Goals of Asthma Management

Roger C. Bone

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

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Copyright 1996 BY THE AMERICAN COLLEGE OF CHEST PHYSICIANS
 reviews
Goals of Asthma Management
A Step-Care Approach
Roger C. Bone, MD, FCCP
The past 15 years have seen a rise in mortality and
morbidity resulting from asthma, despite a concurrent
rise in general knowledge about the disease. The
step-care strategy recognized these changes in its ap¬
to asthma management; however, this ap¬
proach should
proach be used only with attempts to control
environmental allergens. Step-care therapy requires
that 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 instituted
in all asthmatics except the mildest cases; it involves
treatment by inhaled corticosteroids, cromolyn, or
nedocromil. Step-three treatment targets cases of se¬
vere asthma through the use of oral corticosteroids. In
r|^he past 15 years have seenthea rapid expansion of ourof
-"-
knowledge regarding thispathophysiology
asthma. Ironically, however, advance has been
paralleled by an increase in both the frequency of
asthma and in the mortality and morbidity resulting
from asthma. Although this may seem to be a conun¬
drum, it is probable that part of the reason for these
worsening asthma statistics is that physicians are not
aware of these advances and their implications. Re¬
search has now made clear that asthma is an inflam¬
matory disease. This replaces the older and simpler
concept that the roots of this disease are based in
bronchospasm and resultant airways obstruction, which
define the essential physiologic abnormalities of
asthma. This physiologic basis for the disease is so
earlier explanations of asthma s
radically different from
that one researcher has felt justified in
pathogenesisasthma
renaming a "chronic desquamative eosino-
bronchitis."1
philie
This new description ofasthma s pathogenesis makes
necessary alternative clinical approaches to the disease.
bronchospasm toassociated
Although the treatmentitofis also
with asthma is essential, important 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 Arlington
Avenue, Toledo, OH 43614
1056
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Copyright 1996 BY THE AMERICAN COLLEGE OF CHEST PHYSICIANS
all phases of treatment, however, it should be remem¬
bered that patient education is of critical importance.
Education improves patient compliance and is critical
to the successful treatment of asthma.
(CHEST 1996; 109:1056-65)
AHR=airway hyperresponsiveness; EIB=exereise-induced
bronchoconstriction; MDI=metered-dose inhaler; PEF=
peak expiratory flow
Key words: airway hyperresponsiveness; bronchodilator;
circadian rhythm; cytokines; inflammatory response; medi¬
ators
the inflammatory aspect of the disease. Such an
approach to asthma has been described as step-care
treatment of asthma.2,3 This approach is algorithmic in
nature and promotes a graded response during treat¬
ment, depending on the severity of disease. It also
conforms to the guidelines offered by the National
Institutes ofHealth, British Thoracic
Society, and the
International Consensus Report on the Diagnosis and
Management of Asthma.4"6
Pathophysiology
Asthma occurs in phases because the inflammatory
response is composed of a multitude of mediated in¬
teractions, each with its own time frame. The acute
asthmatic response is characterized by wheezing and
coughing. 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 and
other mediators of inflammation resulting in smooth
muscle contraction, increased vascular permeability,
and vasodilation. This early response is rapid, occurring
within minutes, and attracts other inflammatory cells
that join in the response. Glandular activity is also
stimulated by this inflammatory cascade, resulting in
the secretion of mucus into the airways. The mucus
causes coughing and may result in dyspnea if the ob-
Reviews
 Table 1.How Step-Care Affects the Early-Phase and Late-Phase Pulmonary Response*
Early-Phase Late-Phase Mechanism
Therapy Candidates Drug Therapy Response Response of Action
Step-one: Relieve Patients with mild p2-Adrenergic agents, Rapid reversal of Do not prevent Reverse
acute symptoms intermittent albuterol, acute symptoms; inflammation; do mediator-induced
asthma bitolterol, relax smooth not reduce or bronchospasm
