Clinical Commentary Review

IgE-Mediated Multimorbidities in Allergic Asthma

and the Potential for Omalizumab Therapy
Marc Humbert, MDa, Jean Bousquet, MDb, Claus Bachert, MDc, Oscar Palomares, MDd, Pascal Pfister, MDe,
Ioannis Kottakis, MDe, Xavier Jaumont, MDe, Simon Francis Thomsen, MDf,g, and Nikolaos G. Papadopoulos, MDh,i
Le Kremlin-Bicêtre and Montpellier, France; Ghent, Belgium; Madrid, Spain; Basel, Switzerland; Copenhagen, Denmark;
Manchester, United Kingdom; Athens, Greece

Allergic asthma often coexists with different pathological response to treatment, and contribute to the overall
conditions, called multimorbidities, that are mostly of allergic socioeconomic burden of the disease. Immunoglobulin E (IgE) is
nature and share a common underlying inflammatory known to play a central role in the pathogenesis of various allergic
pathophysiological mechanism. Multimorbidities of allergic diseases, including asthma. Thus, IgE-mediated immunologic
asthma may influence asthma control, its severity, and patients’ pathways present an attractive target for intervention in asthma
and multimorbidities. In this review, we discuss the most
frequently reported IgE-mediated multimorbidities in allergic
a
Service de Pneumologie, Hôpital Bicêtre, Le Kremlin Bicêtre, France asthma, including allergic rhinitis, rhinoconjunctivitis, atopic
b
MACVIA-France, Contre les Maladies Chroniques pour un Vieillissement Actif en
dermatitis, vernal keratoconjunctivitis, chronic rhinosinusitis
France, European Innovation Partnership on Active and Healthy Ageing Refer-
ence Site, Montpellier, France with nasal polyps, food allergies, and allergic bronchopulmonary
c
Upper Airways Research Laboratory and Department of Oto-Rhino-Laryngology, aspergillosis. Omalizumab is a recombinant humanized
Ghent University and Ghent University Hospital, Ghent, Belgium monoclonal antibody against IgE and has been in use to treat
d
Department of Biochemistry and Molecular Biology, School of Chemistry, Com- allergic asthma for more than a decade. We comprehensively
plutense University of Madrid, Madrid, Spain
e
Novartis Pharma AG, Basel, Switzerland
review the clinical evidence for omalizumab in the treatment of
f
Department of Dermatology, Bispebjerg University Hospital, Copenhagen, the aforementioned multimorbidities in allergic
Denmark asthma. Ó 2018 The Authors. Published by Elsevier Inc. on
g
Department of Biomedical Sciences, University of Copenhagen, Copenhagen, behalf of the American Academy of Allergy, Asthma &
Denmark
h Immunology. This is an open access article under the CC BY-NC-
Division of Infection, Immunity & Respiratory Medicine, University of Manchester,
Manchester, United Kingdom ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
i
Allergy Department, 2nd Pediatric Clinic, University of Athens, Athens, Greece (J Allergy Clin Immunol Pract 2019;7:1418-29)
No funding was received for this work.
Conflicts of interest: M. Humbert reports personal fees from AstraZeneca, Novartis, Key words: Omalizumab; Asthma; Multimorbidities; Treatment;
Roche, Sanofi, and TEVA, during the conduct of the study; and reports grants and Allergic rhinitis; Rhinoconjunctivitis; Chronic rhinosinusitis with
personal fees from GSK. J. Bousquet reports personal fees and other from Chiesi, nasal polyps; Vernal keratoconjunctivitis; Food allergies;
Cipla, Hikma, Menarini, Mundipharma, Mylan, Novartis, Sanofi-Aventis, Takeda,
Teva, and Uriach; and reports other from KYomed-INNOV, outside the submitted
Allergic bronchopulmonary aspergillosis
work. C. Bachert reports advisory board and presentation fees received from
Sanofi, Novartis, Astra-Zeneca, GSK, ALK, Stallergenes, ASIT Biotech, and
Actobiotics. O. Palomares received lecture fees from Novartis, Sanofi-Genzyme,
Allergic asthma is a chronic disease of the airways involving a
AstraZeneca, Amgen, Inmunotek S.L., Allergic Therapeutics, and Stallergenes; complex interplay between multiple inflammatory cells and
participated in advisory boards from Novartis and Sanofi-Genzyme; and received mediators.1 The disease is characterized by reversible airway
research grants from Novartis, ImmunoTek, and MINECO. P. Pfister, I. Kottakis, obstruction and airway hyperresponsiveness on exposure to aer-
and X. Jaumont are employees of Novartis Pharma AG. S. F. Thomsen has been a oallergens; it is defined by immunoglobulin E (IgE) sensitization,
paid speaker, served on advisory boards, been an investigator, and received
research grants from Novartis. N. G. Papadopoulos has received research support
which is clinically diagnosed based on the presence of a clinically
from Gerolymatos, Menarini, Nutricia, and Vian; speaker fees from AstraZeneca, apparent allergic reaction and an IgE response to specific
Boehringer Ingelheim, HAL, Menarini, MSD, Mylan, Novartis, and Nutricia; aeroallergens.2
participated in advisory boards from ASIT, AZ, Biomay, Chiesi, HAL, Menarini, Although allergic conditions, including asthma, are frequently
Mylan, Novartis, Nutricia, and Wockhardt; serves as the president of REG, CAP;
is a board member of GA2LEN, ResViNET; and is a committee member of
managed as single entities, their coexistence/co-occurrence as
European Academy of Allergy and Clinical Immunology, World Allergy multimorbidities is a common phenomenon. The term multi-
Organization. morbidity is used to indicate the clustering and co-occurrence of
Received for publication November 29, 2018; revised February 27, 2019; accepted diseases with a common pathological mechanism in an individ-
for publication February 28, 2019. ual, where the primary disease is not clear.3 Patients with allergic
Available online March 27, 2019.
Corresponding author: Marc Humbert, MD, Service de Pneumologie, Hôpital
asthma very frequently also present with allergic rhinitis (AR) or
Bicêtre, 78 rue du Général Leclerc, 94270 Le Kremlin Bicêtre, France. E-mail: rhinoconjunctivitis,4 whereas patients with chronic rhinosinusitis
marc.humbert@aphp.fr. with nasal polyps (CRSwNP) often have asthma as a multi-
2213-2198 morbidity. In children, atopic dermatitis (AD) is commonly
Ó 2018 The Authors. Published by Elsevier Inc. on behalf of the American Academy
of Allergy, Asthma & Immunology. This is an open access article under the CC
associated with asthma.5 Along with the aforementioned condi-
BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). tions, allergic bronchopulmonary aspergillosis (ABPA) and food
https://doi.org/10.1016/j.jaip.2019.02.030 allergies represent other multimorbidities.6-11 Multimorbidities

