Leukotriene Modifiers in Pediatric Asthma Management
Hans Bisgaard, MD, DMSc
ABSTRACT. Cysteinyl leukotrienes (Cys-LTs) are me-
diators released in asthma and virus-induced wheezing.
Corticosteroids appear to have little or no effect on this
release in vivo. Cys-LTs are both direct bronchoconstric-
tors and proinflammatory substances that mediate sev-
eral steps in the pathophysiology of chronic asthma, in-
cluding inflammatory cell recruitment, vascular leakage,
and possibly airway remodeling. Blocking studies show
that Cys-LTs are pivotal mediators in the pathophysiol-
ogy of asthma. Cys-LTs are key components in the early
and late allergic airway response and also contribute to
bronchial obstruction after exercise and hyperventilation
of cold, dry air in asthmatics. LT modifiers reduce airway
eosinophil numbers and exhaled nitric oxide levels. To-
gether these findings support an important role for the
Cys-LTs in the asthma airway inflammation. Cys-LT re-
ceptor antagonists (Cys-LTRA) are generally well-toler-
ated. Phase III randomized, controlled clinical trials
(RCT) show that LT modifiers are moderately effective,
apparently with a particular between-patient variability
in their clinical response. The clinical effects of LT mod-
ifiers are additive to those of ␤-agonists and corticoste-
roids. The onset of action of LT modifiers is within 1 to
several days, and not rapid enough to make them useful
as rescue treatment. Although LT modifiers possess some
antiinflammatory activity, they cannot substitute for cor-
ticosteroids for inflammation control. LT modifiers are
alternatives to long-acting ␤-agonists as complementary
treatment to inhaled corticosteroids in pediatric asthma
management because they provide bronchodilation and
bronchoprotection without development of tolerance,
and complement the antiinflammatory activity un-
checked by steroids. In addition, the Cys-LTRA monte-
lukast has been shown to ameliorate asthmatic symp-
toms and provide bronchoprotection in asthmatic
preschool children from 2 years of age, which is of par-
ticular importance in this difficult-to-manage group of
asthmatics. Given their efficacy, antiinflammatory activ-
ity, oral administration, and safety, LT modifiers will
play an important role in the treatment of asthmatic
children. Pediatrics 2001;107:381–390; leukotriene, leuko-
triene receptor antagonists, asthma, pediatrics, manage-
ment, positioning, steroid.
ABBREVIATIONS. LT, leukotriene; RCT, randomized, controlled
clinical trial; AA, arachidonic acid; CO, cyclooxygenase; 5-LO,
5-lipoxygenase; FLAP, 5-LO-activating protein; Cys-LT, cysteinyl
leukotriene; EIB, exercise-induced bronchoconstriction; Cys-
LTRA, Cys-LT receptor antagonist; BAL, bronchoalveolar lavage;
From the Department of Paediatrics, Copenhagen University Hospital,
Copenhagen, Denmark.
Received for publication Jan 31, 2000; accepted May 30, 2000.
Address correspondence to Hans Bisgaard, MD, Dr Med Sci, Department of
Paediatrics, Copenhagen University Hospital, DK-2100 Copenhagen, Den-
mark. E-mail: bisgaard@copsac.dk
PEDIATRICS (ISSN 0031 4005). Copyright © 2001 by the American Acad-
emy of Pediatrics.
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FeNO, exhaled nitric oxide; QID, 4 times daily; FEV1, forced
expiratory volume in 1 second; BID, 2 times daily.
L
eukotriene (LT) modifiers represent the first
new therapeutic class in asthma since the in-
troduction of inhaled steroids in 1972, and they
are the first mediator-specific therapy for asthma.
This treatment is tailored to the known pathophysi-
ology of asthma and represents the first example of
drug development design based on our increased
understanding of the molecular biology of asthma.
The long history is fascinating from its discovery in
1938 as a biologic substance characterized by its par-
ticular slow contracting ability of smooth muscles,
through the unraveling of its chemical nature 4 de-
cades later followed by the awarding of the Nobel
prize in 1982, up to the engineering in the recent
decade of specific receptor antagonists and identifi-
cation of the LT receptor in human bronchioles. LT
modifiers (both receptor antagonists and biosynthe-
sis inhibitors) have proven efficacious in random-
ized, controlled clinical trials (RCTs) of asthma in
adults, children and even preschool children. They
have been rapidly introduced into clinical practice
worldwide, although their position in treatment
guidelines is still evolving. Therefore, it seems timely
to review the role of LTs in asthma airway inflam-
mation and the evidence for the effect of LT modifi-
ers from RCTs with a view to their potential role in
pediatric asthma management.
BIOCHEMISTRY OF LTS (FIG 1)
LTs are 20-carbon unsaturated fatty acids released
from membrane phospholipids via the arachidonic
acid (AA) cascade. Activation of phospholipase A2
results in the release of membrane-bound AA. Free
AA can be converted by cyclooxygenase (CO) to
form prostanoids (prostaglandins, prostacyclin, and
thromboxane) or converted via the 5-lipoxygenase
(5-LO) pathway to form LTs. The AA is presented to
the 5-LO enzyme by the 5-LO-activating protein
(FLAP) resident in the nuclear membrane. The 5-LO
pathway results in the formation of 2 classes of LTs,
the nonpeptide LTs LTA4 and LTB4 and the cysteinyl
leukotrienes (Cys-LTs) LTC4, LTD4, and LTE4. LTC4
is actively transported extracellularly, where subse-
quent cleavage of amino acids yields LTD4 and LTE4.
