Treat Respir Med 2006; 5 (3): 149-158

CURRENT OPINION 1176-3450/06/0003-0149/$39.95/0

© 2006 Adis Data Information BV. All rights reserved.

The Role of Antihistamines in

Asthma Management
Andrew M. Wilson
Biomedicine Group, Faculty of Medicine, Health and Policy Practice, University of East Anglia, Norwich, England

Abstract Histamine is an important mediator in airway inflammation. It is elevated in the airways of asthmatic patients
and is responsible for many of the pathophysiological features in asthma. Antihistamines block the actions of
histamine and also have effects on inflammation which is independent of histamine-H1-receptor antagonism.
Antihistamines have been shown to have bronchodilatory effects, effects on allergen-, exercise-, and adenosine-
monophosphate-challenge testing, and also to prevent allergen-induced nonspecific airways hyperresponsive-
ness. Clinical studies have shown mixed results, and some studies have reported beneficial effects of azelastine,
cetirizine, desloratadine, and fexofenadine on asthma symptoms or physiological measures in patients with
asthma. The combination of an antihistamine and a leukotriene receptor antagonist has been shown to have
additive effects in certain studies. Antihistamines have also been shown to delay or prevent the development of
asthma in a subgroup of atopic children. These data suggest that antihistamines may have beneficial effects in the
management of asthma.

