acting bronchodilator.

The need for rescue medication is a valuable indicator of

asthma control. It measures how often the patient is dys-

pneic enough to require a bronchodilator. In patients withmoderate to severe asthma, additive therapy has been used

as a corticosteroid-sparing strategy. A long-acting -ad-

renergic bronchodilator and a leukotriene receptor antago-

nist each can reduce the maintenance ICS dose by less than

20%.25,26

In choosing an ICS, issues of compliance, drug delivery

device, and proper inhaler techniques are as important as

issues of potency, clinical efficacy, and adverse effects.

Ultimately, lung delivery of the ICS benefits the patient.

The ideal ICS should have high anti-inflammatory activity,

low systemic bioavailability, faster breakdown, and a supe-

rior delivery system.

The potencies of currently available ICSs are as follows:

fluticasone > budesonide = beclomethasone > flunisonide =

triamcinolone, with a ratio relative to fluticasone of 1 to 0.5

to 0.25.27-30 Current evidence does not support an efficacy

difference among the ICSs, but evidence suggests substan-

tial differences in potency. This is an important fact be-

cause differences in potency can be overcome by adminis-

tering equipotent doses (more puffs with the less potent

medications), whereas compounds differing in efficacy

cannot produce the same maximal effect regardless of the

dose of the less efficacious drug. In comparing drugs with

differing potency, differences in systemic activity are im-

portant. A highly potent medication at a lower dose mayhave less absolute systemic availability compared with a

lower potency medication used at an equipotent dose that is

4 times higher to achieve equal clinical efficacy and may

result in higher absolute systemic availability.

Patient education about medication use should be con-

cise and pertinent.31,32 In choosing ICS dosages, cost differ-

ences are important. The monthly cost of fluticasone at 110

g is more expensive at 2 puffs twice daily than fluticasone

at 220 g at 1 puff twice daily. While in the physiciansoffice, the patient must demonstrate the ability to use the

prescribed inhaler properly. In elderly patients, a normal

score on the Mini-Mental State Examination does not rule

out ideomotor apraxia, which can interfere with properinhaler technique.33 A person with arthritis may be unable

to use a pressurized metered-dose inhaler (pMDI).

The 4 skills associated with a good pMDI technique are

slow inspiratory airflow rate, coordination of actuation

with inspiration, breath-holding at end inspiration, and

deep inspiration.34 Dry powder inhalers have the advantage

of a natural coordination between inspiration and genera-

tion of the aerosol cloud. They are simpler to use and need

no spacers. Mouth rinsing is necessary to prevent dyspho-

nia and thrush. Although bulky and less portable, a large-

volume spacer (750 mL) can substantially enhance lung

delivery from a pMDI. The 1-way valved spacers decrease

oropharyngeal deposition. Common mistakes in the use of

a 1-way valved spacer include an inadequately primedspacer with high static electricity, multiple actuations for a

single breath, and delay between actuation and inhalation.

A 1-way valved spacer improves coordination between

actuation of a pMDI and inspiration, and it provides a 20-

second window after actuation into the spacer for inhala-

tion. If inspiration occurs beyond this time, the suspended

particles will adhere to the spacer wall. Multiple actuations

of medication for a single breath into the spacer cause drug

particles to coalesce and increase in size. This decreases

drug delivery to the lung. The spacer should be rinsed

regularly and allowed to air-dry without wiping. Rinsing

reduces the electrostatic charge that causes particles to

adhere to the inner spacer walls.

The potency of the corticosteroid, the dose used, and its

systemic availability determine systemic activity.29,30 The

appropriate selection of a drug delivery device for the pa-

tient, the use of a spacer with a pMDI, and the proper

inhaler technique also influence systemic availability. If

high doses are required, maximizing the actual amount of

drug delivered to the lung (inspired portion) and reducing

the swallowed or intestinal tract absorption achieve a more

favorable benefit-to-risk ratio. The degree of systemic

bioavailability represents an interplay of factors, including

first-pass liver metabolism, elimination and accumulation

in blood, tissue uptake, and receptor occupancy. All ICSshave dose-related systemic adverse effects, but these are

fewer compared with those associated with an equivalent

dose of oral corticosteroids.35 Skin bruising due to high

doses of ICS correlates with degree of adrenal suppression.

The dose-related adrenal suppression ratio of oral pred-

nisolone to inhaled fluticasone is estimated to be equivalent

on a 10- to 1-mg basis. Although there is considerable

degree of interindividual susceptibility, adrenal suppres-

sion can be observed with doses of ICSs greater than 1.5

mg/d (0.8 mg/d for fluticasone). This dose has been associ-

ated with a significant reduction in bone density. No evi-

dence supports important long-term growth effects in

children. In fact, studies show that such children achievepredicted adult height.35 Long-term high-dose ICS use in-

creases the risk of posterior subcapsular cataract, skin

bruising, and to a smaller degree glaucoma. Local adverse

effects include dysphonia and oral thrush.