Cys-LTs are degraded rapidly in the extracellular
space with a very short half-life. LTE4 undergoes
biliary and urinary excretion partly as an end-prod-
uct and is partly oxidized to inactive metabolites.
The Cys-LT1 receptor was recently cloned. In the
normal human lung, expression of Cys-LT1 receptor
PEDIATRICS Vol. 107 No. 2 February 2001 381

Fig 1. AA cascade. CO indicates cyclooxygenase; 5-LO, 5-lipoxy-
genase; FLAP, 5-LO activating protein.
mRNA was observed in bronchial smooth muscle
cells and tissue macrophages, among other cell
types,1 which corroborate the bronchoconstrictive
and proinflammatory nature of Cys-LT. The cloning
of the human Cys-LT1 receptor allows fascinating
future studies into receptor distribution, species dif-
ferences, and possible receptor heterogeneity.
SOURCES OF CYS-LT
LTs are synthesized de novo from cell membrane
phospholipids in response to a variety of biologic
signals including antigen challenge of sensitized tis-
sues. Cys-LTs are produced both by constitutive cells
in the lungs (mast cells and alveolar macrophages)
and by infiltrating cells (eosinophils). LTB4 is pre-
dominantly produced by neutrophils.
Cys-LT production is upregulated in asthma.
Blood eosinophils from children with asthma release
more Cys-LT than do those of controls.2,3 Cys-LT
levels were increased at baseline in asthma patients,4
correlating with disease severity5 and with addi-
tional increases observed during spontaneous at-
tacks,6 allergen challenge,7,8 and exercise-induced
bronchoconstriction (EIB).9,10
LTs also seem upregulated in wheezy disorders in
young children. Alveolar macrophages from wheezy
infants were shown to release more LTB4 than those
from nonwheezy infants.11 Children with wheezing
released significantly more LTC4 in nasopharyngeal
secretions than did healthy controls, and this in-
crease was further augmented in wheezy children
who shed respiratory virus as compared with
wheezy children without evidence of viral infec-
tion.12,13 In infants, increased quantities of eico-
sanoids, correlating with disease severity, were
found in nasopharyngeal secretions during episodes
of acute viral bronchiolitis.14
Cys-LT levels are also increased in airway samples
from infants with severe bronchopulmonary dyspla-
sia and in children with cystic fibrosis.16,17
BIOLOGIC EFFECTS OF CYS-LT
Cys-LTs cause profound bronchoconstriction in
peripheral and central airways and are the most
potent bronchoconstricting agent yet discovered,
382 LEUKOTRIENE MODIFIERS IN PEDIATRIC ASTHMA MANAGEMENT
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about 100 to 1000 times more potent than histamine
and with a more sustained bronchoconstriction.17–20
Asthmatics are hyperreactive to Cys-LTs,17,20 and
Cys-LTs further increase this hyperreactivity18,21,22
as well as the maximum bronchoconstrictor re-
sponse23 probably through an inflammatory mecha-
nism.24
LTD4 specifically increases blood flow in human
skin and airway mucosa and increases the vascular
permeability and interstitial transport of macromol-
ecules in human skin, processes that contribute to
edema.25–27 The escape of plasma proteins into the
tissue provides the source of potent plasma protein-
derived inflammatory mediators, including the ki-
nins and complement and clotting systems, which
may form mucus plugs, inhibit mucociliary clear-
ance, and fuel the inflammatory process.