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of the total antibodies in human serum and has the shortest half-
Abbreviations used life in serum (approximately 2 days).21 IgE binds to high-affinity
ABPA- Allergic bronchopulmonary aspergillosis FcεRI receptors expressed on the surface of mast cells and ba-
AD- Atopic dermatitis sophils and to low-affinity FcεRII receptors expressed on B cells
AR- Allergic rhinitis
and other hematopoietic cells, which significantly enhances the
CRS- Chronic rhinosinusitis
CRSsNP- Chronic rhinosinusitis without nasal polyps
half-life of IgE.22,23 IgE activity is enhanced by specific cell-
CRSwNP- Chronic rhinosinusitis with nasal polyps surface receptor interaction, and the expression is tightly regu-
CSU- Chronic spontaneous urticaria lated in the absence of allergic disease.1,21-23
MeDALL- Mechanisms of the Development of ALLergy program On initial allergen exposure, antigen-presenting dendritic cells
OIT- Oral immunotherapy sensitize naïve T cells to the allergen and direct their develop-
SE- Staphylococcus aureus enterotoxin ment into T-helper-2 (Th2) cells. This induces production of
Spl- Staphylococcus aureusederived serine proteaseelike inflammatory cytokines IL-4 and IL-13 that increase FcεRII
protein expression and trigger B cells to produce allergen-specific
Th2 cells- T-helper-2 cells IgE.21,22 During their class-switching to IgE-secreting plasma
VKC- Vernal keratoconjunctivitis
cells, B cells also express membrane-bound IgE, which assists in
antigen processing and signal transduction. Secreted IgE binds to
the FcεRI on mast cells and basophils and sensitizes them to the
allergen. Repeated allergen exposure leads to cross-linking of
membrane-bound IgE in mast cells and basophils, inducing
have been shown to contribute to poor asthma control and cellular degranulation and the release of histamine, tryptase,
subsequent overtreatment of patients.12 Furthermore, multi- cysteine-leukotrienes, and platelet-activating factors. These cy-
morbidities are associated with increased health care costs in tokines affect the early allergic response manifested in edema,
patients with severe asthma.8,13 In severe allergic asthma, coex- vasodilation, and bronchoconstriction.18,23 The events induced
isting upper airway pathological conditions present a complex in the early response lead to the production and release of cy-
multimorbidity but often share a common pathophysiological tokines and chemokines such as IL-3, IL-4, IL-5, IL-13, CC
mechanism (eg, type 2 immune response) that displays consid- chemokine ligand-5, and granulocyte-macrophage colony-stim-
erable heterogeneity. It is known that inflammation plays an ulating factor, which recruit inflammatory cells such as neutro-
important role in the initiation and progression of multi- phils, eosinophils, basophils, T cells, and macrophages to the site
morbidities of asthma.14 of inflammation.18,23,24 This process is known as the late allergic
IgE has been convincingly linked to the pathophysiology of response, characterized by mucus hypersecretion, airway
allergic asthma and other allergic conditions.15 IgE-mediated inflammation, hyperresponsiveness, and airway remodeling
allergic diseases involve multiple genetic and environmental (Figure 1). Along with the stated role of IgE-induced inflam-
components that interact to determine disease expression and lead matory mediators, it should be noted that the activation of
to heterogeneous and frequently coexisting phenotypes.16 Com- allergen-specific memory Th2 cells by antigen-presenting cells via
plex allergic diseases such as asthma, rhinitis, conjunctivitis, and IgE-facilitated allergen presentation is also key for the clinical
food allergy may be associated with allergen-specific IgE and manifestation of late allergic response.25
nonallergic mechanisms that can coexist in the same patient
(termed allergic comorbidity cluster or multimorbidity) and share
COMPILATION OF LITERATURE ON ALLERGIC
causal mechanisms.16,17 An FP7 European Union project (No.
264357), the Mechanisms of the Development of ALLergy pro- MULTIMORBIDITIES AND CLINICAL EVALUATION
gram (MeDALL), was initiated to identify novel mechanisms of OF OMALIZUMAB
allergy initiation during early childhood through to young adult- To compile relevant literature on multimorbidities to be
hood. Approximately 38% of allergic multimorbidities were included in this review, we conducted a literature search using
associated with IgE sensitization in the MeDALL study; further- the PubMed database. The search using terms “multimorbidity
more, rather than being the sole factor for multimorbidities, IgE OR multimorbidities” and “asthma” yielded a total of 106
sensitization was suggested to be a component of a broader publications. Additional searches were carried out using the
phenotypical presentation of patients characterized by poly- names of individual conditions, for example, “allergic rhinitis”
sensitization and multimorbidity, which was associated with the AND “asthma.” The literature review was carried out for pub-
frequency, persistence, and severity of allergic symptoms.16,18 lication years 1999 to 2018, restricting the articles to humans
In this review, we provide an overview of the major pathological and English language publications. Potentially eligible publica-
conditions with an IgE component presenting as multimorbidities tions were manually screened and reviewed, and nonrelevant
with allergic asthma, and we discuss the available evidence for anti- publications were excluded based on predetermined criteria such
IgE therapy with omalizumab as a viable option in the manage- as excluding editorials, opinion pieces, articles that did not have
ment of patients with IgE-mediated multimorbidities. the full text available, and articles without authors.

