REVIEW

CURRENT
OPINION Endotypes in allergic diseases
Ioana Agache and Liliana Rogozea

Purpose of review
The precision medicine concept is both appealing and challenging. We review here the recent findings in
the endotype-driven approach for major allergic diseases.
Recent findings
Stratified medicine for different allergic diseases can identify patients who are more likely to benefit or
experience an adverse reaction in response to a given therapy and anticipate their long-term outcome and
vital risk. In addition, this approach potentially facilitates drug development and prevention strategies.
Summary
The endotype-driven approach in allergic diseases has tremendous potential, but there are notable barriers
in reaching the new world of precision medicine. Multidimensional endotyping integrating visible
properties with multiple biomarkers is recommended for both type 2 and nontype 2 allergic diseases to
provide evidence that a certain pathway is the key driver for a given patient. Significant healthcare system
changes are required to achieve the expected targets.
Keywords
biomarkers, endotypes, phenotypes, precision medicine, prevention, stratified medicine

INTRODUCTION Personalized medicine is the customization of

The concept of precision medicine is not new, but
advances in genetics, targeted approaches and the
growing availability of real-time health data and
statistical unbiased models provide an opportunity
to turn personalized allergic diseases care into
reality.
Precision medicine is anticipated to have a
major effect on both clinical practice and the devel-
opment of new drugs, diagnostic tests and preven-
&
tion strategies [1,2 ]. Asthma, atopic dermatitis,
allergic rhinitis and chronic rhinosinusitis (CRS)
are umbrella terms for different diseases requiring
an individualized/stratified approach [3,4]
STRATIFIED VERSUS PERSONALIZED
MEDICINE AND THE POWER OF
KNOWLEDGE NETWORK
Stratified/personalized medicine is at the cutting
edge of a new era in healthcare.
Stratified medicine relies on the use of biomark-
ers to group patients into clusters who are: at risk of
developing the disease or evolve with complica-
tions; likely to respond better to one therapy over
other alternatives; and likely to respond better to
preventive measures. Stratified medicine is a step
toward personalized medicine, where management
is tailored to each individual.
healthcare tailored to the individual and relies
mainly on pharmacogenomics. To maximize the
potential of this approach, genetic technologies
and analysis algorithms need to be adapted to fit
clinical needs and to prove cost-effectiveness. More
needs to be done for alignment algorithms, quality-
coverage metrics, tailored solutions for paralogous
or low-complexity areas of the genome and the
adoption of consensus standards for gene variants
interpretation.
The knowledge network is the ‘brain’ of preci-
sion medicine, with the informatics power to aggre-
gate all types of information into an information
commons, stratify it into ‘layers’ of distinct data
types and then discern patterns and connections
within and between layers. This process integrates
information across disciplines, from molecular
pathways to behavioral information. This new
knowledge, in turn, can be visualized and made
accessible to researchers and, as clinical decision
Faculty of Medicine, Transylvania University, Brasov Romania
Correspondence to Ioana Agache, Faculty of Medicine, Transylvania
University, Theramed Healthcare, Pictor Ion Andreescu 2A, 50051,
Brasov, Romania. Tel: +40 728 878386; e-mail: ibrumaru@unitbv.ro
Curr Opin Allergy Clin Immunol 2018, 18:177–183
DOI:10.1097/ACI.0000000000000434