Cys-LTs may have an effect on airway remodeling
in chronic asthma. Cys-LTs have been shown to sig-
nificantly enhance the mitogenesis of cultured hu-
man airway epithelial cells and human bronchial
smooth muscle cells.28 –30 In an animal model, the
increase in bronchial smooth muscle mass after aller-
gen challenge was effectively blocked by Cys-LT re-
ceptor antagonists (Cys-LTRAs).31
Cys-LTs also act on the upper respiratory tract
where they caused a dose-related nasal obstruction,
but not the reflex-mediated symptoms of allergic
rhinitis, such as nasal itching, sneezing, or secre-
tion.26 The significant nasal blockage still present in
allergic rhinitis after antihistamine treatment32 may
be attributable to Cys-LTs-induced nasal mucosal
engorgement; as such nasal obstruction was reduced
by 5-LO inhibition.33,34
The presence of thick, tenacious mucus plugs in
airway lumina is a frequent finding in asthmatic
patients. Mucus may accumulate because of its in-
creased production or resulting from inefficient elim-
ination caused by ciliary dysfunction. LTC4 and
LTD4 are potent airway mucus secretagogues in
vitro.35,36 However, Cys-LTs did not increase nasal
secretion in humans26 nor was a noticeable increase
in mucus production reported by healthy or asth-
matic patients after inhaling Cys-LTs.17–20 This there-
fore casts doubt on the role for Cys-LTs as secreta-
gogues in humans. Cys-LTs have been shown to
cause a slight but progressive slowing of ciliary beat
frequency in human airway cells.37,38 This effect may
contribute to the reduced mucociliary clearance typ-
ical of the asthmatic patient and increase the reten-
tion of inhaled allergens and other possibly noxious
substances. The number of eosinophils in lamina
propria increased by a factor of 10 in asthmatic pa-
tients 4 hours after inhalation of LTE4, although no
such change was observed after inhalation of metha-
choline with a dose eliciting a comparable degree of
bronchospasm.39 Similarly, LTD4 inhalation in-
creased airway eosinophils in asthmatic patients as
measured in cellular differentials of induced sputum
taken 4 hours after challenge.40 The mechanism
seems to be a direct chemotactic activity of Cys-LTs
for eosinophils.41
The role of LTB4 remains obscure. We previously
showed LTB4 to be a potent chemoattractant for eo-
sinophils and neutrophils in human skin.42 How-
ever, inhaled LTB4 had no effect on airway resistance
and responsiveness in both controls and asthmatic
patients.43 Whereas a LTB4 receptor antagonist de-
creased the number of neutrophils in bronchoalveo-
lar (BAL) fluids as expected, it failed to affect the
number of lymphocytes, macrophages, and eosino-
phils in the fluid and failed to reduce bronchocon-
striction.44 LTB4 may thus not be involved in chronic
asthma, although it may be associated with the neu-
trophilia observed in the late response to allergen
challenge and during acute severe asthma.45
EFFECTS OF CYS-LTS BLOCKADE IN MODELS OF
ASTHMA
The development of Cys-LT inhibitors has added
new and compelling evidence to support a central
role of Cys-LTs in asthma pathophysiology. The
early and late responses to allergen challenge are
classic models of asthmatic inflammation that cap-
ture several important aspects of the disease. The
early response is significantly attenuated by Cys-LT
inhibition by approximately 60% to 80% compared
with placebo.46 – 48 The combination of a Cys-LT
modifier and an antihistamine further improved
lung function during the early and the late allergic
reactions.48 Attenuation of the late response has been
observed in most studies on Cys-LT modifiers46,48
although not in all.47 Cys-LT release seems to in-
crease during the late-phase reaction according to
some reports.48,49 In summary, it appears that Cys-
LTs contribute to both the early and late allergic
reactions.
Bronchial hyperreactivity is integral to asthma
pathophysiology and correlates in some studies with
the degree of airway inflammation. Bronchial hyper-
reactivity is reflected in an abnormal response to
inhaled irritants (eg, histamine and methacholine),
exercise, or hyperventilation of cold, dry air. Bron-
chial hyperresponsiveness to methacholine was sig-
nificantly reduced with the use of Cys-LT antago-
nists in certain studies,50,51 even in patients on
concurrent treatment with inhaled corticosteroids.52
In contrast, montelukast exerted no significant effect
on methacholine reactivity in a 12-week treatment of
110 adult asthmatic patients.53 EIB was significantly
attenuated by Cys-LT modifiers.53-56 The protection
was on the order of 40% to 60% in most studies,
irrespective of different potencies of the Cys-LT
modifiers under study. These results suggest the rel-
ative importance of Cys-LTs in EIB. Cold-air induced
bronchoconstriction was also attenuated by Cys-
LTRAs as well as by 5-LO inhibitors.57–59
Eosinophils are considered pivotal cells in the air-
way inflammation of asthma. LT modifiers reduce
airway eosinophilia. The LT synthesis inhibitor
zileuton blunted eosinophilic influx 24 hours after
bronchial segmental allergen challenge, as reflected
by BAL cell counts4,60 and decrease in peripheral
blood eosinophils.61 The Cys-LTRA zafirlukast in su-
praclinical doses decreased the number of eosino-
phils in BAL fluid 48 hours after segmental allergen
challenge.62 Montelukast at the clinical dose reduced
sputum eosinophilia in adult asthmatics.63 The num-
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ber of T cells (CD3 and CD4), mast cells, and acti-
vated eosinophils in bronchial biopsies was reduced
by treatment with pranlukast.64 Peripheral blood eo-
sinophils were consistently reduced by a median
15% by treatment with montelukast in a number of
RCTs comprising a total of 1920 adults,63,65– 68 336
school-aged children,69 and 689 preschool children
with asthma.70 This effect on peripheral eosinophils
was comparable to that of 0.4 mg of inhaled be-
clomethasone dipropionate (BDP).66
Exhaled nitric oxide (FeNO) is also reduced by
treatment with a Cys-LTRA (montelukast). The re-
duction was apparent in children irrespective of con-
current treatment with inhaled corticosteroids and
was noticeable 2 days after start of treatment.71
FeNO probably reflects the eosinophilic inflamma-
tion of the conducting airways.72 A reduction in
FeNO by Cys-LTRAs corroborates the role of Cys-
LTs in the airway inflammation of asthmatics.
Aspirin-sensitive asthma is caused by a specific
mechanism present in a minority of asthmatic pa-
tients. This mechanism is poorly understood but may
be a shunting of the AA substrate from the CO
pathway to the 5-LO pathway, upregulating the
Cys-LT pathway. LT inhibition seems particularly
effective in patients with aspirin-sensitive asthma.
