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review article

Drug Therapy

Christopher H. Fanta, M.D.

From Partners Asthma Center, Division ccording to survey data for which the diagnosis of asthma was
of Pulmonary and Critical Care Medicine, based on a physicians assessment, it is estimated that approximately 7% of
Department of Medicine, Brigham and
Womens Hospital and Harvard Medical Americans have current asthma.1,2 The disease affects people of all races
School, Boston. Address reprint requests and ethnic groups worldwide, from infancy to old age, with slightly more boys than
to Dr. Fanta at the Pulmonary and Critical girls affected and, after puberty, more women than men. Dramatic increases in the
Care Division, Brigham and Womens Hos-
pital, 75 Francis St., Boston, MA 02115, or prevalence of atopy and asthma have occurred over the past few decades in Western-
at ized countries3 and more recently in less-developed nations.4 Estimates suggest that
as many as 300 million persons are affected worldwide.5
This article (10.1056/NEJMra0804579) was
last updated on September 9, 2009, at In the 1970s and 1980s, severe asthmatic exacerbations (as indicated by emer- gency department visits and hospitalizations for asthma) and asthma-related mortal-
ity rose steeply in the United States. Yet despite the persistently high prevalence of
N Engl J Med 2009;360:1002-14.
Copyright 2009 Massachusetts Medical Society.
disease, the most recently available data indicate improved outcomes, with fewer
annual hospitalizations for asthmatic attacks and fewer asthma-related deaths.6
Among the possible explanations for these favorable trends are the more widespread
preventive use of inhaled corticosteroids and the introduction over the past 10 to
15 years of new, highly effective medications and improved medication formulations
for the treatment of asthma.
Airway obstruction in asthma and the consequent symptoms of cough, shortness
of breath, chest tightness, and wheezing are caused by some combination of air-
way smooth-muscle constriction and inflammation of the bronchi. The former can
be severe, leading to life-threatening narrowing and closure of airways, even in the
absence of mucous plugging. Both abnormal smooth-muscle contractility7 and excess
smooth-muscle mass8 may contribute. Airway inflammation in asthma consists of
mucosal, submucosal, and adventitial edema; cellular infiltration, particularly by
eosinophils (and in some cases, neutrophils) and activated helper T lymphocytes9
as well as mast cells that (unlike mast cells in other eosinophilic airway diseases)
infiltrate smooth-muscle bundles10; increased airway secretions, including secreted
mucus, desquamated lining cells, and intraluminal eosinophils; capillary engorge-
ment; hyperplasia of smooth muscle; and deposition of excess collagen, particularly
immediately beneath the basement membrane of the epithelium.11,12
Traditionally, drugs used to treat asthma were categorized according to their pre-
dominant effect relaxation of airway smooth muscle (bronchodilators) or sup-
pression of airway inflammation (antiinflammatory drugs). Newer medications
(e.g., the leukotriene modifiers) and drug combinations (e.g., inhaled corticoster-
oids combined with long-acting -adrenergic agonists) have dual effects, resisting
such traditional dichotomization. Now, asthma medications are classified accord-
ing to their roles in the overall management of asthma (quick relief or long-term
control), a model that is particularly useful when speaking to patients about their
asthma medicines.
All patients with asthma should have available a quick-relief bronchodilator for use
as needed. Consensus opinion suggests that when quick-acting bronchodilators are