Histamine has been known to be an important inflammatory
mediator since the 1900s, when it was shown to cause smooth
muscle contraction[1] and anaphylactoid reactions in laboratory
animals. It is derived from histidine by the action of histidine
kinase, stored in the secretory granules of mast cells and basophils,
and released following cross-linking of high-affinity IgE receptors
on these cells. Release of histamine within the airways results in
airway smooth muscle contraction, mucosal edema, and mucus
secretion, all of which contribute to bronchoconstriction in indi-
viduals with asthma.[2]
In 1927, Best et al.[3] reported that there was a high concentra-
tion of histamine in lung tissue. More recently, Gravelyn et al.[4]
and Casale et al.[5] found higher concentrations of histamine in
bronchoalveolar lavage (BAL) fluid following segmental hyperos-
motic and allergen bronchial challenges, respectively, in individu-
als with and without asthma; there was a significant correlation
between bronchial hyperresponsiveness and histamine concentra-
tion in individuals with asthma.[4,6] Furthermore, there was corre-
lation between BAL fluid histamine concentrations and BAL fluid
eosinophil count in patients with both atopic and extrinsic asth-
ma.[7] Indeed, the concentration of histamine required to cause a
predetermined change in airflow, usually a 20% fall in FEV1, is
used as a diagnostic feature of asthma.
Given the importance of histamine as an inflammatory media-
tor, and its relationship with the severity of asthma, it would be
expected that agents which specifically block its action would be
effective in asthma control. Indeed, the first-generation antihista-
mine chlorpheniramine was shown to have bronchodilatory activi-
ty[8] and bronchoprotection against allergen challenge.[9] However,
this action was achieved when chlorpheniramine was administered
intravenously at doses associated with intolerable adverse effects.
First-generation antihistamines were nonspecific in their action
and also had anticholinergic effects, causing mucus thickening,
which worsens asthma, and sedative effects. These led to the
suggestion that their use in asthma was limited.[10,11] However,
second-generation antihistamines have greater affinity for the
histamine H1 receptor and have fewer adverse effects.[12]
There has been renewed interest in the anti-inflammatory ef-
fects of antihistamine since studies demonstrated that antihista-
mines inhibited the release of histamine from lung tissue in a
manner that was unrelated to histamine-H1 receptor antago-
nism.[13] The majority of antihistamines have been demonstrated to
inhibit the release of histamine and other inflammatory mediators
from leukocytes or endothelial cells in vitro.[4] However, in some
cases the concentrations required for this effect were
suprapharmacological, and in studies where cell viability is not
150
documented it is impossible to determine whether this is a benefi-
cial effect or simply due to drug toxicity. There have been several
detailed reviews on the subject of antiallergic or anti-inflammatory
effects of antihistamines.[14-17]
In a human epithelial cell line, cetirizine has been shown to
inhibit the production of interleukin (IL)-8 at a concentration of
10 ng/mL.[18] Lippert et al.[19] compared the inhibition of
desloratadine (10–9 mol/L) and dexamethasone (10–8 mol/L) on
the release of mediators from human leukemic mast cells and
showed that desloratadine had similar effects to dexamethasone.
Fexofenadine has also been shown to inhibit the histamine-in-
duced release of IL-6 from human lung macrophages,[20] and
cetirizine reduces the H1-receptor activity by stabilizing the recep-
tor in an inactive form.[21]
In vitro studies have shown that fexofenadine[22] and
desloratadine[23] inhibit the release of intercellular adhesion mole-
cule (ICAM)-1 from stimulated nasal and bronchial epithelial
cells, respectively. Ciprandi et al. have shown that the expression
of ICAM-1 on nasal epithelial cells from nasal lavage is reduced
with terfenadine,[24] cetirizine, or loratadine[25] in patients with
rhinitis during natural pollen exposure and with azelastine nasal
spray, out-of-pollen season, following an allergen-specific nasal
challenge.[26] Studies have also shown that cetirizine reduces eosi-
nophil counts in nasal lavage in children with seasonal allergic
rhinitis during the pollen season,[27] and in the BAL fluid in adults
with asthma following an allergen challenge.[28]
Bryce et al.[29] recently reported the anti-inflammatory effect of
desloratadine on models of asthma in mice. Desloratadine, when
given intragastrically during the sensitization period, reduced the
airway inflammation and hyperresponsiveness to methacholine.
When T lymphocytes from ovalbumin-sensitized mice given
desloratadine during sensitization were cultured with ovalbumin,
desloratadine was shown to inhibit helper T cells (Th) type 2 but