LT modifiers resulted in almost complete inhibition
of aspirin-induced bronchoconstriction as well as
symptoms of the skin and gastrointestinal tract.34,73
The aforementioned studies of Cys-LT modifiers
in several asthma models show that Cys-LTs are
pivotal mediators in the pathophysiology of bron-
chial asthma. Clearly, Cys-LTs are not simply bron-
choconstrictors but may also contribute to chronic
inflammatory changes.
EFFECTS OF STEROIDS ON CYS-LT SYNTHESIS
Corticosteroids generally reduce the in vitro pro-
duction of Cys-LTs, presumably through blockade of
the phospholipase enzyme responsible for liberating
AA from the cell membrane phospholipid.74 While
one ex vivo study found that dexamethasone expo-
sure was unable to inhibit stimulated LTC4 release
from alveolar macrophages from wheezy infants,11
many studies do show in vitro inhibition. Indeed,
inhibition of LT formation has been thought to con-
tribute to the efficacy of corticosteroids in the treat-
ment of asthma.75 However, several studies have
highlighted differences between the effects of corti-
costeroids on LT synthesis in vivo and in vitro. In
vivo, baseline excretion of Cys-LTs is not suppressed
by corticosteroids.75,76 Oral prednisone for 1 week
had no effect on LTE4 concentrations in BAL and
urine samples nor was an effect observed on the rise
after local bronchial allergen challenge. The in vitro
synthesis of LTB4 and thromboxane from macro-
phage-rich BAL cells, however, was reduced in the
same patients.77 The inhaled corticosteroid flutica-
sone propionate effectively prevented the asthma
attack from allergen challenge. It had no effect, how-
ever, on increased urinary LTE4 excretion after aller-
gen challenge.78 The reasons for such differences
between in vitro and in vivo data are unknown. It
has been suggested that other mediators present in
REVIEW ARTICLE 383
vivo, such as interleukin 3, may modulate suscepti-
bility to corticosteroids.79 Collectively, these studies
suggest that Cys-LT production is unchecked by cor-
ticosteroids in vivo.
CLINICAL EFFICACY OF CYS-LT MODIFIERS
Zileuton is the only marketed drug with a specific
effect on Cys-LT synthesis via inhibition of the 5-LO
enzyme. Three Cys-LTRAs—pranlukast, zafirlukast,
and montelukast— have been approved in various
markets.
Zileuton
Zileuton is administered orally 4 times daily
(QID). It is metabolized by the cytochrome P450
isoenzymes and may therefore interact with other
drugs metabolized by these enzymes, such as theo-
phylline and warfarin.80,81 The use of zileuton is
hampered by the QID dosing regimen and the re-
quirement for monitoring of liver enzymes.81,82 It is
approved for the treatment of asthma in patients 12
years and older.81 Three RCTs have reported the
effects of 6 to 13 weeks treatment with zileuton61,83,84
while one RCT showed no difference from theo-
phylline treatment.85 Zileuton 1.6 g/day and 2.4
g/day proved modestly effective against placebo in
parallel groups of adult patients with moderate to
severe asthma (mean forced expiratory volume in 1
second [FEV1] 67%–78% predicted; 4 – 6 daily doses
of inhaled ␤2-agonist and 3–5 nocturnal awakenings
per week attributable to asthma) yet without concur-
rent steroid treatment. The top of the dose-response
curve was not ascertained.
There have been no RCTs on the effect of zileuton
in pediatric asthma.
Zafirlukast
Zafirlukast (AstraZeneca, Wilmington, DE) is a
Cys-LTRA approved for treatment of asthma in chil-
dren 7 years and older.86 It is administered orally
twice daily (BID). There is up to a 40% reduction in
bioavailability when zafirlukast is taken with food.87
Zafirlukast is metabolized by the liver, and hepatic
cytochrome P450 is inhibited by therapeutic concen-
trations of zafirlukast. Therefore, there is a risk of
drug interactions, and transient elevations of liver
enzymes have been reported. These reports in pa-
tients receiving high doses of zafirlukast (80 mg BID)
preclude the use of dosages exceeding current label-
ing.87 There is also concern that the recommended
dosage may not achieve optimal inhibition of Cys-
LTs.
Zafirlukast has proved modestly effective for asth-
matics 12 years and older. Three RCTs have reported
the effect of 3 to 12 weeks treatment with Zafirlukast
over placebo. The patients included were adult asth-
matics with moderate to severe asthma (mean FEV1
60 – 68% predicted; 5– 6 daily doses of inhaled ␤2-
agonist and 4 – 6 nocturnal awakenings per week
attributable to asthma), yet without concurrent treat-
ment with steroid.88 –90 Dose-related clinical effect on
daily asthma symptoms, use of as-needed medica-
tion, and baseline lung function were demonstrated.
FEV1 improved by 11% over placebo and use of
384 LEUKOTRIENE MODIFIERS IN PEDIATRIC ASTHMA MANAGEMENT
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␤2-agonist decreased by up to 1 puff per day and
nocturnal awakenings by 2.6 per week as compared
with placebo.88 The number of symptomatic days
was reduced from 27 to 24 per month, and the num-
ber of days without use of ␤-agonists increased from
6.0 to 11.3 per month. The number of health care
contacts decreased from 0.40 to 0.19 per month.91
These effects seem modest, although statistically sig-
nificant. The study failed to define a plateau at the
highest dose used, which may indicate that higher
doses might be more efficacious.