ROLE OF IgE IN ALLERGIC PATHOPHYSIOLOGY IgE-MEDIATED MULTIMORBIDITIES AND THE

The mechanism of allergic asthma and the key role of IgE in EFFECT OF OMALIZUMAB
its pathophysiology have been extensively studied.19,20 Research More than 70% of symptomatic patients with allergy (having at
has demonstrated that IgE plays a fundamental role in the trig- least 1 positive skin prick test or at least 1 specific IgE > 0.35 kU/L)
gering, development, and chronicity of the inflammatory re- may be sensitized and clinically allergic to either 1 (mono-
sponses within the disease.19 IgE constitutes only a small fraction sensitization) or more allergens (polysensitization).15 de Jong
1420 HUMBERT ET AL J ALLERGY CLIN IMMUNOL PRACT
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FIGURE 1. Immunological mechanisms in IgE-mediated allergic diseases. Th2 cell, T-helper-2 cell.

et al26 proposed to use the term “paucisensitization” to describe 2

to 4 sensitizations and “polysensitization” to describe 5 or more
sensitizations. Polysensitization can be categorized into: (1) cross-
reactivity/cross-sensitization, which is the same IgE binding to
several different allergens with common structural features; and (2)
cosensitization, which is the simultaneous presence of different
IgEs that bind to allergens that may not necessarily have common
structural features.27 Important clinical and immunological dif-
ferences exist between patients who are mono- and polysensitized,
which indicates that polysensitization is the expression of a distinct
disease in both children and adults. Persistence of allergic diseases
over time is associated with multimorbidity and/or allergic poly-
sensitization; moreover, polysensitization was shown to be higher
in patients with multimorbidity in comparison with those with a
single allergic disease.15
Some studies in allergic asthma have shown that multi-
morbidities are independent predictors of key asthma out-
FIGURE 2. Multimorbidities associated with severe allergic
comes.28 Therefore, the choice of treatment in patients with
asthma. ABPA, Allergic bronchopulmonary aspergillosis;
severe asthma should be optimized based on any existing mul-
CRSwNP, chronic rhinosinusitis with nasal polyps.
timorbidities as these may define the asthma phenotype and
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TABLE I. Efficacy of omalizumab in patients with allergic rhinitis/rhinoconjunctivitis