not Th1 cytokines. These data suggest that antihistamines may
affect the balance between Th1 and Th2 cytokines and therefore
alter disease progression in susceptible patients exposed to aller-
gen, which may explain the findings of the Early Treatment of the
Atopic Child (ETAC) study discussed in section 3.[30]
1. Antiasthmatic Efficacy
1.1 Bronchodilatory Effect
As detailed above, first-generation antihistamines have been
shown to have a bronchodilatory effect. In a study designed to
compare the antiasthmatic and adverse effect profiles of single
doses of first- and second-generation antihistamines in adult pa-
tients with mild asthma, Wood-Baker and Holgate[31] showed
© 2006 Adis Data Information BV. All rights reserved.
Wilson
greater bronchodilation with second-generation antihistamines
with fewer reports of adverse effects. This amounted to a 9%
improvement in FEV1 with cetirizine, a 6% improvement with
terfenadine, and a 4% improvement with chlorpheniramine. When
the antiasthmatic effects of histamine were studied in children
with asthma, terfenadine 60mg produced a 32% improvement in
FEV1 3 hours after drug administration.[32] Spector et al.[33] evalu-
ated the time course of response in terms of change in FEV1 and
forced expiratory flow at 25–75% of FVC (FEF25–75) with single
does of cetirizine (5, 10, and 20mg) and albuterol (salbutamol)
[180μg]. All doses of cetirizine produced significant bronchodila-
tion over an 8-hour period, in a dose-response manner, whereas the
bronchodilatory effects of albuterol lasted for only 5 hours. Fur-
thermore, the bronchodilatory effects of albuterol and cetirizine
were additive. More recently, Lee et al.[34] showed that FEF25–75,
but not FEV1, was significantly higher after single doses of
fexofenadine, desloratadine, and levocetirizine than placebo.
1.2 Exercise Challenge
Nearly all of the available second-generation antihistamines
have been shown to have a significant, but incomplete,
bronchoprotective effect against exercise challenge. Single doses
of terfenadine have been shown to exhibit bronchoprotection
following exercise challenge in terms of FEV1 in adults and PEF
in children.[32,35] A single 4.4mg dose of azelastine[36] was shown
to produce a small but significant bronchoprotection against exer-
cise-induced asthma, and loratadine 10mg for 3 days reduced the
maximum fall in FEV1 to 16% compared with 29% with placebo,
post-exercise, in children with asthma.[37] Ghosh et al.[38] showed
that oral cetirizine 10mg twice daily for 1 week had no effect
during an exercise challenge, but the fall in FEV1 after exercise
was reduced to 15% and 10% following single doses of nebulized
cetirizine 5 and 10mg, respectively, compared with 23.7% after
placebo. As the authors suggest, an explanation for these results is
that higher lung concentrations of cetirizine would be achievable
via the inhaled route.
1.3 Inhaled Allergen Challenge
Data regarding the effect of antihistamines on the attenuation of
the early and late allergic responses following inhaled allergen
challenge are contradictory. In a study evaluating the effect of a
single (500μg) dose of inhaled beclomethasone and 3 days’ ther-
apy with oral cetirizine (15mg twice daily) on an airways allergen
challenge, the corticosteroid had an effect on the late allergic
response but the antihistamine did not.[39] Rafferty et al.[40] looked
at the early response following inhaled house dust mite challenge
and showed no significant effect with oral (15mg twice daily for 2
Treat Respir Med 2006; 5 (3)
Antihistamines and Asthma
days) or inhaled (1mL of 10 mg/mL) cetirizine. Previous studies
showed that 4 days’ therapy with azelastine (8.8mg twice daily)
had a significant effect on the early but not the late response to
inhaled allergen challenge,[41] and 7 days of cetirizine (15mg twice
daily) had a significant effect on the late but not the early response
in a bronchial provocation test with allergen.[31] Loratadine has
been shown to have no effect on the airway and skin following
allergen challenge at either 10 or 20mg,[42] whereas Hamid et al.[43]
showed 180mg of terfenadine had a significant effect compared
with placebo on both the early- (20% vs 33% fall in FEV1) and
late-phase (15% vs 22% fall in PEF) bronchoconstriction follow-
ing allergen challenge in individuals with atopic asthma.
1.4 Methacholine Challenge
Studies of the effect of antihistamines on methacholine have
been conflicting. Three days of therapy with loratadine (10 or
20mg)[42] or 2 weeks of therapy with azelastine (4mg twice dai-
ly),[44] cetirizine (10mg twice daily),[45] or terfenadine (120mg
twice daily)[46] all showed no change in bronchial hyperrespon-
siveness to methacholine. However, cetirizine has been shown to
inhibit nonspecific bronchial hyperresponsiveness to
methacholine following both inhaled and nasal allergen chal-
lenges.[40,47] Bentley et al.[39] evaluated the effect of 3 days’