Pediatric Study With Zafirlukast
The therapeutic effects of zafirlukast have been
reported in 1 RCT in children. In a randomized,
double-blind, 3-way, crossover study of 39 asthmatic
children from 6 to 14 years old, zafirlukast 5, 10, 20,
and 40 mg and placebo were tested for their effects
on EIB.92 At exercise challenge at 4 hours after dos-
ing, treatment with zafirlukast attenuated the maxi-
mal percentage decrease in FEV1 compared with pla-
cebo (mean value range for maximal FEV1 decrease:
⫺11.9% to ⫺9% after zafirlukast, ⫺17.9% to ⫺16.9%
after placebo) with no apparent dose-response rela-
tion in the range of 5 to 40 mg.
Montelukast
Montelukast (Merck & Co, Inc, Whitehouse Sta-
tion, NJ) is an orally bioavailable Cys-LTRA admin-
istered once daily.93 The drug has been approved for
the treatment of asthma in children 2 years and old-
er.94 There is no difference in bioavailability in young
and elderly patients, and food does not have a clin-
ically important influence with chronic administra-
tion.94 Therapeutic concentrations of montelukast do
not inhibit the cytochrome P450 isoenzymes.
Dose-ranging studies evaluating multiple doses
and dosage schedules of montelukast have been re-
ported in adults with chronic asthma. These studies
have evaluated measures of asthma control, includ-
ing lung function, use of rescue treatment, and
symptom scores. Doses of 10 to 200 mg had similar
efficacy, while 2 mg produced suboptimal re-
sponse.65,67 BID dosing provided no additional ben-
efit over once-daily dosing.67 The bronchoprotective
effect against EIB was also dose-related up to 10 mg
in adult asthmatics, and there was no additional
improvement with higher doses.56
Dose-ranging studies have not been performed in
children. Instead, the pediatric dosage was chosen as
the dosage yielding a pharmacokinetic profile (sin-
gle-dose area under the plasma concentration-time
curve) in children comparable to that achieved with
the 10-mg tablet in adults.95
The effects of 3 to 12 weeks of treatment of mon-
telukast over placebo on chronic asthma in adults
were reported in 5 RCTs.65– 67,68,96 The patients in-
cluded were adult asthmatics with moderate to se-
vere asthma (mean FEV1 60 – 68% predicted; 5– 6
daily puffs of inhaled ␤2-agonist and 4 – 6 nocturnal
awakenings per week attributable to asthma), yet
without concurrent treatment with steroid. Monte-
lukast showed an effect over placebo on daily asthma
symptoms, use of as-needed medication, asthma ex-
acerbations, nocturnal awakenings, and baseline
lung function. Mean improvement in lung function
during montelukast treatment was 6% to 13% over
placebo. Use of rescue was reduced by approxi-
mately 1 puff per day and nocturnal awakenings by
approximately 1 night per week.
The effect of montelukast was compared with that
of 200 ␮g BDP BID in a RCT of adult patients with
moderate to severe asthma (mean FEV1 of 66% of
predicted value, 5– 6 daily doses of ␤-agonist and 5– 6
nocturnal awakenings per week attributable to asth-
ma). Inhaled corticosteroid was more efficacious
than montelukast.66
The complementary effect of montelukast to that
of established treatment with BDP was reported in 2
RCT.96,97 The addition of montelukast provided sig-
nificantly improved lung function, symptom control,
and reduced exacerbation rates compared with be-
clomethasone monotherapy, and allowed tapering of
the steroid dose.
Montelukast provided some bronchoprotection
against EIB in mild asthmatic adults.53 The patients
had mild symptoms and were treated only with in-
haled ␤-agonists as needed. During treatment, mon-
telukast provided a 47% reduction in maximum per-
centage decrease in FEV1 as compared with placebo.
Considerable variation was observed among pa-
tients; 23% had complete protection, whereas an-
other 25% had little or no response.
Tolerance to the effect of montelukast was studied
in adult asthmatics and compared with that of sal-
meterol. An exercise challenge was performed at the
end of the dosing interval (21 hours for montelukast
and 9 for salmeterol) after 3 days, 4 weeks, and 8
weeks of treatment.98 Montelukast exhibited a higher
level of protection, which was maintained when
first- and last-dose effects were compared (58% vs
57% protection), whereas salmeterol showed re-
duced protection (44% vs 30%) over this period at-
tributable to development of tolerance.
Pediatric Studies With Montelukast
Four RCTs with montelukast in pediatrics have
been published.59,69,70,99 Exercise-induced broncho-
protection was studied in asthmatic children. Mon-
telukast provided an ⬃30% reduction in maximum
percentage decrease in FEV1 with 5 mg montelukast
at ⬃20 hours after dosing.99
Montelukast was compared with placebo in 336
children 6 to 15 years old with moderate to severe
asthma (mean FEV1 72% predicted; 2–3 daily doses
of ␤-agonist; 1–2 nocturnal awakenings per week
attributable to asthma).69 Approximately one third of
the children were maintained on inhaled steroids
during the study at a constant dose. The primary
outcome variable, FEV1, increased by a mean of 8%
from baseline, compared with 4% in the placebo
group (P ⬍ .001). The use of inhaled ␤-agonists was
significantly reduced by 0.6 dose per day compared
with a 0.2 dose per day in the placebo group. Asthma
exacerbations were significantly reduced with mon-
telukast (85% of patients) compared with placebo
group (96% of patients). Quality of life was slightly
but significantly higher within all domains for the
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montelukast-treated children. Nocturnal awakenings
did not decline significantly with active treatment.