Study Design No. of patients Primary (or coprimary) endpoint Primary outcome
44
Adelroth et al A randomized, double-blind, placebo- 251 Average daily nasal symptom Significant between-treatment
controlled, parallel-group study severity score (sneezing, itching, differences (P < .001) in favor of
runny, and stuffy nose) from omalizumab were observed in
diary data collected over the average daily nasal symptom
double-blind treatment period severity scores
Casale et al45 A randomized, double-blind, 536 The average daily nasal symptom Average nasal symptom severity and
placebo-controlled, multicenter, severity score duration scores over the entire
dose-ranging study pollen season were consistently and
significantly lower in the
omalizumab 300 mg group vs the
placebo group (P ¼ .002). During
the severe pollen season, average
nasal symptom severity scores were
also significantly lower in the 300
mg (P ¼ .001) and 150 mg (P ¼
.01) omalizumab groups than in the
placebo group
Chervinsky et al46 A randomized, double-blind, 289 Mean daily nasal severity score During 16 wk of treatment, the mean
phase 3 study (as determined from patient daily nasal severity score was
daily diary cards) during significantly lower in omalizumab-
16 wk of treatment treated patients compared with
placebo (P < .001)
Vignola et al47 A multicenter, randomized, 405 Incidence of asthma exacerbations Fewer patients treated with
double-blind, parallel-group, during the 28-wk treatment omalizumab experienced asthma
placebo-controlled study period and the proportion of exacerbations (20.6%) than
patients with improvement in placebo-treated patients (30.1%;
both asthma and rhinitis P ¼ .02). A clinically significant
QoL scores (1.0 point) improvement in both
asthma QoL questionnaire and
rhinitis QoL questionnaire was seen
in 57.7% of omalizumab patients
compared with 40.6% of placebo
patients (P < .001)
Masieri et al48 A longitudinal study 11 General clinical conditions and VAS scores for general
intensity of individual symptoms symptomatology (P ¼ .0125) and
(nasal obstruction, rhinorrhea, symptoms including nasal
itching, sneezing, tearing) using obstruction (P ¼ .005), rhinorrhea
the visual analog scale (VAS; (P ¼ .007), itching (P ¼ .041), and
1 ¼ no symptoms, to sneezing (P < .003) were
10 ¼ worst possible symptoms) significantly reduced with
omalizumab compared with
baseline
Kopp et al49 A randomized, double-blind, 130 Superiority of depigmented specific Combination therapy of SIT with
placebo-controlled, multicenter immunotherapy (SIT) in omalizumab reduced the symptom
study combination with omalizumab load by 39% (P ¼ .0464) over SIT
compared with depigmented SIT monotherapy. This difference was
monotherapy for daily symptom mainly due to reduced symptom
load averaged over the pollen severity (P ¼ .0044)
season of the core study
QoL, Quality of life.

consequently could affect asthma treatment outcomes.29 Indeed, Allergic rhinitis and rhinoconjunctivitis
the American Thoracic Society/European Respiratory Society AR is a symptomatic disorder of the nasal mucus membranes after
guidelines now recognize the identification of multimorbidities allergen exposure, characterized by IgE-mediated inflammation of
as an essential part of treating severe asthma.30 Therefore, the these membranes.32 Compelling evidence exists for the overlap
management of multimorbidities is central to the systematic between AR and asthma.33,34 AR and asthma are characterized by a
approach to overall asthma control.28-31 The multimorbidities in similar inflammatory response as the upper and lower airways have a
asthma discussed in this review are AR/rhinoconjunctivitis, similar cellular structure of ciliated, pseudostratified columnar
vernal keratoconjunctivitis (VKC), AD, CRSwNP, food allergies, epithelium with goblet cells; nevertheless, it should be noted that
and ABPA (Figure 2). differences do exist in the extent of tissue remodeling between the
1422 HUMBERT ET AL J ALLERGY CLIN IMMUNOL PRACT
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TABLE II. Efficacy of omalizumab in patients with asthma and vernal keratoconjunctivitis
Study Design No. of patients Primary (or coprimary) endpoint Primary outcome
53
Sánchez et al Case study 1 Clinical effect of omalizumab in a After 6 wk of omalizumab therapy,
patient with severe vernal the patient presented clinically
keratoconjunctivitis coexistent important improvement in ocular
with asthma symptoms
de klerk et al54 Case study 1 Clinical effect of omalizumab in a Signs and symptoms of vernal
patient with severe vernal keratoconjunctivitis resolved
keratoconjunctivitis coexistent completely with monthly
with asthma subcutaneous omalizumab
treatment
Doan et al55 Retrospective review 4 Clinical effect of omalizumab in Three patients responded to
of case studies patients with severe vernal omalizumab treatment, with a
keratoconjunctivitis coexistent decrease in global symptoms
with asthma (median symptom rating
decreasing from 89 to 29 on a
100-mm visual analog scale),
frequency and in duration of the
inflammatory flares, and also a
decreased need for topical steroid
Occasi et al56 Case study 1 Clinical effect of omalizumab in a After 3 mo of treatment with
patient with vernal omalizumab, asthma control was
keratoconjunctivitis coexistent reached a complete resolution of
with uncontrolled asthma vernal keratoconjunctivitis