1002 n engl j med 360;10 march 5, 2009

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Drug Ther apy

needed for symptom relief more than 2 days per fects are uncommon. Although their effectiveness
week (or more than twice a month for nighttime may be diminished somewhat, inhaled -agonist
awakenings caused by asthmatic symptoms), con- bronchodilators are not contraindicated in patients
troller medications should be prescribed.2,13 who are simultaneously taking beta-blockers.22,23
The decision about which of the various short-
Quick R el ief acting -agonists to use is based largely on cost
and the patients or physicians preference. Pir-
Quick-acting -adrenergic agonists administered buterol is the only one available in a breath-actu-
by inhalation are the most effective therapy for ated metered-dose inhaler, a device meant to op-
rapid reversal of airflow obstruction and prompt timize medication delivery by releasing a spray of
relief of asthmatic symptoms. Most widely used medication only on the patients initiation of in-
are the short-acting, 2-selective, adrenergic ago- spiration. Levalbuterol, the purified d-rotatory
nists: albuterol (commonly known as salbutamol isomer of albuterol, was developed for the pur-
outside the United States), levalbuterol, and pir- pose of eliminating side effects, which some ar-
buterol (Table 1). Metaproterenol delivered by me- gue are limited to the s-rotatory isomer.24 How-
tered-dose inhaler has recently been withdrawn ever, when delivered by metered-dose inhaler,
from the market. levalbuterol has an efficacy and side-effect pro-
The short-acting -agonists all have an onset file that is indistinguishable from that of the
of action in 5 minutes or less, with a peak effect racemic mixture of molecules in albuterol.25 Al-
in 30 to 60 minutes and a duration of action of buterol has been made available in a metered-
4 to 6 hours.14 With regular use of a bronchodi- dose inhaler free of chlorofluorocarbons (CFCs),
lator (four or more times daily), the potency (as and CFC-containing albuterol inhalers were tak-
measured by the increase in maximal expiratory en off the market on December 31, 2008.26 Like
flow) does not decline, but the duration of action CFCs, the alternative propellant, hydrofluoro
is slightly shortened.15,16 Because a regular sched- alkane (HFA), is inert in the human airway, but
ule of administration four times a day does not unlike CFCs, it does not contribute to depletion
improve outcomes, as compared with as-needed of the stratospheric ozone layer. For more infor-
administration17 (and, in patients with certain mation on HFA-containing metered-dose inhalers,
genotypic variants of the -receptor, may have a see the Supplementary Appendix, available with
deleterious effect),18,19 the short-acting -agonists the full text of this article at A Supple-
are recommended for use only as needed for relief mentary Video, also available at in an
of symptoms (or before anticipated exposure to article by Hendeles et al.,26 demonstrates the use
known asthmatic triggers, especially exercise). The of an HFA albuterol inhaler. The HFA inhalers
practice of administering a short-acting -agonist are equipotent to the CFC-propelled inhalers,27
before using an inhaled corticosteroid to improve can be used with valved holding chambers (spac-
delivery of the corticosteroid to the lower airways ers) in patients with poor inhalational technique,28
has been abandoned as unnecessary.20 Similarly, and provide bronchodilation comparable to neb-
there is no need for patients to wait more than ulized albuterol when a sufficient number of
10 to 15 seconds between puffs when a dose of puffs is administered and inhalational technique
two or more puffs is recommended.21 is good.29
In patients with moderate or severe airflow Short-acting -agonists that are to be swal-
obstruction, a log-linear doseresponse curve for lowed, in either tablet or liquid form, should be
bronchodilation can be demonstrated for short- discouraged, despite their seeming convenience
acting -agonists administered at very high doses (especially for very young children). They take
(up to 4000 g of albuterol by metered-dose in- longer to start working, are less potent, and are
haler).15 Dose-dependent, sympathomimetic-type associated with more frequent side effects than
side effects, including tremor, anxiety, heart pound- inhaled short-acting -agonists.30 Similarly, anti-
ing, and tachycardia (but not hypertension), are cholinergic bronchodilators such as ipratropium
common, and a small dose-dependent decrease in are not recommended (or approved by the Food
serum potassium and magnesium levels is detect- and Drug Administration [FDA]) for quick relief
able. However, at the usual dose (two puffs per of asthmatic symptoms. They take longer to start
administration), unpleasant stimulatory side ef- working (20 to 30 minutes) and cause less bron-

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Table 1. Short-Acting -Adrenergic Agonists.*

No. of Doses
per MDI Rating in
Drug Brand Name Formulation Dose Canister Pregnancy Comments
Albuterol Ventolin (GlaxoSmithKline), ProAir MDIHFA 90 g/puff 200 C CFC-driven albuterol MDIs were taken
(Teva), Proventil (Schering off the market on December 31,

Plough) 2008; generic albuterol HFA inhal-

ers are not yet available
AccuNeb (Dey), generic Liquid for nebulization 0.63, 1.25, or 2.5 mg/vial; C
5 mg/ml
Proventil Repetabs, Vospire ER Extended-release tablets 4 or 8 mg C
(DAVA Pharmaceuticals)
Proventil, generic Tablets 2 or 4 mg C

Generic Syrup 2 mg/5 ml C

Levalbuterol Xopenex (Sepracor) MDIHFA 45 g/puff 200 C Single stereoisomer derived from
n e w e ng l a n d j o u r na l


The New England Journal of Medicine


Liquid for nebulization 0.31, 0.63, or 1.25 mg/vial C

Metaproterenol Alupent (Boehringer Ingelheim), Liquid for nebulization 10 or 15 mg/vial; 50 mg/ml C Less 2 selectivity than albuterol; man-

n engl j med 360;10 march 5, 2009

generic ufacture of metaproterenol MDI
was discontinued in July 2008

Copyright 2009 Massachusetts Medical Society. All rights reserved.

m e dic i n e

Alupent, generic Tablets or syrup 10 or 20 mg; 10 mg/5 ml C

Pirbuterol Maxair (Graceway) MDICFC 200 g /puff 400 C Breath-actuated MDI

* CFC denotes chlorofluorocarbons, HFA hydrofluoroalkane, and MDI metered-dose inhaler.

A pregnancy rating of C indicates that a risk to the fetus cannot be ruled out.