1528-4050 Copyright ß 2018 Wolters Kluwer Health, Inc. All rights reserved. www.co-allergy.com
Outcome measures
KEY POINTS
 The stratified approach for allergic diseases favors the
development of new tools to predict and prevent
disease, select the best treatment, reduce side-effects for
individual patients and to streamlining healthcare in a
cost-efficient way.
 There are notable barriers in applying stratified
medicine in clinical practice because of biomarkers
validation and qualification, the dissociated effect of
targeted treatment, big data translation into clinical
decision algorithms and the integrative analysis of the
exposome interference.
 Multidimensional endotyping integrating visible
properties with multiple biomarkers is recommended for
both type 2 and nontype 2 allergic diseases to provide
evidence that a certain pathway is the key driver for a
given patient.
 Significant healthcare system and societal changes are
required to achieve the expected targets.
algorithms, to healthcare practitioners. Building
the knowledge network is a vast and continuous
undertaking.
DISEASE PHENOTYPES, ENDOTYPES AND
BIOMARKERS
The phenotype comprises all the visible properties
related to that particular disease from clinical and
demographic traits to organ physiology and anat-
omy (hyperreactivity, barrier function and remod-
eling), inflammation type (eosinophilic or
noneosinophilic), response to treatment, short-term
and long-term risk. Phenotypes are frequently over-
lapping and moreover do not necessarily relate to or
give insights into the underlying pathogenic mech-
anism, which is better described by the endotype
[3,5]. A successful endotype should link the key
pathogenic mechanism with the phenotype via bio-
&
markers [6,7,8 ]. New approaches for defining aller-
gic diseases endotypes are available, from targeted
immune interventions to more accessible tools for
immunophenotyping and new statistical tools [9].
Omics measurements (transcriptomics, proteomics
and metabolomics) have been utilized to link the
molecular characteristics to visible properties of
& &
asthma, atopic dermatitis and CRS [10 ,11 ]. There
are several drawbacks of the clustering method use
for omics data such as longitudinal stability of the
clusters, reproducibility in different populations,
statistical robustness of the studies and responsive-
ness to intervention [12]. Research shifted from the
investigator-imposed subjective disease clustering
178 www.co-allergy.com
(hypothesis driven) toward unbiased, data-driven
models using the biomarkers/endotypes approach
[9]. Multidimensional endotyping integrating mul-
tiple biomarkers with visible properties is recom-
mended for both type-2 and nontype-2 allergic
diseases to provide evidence that a certain pathway
is the key driver for a given patient [13,14 ] (Fig. 1).
&
ASTHMA ENDOTYPES
On the basis of cellular profile of induced sputum,
several asthma phenotypes are in use today: eosino-
philic, neutrophilic, mixed granulocytic and pauci-
granulocytic [15]. The phenotype of eosinophilic
asthma is in the spotlight of the endotype-driven
approach and is more precisely defined [16]. Eosin-
ophilic asthma is associated with the type-2 gene
&
signature [11 ,17]; however, it is not equivalent to
& &
the type-2 asthma endotype [11 ,13,14 ].
Two main asthma endotypes, type-2 and non-
type 2, are defined by the level of type 2 T helper and
innate lymphoid cell activity and mediators.
The type-2 asthma endotype is the perfect exam-
ple of a complex endotype with three major sub-
endotypes: immunoglobulin (Ig)E, interleukin (IL)-
5 and IL-4/IL-13. The contribution of the barrier
dysfunction, neurogenic inflammation or the
inflammatory cell activity in the airways versus
numbers is not fully investigated [7,9]. Transcrip-
tomic and metabolomic signatures are useful to
& &
stratify this endotype [10 ,11 ,18,19,20 ]. In addi-
&
tion, non type-2 pathways can be upregulated in
type-2 asthma. Mixed endotypes (type 2 and type 1
or type 2 and type 17) were described both for severe
&
and milder asthma [14 ,21–23,24 ,25].
&
The endotype-driven approach for type-2 asthma
relies on several biologics targeting the three main
pathways: anti IgE (omalizumab), anti IL-5 (mepoli-
zumab, reslizumab and benralizumab) and anti IL-4/
IL-13 (dupilumab, tralokinumab and lebrikizumab).
Both omalizumab and all anti-IL-5 interventions
have shown long-term efficacy and safety, with a
consistent effect on decreasing asthma exacerbations
by approximately half, with no significant difference
& &&
between them [26,27,28 ,29 ,30–34]. An additional
steroid-sparing effect was also demonstrated [35,36].
However, the effects on lung function and quality of
& &&
life are not so impressive [28 ,29 ,30]. In addition,
they might not influence cell activation phenotype
&
[37 ]. Targeting IL-13 alone (lebrikizumab and tralo-
kinumab) failed to provide a consistent effect on
asthma exacerbations or lung function [38–40].
Simultaneous targeting of both IL-4 and IL-13 with
dupilumab has better impact on exacerbations and
lung function [41]. Other biologics targeting IL-33,
thymic stromal lymphopoietin (TSLP) (tezepelumab)
Volume 18  Number 3  June 2018
 Endotypes in allergic diseases Agache and Rogozea

The unbiased approach for endotyping

Visible properes Molecular biomarkers

Muldimensional endotyping
(topological data analysis, Bayesian network analysis, etc)

Cluster Cluster Cluster Cluster Cluster

1 2 3 4 X
Clinical Cluster stability and reproducibility Responsiveness
relevance/biological in different populaons to intervenon
plausibility

Translaon into clinical decision algorithm/drug

development programme/validated research tool

FIGURE 1. An unbiased analytical approach is best suited to identify the mechanistic pathways generating endotypes.
Multidimensional endotyping integrates visible properties with molecular biomarkers/omics data using statistical methods
coupling unsupervised pattern detection with network visualization. The approach facilitates the identification of novel
relationships in complex, heterogeneous data sets, allowing for data-driven hypothesis generation that may uncover disease
mechanisms. Clusters generated are unbiased by any preexisting hypothesis, but they need to be validated in terms of clinical
relevance, stability, reproducibility and responsiveness. The major last step is the translation of the new unbiased data-driven
model into relevant tools for clinical practice, research and drug development.