mesylate, muscle reverse airway
metaproterenol hyperresponsiveness
sulfate, pirbuterol
acetate, terbutaline
sulfate
Anticholinergic agent: Produces Unknown Unknown
ipratropium bronchodilation by
bromide inhibiting vagally
mediated
bronchoconstriction
Step-two: Protect Patients with other Aerosol Effective therapy Prevent and Inhibit
against and than the mildest corticosteroids: effectively manage inflammatory cell
manage case of asthma; Beclamethasone inflammation; influx; stimulate
inflammation with step-two therapy dipropionate, inhibit mucus production of
agents that have should probably be flunisolide, release; reduce or lipocortin, thereby
few toxic effects used in all patients triamcinolone reverse AHR preventing
with asthma acetonide formation of
prostaglandins and
leukotrienes
Other: Cromolyn Prophylactically block Block Stabilize and prevent
sodium, inflammation prophylactically; mast cell
nedocromil reduce AHR degranulation
Step-three: Control Patients with asthma Oral corticosteroids: Ineffective Prevent and manage Inhibit inflammatory
severe refractory to Methylprednisolone, inflammation; cell influx;
exacerbations step-one and prednisolone, inhibit edema stimulate
step-two agents prednisone formation and production of
mucus release; lipocortin, thereby
reduce or reverse preventing
increased AHR formation of
prostaglandins and
leukotrienes
*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 with
permission from Bone RC. Step care for Asthma. Journal of Challenges in Asthma 1992; 1:1-8.
struction is significant. Wheezing results from the term response leaves the tissues sensitized and any
contraction of airway smooth muscle in bronchospasm. further interaction with allergens may cause a dramatic
The longer-term result of this inflammation is a response, termed hyperresponsiveness. The terms ex¬
cellular infiltrate consisting of eosinophils, neutrophils, trinsic and intrinsic have long been used to define
and basophils, all of which release additional mediators asthma, the former being associated with high circu¬
of inflammation. The number of lymphocytes and lating IgE levels and a positive response to skin pricks
monocytes within the lung increase within
cells may be particularly important in bringing about
12 h. These with allergens. Although our current understanding of
asthma does not allow us to fully explain this difference,
the chronic form of inflammatory response in asthma it could be that these two forms are actually different
through the release of cytokines and arachidonic
derived mediators.7 This activity takes place in a time
acid- phasesbe oflostthe same disease. Systemic responsiveness
may with age, turning the extrinsic into the in¬
frame of from 2 h to several days and longer following trinsic form of the disease.8
activation of the mast cells by antigen. This is called the Long-term inflammation is also associated with an¬
late-phase response.
One important effect of this inflammation is the
other detrimental response.that of fiber deposition.
Inflammation mediators have powerful effects on a
sensitization and disruption of the airway lining, which variety of cell types, including that of inducing the
in
can, turn, cause irritation with reflex coughing. This genes for various connective tissue fibers. Although
nonspecific bronchial reactivity may underlie
forms of asthma as exercise- and cold-induced asthma
such this may be appropriate in areas where severe tissue
destruction has occurred, it is not advantageous in
and other responses to environmental changes, inhaled chronic asthma. Fibrosis, together with smooth muscle
irritants, and infectious stimuli. Additionally, this long- hypertrophy, thickens the airway walls and causes fur-
CHEST /109 / 4 / APRIL, 1996 1057
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Copyright 1996 BY THE AMERICAN COLLEGE OF CHEST PHYSICIANS
 OH OH 9" OH 9* OH CH3
CH2H5 CH3
OH-f VCH-CH2-NH-CH3 0H
"\I/CH~ CH2~NH~9HCH3 /r~VcH-CH2-NH-CH
OH CH3
Adrenaline Isoetharine Metaproterenol
OH
NCH, 2 OH CH3
OH OH CH3 /""VcH-CHg-NH-C
CH-CH2-NH-C-CH3
^ CH2~NH -9HCH3
OH-^VCH- OH
-n-
OH-^
OHCH3
VCH-CH2-NH-C-CH3
oV
Albuterol
.>
CH3
Isoproterenol Terbutaline
Figure 1. First-generation (3-adrenergic agonists. These are the
older p-agonists that are generally shorter acting and less specific OH
\
for p2~adrenergic receptor. These are rarely used today.

ther obstruction.