TABLE III. Efficacy of omalizumab in patients with chronic rhinosinusitis

Study Design No. of patients Primary (or coprimary) endpoint Primary outcome
71
Gevaert et al A randomized, double-blind, 24 The difference in total nasal There was a significant decrease in
placebo-controlled study endoscopic polyp scores total nasal endoscopic polyp
compared with baseline after scores after 16 wk in the
16 wk of treatment omalizumab-treated group
(2.67, P ¼ .001) compared
with baseline
Vennera Mdel et al72 Case studies 19 The size of NP scored in both nasal NP size was significantly reduced at
cavities using nasal endoscopy. the end of follow-up vs baseline
Scored as 0 (no polyp), 1 (polyps (P ¼ .035). No patient needed
restricted to the middle meatus), additional surgery during
2 (polyps in the middle meatus omalizumab treatment
but not reaching the upper edge
of the inferior turbinate), 3
(polyps between the upper and
lower edges of the inferior
turbinate), and 4 (large polyps
reaching the floor of the nasal
fossa), with a bilateral total score
ranging from 0 to 8
Penn and Mikula73 A retrospective study 8 Effect of omalizumab on recurrence The nasal polyp scores significantly
of nasal polyps after endoscopic improved in the omalizumab-
sinus surgery using sinus treated patients than in the
computed tomography and nasal preoperative group
endoscopic examination

NP, Nasal polyps.

nose (in AR) and bronchi (in asthma).34,35 Several epidemiologic study.38 Previous epidemiological studies have reported that up to
studies have provided strong evidence for the association of the 40% of patients with AR also developed asthma and up to 80% of
development of asthma with a previous history of either seasonal or patients with asthma reported having AR.33,39,40 In a recent study,
perennial AR.36,37 Large worldwide studies such as The Interna- the coexistence of asthma and AR was found to be the most common
tional Study of Asthma and Allergies in Childhood epidemiological allergic multimorbidity,41 supporting the “one airway, one disease”
research program conducted between 2002 and 2003 showed that hypothesis and common epidemiologic, pathologic, and physiologic
the prevalence of asthma, AR, allergic rhinoconjunctivitis, and other characteristics, and a common therapeutic approach for both rhinitis
allergic diseases had risen when compared with 5 years before the and asthma.42 The association of rhinoconjunctivitis and asthma
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TABLE IV. Efficacy of omalizumab in patients with atopic dermatitis

Study Design No. of patients Primary (or coprimary) endpoint Primary outcome
78
Iyengar et al Randomized, placebo-controlled 8 Levels of thymic stromal All patients receiving omalizumab
study lymphopoietin (TSLP), thymus had substantially decreased levels
and activation-regulated of TSLP, OX40L, TARC
chemokine (TARC), OX40 (involved in T-helper-2
ligand (OX40L), and other polarization) and IL-9 compared
cytokines involved in atopic with placebo. Patients who
dermatitis (AD) measured by received omalizumab showed
using cytometric bead arrays; SCORAD score reductions of
Scoring Atopic Dermatitis approximately 20% to 50%
(SCORAD) scores
Heil et al79 An explorative single center, 20 Effect of omalizumab on Omalizumab: (1) reduced free serum
randomized, placebo-controlled, immunological disease parameters IgE, (2) lowered surface IgE and
double-blind mechanistic study assessed throughout the study: FcεRI expression on different
flow cytometry, immunohistology, peripheral blood mononuclear
and the measurement of serum IgE cells, (3) reduced the saturation of
levels FcεRI with IgE, (4) increased the
number of free FcεRI, and (5)
lowered the number of IgEþ, but
not of FcεRIþ cells in skin
Sheinkopf et al82 Prospective analysis of 21 AD severity at 0, 1, 3, 6, and All patients showed clinical and
treatment efficacy 9 mo via an Investigator statistically significant
Global Assessment index improvement of their atopic
based on a modified dermatitis from month 0 to months
SCORAD index 1, 3, 6, and 9 on treatment with
omalizumab

symptoms was shown to be frequent and associated with more severe presented the findings from a few key relevant case studies in
asthma symptoms in patients with concomitant AR.43 Table II.