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Drug Ther apy

chodilation than inhaled -agonist bronchodila- Changes include fewer mast cells, eosinophils,
tors.31 Anticholinergic bronchodilators should be T lymphocytes, and dendritic cells in the mucosa
used only in the rare case of a patient with intol- and submucosa38; reduced goblet-cell hyperplasia
erance to all -agonist bronchodilators or for the and epithelial-cell injury39; and decreased vascu-
treatment of severe asthmatic attacks32 or asth- larity.40
matic attacks induced by beta-blockers.2 Along with suppression of airway inflamma-
A novel approach to asthma management, not tion, nonspecific bronchial hyperresponsiveness
yet adopted in the United States, combines a short- typically decreases by a factor of two to four.41
acting -agonist with an inhaled corticosteroid Beneficial clinical outcomes include fewer asth-
in a single device, administered as needed for matic symptoms, increased lung function, im-
symptom relief. Use of the device has been asso- proved asthma-specific quality of life, and fewer
ciated with favorable outcomes in patients with asthmatic exacerbations, including severe attacks
mild asthma, as compared with the use of al- resulting in hospitalization42 or death.43 Optimis-
buterol alone as needed.33 Similarly, the long-act- tic predictions to the contrary, evidence is for the
ing -agonist bronchodilator with a quick onset most part lacking to indicate that long-term use
of action (formoterol) is being used in combina- of inhaled corticosteroids can prevent the pro-
tion with an inhaled corticosteroid in a single in- gressive decline in lung function observed in some
haler for both maintenance and rescue therapy.34,35 persons with asthma.44,45 Inhaled steroids sup-
The safety of this approach in a broad and diverse press but do not cure asthmatic inflammation: in
patient population remains to be ascertained. a stable phase of the disease, markers of airway
inflammation (e.g., exhaled nitric oxide concen-
L ong -Ter m C on t rol trations and sputum eosinophilia) and bronchial
hyperresponsiveness return to baseline approxi-
Achieving good long-term control of asthma (in- mately 2 weeks after the use of inhaled cortico
frequent asthmatic symptoms, an unrestricted steroids has been stopped.46,47
level of activity, normal or near-normal lung func- Not all patients benefit equally from inhaled
tion, and rare asthmatic attacks requiring emer- corticosteroids. For instance, current cigarette
gency care) requires a multifaceted approach: avoid- smokers are less likely to derive the same anti
ance of environmental stimuli that can provoke asthmatic effects as nonsmokers.48 Neutrophilic
bronchoconstriction and acute and chronic airway inflammation of the airways is less likely to re-
inflammation; monitoring of changes in disease spond to treatment than is eosinophilic inflam-
activity; in some cases, allergen immunotherapy; mation. Genetic differences in persons with asth-
and drug therapy. The use of controller medica- ma may also be predictive of nonresponsiveness
tions should be intensified (or stepped up) until to corticosteroids.49
good asthma control is achieved, including a re- Most of the currently available inhaled cortico
duction of the number of asthmatic attacks re- steroids, when swallowed and systemically ab-
quiring systemic corticosteroids to no more than sorbed from the gastrointestinal tract, undergo
one yearly. Inhaled corticosteroids constitute the extensive first-pass metabolic inactivation in the
drug class that has had the greatest effect in help- liver before reaching the systemic circulation.50
ing patients achieve well-controlled asthma. In addition, because in general less than 20% of
the delivered dose is deposited onto the airways,
Inhaled Corticosteroids only small amounts are available for systemic ab-
Corticosteroids have proved effective in the treat- sorption across the respiratory tract mucosa. With
ment of asthma, as they have in many other in- the use of changes in hypothalamicpituitary
flammatory diseases, because of their multiplicity adrenal function as an assay, a systemic effect can
of antiinflammatory activities, including a broad be seen with inhaled-corticosteroid administra-
effect on the transcription (both up-regulation and tion at doses as low as 88 g of fluticasone per
down-regulation) of many genes.36,37 In airway- day.51 However, virtually no clinically important,
biopsy specimens from patients with asthma who long-term adverse systemic effects are observed
have had prolonged treatment with inhaled corti- among adults taking low-to-medium doses. At
costeroids, the histologic abnormalities that are high doses (usually >1000 g of beclomethasone
typical of asthma have been shown to diminish. per day or the equivalent), the risks of skin bruis-

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Table 2. Inhaled Corticosteroids.*