H3C
&\ OH CH3
CH-CH2- NH-CH
CH3
There is a strong circadian rhythmicity to the oco OH CH3 Pirbuterol
severity of asthma that exhibits its worst symptoms
between 3 and 5 am. A form of asthma termed
H3C-/JV0CO 4> CH-CH2- NH-CH
CH3
nocturnal asthma, in which the patient awakes during Bitolterol
the night with breathing difficulties, is often seen. Figure 2. Second-generation P-adrenergic agonists. These are
Pulmonary function values in nocturnal asthma may more specific for the p2-adrenergic receptor and have a longer du¬
vary by as much as 50% between 4 pm and 4 am.9 ration of action than the first-generation drugs. These agents are
During the night, increased numbers of inflammatory used as for acute exacerbations of asthma.
step-one agents
cells can be found in the BAL of patients with noctur¬
nal asthma.10 This form of disease may be responsible
for half of all asthma deaths. Although the cause of allergens play a major role in asthma is undisputable.
these circadian swings in severity is not fully under¬ The levels of allergen exposure clearly influence the
stood, there is undoubtedly input from a variety of prevalence of airway hyperresponsiveness (AHR) in
different factors. These swings may have direct and sensitized subjects. Sensitization to house dust-mite
indirect effects on the airways. allergens and to mold spores in dry climate has been
Patients with asthma may have disease of widely reported.than cathouse
The dust-mite allergens are more im¬
varying seriousness; symptoms may range from mild, portant and cockroach allergens and
in predispos¬
episodic wheezing to The acute exacerbations with life- ing children
12,13
to increased sensitization morbidi-
threatening dyspnea. episodic and circadian na¬
ture of asthma s symptoms are important consider¬ The prevalence of asthma appears to be more com¬
ations during the assessment of a patient. Wheezing, mon in some urbanized regions. Air pollution has been
breathlessness, and cough occurring in an episodic implicated in the increased prevalence of asthma.
fashion are the hallmarks of asthma. Because of this Studies have indicated that lifestyle factors associated
episodic nature, detailed pulmonary function tests
cannot be performed frequently enough to provide
with modern living conditions increase the symptoms.
For example, children living in industrial regions may
much useful information. However, measures of the have more severe airway responsiveness than children
peak expiratory flow will be useful because they can be
obtained easily at any time with small peak expiratory
livingandinitsrural regions.14'15
effects
Exposure to passive smok¬
flow gauges that can be used at home. Drug therapy
ing on lung function have been studied.
Babies whose mothers smoke have increased hair co¬
should be preceded by an attempt to control the tinine and nicotine levels. Cotinine levels in young
patient's exposure to environmental allergens and children are related to the number ofsmokers to whom
irritants. the child is exposed. Other factors such as socioeco-
Environmental risk factors in the development of nomic class and inadequate home ventilation may in¬
asthma appear to be potentially preventable. It may be crease exposure and enhance its effects.16'17 Since it is
safe to assume that changes in lifestyle and exposure to well documented that allergens increase the severity of
allergens inandthesometimes dietary factors may be re¬ both AHR and morbidity, it is important that new ap¬
sponsible development of asthma. However, diet
as a risk factor is circumstantial. Asthma has a multi-
proaches to avoid allergen exposure be explored. New
methods may help reduce the incidence of asthma in
factorial etiology and several factors may play inde¬ all situations. Reduction ofrisk in even a minority ofthe
pendent roles in its development.11 The evidence that children would lead to an important public health
1058 Reviews
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Copyright 1996 BY THE AMERICAN COLLEGE OF CHEST PHYSICIANS
 Table 2.Agents to Consider in Step-Two Care*
Agent Route Dosage
Aerosol corticosteroids
Beclomethasone MDI, 43 ug per puff 8 puffs or 336 ug; reduce to 2 puffs twice
per day when asthma is stable
Triamcinolone
Flunisolide 4 puffs or 1,000 pg; reduce to 2 puffs twice
per day when asthma is stable
Antiallergics
Triamcinolone 8 puffs or 800 ug; reduce to 2 puffs twice
per day when asthma is stable
Cromolyn sodium
Antiallergics
Cromolyn sodium MDI, 800 ug per puff 2 puffs, 4 times per day
Nedocrimil MDI, 1.75 mg per puff 2 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 and seasonal increase in bronchial responsiveness to meth¬
markedly reduced allergen exposure include use of acholine. Nasal corticosteroids may have a protective