therapy with oral cetirizine 15mg twice daily and a single dose of
inhaled beclomethasone on methacholine challenge 3 hours after
inhaled allergen challenge in individuals with asthma. There was a
significant increase in hyperresponsiveness to methacholine fol-
lowing placebo (2.4-fold) but not with cetirizine (1.8-fold differ-
ence) or beclomethasone (1.5-fold difference). Aubier et al.[47]
performed a bronchial challenge test with methacholine, 1 and 6
hours after a nasal allergen challenge, in a placebo-controlled
crossover study outside the pollen season in patients with seasonal
allergic rhinitis and asthma. There was no difference in the
methacholine dose causing a 20% fall in FEV1 (PD20) with
cetirizine or placebo 1 hour after allergen challenge; however,
there was a significant increase in the methacholine PD20, 6 hours
after the challenge, with cetirizine 10 mg/day for 2 weeks. This is
in contrast to the studies with azelastine and cetirizine, which
showed no effect on the allergen-induced nonspecific hyper-
responsiveness.[41,48]
1.5 Indirect Challenges
Antihistamines have also been evaluated in terms of nonspecif-
ic bronchial challenges such as adenosine monophosphate (AMP),
which has recently been shown to be more related to allergic
airway inflammation than methacholine bronchial challenge.[49]
Terfenadine 180mg was shown to induce a 4-doubling dose shift
© 2006 Adis Data Information BV. All rights reserved.
151
in provocative concentration causing 20% fall in FEV1 (PC20) of
AMP[50] or a 80% inhibition of bronchoconstrictor response to
AMP with no further effect at a dose of 600mg.[51] Lee et al.[34]
also showed bronchoprotection against AMP with single doses of
fexofenadine, levocetirizine, or desloratadine. Significant
bronchoprotection is also afforded by terfenadine against ultrason-
ic nebulized distilled water[52] and hypertonic saline,[53] both of
which cause changes in the osmotic potential of the airways
which, like AMP, activates mast cell degranulation with resultant
inflammatory mediator release. Lee et al.[54] compared the effects
of 1 week’s treatment with fexofenadine 180mg or montelukast
10mg with placebo in mild-to-moderate skin prick-positive asthma
patients who were receiving inhaled corticosteroids. In terms of
AMP bronchial challenge testing, there were significant improve-
ments (as PC20) with fexofenadine (127 mg/mL) and montelukast
(121 mg/mL) compared with placebo (78 mg/mL). There was no
significant difference between antihistamine and leukotriene re-
ceptor antagonist. However, Fardon et al.[55] showed no additional
effect, in terms of AMP bronchial challenge, of fexofenadine
180mg only daily when added to either fluticasone or fluticasone:
salmeterol combination in patients with mild to moderate asthma.
2. Clinical Studies
In 1997, Van Ganse et al.[56] reported on a meta-analysis of
studies using ketotifen and other second-generation antihistamines
in asthma management and concluded that their findings “[did] not
support the use of these medications in the treatment of asthma.”
They found an improvement of 13 L/min in morning peak flow
(their primary endpoint) which was statistically, but not clinically,
relevant. Reliever rescue requirement was also significantly re-
duced but by only 0.4 doses per day. Furthermore, there were
reported adverse effects in nearly all of the studies, and overall the
incidence of sedation between antihistamine and placebo was
statistically significant. On reviewing the data, however, the newer
antihistamines (excluding ketotifen and pemirolast) are shown to
have a greater antiasthmatic effect. Recently, Walsh et al.[16] and
Nelson[57] have reviewed the role of antihistamines in the manage-
ment of asthma.
2.1 Cetirizine
Patients with seasonal allergic asthma were shown to have
statistically significant improvements in asthma symptoms, spi-
rometry, and rescue inhaler usage after 2 weeks or 3 months of
treatment with oral cetirizine 10mg twice daily.[58,59] In the study
by Bruttmann et al.,[58] 47 patients were enrolled into a placebo-
controlled parallel study. All subjects had a history of allergy to
grass pollen and the majority had moderately severe nocturnal
Treat Respir Med 2006; 5 (3)
152
wakenings with asthma and moderately severe rhinorrhea. The
FEV1 after treatment with cetirizine was 93% predicted compared
with 82% predicted in the placebo group. There were also signifi-
cant improvements in nocturnal asthma attacks and rhinorrhea.
The same daily dosage of cetirizine (20mg once daily) showed a
benefit in terms of chest tightness, wheezing, shortness of breath,
and nocturnal asthma, but not in terms of peak flow or rescue
inhaler usage, in patients with perennial asthma over a 4-month
period.[60] Bousquet et al.[61] showed a dose-response effect, with a
higher dose of cetirizine 15mg twice daily being more effective
than 10mg twice daily. In one of only a few studies to evaluate the