No. of Doses Rating in
Drug Brand Name Formulation Dose per Inhalation per Canister Pregnancy Patient Age Comments
g yr
Beclomethasone Qvar (Teva) MDIHFA 40 or 80 100 C 5 Prepared as an aerosol
solution (rather than
suspension), with
smaller particle size
Budesonide Pulmicort DPI or suspension DPI: 90 or 180; suspen- DPI: 60 or 120; suspen- B DPI: 6; suspension Built-in dose counter
(AstraZeneca) for nebulization sion for nebulization: sion for nebulization: for nebulization:
250 or 500 prefilled single-dose 18
Ciclesonide Alvesco (Sepracor) MDIHFA 80 or 160 60 C 12 Prepared as an aerosol
solution, activated
by airway esterases,
approved for twice-

daily use
Flunisolide Aerobid (Forest MDICFC 250 100 C 6 Available with menthol
Laboratories) flavoring as
Fluticasone Flovent MDIHFA or DPI MDIHFA: 44, 110, or MDIHFA: 120; DPI: 60 C 4 Built-in dose counter
(GlaxoSmithKline) 220; DPI: 50 or 100 with both MDI
and DPI
Mometasone Asmanex (Schering- DPI 110 or 220 30; 30, 60, 120 C 4 Approved for once-daily
Plough) use; built-in dose
Triamcinolone Azmacort (Abbott) MDICFC 75 240 C 6 Built-in small-volume
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The New England Journal of Medicine


In combination with
Budesonide with Symbicort MDIHFA 80 or 160 (with 4.5 g 120 C 12 2 Puffs twice daily; built-

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formoterol (AstraZeneca) of formoterol) in dose counter
Fluticasone with Advair MDIHFA or DPI MDIHFA: 45, 115, or MDIHFA:120; DPI: 60 C MDIHFA: 12; MDIHFA: 2 puffs twice

Copyright 2009 Massachusetts Medical Society. All rights reserved.

m e dic i n e

salmeterol (GlaxoSmithKline) 230 (with 21 g of DPI: 4 daily; DPI: 1 inhala-

salmeterol); DPI: tion twice daily; built-
100, 250, or 500 in dose counter
(with 50 g of

* Fluticasone and mometasone are more potent, microgram for microgram, by a factor of approximately 2:1 than beclomethasone, budesonide, and flunisolide. The most recently re-
leased inhaled corticosteroid, ciclesonide, is an ester prodrug inactive until hydrolyzed to desisobutyryl-ciclesonide by esterases endogenous to airway epithelium. Preliminary data
suggest that ciclesonide is associated with a lower incidence of oral candidiasis than fluticasone58 and is not associated with growth retardation in children when given in conventional
doses.59 Mometasone has been approved for once-daily use, although it is likely that other inhaled corticosteroids can also be administered once daily for patients with mild, well-con-
trolled asthma.60,61 CFC denotes chlorofluorocarbons, DPI dry-powder inhaler, HFA hydrofluoroalkane, LABA long-acting -agonist, and MDI metered-dose inhaler.

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A pregnancy rating of B indicates that there is no evidence of fetal risk in humans, and a rating of C that a risk to the fetus cannot be ruled out.
Other formulations are available outside the United States.
Drug Ther apy

ing, cataracts,52 elevated intraocular pressure,53 contained only 42 g of medication. Since then,
and accelerated loss of bone mass54 increase. In additional corticosteroid preparations have become
children, growth retardation is a concern. Expect- available, including drugs that are more potent,
ed growth decreases by an average of approxi- deliver a larger dose per inhalation, and are rec-
mately 1 cm in the first year after instituting in- ommended for use once or twice daily, features
haled corticosteroids in growing children,45,55 but that have contributed to improved efficacy and
evidence from studies in prepubescent school-age compliance (Table 2).
children suggests that even when these children There are differences among the various in-
continue to receive long-term treatment with in- haled corticosteroids.62,63 For the most part, choic-
haled corticosteroids, they ultimately reach their es are based on the convenience of the dosing
normal predicted height.45,56 schedule (once or twice daily) and method of de-
Pharyngeal and laryngeal side effects of in- livery (metered-dose inhaler, dry-powder inhaler,
haled corticosteroids include sore throat, cough- or suspension for nebulization), the starting dose
ing on inhalation of the medication, weak or and flexibility in making dose adjustments, the
hoarse voice, and candidiasis. Rinsing the mouth cost to the patient, and observed side effects. Only
after each administration of the medication and minor differences in the products therapeutic
using a valved holding chamber when it is deliv- outcomes have been found.
ered with a metered-dose inhaler are two tech- The use of high-dose inhaled corticosteroids
niques that can minimize the risk of oral candidi- has proved effective for the control of severe per-
asis (thrush). (Use of the valved holding chamber sistent asthma.64 However, the dosetherapeutic-
also reduces the amount of medication available response (improvement in expiratory flow) curve
for systemic absorption from the oropharynx.) for inhaled corticosteroids is relatively flat, where-
Cough can usually be overcome by changing ei- as the dosesystemic-absorption curve appears to
ther the inhaled corticosteroid medication or the be linear.51 As a result, strategies that can achieve
delivery system. Dysphonia, generally intermittent, asthma control without using high doses of in-
is thought to be due to laryngeal edema and mu- haled corticosteroids are desirable, and reduction
cosal thickening or possibly myopathy.57 It usually of the inhaled-corticosteroid dose in patients with
resolves with temporary cessation of the medica- well-controlled asthma (referred to as stepping
tion and may also do so with a change in aerosol down treatment) can often be achieved without
generation and flow pattern (e.g., switching from diminishing asthma control.65
a dry-powder inhaler to a metered-dose inhaler
with valved holding chamber.) Inhaled Long-Acting -Agonist Bronchodilators
When first introduced for the treatment of The inhaled long-acting -agonists, salmeterol and
asthma in the mid-1970s, the inhaled cortico formoterol (Tables 2 and 3), have largely replaced
steroid beclomethasone was prescribed for use the older long-acting bronchodilators orally ad-
four times daily, and each puff of medication from ministered, slow-release albuterol and theophyl-
a metered-dose inhaler sold in the United States line. Long-acting -agonists are potent broncho-