Sustained-release theophylline improves sleep, exercise

tolerance, and airway function.36 Theophylline is less effec-

tive than inhaled -agonists and has more adverse effects.The advent of long-acting inhaled

2-agonists has further

diminished the clinical use of theophylline in combination


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therapy for moderate to severe persistent asthma. The vari-

able clearance, narrow therapeutic index, drug interactions,

severity of toxic reactions, frequent monitoring, and atten-

tion to dosing have contributed to the diminished impor-

tance of theophylline in the treatment of asthma.Leukotriene receptor antagonists are not as potent as

long-acting -adrenergic bronchodilators,20 but they are

convenient and potentially anti-inflammatory. Leukotriene

receptor antagonists block an important mediator pathway

that is not affected by corticosteroids.37 An advantage of

leukotriene receptor antagonists over long-acting -adren-ergic bronchodilators is the lack of tachyphylaxis in pre-

venting exercise-induced bronchoconstriction (EIB).38

Also, they can be useful in reducing daytime symptoms

and nocturnal awakenings as well as mild cold-induced

bronchoconstriction and EIB.

EXERCISE-INDUCED BRONCHOCONSTRICTION

Exercise-induced bronchoconstriction refers to the tran-

sient narrowing of the airways after exercise, defined by a

decrease in FEV1

of at least 10% to 15%.39 A drying effect

and heat loss occur when a large volume of air moves

through the airways during vigorous exercise.40,41 Exercise

provokes bronchoconstriction in 40% to 80% of the popu-

lation with clinically recognized asthma. In healthy non-

asthmatic subjects, exercise increases FEV1. Exercise-

induced bronchoconstriction is associated with mediator

release. Although EIB correlates with methacholine

(r=0.54) and histamine (r=0.44), 30% to 45% of subjects

with EIB have no bronchoconstriction response to inhaledhistamine.40

Exercise-induced asthma is an important feature of

childhood and adult asthma. The overall control of airway

inflammation, intensity of exercise, degree of airway hy-

perreactivity, ambient temperature and humidity, and pres-

ence of allergens and air pollutants determine the severity

of exercise-induced asthma. Exercise-induced broncho-

constriction is one of the first symptoms of asthma to

emerge and the last to resolve after treatment with an ICS.

The presence of EIB in patients with asthma may be an

indication that airway inflammation is currently active.

Treatment with an ICS is necessary to reduce EIB in such

patients. The severity of EIB correlates with the number ofasthma attacks per year. Patients should be informed that

an ICS before exercise or short-term use of an ICS does not

relieve EIB. Ascertaining that the concurrent dose of ICS is

sufficient is important. To control EIB, higher doses of an

ICS are required compared with doses sufficient to control

other symptoms of asthma, including cough or nocturnal

awakening. By controlling the underlying airway inflam-

mation in patients with asthma, ICS should attenuate EIB

by at least 50%.

Specific therapy for EIB depends on whether symptoms

arise during scheduled activities (gym or football practice)

or during spontaneous increases in activity that is part of

daily living (running after a child or free play during re-

cess). Premedication with albuterol plus a warm-up ex-ercise may prevent EIB during scheduled exercises. The

use of submaximal exercise up to 80% of the maximum

aerobic output, warm-up exercises in hot humid air (steam

room), and warm-up sprints of 30 seconds duration at

least 2 minutes apart 30 minutes before exercise should

prevent EIB in 50% of patients within 60 minutes and last 2

to 4 hours. Regular use of albuterol does not decrease

effectiveness of premedication to prevent EIB.42 Besides

albuterol, mast cell stabilizers like cromolyn sodium and

nedocromil are second-line choices because they are less

effective than 2-agonists. An additive effect on broncho-

protection is observed when cromolyn and a 2

-agonist are

used together.

For spontaneous increases in activity during work or

recess when premedication can be difficult, a leukotriene

receptor antagonist or a long-acting 2-bronchodilator can

be added. These have the advantage of twice-daily or daily

dosing and are convenient, especially for children. With

intermittent use, the long-acting bronchodilators salmeter-

ol and formoterol are potent in almost completely blunting

EIB for 4 to 12 hours. Some patients develop tolerance to

the bronchoprotective function of long-acting broncho-

dilators with regular treatment. This loss of bronchopro-

tection against EIB occurs with a once-daily dose of sal-

meterol and with the recommended twice-daily dose.Tachyphylaxis can occur as early as the fifth dose. Both

airway cooling and drying during exercise stimulate the

release of mediators, including leukotrienes. Leukotriene

synthesis inhibitors and receptor antagonists have been

shown to protect against EIB to a lesser degree compared

with premedication with albuterol or with a long-acting

bronchodilator. There is no loss of bronchoprotection to

EIB with leukotriene antagonists.