Clinical evaluation of omalizumab. Both randomized- Chronic rhinosinusitis

controlled and observational-type clinical studies have demon- Chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) or
strated the effectiveness and safety of omalizumab in patients with without (CRSsNP) involves long-term inflammation of the
AR. The study populations included patients with a history of paranasal sinus mucosa for a minimum of 12 weeks; specifically
seasonal or perennial AR as well as those with seasonal AR and in CRSwNP, patients may suffer with the condition for de-
concomitant severe asthma. In these studies, omalizumab provided cades.57,58 Patients with CRSwNP are especially prone to
improvement in symptoms, as indicated by significantly lower develop asthma and show an incidence of asthma of 20% to 70%
symptom scores on treatment, reduction in concomitant and dependent on the degree of type 2 inflammation in the polyp
rescue medication use, improved quality of life, decreased IgE mucosa.59 CRSwNP is prevalent in 4% of the asthmatic patients
levels, and reduction in asthma exacerbations. The findings from a and around 15% of nonatopic asthmatic patients; however, these
few key relevant clinical studies are presented in Table I. figures may be higher when patients are thoroughly investigated,
including nasal endoscopy.17 It is important to note that the
Vernal keratoconjunctivitis conventional phenotyping of CRS into CRSwNP and CRSsNP
VKC is a chronic relapsing allergic eye disease with immediate might not adequately reflect the pathophysiological variety
and delayed hypersensitivity reactions (both IgE and non-IgE among patients with CRS; in this regard, distinct inflammatory
mediated) that can result in significant visual loss.50 Conven- endotypes have been identified within patients with CRS, which
tional therapy for allergic conjunctivitis is generally not adequate largely correlated with phenotypes and further differentiated the
for VKC;51 in a large retrospective study, almost 85% of patients phenotypes.59 The GA2LEN study showed that there is a very
with VKC required treatment with topical corticosteroids at strong association of CRS with asthma; almost 40% of patients
some point during follow-up.52 with asthma suffered from comorbid CRS.60 Higher levels of
sputum and serum eosinophils, and exhaled nitric oxide levels, in
Clinical evaluation of omalizumab. A few reports have patients with CRS suggest that it is closely related to lower airway
shown promising results of omalizumab in the treatment in inflammation in severe asthma.61 CRSwNP is associated with
both adults and children with VKC coexisting with asthma, local immunoglobulin hyperproduction and the presence of IgE
without the excessive adverse effects associated with topical antibodies against Staphylococcus aureus enterotoxins (SEs), also
corticosteroid therapy. It should be noted that these findings called staphylococcal superantigens.62 This is in line with the
are mostly from case studies and thus are from a very small evidence that both CRSwNP and asthma show increased nasal
patient population. Therefore, controlled studies in a larger S. aureus colonization.63-65 S. aureusederived serine
number of patients are required to determine the treatment proteaseelike protein (Spl) D and other proteases secreted by
regimen with omalizumab in patients with VKC. We have S. aureus have recently been identified as inducers of allergic
1424 HUMBERT ET AL J ALLERGY CLIN IMMUNOL PRACT
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TABLE V. Efficacy of omalizumab in patients with food allergies

Study Design No. of patients Primary (or coprimary) endpoint Primary outcome
92
Andorf et al A blinded, phase 2, randomized, 48 Proportion of patients who passed At week 36, a significantly greater
controlled study double-blind, placebo-controlled proportion of the omalizumab-
food challenges to at least 2 of treated (30 [83%] of 36) vs placebo
their offending foods at week 36 (4 [33%] of 12) participants passed
double-blind, placebo-controlled
food challenges to 2 or more of
their offending foods (odds ratio:
10.0, 95% CI 1$8-58$3, P ¼
.0044)
Rafi et al96 A prospective pilot study 22 Symptoms and severity of allergic All patients displayed significant
reaction before and after improvement as shown by a
omalizumab treatment for 1-y decrease/lack of symptoms on re-
duration exposure to sensitized foods.
Clinical improvement by the sixth
dosage of omalizumab (150-300
mg every 2-4 wk) was noted by
history and physical examination
Sampson et al97 A phase 2, randomized, 14 Tolerability to peanut in allergic Omalizumab increased the
double-blind, parallel-group, patients tolerability to peanut: 4 (44.4%)
placebo-controlled study omalizumab-treated subjects vs 1
(20%) placebo-treated subject
could tolerate >1000 mg peanut
flour during an oral food challenge
after 24 wk of treatment with study
drug (P ¼ .324)
Wood et al99 A double-blind, 57 Sustained unresponsiveness, defined At month 28, a total of 24 (88.9%)
placebo-controlled study as the absence of dose-limiting omalizumab-treated patients and
symptoms in both month 28 and 20 (71.4%) placebo-treated
month 32 oral food challenges, ie, patients passed the
sustained unresponsiveness “desensitization” oral food
measured after 8 wk off of milk challenge (P ¼ .18). At month 32,
oral immunotherapy in patients sustained unresponsiveness was
treated with omalizumab vs observed in 48.1% in the
placebo omalizumab group and 35.7% in
the placebo group (P ¼ .42)
Schneider et al100 Desensitization study 13 Rate of desensitization to peanut After pretreatment with omalizumab,
allergy all patients tolerated the initial 11
desensitization doses given on the
first day, including the maximum
dose of 500 mg peanut flour,
requiring minimal or no rescue
therapy
MacGinnitie et al101 Desensitization study 37 Rate of desensitization to peanut The median peanut dose tolerated on
allergy the initial desensitization day was
250 mg for omalizumab-treated
patients vs 22.5 mg for placebo-
treated patients. Twenty-three
patients receiving omalizumab vs 1
patient receiving placebo passed
the 4000 mg food challenge
CI, Confidence interval.