greater allergen-free furniture and homes, mattress effect in patients with airway reactivity, perennial
covers, and improved ventilation.18"20 rhinitis, and asthma. Thus, rhinitis should be treated
Allergen-specific immunotherapy has been used for aggressively in all patients with allergic asthma.2526
many years in the treatment of asthma. Recent trials Other factors that have been implicated in the de¬
indicated that immunotherapy reduces asthma symp¬ velopment ofandasthma are psychological factors. The
toms caused by house dust mites, cat dander, Alter- prevalence importance psychogenic factors in
of
naria and Cladosporium molds, and grass, birch tree, asthma have been debated but evidence suggests that
and ragweed pollen.21 Use of immunotherapy remains psychological stressors can lead to clinically significant
controversial because to my knowledge, no study has deterioration in asthma control.27"29 It is known in
defined the amount of medication required that can certain asthma patients that psychological factors play
significantly control the symptoms. Immunotherapy
for at least 3 years is optimal in patients with seasonal
an important role in the stability or instability of the
disease and the patients' ability to participate in cogent
rhinitis.22 New forms of immunotherapy (sub-
allergicand self-management planning.were
In a recent study, agora¬
lingual oral) have recently been tried in an attempt
to improve on convenience, with beneficial results.23^4
phobia and panic disorder more frequendy seen
in patients with asthma in outpatient clinics than in the
Treatment of allergic rhinitis may result in an improve¬
ment in asthma symptoms. In the patient with allergic
general population.30 In inthat study, significant im¬
provement was observed patients who had autoge-
rhinitis, nasal corticosteroid therapy may prevent the nic therapy. Autogenic therapy is a psychophysiologic
Table 3.Management Plan Based on Measurement of PEF*
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
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Copyright 1996 BY THE AMERICAN COLLEGE OF CHEST PHYSICIANS
 Table 4.Example of Management Plan*
Potential Normal PEFf 550 L/min
Routine treatment
Corticosteroid inhaler puff 2xday
Inhaled P-sympathomimetic inhaler as required
PEF <400 L/min: Increase inhaled corticosteroid to 1 puff 4xday and inhaled P-sympathomimetic as required
PEF <250 L/min: Prednisone, 40 mg/d until PEF >500 L/min, then prednisone, 20 mg/d for same number of days
PEF <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 improving respi¬
function.
in
ratory
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 should
be to reduce bronchospasm and the inflammatory
changes. Recently, the emphasis in the treatment has
moved 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 the
inflammatory processes underlying asthma.
Step-Care Therapy
Step-care therapy is a systematic management ap¬
proach forthatthethecontrol offirstasthma. Step-care therapy
requires patient be categorized as to the
severity of disease (Table 1). Based on the severity of
the disease, therapeutic approaches have been de¬
signed (step-one, step-two, or step-three therapy).4
Step-One Therapy
Step-one therapy is appropriate for patients who
manifest mild symptoms on rare occasions. The life¬
style of these patients is not affected greatly by the
disease. The clinical goal of step-one therapy is to
provide prompt relief from the symptoms, which may
be achieved usually with short-acting inhaled bron¬
chodilators. Inhalers containing epinephrine are still
available without prescription and provide moderate
but 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 isreceptors are present in the lungs,
bronchodilation 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-h
duration of action, and those that are long acting have
a duration of action of more than 12 h. p-Adrenergic
agonists achieve their effects by binding to P2-adren-
1060
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Copyright 1996 BY THE AMERICAN COLLEGE OF CHEST PHYSICIANS
ergic receptors. These receptors belong to a large
group of receptors whose effects are brought about by
a 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, cyclic
adenosine monophosphate has the effect of relaxation,
thus increasing the diameter ofthe airway. P2-Agonists
have nonbronchodilator effects in addition to bron¬
chodilation. The nonbronchodilator effects include
enhancement of mucocilliary clearance, inhibition of
cholinergic neurotransmission, enhancement of vascu¬
lar integrity, and inhibition of mediator release from
mast cells, basophil, and also other cells. For relief of
acute symptoms, and also for prevention of exercise-in¬
duced bronchospasm, more specific P2-adrenergic ag¬