The onset of action of montelukast occurred within 1
day after the first dose. There was no evidence of
development of tolerance during the 8-week treat-
ment period.
Subsequent subanalyses focused on 122 patients
receiving concurrent treatment with inhaled cortico-
steroids. In this subgroup, FEV1 improved 9.4% with
montelukast compared with 4.7% with placebo. In
the 206 children with no concurrent corticosteroid
treatment, FEV1 improved 9.2% with montelukast
versus 5.2% with placebo.100 These results show that
the treatment effect of montelukast was additive to
that of concurrent corticosteroid treatment.
We recently documented the bronchoprotective ef-
fect of montelukast in asthmatic preschool children
⬍6 years old. Cold-air hyperventilation caused a 17%
increase in airway resistance after pretreatment with
montelukast compared with 47% after placebo pre-
treatment (P ⬍ .01).59 The bronchoprotective effect
seemed independent of concurrent steroid treatment.
This indicates clinically significant bronchoprotec-
tion with montelukast for the difficult-to-treat pop-
ulation of asthmatic toddlers.
Montelukast caused significant improvement in
the overall asthma control in patients 2 to 5 years old.
The effect of montelukast was recently reported in a
RCT of 689 children 2 to 5 years old with physician-
diagnosed asthma (defined as at least 3 episodes
within 1 year before start of study).70 Treatment en-
tailed 4-mg chewable montelukast tablets once daily
for 12 weeks after a run-in period. Twenty-seven
percent of the patients received concomitant inhaled
corticosteroids, and 13% inhaled cromolyn at a con-
stant daily dose. There were no notable differences
between treatment groups in the incidence of clinical
and laboratory adverse experiences except that a sig-
nificantly smaller percentage of patients on monte-
lukast than on placebo reported adverse respiratory
experiences. Montelukast caused a significant reduc-
tion in days with symptoms, daytime asthma symp-
tom scores, days of ␤-agonist use, use of corticoste-
roid rescue, and peripheral blood eosinophils.70
Montelukast caused significant improvement in
asthma control in patients 2 to 5 years old.
In summary, Cys-LTRAs have proved moderately
effective in asthmatic children from 2 years of age
and older, an effect which appears to be complemen-
tary to current corticosteroid treatment.
MODE OF ACTION OF LT MODIFIERS
LT modifiers do not fit into the traditional group-
ing of bronchodilators and antiinflammatory drugs.
They have bronchodilatory properties, which in asth-
matics are additive to the activity of ␤-ago-
nists.83,101,102 This makes them useful as adjunctive
therapy, but they should never substitute for ␤-ago-
nists in rescue therapy because of their slow onset of
action although studies in acute asthma with intra-
venous formulations are in progress. In contrast to
␤-agonists, LT modifiers do not induce bronchodila-
tion in healthy volunteers.103 This suggests that per-
sistent activation of Cys-LT receptors, resulting in
REVIEW ARTICLE 385
increased airway tone, is an integral and specific
component of asthma inflammation that is not
present in people without asthma.
LT modifiers provide some antiinflammatory ef-
fects, as reflected in reduced airway eosinophilia,
reduced FeNO levels, and modified microvascular
permeability. However, the inflammation is not
checked to the same extent as with corticosteroids.
Therefore, LT modifiers could not substitute steroids
for antiinflammatory control.
Most of the improvement in airway function oc-
curs within the first treatment day, although delayed
effects have been reported in some trials.58,83,104
Cys-LTRAs have been found to have complemen-
tary effects to those of corticosteroids in chronic
asthma in agreement with the apparent lack of effect
by steroids of the Cys-LT release. Dose tapering from
the required high-dose corticosteroid monotherapy
was facilitated by addition of Cys-LTRAs.96,97,104,105
Patients do not appear to develop tolerance to LT
modifiers, even in 24-month extensions of clinical
trials, and no rebound effect is observed after treat-
ment is ended.
ADVERSE EFFECTS OF LT INHIBITORS
Cys-LTRAs are generally well-tolerated. The ma-
jority of reported adverse events were mild or tran-
sient. The Cys-LTs do not seem necessary for normal
homeostasis. Speculatively, these mediators, like oth-
ers such as histamine, may be remnants of phylogen-
esis that are essential at earlier stages of develop-
ment. Knock-out mice in which the gene for 5-LO is
inactivated showed no abnormalities except that
their responses to various inflammatory insults were
occasionally abnormal.106
A clinical syndrome characterized by pulmonary
infiltrates, cardiomyopathy, and eosinophilia was
described in a small subset of 8 patients who had
been treated with zafirlukast.107 In this report, all
patients who developed the syndrome had been de-
pendent on corticosteroids. Other reports have de-
scribed individual cases of similar eosinophil syn-
dromes unrelated to steroid withdrawal. This has
been noted with zafirlukast and with montelukast,
though not with zileuton108 –110 suggesting a class
effect, albeit quite rare.
