PEDIATRICS Vol. 108 No. 2 August 2001, p. e36
ELECTRONIC ARTICLE:
Treatment of Childhood Asthma With Anti-Immunoglobulin E Antibody
(Omalizumab)
Received Jan 3, 2001; accepted Apr 23, 2001.
,
,,, and
From the * National Jewish Medical and Research Center, Denver,
Colorado; Background and Objective. There seems
to be a strong causal relationship between allergy and the origins of
asthma. Susceptibility to both is determined by a combination of
genetics and environment acting through a complex network of cytokines.
Nearly 90% of affected children have positive skin tests indicating
the presence of specific immunoglobulin E (IgE), with sensitivity to
house dust mite, Alternaria, cockroach, cat, and dog most closely
linked to the disease. Greater exposure to house dust mite during
infancy leads to earlier onset of wheezing, and elevated serum IgE
levels correlate with the appearance of asthma symptoms. Specific IgE
binds to high-affinity (Fc Methods. Participants were 334 males and premenarchal
females aged 6 to 12 years, with moderate to severe allergic asthma
requiring treatment with inhaled corticosteroids. During a run-in
phase, all children were switched to equivalent doses of beclomethasone dipropionate (BDP), and the dose was adjusted to assure maintenance of
asthma control achieved with previous corticosteroid treatment. Children were randomized to subcutaneously administered placebo (N = 109) or omalizumab (N = 225) at a dose based on body weight and initial serum IgE (0.016 mg/kg/IgE [IU/mL] per 4 weeks). BDP dose (initial range 168-420
µg/d) was kept stable for 16 weeks (stable-steroid phase), reduced
over 8 weeks to the minimum effective dose (steroid-reduction phase),
and maintained constant for the final 4 weeks.
Results. More participants in the omalizumab group
decreased their BDP dose, and their reduction was greater than that of
the placebo group (median reduction 100% vs 66.7%). BDP was withdrawn
completely in 55% of the omalizumab group versus 39% of the placebo
group. The incidence and the frequency of asthma exacerbations requiring
treatment with doubling of BDP dose or systemic corticosteroids were
lower in the omalizumab group. The treatment differences were
statistically significant during the steroid-reduction phase, during
which fewer participants in the omalizumab group had asthma exacerbation episodes (18.2% vs 38.5%), and the mean number of episodes per patient was smaller than with placebo (0.42 vs 2.72). Five
asthma exacerbations requiring hospitalization all occurred in the
placebo group.Participants' and investigators' global evaluations of treatment
effectiveness were more favorable for omalizumab than placebo. Investigators rated effectiveness excellent for 31.5% of the
omalizumab group versus 16.3% of the placebo group and good for 44.7%
of the omalizumab group versus 32.7% of the placebo group. There was little change in asthma symptom scores or spirometry
measurements during either the stable-steroid or steroid dose-reduction phase, with minimal differences between the treatment groups. The requirement for rescue medication in the omalizumab group during
both the stable-steroid and steroid dose-reduction phases was
consistently lower than at baseline. At week 28, the median number of
puffs of rescue medication taken daily was 0 in the omalizumab group
and 0.46 in the placebo group. The change from baseline was significant
in favor of omalizumab. Over the entire treatment period, patients in the omalizumab group
missed a mean of 0.65 school days, compared with a mean of 1.21 days in
the placebo group. The mean number of unscheduled medical contacts
attributable to asthma-related medical problems was significantly
smaller in the omalizumab group than in the placebo group throughout
the treatment period (0.15 vs 5.35). Median reduction in serum free IgE was 95% to 99% among omalizumab
patients. Median free IgE ranged from 133 to 790 IU/mL at baseline and
was in the range of 6 to 9 IU/mL during the treatment period. The
dosing scheme used in the trial therefore effectively reduced serum IgE
in patients with initial concentrations as high as 1300 IU/mL. There
was no reduction in free IgE in the placebo group.Omalizumab treatment was well tolerated. There were no serious
treatment-related adverse events. The frequency and types of all
adverse events were similar in the omalizumab and placebo groups. The
majority of adverse events were mild to moderate in severity. No
adverse events suggestive of serum sickness or immune complex formation
were observed. Study-drug-related adverse events occurred more
frequently in the omalizumab group than in the placebo group (6.2% vs
0.9%). Urticaria was reported in 9 omalizumab patients (4%) compared
with 1 (0.9%) placebo patient and was mild or moderate in nearly all
cases.
Conclusion. Treatment with omalizumab is safe in children
with asthma. It reduces the requirement for inhaled corticosteroids
while protecting against disease exacerbation.
Southern California Research Center, Mission Viejo,
California; § University of Illinois, Peoria, Illinois; Novartis
Pharmaceuticals, East Hanover, New Jersey; ¶ Allergy & Asthma Research
Institute, Louisville, Kentucky; and # Schering-Plough Corporation,
Kenilworth, New Jersey. (Work was done during tenure at Novartis
Pharmaceuticals, East Hanover, New Jersey.)
RI) receptors on mast cells and basophils.
The IgE-mediated reactions that follow exposure of sensitized mast
cells to an allergen are designated early- and late-phase asthmatic
responses (EAR and LAR). EAR is characterized by release of histamine
and other preformed mediators within 1 hour of allergen exposure. It is
often followed by LAR, an infiltration of the airways by inflammatory
cells associated with an episode of more prolonged, and usually more
severe airflow obstruction, 4 to 8 hours after antigen exposure.
Chronic airway symptoms result from persistent LAR caused by continuous
allergen exposure. IgE antibodies are capable of passive transfer of
both EAR and LAR sensitivity. IgE-mediated mast cell activation
contributes to chronic tissue eosinophilia and airway remodeling, with
permanent loss in pulmonary function.Omalizumab (rhuMAb-E25) is a recombinant, humanized, monoclonal
anti-IgE antibody of mouse origin developed for the treatment of
IgE-mediated diseases. Omalizumab binds to free IgE at the same site as
the high-affinity receptor. Although it attaches to free IgE, it does
not bind to IgA, IgG, or cell-bound IgE. It therefore does not induce
cross-linking of cell-bound IgE, which would lead to the release of
allergic mediators. It has been reported to decrease serum IgE levels
in a dose-dependent manner, inhibit EAR and LAR, and cause a
down-regulation of FcRI receptors on basophils. Omalizumab has been
reported to be safe and effective in improving asthma control and
reducing the requirement for oral and inhaled corticosteroids. This
double-blind, randomized, placebo-controlled study evaluated the
safety, steroid-sparing effects, and impact on disease exacerbations of
omalizumab in the treatment of childhood asthma.
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