onists are preferred. They act rapidly (with a rapid peak
effect) 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 nocturnal
asthma and (2) their short duration of protection
against exercise-induced bronchospasm. Both limita¬
tions are related to the short duration of action of these
agents. These agents should be used as occasion
requires for asthma symptoms. They should not be
used unless there is a deterioration in peak flow or
development of symptoms. Among the short-acting
drugs 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 subtype
found in the lung airways and have fewer cardiac
effects. The adrenergic receptors themselves have also
been the subject of intense interest, being almost
ubiquitously expressed by human cells. The cloning of
this gene has helped researchers to find new subtypes
of the gene, while space-filling models have helped
researchers to understand the finer points of receptor-
ligand interactions.31 are the most effective bron¬
P2-Adrenergic agonists
chodilators for the treatment of acute episodes of
asthma and for the prevention of exercise-induced
Reviews
 9 H
H-C-N
CH, /=
OH -{ V-CH(OH)CH NHCHC /"0CH3
Formoterol
HOCH2
0H A yCH(°H)CH2NHCH2CH2CH2CH2CH2CH2OCH2CH2CH2CH"\ /
Salmeterol
Figure 3. Third-generation P-adrenergic agonists. These are more
selective for the P£-adrenergic receptor and have a longer duration
of action than the first- and second-generation agents. Salmeterol
has been recently approved for use in the United States. See text
for recommendations regarding use of these agents.
bronchoconstriction. The long-acting P2-adrenergic
agonists prevent nocturnal asthma and provide pro¬
longed protection against exercise-induced broncho¬
constriction. The long-acting P2-adrenergic agonists
should be administered only at regular, prescribed in¬
tervals. Short-acting P2-agonists should be given in¬
stead of additional doses to relieve symptoms. Inhaled
P2-adrenergic agonists remain the most important class
of bronchodilators currently available. When used ap¬
propriately,ofthey provide safe and effective relief of
symptoms airflow obstruction.32
An important hindrance to achieving the full bene¬
fits offered by P-agonists is the improper use of
metered-dose inhalers (MDIs); as many as 50% of
patients using MDIs do so incorrectly. These patients
are not appropriately treated. Misuse often continues
even after repeated rounds of instruction.33 The most
significant problem seems to be coordinating the acti¬
vation of the canister with an appropriate inhalation.
Althoughoften
the use of spacer devices is recommended,
do not carry them or do not use them.
patients
A patient's MDI technique should be observed care¬
fully by the physician who prescribes it. Other common
problems with MDI use include failure to shake the
canister before the use, inadequate breath holding, and
the failure to wait between puffs. Correct use of MDI
is a skill taught through patient education.
To overcome this problem, an auto inhalation device
has been introduced. This device is triggered by the
patient's inhalation rather than by hand actuation.
Pulmonary function in patients receiving pirbuterol
acetate via a MAXAIR Autoinhaler (3M Pharmaceuti¬
cals; St. Paul, Minn) and those patients using standard
MDIs were compared. Both systems produced similar
results in spirometry. This may be due to the two puffs
of perbuterol regardless of the delivery system. Auto-
inhalers are as effective as correctly used MDIs and are
a viable alternative for patients who have coordination
problems with the standard MDI. Children whose
peak inspiratory flow rate is less than 0.5 L/s may not
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Copyright 1996 BY THE AMERICAN COLLEGE OF CHEST PHYSICIANS
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 the
treatment of mild, occasional asthma (step-one thera¬
py), after inhaled P-agonists are used. Vagal tone
releases aeetylcholine at nerve endings on the airways,
resultingthein anumbers
tonic smooth muscle contraction. Al¬
though of acetylcholinergic receptors
within 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 be
additive with P-agonists in providing relief to patients
with asthma.36 Patients with nocturnal asthma may
derive additional benefits from treatment with anti¬
cholinergics. Because of the increase in vagal tone that
occurs during sleep, aeetylcholine release at the airway
smooth muscle may be implicated as a cause of
nocturnal asthma, making anticholinergics an appro¬
priate therapy in some patients. Inhaled ipratropium
on waking has been shown to be effective in this con¬
dition.37
Theophylline and other methylxanthines improve
pulmonary function, although the mechanisms by
which they work have not been described adequately.