asthma.66 The Spls act as allergens and superallergens, shifting continuously activating mast cells in patients with NP.69 IgE to
the immune reaction further into type 2 inflammation.54,66 The SEs can be measured in serum, and SE-induced IgE levels have
presence of both the enterotoxins and the Spls has been been shown to be a risk factor for asthma severity.65,70 In
demonstrated in the upper airway mucosa using proteomics.67 addition, increased levels of total IgE were predictive of asthma
Studies have shown the presence of polyclonal-specific IgE, comorbidity in patients with CRSwNP.66
including IgE to SEs, a high total IgE level, and a high prevalence
of asthma in patients with NP;68 it has been postulated that Clinical evaluation of omalizumab. Omalizumab was
mucosal polyclonal IgE contribute to persistent inflammation by found to be effective in reducing the severity of nasal polyps in
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TABLE VI. Efficacy of omalizumab in patients with allergic bronchopulmonary aspergillosis

Study Design No. of patients Primary (or coprimary) endpoint Primary outcome
107
Aydın et al A retrospective 14 Lung function, asthma control test Treatment with omalizumab resulted
chart review score, mean oral corticosteroid in: (1) significant increase in FEV1
usage, asthma exacerbations, from baseline (P ¼ .02); (2)
hospitalization increase in mean asthma control
test score at all time points
compared with the basal score
(P ¼ .001); (3) significantly
decreased mean oral corticosteroid
dosage (P ¼ .001); and (4) zero
exacerbation and hospitalization
rate at the final assessment. Eleven
of the patients (78.6%) responded
perfectly to omalizumab
Voskamp et al108 A randomized, double-blind, 13 Number of exacerbations Rate of exacerbations decreased
placebo-controlled, significantly in the active treatment
cross-over study phase compared with the placebo
phase (2 vs 12 events, P ¼ .048)
FEV1, Forced expiratory volume in 1 s.

patients with coexisting severe asthma. We have presented the immune pathways.83 Most commonly encountered food aller-
outcomes of a few key relevant clinical studies in Table III. It gens include milk, eggs, tree nuts, peanuts, soy, wheat, fish, and
should be noted that the evidence presented here is mainly from shellfish. IgE-mediated food allergy can affect all ages, impacts
noncontrolled and case studies, which included a low number of quality of life, and can lead to very severe—even fatal—reactions
patients; in this regard, larger controlled clinical trials would be as well as cross-reactive IgE responses to inhalant allergens.84
needed to determine the generalized efficacy and regimen of Overall, the prevalence of food allergies ranges from less than
omalizumab in these patients. Currently, the effectiveness of 0.2% to more than 10%; the prevalence is influenced by factors
omalizumab in nasal polyps (with or without concurrent asthma) including age (eg, egg and milk are major allergens in children
is being explored in 2 ongoing phase 3 randomized clinical trials but disappear later in life) and geographical location.85 An EU-
(Clinicaltrials.gov: NCT03280550, NCT03280537). funded integrated project (EuroPrevall) was conducted to pro-
vide a framework for identification of risk factors and manage-
Atopic dermatitis ment of food allergies by examining the complex interactions
AD, AR, and asthma are said to form the triad of atopic between food intake and metabolism, immune system, genetic
diseases. AD is one of the most common allergic skin disorders background, and socioeconomic factors.86 In the INCO Euro-
found in children. The prevalence of AD is up to 24% in Prevall study, probable food allergy was defined as self-reporting
developed countries, and has risen in recent years together with of adverse symptoms after the consumption of food and a specific
an increased prevalence of asthma, representing a major burden IgE level of 0.35 kUA/L to the same food.87 Children suffering
on health care cost.74,75 AD is frequently associated with elevated from coexisting food allergies and asthma were at increased risk
serum IgE levels in individuals with a history of allergies and of severe anaphylaxis, which can be fatal, particularly if their
respiratory symptoms such as AR and allergic asthma.17 The asthma was uncontrolled.88 Although it is known that allergic
epidermal and dermal dendritic cells both express high-affinity reactions to food can trigger lower respiratory symptoms and
FcεRI receptors on their cell surface. It has been estimated that asthma, food allergy generally does not present with chronic or
approximately one-third of young patients with AD develop isolated respiratory symptoms.88
asthma.76 Moreover, a significant relationship has been demon-
strated between the severity of AD and bronchial asthma, and the
Clinical evaluation of omalizumab. Oral immunotherapy
duration of the skin lesions.77
(OIT) is more effective than other routes in the treatment of
Clinical evaluation of omalizumab. Overall, omalizumab food allergies, but safety has been a major limitation due to the
was not markedly effective in treating AD in patients with risk of adverse reactions.89 To improve the safety profile of OIT
asthma78-82 (Table IV). Moreover, recommendation for its use in and maintain or increase its efficacy, adjuvant therapy with
clinical practice for patients with AD awaits evidence from larger omalizumab has been explored in several trials in severe peanut
randomized controlled trials.80 The Atopic Dermatitis Anti-IgE allergy, milk allergy, egg allergy, and multiple food allergy, with
Paediatric Trial is one such randomized study that will assess significant clinical improvement in both adults and children.90-92
whether omalizumab improves AD compared with placebo in Recent evidence has suggested that the concomitant use of
patients with coexisting asthma.81 omalizumab with OIT can improve OIT protocols and out-
comes in patients with food allergies.93-96 This effect correlated
Food allergies with the effect of omalizumab on basophil reactivity, which may
Food allergies are immune-mediated adverse reactions to play a vital role in the early events of allergic response to
various foods that may involve IgE-mediated immediate hyper- food.94-96 In addition, several studies have assessed the effect of
sensitivity reactions, delayed noneIgE-mediated reactions, or anti-IgE monotherapy in patients with food allergy. In a phase 2
contributions from both IgE-mediated and noneIgE-mediated study, omalizumab was shown to significantly increase the
1426 HUMBERT ET AL J ALLERGY CLIN IMMUNOL PRACT
MAY/JUNE 2019