or chemoattractant receptor-homologous molecule
expressed on Th2 cells receptor (fevipiprant and
&
timapiprant) are under investigation [42 ,43]. The
effect of tepezelumab on asthma exacerbations was
independent of baseline blood eosinophil counts
thus supporting the role of non-type 2 mechanisms
in the complex type-2 asthma endotype.
Knowledge on the non type-2 asthma endotypes
is quite limited, hence its targeted management is
lacking completely. Several subendotypes can be
postulated such as the activation of the inflamma-
sone pathway [IL-1b/tumor necrosis factor a (TNF-a)/
IL-6/nuclear factor kB], the IL-17 pathway, the mixed
T1/T2//T17 endotype and the extensive remodeling
& &
subendotype [4,44,45 ,46 ,47–50]. All except the
mixed endotype are usually nonsteroid-responsive.
Patients with recurrent infective exacerbations might
respond to antibiotics and macrolides have demon-
&
strated some effectiveness [51 ,52]. Identifying the
causative pathogen through molecular microbiology
and extended cultures may help direct antibiotic
therapy. Several key steps in neutrophil recruitment
can be targeted [4]. A few drugs targeting the neutro-
philic pathway [CXC chemokine receptors (CXCR2)
antagonists, 5-lipoxygenase-activating protein
inhibitors, anti-IL-17 and anti-TNF-a) have been
developed, although there are currently no active
phase 3 trials. Despite the severity of their disease,
currently, there are no treatment options for patients
with the mixed subendotype. Steroid responsiveness
should be tried first possibly using ultrafine particles
to control the small airways dysfunction. If steroid
unresponsive inhibitors of phosphoinositide 3
kinase, Janus kinase (JAK) or MyD88, key signaling
molecules for the T1, T2 and T17 cytokines or a
combination of antitype-2 targeted treatment, anti
CXCR2 and macrolides deserve further evaluation.
For the inflammasome subendotype, targeting the
TNF-a pathway (etanercept, infliximab and adalimu-
mab) seems logical although risky because of the
notable adverse events. Other targeted interventions
have better safety profile: IL-1b (anakinra), IL-6 (toci-
lizumab and atlizumab), negative antiinflamatory
feedback with IL-37, blockade of the costimulatory
signal CD80 or CD86-CD28 (Abatacept). Targeting
the IL-17 pathway with brodalumab proved to be
quite disappointing, probably because of bulk
patients selection in the trial. IL-33, Sialic acid-bind-
ing Ig-like lectin (Siglec)-9 and High mobility group
box 1/ Receptor-for-Advanced-Glycation-End-prod-
ucts are additional potential targets for this subendo-
type [53,54]. Paucigranulocytic asthma may not need
anti-inflammatory therapy as symptoms may be
driven solely by smooth muscle dysfunction or