Theophylline has a narrow therapeutic index and may
be toxic at doses just above those effective for asthma
treatment. Various guidelines for asthma management
recommend the use of theophylline or aminophylline
in cases that respond poorly to aerosol MDIs and for
short-term exacerbations. Theophylline is regarded as
a weak bronchodilator with a high toxicity potential and
its use has been declining. Recently, however, theo-
phylline's properties as an anti-inflammatory agent and
an immunomodulator have been emphasized. Al¬
though serious drug toxic reactions, including cognitive
and behavioral side effects, have been reported, theo¬
phylline canbecause
add to and prolong the responses to
P-agonists it is also a weak anti-inflammatory
agent. It should be considered for use in asthmatic
patients 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, with
a serum concentration of 5 to 10 mg/L, may have a
significant effect in patients with unstable asthma.
Theophylline, therefore, may have a more significant
role 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 Therapy
When a patient with mild asthma begins to use in¬
haled bronchodilators on a regular basis, it is a sign that
the disease is worsening and that step-two therapy
should be instituted (Table 2). Step-two therapy con¬
sists of daily medication with anti-inflammatory agents
such as inhaled corticosteroids nedocromil or cro¬
molyn plus bronchodilators (inhaled P2-agonist as oc¬
casion requires, oral theophylline, oral P2-agonist). The
mainstay of this treatment level is an inhaled cortico¬
steroid. Corticosteroids act by decreasing the inflam¬
mation that underlies hyperresponsivity and broncho¬
spasm. The goal of their use is to manage the late-phase
inflammatory response while minimizing treatment
side effects. Inhaled corticosteroids have been shown
to provide a protective effect against the deterioration
in lung function seen with prolonged regular use of
inhaled bronchodilator therapy alone.39
Studies have shown that inhaled corticosteroids have
little effect on exercise-induced bronchoconstriction
(EIB), unless it is taken for several weeks.4041 Al¬
corticosteroids have the ability to attenuate
thoughinhaled
EIB, corticosteroids will not replace inhaled
P2-agonists cromolyn as the best prophylactic
or
treatment for EIB. Inhaled corticosteroids have the
ability to prevent or reduce airway inflammation and
AHR. The anti-inflammatory effect of inhaled corti¬
costeroids in the treatment of asthma has been dem¬
onstrated in several studies. Inhaled corticosteroids
have been shown to decrease eosinophil number and
density as well as improve epithelial quality and reduce
inflammatory cell infiltrate.42"44 involved in the
There are several mechanisms
inflammatory response The that may be influenced by
corticosteroid therapy. two important areas that
have been investigated are the decreased production of
cysteinyl leukotrienes and interference with the action
of proinflammatory cytokines. Cysteinyl leukotrienes
are 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 is
not attenuated. It is known that corticosteroid treat¬
ment in vitro will inhibit phospholipase A2 responsible
for eicosanoid synthesis. The increase in leukotriene E4
excretion 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 production
without influencing urinary leukotriene E4.45 Corti¬
costeroids have been known to reduce airway levels of
proinflammatory cytokines in patients with asthma.
A recently developed technique that should consid¬
erably improve treatment is the implementation of
peak flowmeters. These small, easy-to-use gauges
1062
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Copyright 1996 BY THE AMERICAN COLLEGE OF CHEST PHYSICIANS
allow patients to measure their own peak expiratory
flow rates at home. The difference between morning
and evening peak flow rates provides an estimation of
the airway reactivity. When the difference exceeds
approximately 20% of the peak flow rate, additional
therapy should be considered. Education, again, is the
key word: properly instructed patients should be able
to increase their own treatment dosage with inhaled
corticosteroids at the first sign of an exacerbation.