Table 3. Inhaled Long-Acting -Agonist Bronchodilators.*

Rating in
Drug Brand Name Formulation Dose Patient Age Pregnancy Comments
g yr
Arformoterol Brovana (Sepracor) Liquid for aerosolization 15/vial Adults C Approved for COPD
but not asthma
Formoterol Foradil (Schering-Plough) Single-dose DPI 12/capsule 5 C Rapid onset of action
Perforomist (Dey) Liquid for aerosolization 20/vial Adults C Approved for COPD
but not asthma
Salmeterol Serevent (GlaxoSmithKline) DPI (60 doses per device) 50/inhalation 4 C Multidose DPI

* COPD denotes chronic obstructive pulmonary disease, and DPI dry-powder inhaler.
A pregnancy rating of C indicates that a risk to the fetus cannot be ruled out.

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The n e w e ng l a n d j o u r na l of m e dic i n e

dilators (with a bronchodilator effect similar to two classes of medications: in vitro studies show
that of the short-acting -agonists), have sustained that corticosteroids improve -receptormediated
activity for more than 12 hours, and because of signaling in the lung, and -agonists enhance
their high degree of adrenergic -2 specificity, have the transcription of genes under the influence of
few side effects (generally mild sympathomimet- corticosteroids.75 Combination therapy (a long-
ic-type stimulation, including occasional muscle acting -agonist combined with an inhaled cor-
cramps and tachycardia).66 They have none of the ticosteroid in a single inhaler) (Table 2) ensures
fooddrug and drugdrug interactions that com- concomitant use of an antiinflammatory drug
plicate the use of theophylline, and toxicity from and optimizes compliance because of greater con-
drug overdosing is exceedingly rare, in contrast venience. Its major disadvantage is that adjusting
to the effects of theophylline overdosing. the dose of inhaled corticosteroids without chang-
As with short-acting -agonists, regular use ing the dose of -agonist (e.g., increasing the
of long-acting -agonists results in only mild corticosteroid dose during an asthmatic exacer-
tachyphylaxis to the maximal bronchodilator ef- bation) requires changing devices or adding a
fect and the duration of action of these drugs.66 separate inhaled corticosteroid inhaler.
In contrast, the bronchoprotective effect of long- The life-changing benefit that many patients
acting -agonists (i.e., their inhibition of exer- with moderate or severe persistent asthma have
cise-induced bronchoconstriction) rapidly wanes experienced with the use of a long-acting -agonist
with regular use,67,68 a contrary pharmacologic together with an inhaled corticosteroid must be
effect that has not been fully explained. With rare counterbalanced against the results of the Salmet
exceptions,69 the quick symptom relief provided erol Multicenter Asthma Research Trial (SMART),76
by short-acting -agonists is not impeded by regu- in which the addition of a long-acting -agonist
lar use of long-acting -agonists.70 Variation in to usual therapy was associated with an in-
the structure of the -adrenergic receptor, as de- creased risk of fatal and near-fatal asthmatic
termined by genetic polymorphisms that are com- attacks, as compared with usual therapy alone.
mon in the U.S. population (15 to 20%), may limit It has been pointed out that a minority of sub-
the effectiveness of long-acting -agonists in some jects in SMART were taking inhaled corticoste
patients.71 roids and that no increased asthma-related mor-
The fact that long-acting -agonists can pro- tality has ever been reported among patients
vide sustained improvement in lung function may taking both a long-acting -agonist and an in-
tempt clinicians to use them as a long-term con- haled corticosteroid.77,78 Nonetheless, the mech-
troller medication without concomitant use of an anism by which salmeterol caused a greater num-
antiinflammatory inhaled corticosteroid. However, ber of asthma-related deaths, among both black
this strategy results in unsuppressed airway in- and white subjects, remains uncertain, and a black-
flammation and an unacceptably high rate of box warning is therefore included in the prescrip-
asthmatic exacerbations.47 Long-acting -agonists tion-labeling information (or package insert) for
should not be used without concomitant antiin- all products containing either salmeterol or for-
flammatory therapy in the treatment of asthma. moterol. In addition, national and international
As therapy added to or combined with inhaled expert panels2,13 have recommended the use of
corticosteroids, long-acting -agonists have proved long-acting -agonists only for patients in whom
effective in reducing daytime and especially night- inhaled corticosteroids alone either have failed
time symptoms, improving lung function, reduc- to achieve good asthma control or, for initial
ing the risk of exacerbations, and minimizing the therapy, would not be expected to bring about
required dose of inhaled corticosteroids.72 Com- good control. Future guidelines on the treatment
parisons of the use of inhaled corticosteroids in of asthma will need to wrestle with appropriate
combination with long-acting -agonists and application of the recent observation that once-
the use of higher doses of inhaled corticoste daily administration of a long-acting -agonist in
roids alone show that the combination therapy is combination with an inhaled corticosteroid pro-
associated with more favorable outcomes (while vides good control in patients with mild persis-
maintaining lower exposure to corticosteroids).73,74 tent asthma.79
Pharmacologic evidence provides theoretical sup- Features distinguishing the two long-acting
port for a favorable interaction between these -agonists are both practical and theoretical.80