antiasthmatic effect of an antihistamine at conventional doses,
Grant et al.[62] showed significant improvements in asthma symp-
toms over a 6-week period (not significant at week 3) in 93
patients with allergic rhinitis and asthma randomized to treatment
with cetirizine 10 mg/day or placebo. Although there was no
improvement in spirometry, a significantly greater number of
patients treated with cetirizine (93%) than with placebo (74%)
completed the study. Furthermore, there were significant improve-
ments in chest tightness, wheezing, shortness of breath, cough, and
nocturnal asthma. Indeed, for the total symptom score, cetirizine
was significantly better than placebo for 5 of the 6 weeks of the
study. While more patients receiving cetirizine complained of
fatigue or somnolence, the total number of adverse events was
similar to that with placebo.
2.2 Terfenadine and Fexofenadine
Terfenadine has also been shown to have antiasthmatic effica-
cy, although at high doses. Indeed, with a daily dose of 540mg,
Rafferty et al.[63] showed significant improvements in asthma
symptoms and PEF. Taytard et al.[64] demonstrated a significant
improvement in asthma symptoms, PEF, and rescue inhaler re-
quirement in patients with mild asthma receiving oral terfenadine
120mg twice daily, whereas with the same dose in severe asthma
there was no significant effect on any measure of asthma control,
apart from nocturnal wakenings.[65] In the study by Lee et al.[54]
comparing fexofenadine 180mg and montelukast 10mg with pla-
cebo, there were improvements with fexofenadine in terms of
diary card data. In terms of PEF, fexofenadine showed a signifi-
cant improvement in mean morning (442 L/min) and evening (440
L/min) values compared with placebo (425 and 424 L/min, respec-
tively). There was also a significant reduction in morning (fex-
ofenadine 0.4 puffs; placebo 0.8 puffs) and evening (fexofenadine
0.8 puffs; placebo 1.4 puffs) medication requirement but not
symptom scores. Although these improvements were statistically
significant, they were small and may not be clinically relevant.
© 2006 Adis Data Information BV. All rights reserved.
Wilson
2.3 Azelastine
Busse et al.[66] compared the corticosteroid-sparing effect of
placebo and azelastine 6mg in a dose-down titration study of
inhaled corticosteroids (ICS) in patients with moderately severe
asthma. Patients on azelastine had a significantly greater ICS dose
reduction (4.9 vs 3.1 puffs/day), which was sustained during a
3-month maintenance period. Gould et al.[67] showed a significant
effect with azelastine in terms of peak flow and asthmatic symp-
toms, whereas Balzano et al.[68] showed no effect with this drug in
patients with extrinsic or atopic asthma.
2.4 Loratadine and Desloratadine
Although loratadine has not been shown to be beneficial in
managing asthma,[69] desloratadine, its active metabolite, has been
shown to produce significant effects on asthma symptoms and
reliever inhaler requirements in patients with seasonal allergic
rhinitis and mild asthma.[70] In a study by Baena-Cagnani et al.,[71]
the antiasthmatic efficacy of desloratadine (5mg) was compared
with that of montelukast (10mg) and placebo, each for 4 weeks, in
818 patients with seasonal allergic rhinitis with increased asthma
symptoms in the autumn. All patients had mild asthma, with an
FEV1 >70% predicted, and required rescue bronchodilator therapy
only. There were significant improvements with both treatments in
terms of total asthma symptom severity scores (the primary
endpoint), rescue β-agonist usage, and, in a small subset of pa-
tients with FEV1 <80% predicted, there were improvements in
spirometry (figure 1). There was no significant difference between
desloratadine and montelukast, but the latter was numerically
superior for all endpoints.[71]
2.5 Tachyphylaxis
There are some data to suggest that patients develop tolerance
or tachyphylaxis to regular antihistamine therapy. Spector et al.[72]
showed that the bronchodilator effect of a single dose of
terfenadine 60mg was no longer significant after 1 week of twice-
daily administration in 12 allergic asthmatic individuals. Ghosh
and co-workers[73] showed significant tolerance to the bronchopro-
tective effects of cetirizine (15mg twice daily) during histamine
challenge, with a 2-fold reduction in PC20 after 1 week compared
with single dose in patients with atopic asthma. Similarly, modest
bronchodilation was seen after single but not after three daily
doses of cetirizine 20mg in individuals with asthma.[74] However,
tolerance was not seen with desloratadine in the study by Baena-
Cagnani et al.,[71] where improvements in the asthma symptom
score were seen after 4 weeks compared with the first dose of
treatment. Also, levocetirizine was shown not to exhibit tachyphy-
laxis in terms of change in AMP bronchial responsiveness, with no
Treat Respir Med 2006; 5 (3)
Antihistamines and Asthma 153