A self-management plan in the treatment of adult
asthma has been devised that is specifically designed to
tackle the factors that contribute to death from asthma
(Tables 3 and 4). This is a management regimen based
on regular objective assessment of airflow obstruction
in association with adequate inhaled corticosteroid
treatment. This method was used in a study46 and has
been shown to be effective for adults with chronic se¬
vere asthma. The management plan is incorporated
with several different treatment guidelines. The com¬
bination of these guidelines may have contributed to
the beneficial effect. The aim ofthis regimen is to start
treatment with oral corticosteroids in sufficient dosage
when 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 reducing
symptoms ofasthma and also improving lung function.
Cromolyn sodium and such related compounds as
nedocromil sodium are another form of therapeutic
agent appropriate for step-two therapy. Although their
exact mechanisms of action are unknown, they appear
to inhibit the release of inflammatory mediators by
mast cells. By stopping the early-phase reaction in
asthma, the tendency toward inflammation may be
arrested before it starts. One of the most important
problems with inhaled corticosteroids and cromolyn or
nedocromil is the failure of patients to follow their
treatment regimens. To the patient conditioned to the
rapid and dramatic beneficial effects provided by the
P-agonists, these drugs appear to be ineffective; addi¬
tionally, they are relatively expensive. Failure to com¬
ply with the treatment regimen is common; patients
must be instructed that these anti-inflammatory drugs
alleviate the inflammatory response and that the ben¬
efits are long term and aimed at preventing exacerba¬
tions, rather than treating them. This approach also
appears to inhibit both the late-phase reaction in
asthma and the dramatic response usually obtained
from challenges with allergens.
Longer acting inhaled P2-adrenergic-agonist have
overcome many of the shortcomings of previously
available drugs (Fig 3). Currently, long-acting agonists
with 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,
Reviews
while the use of formoterol is still being considered.
The longer-acting p-agonists are more selective for the
P2-adrenergic receptor and their activity persists for a
longer period of time at the receptor site. Salmeterol
is indicated for long-term, twice-daily administration in
the maintenance treatment of asthma and in the pre¬
vention of bronchospasm in patients 12 years of age
and older with reversible obstructive airways disease,
including patients with symptoms of nocturnal asthma
who require regular treatment with inhaled, short-
term P2-agonists. It should not be used in patients
when asthma can be managed with occasional use of
short-acting p2-agonists.
Salmeterol should never be used more than twice
daily. Increasing its use in an acute attack is inappro¬
priate and may be dangerous. Salmeterol should not be
used to treat acute asthma symptoms because it has a
slower onset of action.47 Patients must be provided
short-acting,Patients
inhaled P2-agonist for treatment of acute
symptoms. using salmeterol may feel well
enough Thismay
and discontinue the anti-inflammatory
therapy. discontinuation could cause a serious
exacerbation of asthma because salmeterol is not a
substitute for oral or inhaled corticosteroid therapy. Its
usemay be beneficial in
patients with nocturnal asthma
and exercise-induced asthma as maintenance thera¬
py48"51
Althoughofsalmeterol is a major advance in
asthma based on the available
the
treatment data,
salmeterol should be reserved for patients who are al¬
ready receiving step-two anti-inflammatory therapy.48
Longer-acting agents improve sleep quality, morning
peak-flow measurements, and nocturnal symptoms.49
In one 12-month trial of salmeterol vs albuterol, there
was no deterioration with long-term administration.