HETEROGENEITY OF LT MODULATION
Many reports have indicated heterogeneity in the
effects of LT modifiers in asthmatic patients, as is
observed with other asthma therapies as well. Often,
only 2 of 3 patients experienced protection with LT
modifiers in asthma models.46,53,54,57 This may indi-
cate that the relative contribution of Cys-LT-depen-
dent bronchoconstriction to asthma differs from pa-
tient to patient.111 Genetic polymorphism in the 5-LO
pathway enzymes may underlie the variable re-
sponse to Cys-LT modifiers.112 The number of cells
with lipoxygenase activity in bronchial mucosal bi-
opsies from patients with asthma has been found to
be significantly higher than in healthy patients113
and thus some variability within asthmatic patients
might be expected. Also, a genetic polymorphism in
LTC4 synthase has been reported with a particularly
386 LEUKOTRIENE MODIFIERS IN PEDIATRIC ASTHMA MANAGEMENT
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high frequency in patients intolerant to aspirin114
and the number of cells expressing LTC4 synthase
has been shown to be significantly increased in bron-
chial biopsies taken from patients with aspirin-sen-
sitive asthma compared with aspirin-tolerant asth-
matics and normal controls.115
It is still unclear whether the asthma population
of responders and nonresponders fall into a bi-
modal distribution or a simple, continuous uni-
modal distribution. It is probable that there is a
unimodal response to all asthma medications, in-
cluding corticosteroids,66 long-acting ␤-agonists116
and Cys-LTRAs66 with some having little or no effect
and others yielding good response. If an outcome is
small in comparison with the scatter of the outcome
measure, a certain percentage of patients will seem-
ingly experience no effect from the treatment.
Whether such apparent nonresponse is attributable
to heterogeneity in asthma pathophysiology or a
simple stochastic phenomenon can only be deter-
mined via design of RCTs exploring whether the
group of suspected nonresponders consistently com-
prises the same patients in repeat tests and whether
such nonresponders respond to other treatments, ie,
N-of-one studies.
POSITIONING LT MODIFIERS IN PEDIATRIC
ASTHMA MANAGEMENT
Most available studies on LT modifiers have
sought to prove the concept of the treatment; few
studies have addressed treatment in patient groups
relevant to our current treatment algorithms. With
few exceptions, the available studies have been con-
ducted in adult asthmatics, and pediatric evidence
has been limited to 5 RCTs.59,69,70,92,99
Asthmatic Toddlers and Infants
Most children with chronic asthma first show
symptoms as toddlers or infants. There is reason to
believe that moderate to severe asthmatic symptoms
in young children are early signs of underlying air-
way inflammatory disease. No evidence exists, how-
ever, of how the pathophysiology of mild, intermit-
tent asthmatic symptoms in young children relates to
asthma pathophysiology. A separate entity may exist
related not to chronic asthma but rather to viral-
induced airway inflammation. Inhaled corticoste-
roids are effective in treating moderate to severe
asthmatic symptoms in infants and toddlers.117,118
However, safety is of particular concern in infants
and toddlers, and inhalation therapy is cumbersome
for some of these children. Therefore, inhaled corti-
costeroids are only used in children with persistent
symptoms.
Patients with mild symptoms for whom steroid
treatment is not appropriate are often treated with
regular oral bronchodilators (with little documented
efficacy) or with inhaled ␤-agonists. Intermittent
treatment of young children with short-term reliev-
ers is often insufficient, as treatment decisions and
drug delivery depend on a trained caretaker, who
frequently has to leave observation and care of the
child to others for large parts of the day. Therefore, a
long-term treatment effect is of special importance
for young children. LT modifiers present an interest-
ing option for young wheezy children because of
their oral administration, good safety profile, pro-
longed effect, and partial antiinflammatory effects.
Two of the 4 reported pediatric studies addressed
the effect of montelukast on 2- to 5-year-old asth-
matic children.59,70 This study showed bronchopro-
tection and reductions in symptoms, need for rescue
treatment, asthma exacerbations, and peripheral eo-
sinophils. It is important to compare the efficacy of
Cys-LTRAs with those of inhaled steroids and in-
haled ␤-agonists. Viral-induced wheezers should be
specifically addressed in future studies of LTRA.
Based on evidence thus far, LT modifiers may play
an important role as first-line treatment of young
wheezy children with mild recurrent symptoms.
Mild Asthma
There are no pediatric studies addressing asthma
control in children with mild persistent symptoms.
Moderate to Severe Asthma
The patients in most of the published Phase III
trials in adults and children had moderate to severe
asthma and are candidates for corticosteroid treat-
ment according to the consensus guideline but only
subgroups actually received steroids. In these stud-
ies, the Cys-LTRA proved modestly effective. The
patients’ asthma was insufficiently controlled de-
spite active treatment. Nocturnal awakening, a factor
that may help predict asthma mortality, still oc-
curred 2 to 4 times per week on average with active
treatment.65,69,88 Rescue medication use was still re-
quired 2 to 5 times per day during active treatment.88
Such symptom severity would necessitate corticoste-
roid treatment according to consensus guidelines.