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Drug Ther apy

The onset of action of formoterol occurs within Montelukast is available in chewable tablets and
5 minutes, a period similar to that for short-act- oral granules (to be mixed with food) for young
ing -agonists, whereas salmeterol has a slower children. The recommendation to administer
onset of action (15 to 20 minutes). For this rea- montelukast once daily in the evening was based
son, in some countries other than the United on the timing of its use in the seminal trials
States, a combination formoterolinhaled-corti- submitted to the FDA at the time of application
costeroid inhaler is recommended both for quick for approval. No data indicate a greater benefit
relief of asthmatic symptoms and, when used with administration in the evening as compared
regularly, for long-term control.34 Formoterol is with dosing at any other time of day.87
a full agonist in its action at the -receptor, where- Zileuton inhibits production of the cysteinyl
as salmeterol is a partial agonist (and partial an- leukotrienes (and of leukotriene B4, a potent
tagonist). The implication of this pharmacologic chemoattractant for neutrophils) by antagonizing
distinction, particularly as it might apply to the the action of 5-lipoxygenase. An extended-release
risk of fatal asthmatic attacks, is uncertain. formulation is now available, making twice-daily
dosing possible. No clinical trial has directly com-
Leukotriene Modifiers pared the efficacy of zileuton with that of a
The cysteinyl leukotriene-receptor antagonists, leukotriene-receptor antagonist or has tested the
montelukast, zafirlukast, and pranlukast (the last effects of their use in combination. Some clini-
not available in the United States) (Table 4), block cians have found zileuton to be more beneficial
the action of leukotriene C4, D4, and E4 at the than leukotriene-receptor antagonists in triad
type 1 cysteinyl leukotriene receptor.81 Broncho- asthma (asthma, aspirin sensitivity, and nasal
dilation occurs within hours of the first dose and polyposis), in terms of both controlling asthma
is maximal within the first few days after admin- and shrinking nasal polyps.88
istration.82,83 Levels of circulating blood eosino- Zileuton causes a reversible chemical hepatitis
phils decrease in response to treatment with leu- in 2 to 4% of patients. Hepatic function should be
kotriene-receptor antagonists.82,83 However, when monitored monthly for the first 3 months of ther-
indirect measures of airway inflammation (e.g., apy, about every 3 months for the remainder of
sputum eosinophilia and levels of exhaled nitric the first year, and periodically thereafter. Reports
oxide) are used to determine the outcome, the of the emergence of the ChurgStrauss syndrome
effect of leukotriene-receptor antagonists on air- (an eosinophilic vasculitis with granulomatosis
way inflammation, as compared with that of pla- complicating the course of asthma) in patients
cebo, has been variable.84-86 recently started on a leukotriene-receptor antago-
Leukotriene-receptor antagonists can be ad- nist (often with concomitant tapering of oral cor-
ministered as tablets once (in the case of montelu- ticosteroids)89,90 may reflect unmasking of pre-
kast) or twice (in the case of zafirlukast) daily. existing cases of ChurgStrauss vasculitis,91,92

Table 4. Leukotriene Modifiers.

Rating in
Drug Brand Name Formulation Dose Patient Age Pregnancy* Comments
mg yr
Montelukast Singulair Granules, chewable Granules: 4; chewable Granules: 12; chewable B Once-daily use
(Merck) tablets, or tablets tablets: 4 or 5; tablets: 25 for the
tablets: 10 4-mg dose, 614 for
the 5-mg dose; tab-
lets: 15
Zafirlukast Accolate Tablets 10 or 20 511 for the 10-mg B One tablet twice daily
(AstraZeneca) dose, 12 for the
20-mg dose
Zileuton Zyflo (Cornerstone Extended-release 600 12 C Two tablets twice daily
Therapeutics) tablets (after meals)

* A pregnancy rating of B indicates that there is no evidence of fetal risk in humans, and a rating of C that a risk to the fetus cannot be ruled out.