Placebo
Desloratadine 5mg investigators enrolled 817 children aged 1–2 years with atopic
Montelukast 10mg dermatitis and an atopic history in a parent or sibling into a
a AM instantaneous
TASS AM/PM reflective TASS
randomized, parallel, double-blind study comparing oral cetirizine
After dose 1 Weeks 1-2 Weeks 3-4 (0.25 mg/kg twice daily) and placebo. When the study was ex-
Mean reduction from baseline in TASS

-0.4 amined as a whole, there was no difference in the number of

-0.6 children who developed asthma between the two groups. Howev-
-0.8 er, when subgroup analyses were performed in children with an
-1.0 * elevated baseline serum IgE level to grass pollen or house dust
-1.2 * mite, the risk of developing asthma with cetirizine treatment was
-1.4 nearly halved over an 18-month period. The results of a further
18-month follow-up have now been reported and still show statis-
*
-1.6 *
**
-1.8 ** tically significant benefits of asthma prevalence in these groups of
**
children, treated with cetirizine, after 3 years.[77]
b
0.25 **
Mean change in FEV1 from baseline (L)

*
0.20
0.15
0.10
0.05
0
Fig. 1. (a) Mean reductions in total asthma symptom scores (TASS) rela-
tive to baseline after the first dose and across the duration of treatment with
placebo, desloratadine (5mg), and montelukast (10mg). (b) Mean change
from baseline in FEV1, in patients with baseline FEV1 <80% predicted,
following placebo, desloratadine (5mg) and montelukast (10mg). Morning
(AM) instantaneous TASS were scored after taking a single dose; AM/
evening (PM) reflective scores represent patient symptoms over a period
of time. There were significant differences between placebo and both ac-
tive treatments but no significant difference between montelukast and
desloratadine. * p < 0.05, ** p < 0.001 vs placebo. (Reproduced from
Baena-Cagnani et al.[71] with permission, S. Karger AG, Basel.)
difference between a single dose of 5mg levocetirizine and week’s
therapy with 5mg daily (both 1.5-doubling dose shift from base-
line).[75]
3. Asthma Prevention
Another area of asthma management, which may be controver-
sial, is the effect of antihistamines in preventing the onset of
asthma in children. Bustos et al.[76] investigated the effect of
ketotifen or placebo on the prevention of asthma in a parallel study
in children with a family history and elevated serum IgE levels.
After 3 years’ follow-up, 3 of 45 patients in the ketotifen group
had developed asthma compared with 15 of 40 in the placebo
group, which was statistically significant. In the ETAC study,[30]
4. Combination Therapy
There has been an interest in combining antihistamines with
leukotriene receptor antagonists (LTRA) to block the effects of
both of these mediators on the inflammatory cascade.[78] Benefi-
cial effects of combining these classes of drugs have been demon-
strated in in vitro studies[79] and with allergen challenge.[80] Reicin
et al.[81] performed a study to investigate a posssible additive effect
of loratadine (20mg once daily) when added to montelukast (10mg
once daily) in 117 patients with asthma; 95% of the study patients
had concomitant seasonal allergic rhinitis. The combination had a
significantly greater effect on the percentage change in FEV1 from
baseline (the primary endpoint) than montelukast alone. However,
this only amounted to a 4.15% change, which may not be clinically
relevant. There were also significant improvements in peak flow,
symptoms scores, and rescue inhaler requirement in the combina-
tion therapy group compared with the monotherapy group.
Brannan et al.[82] investigated the effects of fexofenadine
180mg and montelukast 10mg on airway sensitivity to and recov-
ery from inhaled mannitol challenge in a placebo-controlled study
of patients with mild asthma. Inhaled mannitol challenge, which
causes bronchoconstriction by release of mediators from mast
cells,[83] correlates well with exercise challenge testing[84] and has
been shown to be a predictive marker of asthmatic exacerba-
tions.[85] Compared with placebo, fexofenadine exhibited signifi-
cantly greater bronchoprotection to mannitol (the provocative dose
of mannitol to cause a 15% fall in FEV1 [PD15] was significantly
greater with fexofenadine compared with placebo); however, there
was a longer time to recovery of FEV1 back to baseline values in
patients treated with fexofenadine. In contrast, montelukast did not
significantly alter the PD15, but recovery of FEV1 to baseline
occurred significantly more quickly with montelukast compared
with placebo (figure 2). Following this study, Currie et al.[86]
showed that the combination of fexofenadine and montelukast