Thus, LT modifiers would not be considered suffi-
cient monotherapy for moderate to severe asthma
based on the available evidence.
Children with moderate to severe asthma symp-
toms may require high doses of inhaled corticoste-
roids, but their symptoms may not be sufficiently
controlled by such steroids. Inhaled steroids do not
always normalize asthmatic airways, and bronchial
hyperreactivity rarely normalizes. Also, some evi-
dence shows that adult patients on high-dose inhaled
steroids still have signs of ongoing eosinophilic in-
flammation.119,120 This may indicate that corticoste-
roids cannot control all aspects of asthma inflamma-
tion, including the unchecked release of Cys-LTs. An
increase in the dose of inhaled steroids is not accom-
panied by a proportional increase in asthma control,
whereas systemic bioavailability and risk of systemic
adverse events are proportional to the dose.121
Therefore, add-on therapy such as long-acting ␤-
agonist therapy or LTRA should be considered be-
fore additional increases are made in the doses of
corticosteroids for children who remain symptom-
atic despite moderate use of inhaled corticosteroids.
Long-acting ␤-agonists, however, are purely bron-
chodilators and have no antiinflammatory effect.
They are marginally effective on lung function, and
some tolerance develops to the bronchoprotective
effect after repeated dosing.116 Accordingly, there is
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a need for a corticosteroid-sparing complementary
treatment with antiinflammatory properties to check
all aspects of airway inflammation in asthma. When
added to established corticosteroid treatment in
adults with moderate to severe asthma, LT modifiers
showed a complementary effect.96,97,100,104,105 Sub-
analyses in a pediatric study also found a comple-
mentary effect from LTRA in children treated with
inhaled corticosteroids.100 Such a complementary ef-
fect is consistent with the unchecked release of Cys-
LTs during asthma despite corticosteroid treatment.
Accordingly, there is a good rationale for positioning
LT modifiers as complementary to corticosteroid
treatment in children whose symptoms are not opti-
mally controlled with a moderate dosage of steroids
such as 400 ␮g/day. To support such positioning,
RCTs should assess the potential of LT modifiers as
corticosteroid-sparing drugs for children. Long-term
trials are necessary, and it may be worthwhile to
investigate the potential additive effects of LT mod-
ifiers on very low doses of inhaled corticosteroids.
Additional insight is required into how this new
treatment modality compares with long-acting
␤-agonists.
EIB
EIB is a cardinal symptom in pediatric asthma.
Ability to interact in a play environment is essential
to the social and physical development of the child,
making this the most important symptom to treat
from the child’s perspective.
The current guidelines emphasize the use of short-
acting ␤-agonists for EIB. This is, however, an insuf-
ficient solution for most children. Typically, children
do not have a scheduled life in which exercise is
planned ahead of time. Rather, exercise is spontane-
ous. Therefore, the recommendation to use short-
acting ␤-agonists 15 minutes before exercise is sel-
dom realistic for children, as it is for adults.
Therefore, long-term coverage is preferable in chil-
dren for protection against EIB.
EIB is not a separate form of asthma but a reflec-
tion of general disease control and bronchial hyper-
reactivity. Because it improves with better asthma
control, inhaled corticosteroids can be used to treat
EIB and provide full-time coverage. Long-acting
␤-agonists generally provide 12-hour coverage
against EIB, but some tolerance develops after re-
peated dosing and bronchoprotection is heteroge-
neous. Also, ␤-agonists offer no antiinflammatory
control.116 There is a need for an asthma medication
that provides long-lasting bronchoprotection with an
antiinflammatory component. LT modifiers may
provide both of these. The bronchoprotective effect
of LT modifiers should be compared with long-act-
ing ␤-agonists as complementary treatment for chil-
dren with poorly controlled asthma despite estab-
lished steroid treatment.
CONCLUSION
Given their efficacy, partial antiinflammatory ac-
tivity, safety, and oral availability LT modifiers may
be used as first-line treatment of young wheezy pre-
school children with mild recurrent symptoms.
REVIEW ARTICLE 387
 In asthmatic school children monotherapy with LT
modifiers cannot sufficiently control moderate to se-
vere asthma, and their efficacy in mild asthma has
not been studied. Therefore, based on the presently
available data, these drugs should be used as com-
plementary treatment to be added to inhaled corti-
costeroids in asthmatic school children. Additional
research issues that must be addressed include the
effects of LT modifiers on inflammation and long-
term disease control, long-term safety, effects on de-
velopment and progression of disease in later life,
and potential disease-modifying effects. Until these
issues are addressed and studied, the positioning of
LT modifiers in pediatric asthma management must
be approached with a pragmatic perspective.
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 Leukotriene Modifiers in Pediatric Asthma Management
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 Leukotriene Modifiers in Pediatric Asthma Management
Hans Bisgaard
Pediatrics 2001;107;381
DOI: 10.1542/peds.107.2.381

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/107/2/381.full.html

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2001 by the American Academy
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

Downloaded from pediatrics.aappublications.org at University of Pennsylvania Library on April 12, 2015