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The n e w e ng l a n d j o u r na l of m e dic i n e

although the possibility of a causal association in whom good asthma control is not achieved
remains debated.93 In general, the leukotriene- with the use of a leukotriene modifier, transition
receptor antagonists have been considered virtu- to an inhaled corticosteroid is indicated. For pa-
ally free of side effects, and one (montelukast) has tients with more severe asthma, the addition of
been approved for the treatment of asthma in a leukotriene-receptor antagonist to a low dose of
children as young as 1 year old. Recent postmar- an inhaled corticosteroid may improve asthma
keting reports have described a few cases in which control,104,105 but other treatment combinations
depression and suicidal ideation developed in chil- (specifically, an inhaled corticosteroid plus long-
dren taking montelukast. No cause-and-effect rela- acting -agonist) are more effective.106,107
tionship has been established, and on review of all
available placebo-controlled clinical trials data, the Anti-I g E Therapy
FDA found no increased risk of suicidal ideation The anti-IgE monoclonal antibody, omalizumab,
or suicide for any of the leukotriene modifiers. is the first biologic immunoregulatory agent avail-
The possibility of medication-induced mood and able to treat asthma. It binds to the portion of IgE
behavioral changes remains under review.94 that recognizes its high-affinity receptor (FcR1)
Because of their perceived safety and conve- on the surface of mast cells and basophils. When
nience, leukotriene-receptor antagonists have given intravenously, omalizumab reduces circu-
largely replaced the cromoglycates (cromolyn and lating IgE levels by 95% and can result in levels
nedocromil) as the noncorticosteroid treatment of of free IgE of 10 IU per milliliter or less, a target
choice, especially for young children, in whom thought to be clinically relevant for inhibiting al-
medication delivery by aerosol is often a struggle. lergic reactions in the airways.108 Its use also re-
Cromolyn requires administration four times daily sults in down-regulation of expression of FcR1
by metered-dose inhaler or nebulizer, provides on the surface of mast and other immune-modu-
limited long-term asthma control, and unlike lating cells (basophils, monocytes, and dendritic
leukotriene-receptor antagonists, has never been cells).109 In contradistinction to allergen immuno-
shown to have an additive benefit when used in therapy, treatment with omalizumab is not restrict-
combination with inhaled corticosteroids. ed in its effects to any specific allergen or group
Short-term, double-blind, placebo-controlled of allergens.
trials have shown improved lung function, better Omalizumab is administered subcutaneously
scores on asthma-related quality-of-life question- every 2 or 4 weeks, depending on the dose. The
naires, and fewer asthmatic attacks among pa- dose is based on the patients weight and blood
tients treated with leukotriene modifiers.82,83,95,96 IgE level. Reactions at the injection site (e.g., hives)
Persons with asthma who are obese,97 who are uncommon, and systemic allergic reactions
smoke cigarettes,48 or who have associated aspi- (i.e., anaphylaxis) occur in 1 to 2 patients per 1000.
rin sensitivity88,98,99 may particularly benefit from Most but not all systemic reactions occur within
treatment with leukotriene modifiers. In the fu- 2 hours after administration of the first few doses.
ture, identification of specific interindividual vari- Patients are asked to remain under medical obser-
ations in the genes coding for enzymes along the vation for 2 hours after each of their first three
leukotriene metabolic pathway may prove clini- injections and for 30 minutes after each subse-
cally useful in predicting whether a patient will quent injection and to carry with them for the next
have a response to treatment.100 Currently, a thera- 24 hours prefilled epinephrine-containing auto-
peutic trial is often used; symptomatic and objec- injectors for self-administration, if needed.110
tive improvement, if they are to occur, are gener- Omalizumab is indicated for the treatment of
ally observed within the first month of therapy. moderate and severe persistent asthma when in-
Overall, inhaled corticosteroids provide bet- haled corticosteroids, long-acting -agonists, and
ter asthma control than leukotriene modif i leukotriene modifiers have not provided adequate
ers.86,96,101-103 As a result, an inhaled corticoste control or cannot be used because of intolerable
roid is the recommended drug of first choice in the adverse effects. The currently approved dosing
treatment of patients with persistent asthma, in- range for omalizumab limits administration to
cluding children of all ages.2 Leukotriene-recep- patients with blood IgE levels between 30 and
tor antagonists are an alternative treatment for 700 IU per milliliter; documented sensitization
mild persistent asthma. For patients of any age to a perennial aeroallergen (e.g., dust mites, ani-

1010 n engl j med 360;10 march 5, 2009

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Drug Ther apy

mal dander, mold, or cockroaches) is an additional

criterion for patient selection.