© 2006 Adis Data Information BV. All rights reserved. Treat Respir Med 2006; 5 (3)
154 Wilson

resulted in significant improvement in bronchial hyperresponsive-
ness to mannitol and AMP with a faster recovery of FEV1 to
baseline values, compared with placebo, following the challenges.
These data suggest that antihistamines and LTRA have different
mechanisms of action and can be combined to have a greater effect
on mannitol challenge than either drug alone. More recently,
David et al.[87] compared desloratadine, montelukast or their com-
bination in terms of early asthmatic response to allergen challenge
and showed that although desloratadine had no significant effect
compared to placebo, the combination of both desloratadine and
montelukast was superior to either treatment alone.
Two studies looked at the effect of loratadine (10mg single
dose or 10mg twice daily for 2 weeks, respectively) and an LTRA
either alone or in combination following an exercise challenge test
in individuals with asthma.[88,89] These studies showed a
bronchoprotective effect of a single dose of montelukast 10mg[88]
or 2 weeks’ therapy with zafirlukast 80mg twice daily,[89] but no
significant bronchoprotection was noted with loratadine either
alone or in combination with LTRA. These results were contrary
a c
0 Placebo
Reduction from baseline FEV1%
to those of the study by Baki and Orhan[37] and to a hypothesis that
exercise-induced bronchospasm is caused by mast cell degranula-
tion with histamine release.[90] Possible reasons for this may be the
choice of antihistamine, the greater bronchoconstrictive effect of
leukotriene than histamine mediators,[91] or that the patients had
mild asthma and the exercise challenges were submaximal.[92]
To compare the antiasthmatic efficacy of inflammatory media-
tor blockade versus topical corticosteroid therapy, 14 patients with
seasonal allergic rhinitis and asthma were enrolled into a placebo-
controlled crossover study that compared the efficacies of inhaled
budesonide 400μg plus intranasal budesonide 200μg with those of
oral montelukast 10mg plus oral cetirizine 10mg.[93] There were
significant improvements in the domiciliary PEF rate, rescue
inhaler requirement, asthma symptoms, and daily activity score
with both treatments compared with placebo, but there was no
significant differences between treatment groups (figure 3). For
AMP bronchial challenge there was an improvement, compared
with placebo, for montelukast plus cetirizine but not with budeso-
nide, whereas for exhaled nitric oxide there was significant sup-
Fexofenadine

500 -5
PD15 to mannitol (mg)

400 -10

300 -15

200 -20

100 -25

0 -30
Placebo Fexofenadine
0 5 10 15 20 25 30
Time following mannitol challenge (min)

b d Montelukast
Placebo
500
Salbutamol
Reduction from baseline FEV1 (%)

0
PD15 to mannitol (mg)

400
-5
300
-10
200
-15
100
-20
0
Placebo Montelukast -25
0 5 10 15 20 25 30
Fig. 2. Individual values for the provoking dose of mannitol to cause a 15% fall in FEV1 (PD15) following (a) fexofenadine 180mg and placebo or (b)
montelukast 10mg and placebo. Percentage reduction from baseline FEV1 (mean ± SEM) and spontaneous recovery after challenge with inhaled mannitol
following treatment with (c) fexofenadine and placebo or (d) montelukast and placebo and albuterol (salbutamol). (Reproduced from Brannan et al.,[82] with
permission.)