tolerability of allergic patients to peanut compared with placebo outcomes of any coexisting conditions.112,113 A retrospective,
on oral food challenge, although this study was stopped early.97 observational study that assessed the efficacy of omalizumab in
A placebo-controlled study that evaluated the efficacy of anti-IgE patients with asthma and other concomitant allergic diseases such
monotherapy (with talizumab) in patients with peanut allergy as rhinosinusitis, AD, and ABPA showed improvement in
showed that the threshold of sensitivity to peanut on oral food symptoms of these allergic diseases, suggesting that omalizumab
challenge was significantly increased with this therapy.98 Table V has a role in allergic disease beyond its current use.114 Even
describes the details of key clinical studies that evaluated the beyond diseases with an atopy component, omalizumab reduced
efficacy of omalizumab in patients with food allergy. bronchial mucosal IgEþ mast cells, downregulated FcεRI
expression, and improved lung function despite withdrawal of
Allergic bronchopulmonary aspergillosis conventional therapy in nonatopic asthmatics.115,116
ABPA is an allergic pulmonary disorder caused by hypersen- In spite of common components in their pathogenesis, allergic
sitivity to the fungus Aspergillus species (most commonly diseases are still viewed as independent conditions. Although the
Aspergillus fumigatus). ABPA is also sometimes classified as a nature of the association among different allergic diseases is still
distinct endotype of asthma based on its specific pathophysio- under investigation, it is acknowledged that they tend to cluster
logical mechanisms. Globally, it has been reported that over 4.8 and patients may present with concomitant or consecutive dis-
million patients with asthma have ABPA; however, the exact eases, that is, allergic multimorbidities. Studies that will assess the
prevalence of this disease is still unknown.102 According to the relationship between coexisting diseases in groups of patients
International Society for Human and Animal Mycology working with different allergic sensitizations will provide important in-
group, the prevalence of aspergillus sensitization in patients with sights into the impact of multimorbidities. Furthermore, despite
asthma ranged from 5.5% to 38.5%, and the prevalence of the growing evidence for the application of anti-IgE therapy in
ABPA varied between 2.5% and 22.3%, with a pooled preva- IgE-mediated multimorbidities of allergic asthma, larger and
lence of 8.4% in asthma.103 The fungal antigens from well-designed clinical studies may further confirm the efficacy
A. fumigatus cause a type I (IgE-mediated) reaction that is and safety of the use of omalizumab. It should be noted that
responsible for presentation of ABPA. Type III (IgG-mediated because patients with allergic multimorbidities may exhibit
immune complex) and type IV (cell-mediated) responses have higher levels of IgE than those indicated in the dosing table for
also been implicated, but tissue invasion does not occur. asthma, the dosages of anti-IgE treatments would need to be
Therefore, the total IgE levels are generally high in ABPA.104,105 adjusted to achieve optimal efficacy in treating these conditions.
Future research may provide a better understanding of the
Clinical evaluation of omalizumab. A systematic review interplay between multimorbidities and allergic asthma, thus
of 102 cases from 30 publications showed that treatment helping to identify targeted treatments and improve clinical
with omalizumab reduced serum free IgE levels in patients outcomes in these coexisting allergic diseases.
with ABPA, especially in those with a baseline IgE level of
>1000 IU/mL, and also reduced asthma exacerbations, thus
showing potential benefits in severe ABPA.106 In addition, Acknowledgments
retrospective analysis of case studies and randomized studies have Medical writing and editorial support for this manuscript was
demonstrated that omalizumab improved asthma symptoms and provided by Anjana Mallela and Rahul Lad of Novartis
lung function in patients with asthma and ABPA107,108 Healthcare Private Limited, Hyderabad, India, which was funded
(Table VI). However, larger randomized, double-blind, by Novartis Pharma AG (Basel, Switzerland) in accordance with
placebo-controlled trials are required to establish the effective- Good Publication Practice (GPP3) guidelines (http://www.
ness of omalizumab in this patient population.106 ismpp.org/gpp3).

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