Step down treatment to minimize

short- and long-term side effects,
Add anti-IgE monoclonal
Omalizumab has been approved for use in antibody (omalizumab)

cost, and inconvenience

Step up treatment to achieve
adults and children 12 years of age or older. For
patients in this age range, the drug has not been Inhaled steroid + LABA + LTM

asthma control
shown to be disease modifying in the sense that Inhaled steroid + LABA
it is not known to prevent long-term changes in (or inhaled steroid + LTM)
lung function or to result in a disease remission Inhaled steroid
(as indicated by drug discontinuation without re- (or LTRA)
currence of asthmatic symptoms). Treatment with
SABA, as needed
omalizumab has been found to reduce the fre-
quency of asthmatic exacerbations, even among
patients already taking many other controller Figure 1. Stepped-Care Approach to Asthma Treatment.
medications.111 In patients treated with an in- This simplifiedICM
stepped-care Fanta
AUTHOR:approach RETAKE is 1st
to asthma treatment constructed
around the central FIGURE:
REG F role 1 of 1 corticosteroids. For each of the
of inhaled overlap-
haled corticosteroid alone, the addition of oma 3rd
ping steps, theCASE
dose of the inhaled corticosteroid can Revised
be adjusted as need-
lizumab, as compared with placebo, permitted a ed to achieve the
EMailgoal of well-controlled asthma
Line 4-Cwhile minimizing
SIZE the long-
greater reduction of the inhaled-corticosteroid term risks associated ARTIST:
with hights doses.H/T
LABA denotes
H/T long-acting
22p3 -agonist,
dose, with preserved or slightly improved lung Combo
LTM leukotriene modifier, LTRA leukotriene-receptor antagonist, and SABA
function and with slightly less need for a rescue short-acting -agonist. AUTHOR, PLEASE NOTE:
Figure has been redrawn and type has been reset.
bronchodilator.112,113 Please check carefully.
One of the greatest drawbacks to the more
JOB: 36010 ISSUE: 03-05-09
widespread use of omalizumab is cost, roughly patients receiving regular controller therapy for
$10,000 to $30,000 per year for the drug alone. their asthma. 115,116

Pharmacogenetic markers predictive of a favor- When symptoms persist despite medication

able response would be highly desirable, given compliance and good inhalational technique, use
the large cost of a therapeutic trial lasting 4 to of a long-acting -agonist in combination with
6 months. Observations to date suggest that tra- an inhaled corticosteroid has proved to be the
ditional clinical characteristics at baseline cannot most effective next step, since it addresses both
reliably predict which patients will have a response aspects of airway narrowing in asthma: broncho-
to anti-IgE therapy.114 constriction and airway inflammation. A novel
option for patients with refractory allergic asthma
C onclusions is therapy with an anti-IgE monoclonal antibody.
Asthma control can often be achieved by in-
When asthma symptoms are infrequent, short- creasing the dose of inhaled corticosteroids. How-
lived, and mild, occasional administration of a ever, at high doses, the potential for long-term
quick-acting bronchodilator to reverse smooth- adverse effects becomes a concern. Thus, once
muscle constriction in the airways is an acceptable control of asthma has been achieved for a period
approach. However, as symptoms become more of 3 to 6 months, efforts should be made to reduce
frequent or more severe, the emphasis changes to the dose of inhaled corticosteroids to the low-to-
prevention of symptoms (and of asthmatic attacks) moderate range. Use of long-acting -agonists,
(Fig. 1). By suppressing airway inflammation, an leukotriene modifiers, and anti-IgE therapy can
inhaled corticosteroid used once or twice daily facilitate a reduction of the dose of inhaled cor-
reduces the frequency of episodic bronchoconstric- ticosteroids while maintaining asthma control.
tion and lessens the risk of asthmatic attacks. In Dr. Fanta reports receiving educational grants for Partners
low-to-moderate doses, corticosteroids adminis- Asthma Center from AstraZeneca, Boehringer Ingelheim, Genen-
tered by inhalation are safe for long-term use, even tech, GlaxoSmithKline, Graceway Pharmaceuticals, Merck, No-
vartis, Sanofi-Aventis, Schering-Plough, and Sepracor and reports
in young children. An alternative to a corticoster- that Partners Asthma Center has provided educational training
oid for mild asthma is a leukotriene-receptor an- programs for employees of Genentech, Merck, and Novartis. No
tagonist, which is directed at blocking a specific other conflict of interest relevant to this article was reported.
I thank Drs. Joshua Boyce, Kenan Haver, and Elliot Israel of
inflammatory mediator in asthma. Influenza and Partners Asthma Center for their thoughtful comments and
possibly pneumococcal vaccines are indicated for helpful suggestions on an earlier version of this article.

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The n e w e ng l a n d j o u r na l of m e dic i n e

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