Combination therapy is an important advance in the

treatment of asthma. The clinician can tailor the therapeutic

regimen according to the patients needs. Although this is

not a new concept, combination therapy allows clinicians

to articulate and refine the ways in which patient symptomscan be matched with treatment.

REDUCTION IN ASTHMA EXACERBATION

The key to preventing asthma exacerbation in patients with

persistent symptoms is regular use of an inhaled glucocorti-

coid. In patients with mild to moderate asthma, a single

maintenance dose of budesonide at bedtime can reduce the

frequency of asthma exacerbation. A high dose of inhaled

budesonide is more effective than a low dose of budesonide


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or low-dose budesonide plus formoterol in preventing ex-

acerbation.43 A recent study showing decreased exacerba-

tion rates in patients using ICS therapy and a long-acting

bronchodilator compared with maintenance with a corti-

costeroid alone may have reflected patient selection biasand an inadequate dose of the ICS alone.22 Regular ICS use

in these patients resulted in fewer and briefer episodes with

less severe exacerbation. In children with intermittent

symptoms arising usually after a viral upper respiratory

tract infection, continued regular use of an ICS after exac-

erbation resolution did not prevent future exacerbation.44

If a patient has had an acute exacerbation, a 2-week

course of a systemic glucocorticoid plus an ICS boost may

be necessary to control symptoms and airway inflamma-

tion. Studies suggest that tapering prednisone in all patients

after a brief burst of prednisone may be unnecessary.45,46

Tapering the corticosteroid may be appropriate in patients

who require daily prednisone or have received frequent

prednisone bursts. Prolonged adrenal suppression is un-

common during a 2- to 3-week course of prednisone at 0.4

to 0.6 mg/kg per day. Because of concurrent use of an ICS

boost, concern about inadequate anti-inflammatory therapy

if prednisone is not tapered over time is no longer an issue.

In recent studies, ICSs have been useful in acute asthma.

Dosages of 2 mg (10 puffs) of inhaled fluticasone daily,

800 g (4 puffs) of budesonide, and 6 mg/h (24 puffs) of

flunisolide were used for acute asthma with good re-

sults.18,47,48 In adults, this strategy was as effective as 40 mg

of prednisone in resolving an acute exacerbation of asthma.

In children, prednisone may be a better choice because oftheir inability to tolerate the ICS dose.49

SMALL AIRWAY INVOLVEMENT IN ASTHMA

Autopsy studies, bronchoscopic biopsies, and radiographic

imaging studies reveal that the small airways (


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Questions About Asthma Therapy

1. Which one of the following is the bestoption when apatient with cat allergies who is taking an ICS

presents with increasing symptoms?

a. Increase the ICS doseb. Add a long-acting bronchodilatorc. Add a leukotriene receptor antagonistd. Tell the patient to get rid of the cate. Add theophylline

2. Which one of the following statements about use of anICS in patients with mild to moderate asthma isfalse?

a. It is the most reliable anti-inflammatory agentavailable

b. It is useful as maintenance therapy for patients withepisodic flares associated with viral upperrespiratory tract infection

c. It reduces asthma exacerbationsd. It reduces exercise-induced asthmae. It reduces hospitalization

3. Which one of the following statements aboutexercise-induced asthma isfalse?

a. It is caused by drying and rewarming of theairways

b. It is the first symptom to appear and the last toresolve during an exacerbation

c. It can be controlled with higher doses of an ICSd. It can be prevented by premedication with albuterole. It is ruled out by a negative methacholine challenge

4. Which one of the following statements aboutinvolvement of the small airways in asthma is true?

a. The peak flow rate measures obstruction of thesmall airways

b. The FEV1

measures obstruction of the smallairways

c. Inflammation is present in the small airways ofpatients with asthma

d. Dry powder inhalers produce smaller aerosolizedparticles than do HFA-based inhalers

e. HFA-based inhalers have less lung depositioncompared with dry powder inhalers

5. Which one of the following is true regardingleukotriene receptor antagonists and long-acting

2-adrenergic agonists?

a. Both are equipotent as bronchodilatorsb. Long-acting

2-adrenergic agonists are more

effective as corticosteroid-sparing agents than areleukotriene receptor antagonists

c. Both are anti-inflammatoryd. Both are effective in blunting EIBe. Either is a better alternative to an ICS as

monotherapy for asthma

Correct answers:1. d, 2. b, 3. e, 4. c, 5. d

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