© 2006 Adis Data Information BV. All rights reserved. Treat Respir Med 2006; 5 (3)
Antihistamines and Asthma 155

a b
500
1.5
Rescue inhaler requirements (units)
*

Peak expiratory flow (L/min)

*
1.0 * *
475

0.5

450

0
0

c d
1.00 1.00
Asthma symptom score (units)

Daily activity score (units)

2.0
0.75

1.5
* *
0.50
*
1.0
*

0.25
0.5

0 0
Placebo Budesonide Montelukast + Placebo Budesonide Montelukast +
cetirizine cetirizine
Fig. 3. Mean ± SEM for rescue inhaler requirement (a), peak expiratory flow rate (b), asthma symptom score (c), and daily activity score (d) for placebo,
400μg inhaled and 200μg intranasal budesonide once daily, and oral montelukast 10mg plus oral cetirizine 10mg in patients with allergic rhinitis and
asthma. * p < 0.05 vs placebo. (Reproduced from Wilson et al.,[93] with permission.)

pression with the corticosteroid but not the combined mediator
antagonists. However, this was a small study and it needs to be
repeated with larger numbers of patients.
5. One Airway Disease
There is considerable evidence that asthma and rhinitis are
associated conditions and may be considered to be different ex-
pressions of the one airway disease.[94-97] The mechanisms of the
allergen response in both diseases are similar, the allergens that
provoke symptoms in asthma and allergic rhinitis parallel one
another, and the mediator and cellular responses to allergen expo-
sure have similar patterns. Furthermore, treatment of nasal disease
with intranasal corticosteroids improves bronchial hyperrespon-
siveness[98] and asthma control.[99] In case-control studies it has
been shown that intranasal corticosteroid therapy has significant
beneficial effects in reducing asthma exacerbations, with an over-
all relative risk of 0.7 (0.57–0.99) for an emergency department
visit[99] and 0.56 (0.42–0.76) for hospital admissions.[100] Many of
the clinical studies showing beneficial effects with antihistamines
were performed in patients with allergic rhinitis and asthma and
therefore part of their antiasthmatic efficacy could have been by
controlling nasal inflammation.
6. Conclusion
The data discussed here suggest that antihistamines have an
anti-inflammatory action which is more than simple antagonism of
H1-receptors, as they have the potential to inhibit the production of
cytokines from inflammatory cells in vitro. There is also evidence
to suggest that antihistamines have bronchodilatory effects and
bronchoprotective effects against a range of different challenge
tests, including allergen, exercise, and AMP challenge testing, in
the clinical laboratory setting. However, antihistamines are gener-
ally ineffective against methacholine challenge testing. Further-
more, there is conflicting evidence as to their bronchoprotective
effect on the allergen-induced nonspecific airways hyperrespon-
siveness, with some studies showing improvements in
methacholine challenge following allergen challenge and others
not showing beneficial effects.
Clinical studies also report mixed results, although several
studies have reported significant benefit in terms of asthma symp-

© 2006 Adis Data Information BV. All rights reserved. Treat Respir Med 2006; 5 (3)
156
toms and/or physiological measures. However, the majority of
these studies have used doses that are currently not licensed and
have been evaluated in individuals who have both asthma and
rhinitis. Given the beneficial effects of treating nasal disease when
managing asthma, much of this effect may be due to control of
nasal inflammation. A few studies have evaluated the issue of the
effect of antihistamines in delaying or preventing the development
of asthma and have suggested that there may be a beneficial effect
of antihistamines in certain atopic children. There has been interest
in combining an antihistamine with an LTRA, as these drugs have
been shown to have additive effects in some bronchial challenge
tests and to produce clinical improvements in pulmonary function.
In a small study, the effect of montelukast and cetirizine was not
different from that of budesonide, but this requires confirmation in
a larger study. In conclusion, although antihistamines are not
indicated for first-line use in patients with asthma, they may be
considered in patients with seasonal allergic rhinitis and asthma,
who refuse to take ICS, particularly in combination with a LTRA.
Acknowledgments
To conduct clinical research studies and speak at meetings, the author has
received funding from: Aventis Pharma, Bridgewater, USA, who make fex-
ofenadine; Schering-Plough Corporation, Welwyn, UK, who make loratadine
and desloratadine; and UCB Pharma, Brussels, Belgium, who make cetirizine
and levocetirizine. No funding was received for assistance in the preparation
of this article.
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Correspondence and offprints: Dr Andrew M. Wilson, Biomedicine Group,
Faculty of Medicine, Health and Policy Practice, University of East Anglia,
Norwich NR4 7TJ, England.
E-mail: a.m.wilson@uea.ac.uk
Treat Respir Med 2006; 5 (3)