Salmeterol has also been shown to be effective for
protection against EIB for up to and including 12 h in
patientswith mild to moderate asthma.52
Step-Three Therapy
Step-three therapy is reserved for patients whose
asthma is not controlled by step-two treatment and
consists of more aggressive forms of anti-inflammatory
treatment, the mainstay of which is oral corticosteroids
at doses high enough to stop the inflammation. The
incidence of side effects, which can be serious with
high-dose corticosteroids, is decreased by the use of
agents with a short duration of action, such as pred¬
nisone. It is critical that treatment with these be insti¬
tuted at the first indication of uncontrolled asthma. Too
often in fatal asthma, anti-inflammatory drugs were
administered too little and too late. Oral dosages of
prednisone as high as 40 to 60 mg/d may be used for
up to 2 weeks to counter serious exacerbations of
asthma. Following such treatments, corticosteroid dos¬
ages should be tapered to maintenance levels of aero¬
Downloaded from www.chestjournal.org on March 27, 2009
Copyright 1996 BY THE AMERICAN COLLEGE OF CHEST PHYSICIANS
sol-administered drug. When a patient is particularly
difficult 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 side
effects of corticosteroid use as suppression of the ad¬
renal gland, hypertension, and aseptic necrosis. Other,
less serious effects of this medication may include fluid
retention, 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 of step-two therapy. Through appropriate use of
the peak flowmeter, patients should be able to antic¬
ipate exacerbations and increase their dosage of corti¬
costeroids accordingly. The goal of this form of patient-
dispensed medication is to prevent the exacerbations
of asthma that may require hospitalization and more
radical forms of treatment.
The above ideas are consistent with the guidelines
developedThe in 1991 by the National Asthma Education
Program. guidelines can be summarized in four
key points: (1) pharmacologic therapy; (2) appropriate
monitoring; (3) patient education; and (4) control of
the environmental allergens and irritants that cause
asthma. Recent studies have shown that inadequate
patient education remains an impediment to appro¬
priate treatment.53 One study has obtained promising
results with the use of small-group instruction, which
resulted in improved asthma control, even when
compared with a program ofindividualized instruction.
Not only did the patients derive support from within
the group, but educators seems more at ease and were
better able to understand the problems associated with
treatment.54 To achieve adequate patient education,
the patient-physician relationship must work well so
that the patient can be taught how benefits may be
derived from treatment. They must understand the
long-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 their
therapy, they are more likely to comply with the
treatment and their asthma will be better managed.
New Treatments
Leukotrienes, which are products of 5-lipoxygenase
pathway of arachidonic acid metabolism, are thought
to be important mediators in the pathogenesis of
asthma. Their biological activity produces changes that
are similar to those seen in asthma. It was demon¬
strated that 5-lipoxygenase inhibitors or leukotriene
receptor antagonists give good protection to patients
undergoing acute allergen laboratory.
challenge in the was devel¬
Recently, a new drug, Zileuton (Leutrol)
oped,55,56which is an iron ligand inhibitor 5-lipoxygen¬
of
ase.
CHEST /109 / 4 / APRIL, 1996 1063
 Several other new anti-inflammatory drugs have
been developed. These drugs, which are currently
being tested, may change the treatment strategy in the
future. Although these dings show promise in preclin-
ical and early clinical trials, their efficacy and safety
have not been determined.57 One ofthe new drugs that
has reached phase 3 testing is Zafirlukast, a leukot-
riene-receptor blocker shows great promise as an an¬
ti-inflammatory agent. This drug binds specifically with
a high degree of affinity to the leukotriene D and leu¬
kotriene E receptors, whereas the steroids block
inflammation by inhibiting cytokine production.58 Zile¬
uton acts by inhibiting the breakdown of arachidonic
acid in the first biosynthetic step to forming leukot¬
rienes.59 Vasoactive intestinal peptide and antagonists
to platelet activating factor are being developed for
possible use in the treatment of asthma.60 Specific
monoclonal or polyclonal antibodies, genetically mod¬
ified or mass-produced endogenous molecules, and
any other tools that can interfere with the pathogene¬
sis of asthma and inflammation may become available
in the future.57
Management ofasthma has become one of the most
important challenges to the medical profession be¬
cause of its increasing occurrence and the conse¬
quentlyhasunexplained mortality. Increasingly poor air
quality been expressed as one ofthe reasons for the
rise in mortality. The multifactorial nature of the dis¬
ease explainswhilewhyothers
some patients respond to some
do not. The essential part of
treatments
the diagnosis should be the determination of patient's
response to various treatments. The future looks
promising as several new drugs with various anti-
inflammatory actions may become available for use in
the treatment of asthma.
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CHEST /109 / 4 / APRIL, 1996 1065
 Goals of Asthma Management
Roger C. Bone
Chest 1996;109; 1056-1065
DOI 10.1378/chest.109.4.1056
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