1528-4050 Copyright ß 2018 Wolters Kluwer Health, Inc. All rights reserved. www.co-allergy.com 179
Outcome measures
extensive remodeling. Patients with proven airway
hypereactivity (AHR) may benefit from mast cell-
directed therapies or smooth muscle-directed thera-
pies such as long-acting antimuscarinic antagonists
(tiotropium and umeclidinium) or bronchial ther-
moplasty [55–62].
ENDOTYPES OF ALLERGIC RHINITIS AND
CHRONIC RHINOSINUSITIS
Similar to asthma, a type 2 and non type-2 endotype
can be described for rhinitis. The type 2 endotype is
usually attributed to allergic rhinitis. Epithelial-
derived TSLP, IL-33 and IL-25 can initiate or aggra-
vate a type-2 immune response [4]. Neurogenic
and epithelial barrier dysfunction subendotypes
are particularly relevant for rhinitis. The neuro-
genic subendotype is characterized by a relative
overexpression of transient receptor potential
(TRP) channels on trigeminal nerves and high con-
centrations of substance P and neurokinins and is
related to nasal hyperreactivity (NHR) [4]. Epithelial
dysfunction can be primary or secondary to type-2
or type-1 immune response–induced inflamma-
tion. It can be divided roughly into the ciliary
and barrier dysfunction, with reduced expression
of zonula occludens 1 and occludin-1 facilitating
subepithelial migration of exogenous immune-
stimulating molecules [63,64]. In addition, there
are several modulators of endotype expression,
such as the environment, microbiome, lifestyle
and nasal anatomy.
Less is known about the endotype-driven treat-
ment in allergic rhinitis. In the posthoc analysis,
dupilumab significantly improved nasal symptoms
in patients with uncontrolled asthma and comorbid
persistent allergic rhinitis [65]. In patients with
allergic rhinitis, the topical combination azelastine
hydrochloride and fluticasone propionate reduced
NHR, levels of substance P and b-hexosaminidase
&
[66 ]. The reduction in b-hexosaminidase levels
paralleled increased barrier function and completely
reversed eosinophilic inflammation. Repeated
applications desensitized sensory neurons express-
&
ing TRPA1 and TRPV1 [66 ].
The distinction between CRS with (CRSwNP)
and without nasal polyps (CRSsNP) is insufficient
to clearly define subgroups with uniform patho-
physiology. Inflammatory processes in CRS are
quite complex. Although type-1 cytokines are
mostly found in CRSsNP and type-2 cytokines in
CRSwNP, there is a substantial overlap, and several
other cytokines and biomarkers have also been
detected [67,68]. In addition, there is a wide varia-
tion of the endotypes with the geographic region
[69]. Anticytokine antibodies were also described,
180 www.co-allergy.com
indicating disruption of immune tolerance and
mucosal autoimmunity, with the highest levels of
anti-IL-5 and anti-IL-17A antibodies in CRSwNP
[70]. Serum periostin and the blood eosinophil-
to-basophil ratio are novel biomarkers for patients
with CRSwNP [71–73].
ATOPIC DERMATITIS ENDOTYPES
There is a high unmet medical need to define endo-
types of atopic dermatitis because of significant
implications for risk stratification and targeted ther-
apies. Three main phenotypes of atopic dermatitis
are described: non-lesional skin, acute disease flares
and chronic remitting relapsing atopic dermatitis
[4]. The type-2 endotype is present in all, with a peak
in acute disease flares. TH22-driven and TH17-
driven inflammation adds to the type-2 endotype
in the nonlesional skin, whereas TH22-driven and
TH1-driven inflammation is prominent in patients
with the chronic form [4,74,75]. Epithelial dysfunc-
tion is a key mechanism partnering with the dysre-
gulated immune response [4,76].
The evaluation of potential biomarkers stretches
from noninvasive serum cytokines clusters [77] to
expression profiling of skin biopsy specimens [78]
and to targeted anti IL-4/IL-13 interventions. Several
biomarkers were related to severity of atopic derma-
titis, from chemokine (C-C motif) ligand 17 and
filagrin mutations to expansion of circulating follic-
ular T helper cells or exaggerated IDO1 expression
and activity in Langerhans cells [76,79,80].
The pipeline of targeted topical and systemic
therapies for atopic dermatitis is expanding, based
on the growing understanding of its mechanisms,
and is particularly focused on suppressing the
skewed immune activation with beneficial clinical
effects on the overall skin condition, as well as on
comorbidities such as asthma or food allergy. Addi-
tional effect on pruritus and the disturbed micro-
biome has other potential advantages. Robust
evidence of the efficacy of novel immunologic
approaches in atopic dermatitis is available for dupi-
lumab. Two short (16 weeks) phase III trials showed
a significant effect of dupilumab on signs and symp-
toms of atopic dermatitis [81]. Two long-term trials
(1 year) confirmed its efficacy with acceptable safety
[82,83]. Other targeted interventions are under
investigation: topical phosphodiesterase 4 (PDE4)
and JAK inhibitors, biologics inhibiting type-2/
TH22/TH17 cytokines (lebrikizumab, tralokinumab,
nemolizumab and ustekinumab), orally adminis-
tered small-molecule inhibitors targeting thymus
and activation-regulated chemokine, PDE4, the his-
tamine 4 receptor and JAK or specifically itching
(neurokinin 1 receptor inhibitors) [84,85].
Volume 18  Number 3  June 2018

CHALLENGES FOR THE STRATIFIED
MEDICINE APPROACH FOR ALLERGIC
DISEASE
The majority of biomarkers described for allergic
diseases predict treatment response and very few
forecast disease risk and progression. Most of the
biomarkers are suitable only for research setting, few
of them are validated and none of them is qualified
[9]. Biomarkers are highly variable across age, dis-
ease severity and in time; thus, longitudinal evalua-
tion of the biomarkers and the stability of a given
endotype is essential. For type-2 asthma, an exhaus-
&
tive list of biomarkers is described [8 ], which is not
applicable at the point of care. Oversimplification
by choosing the noninvasive and easily measurable
biomarkers [4] runs into the problem that same
biomarkers (e.g. blood eosinophils) predict the effi-
cacy of all type-2 targeted interventions.
Same target/biomarker might not show consis-
tent validity. After successful reduction of asthma
exacerbations with omalizumab, targeting the IgE
pathway with a different monoclonal antibody
failed to reach a meaningful outcome [86]. Lebriki-
zumab failed in phase 3 studies [39]. In severe
asthma, periostin was associated with lung eosino-
philia, serum IgE and blood eosinophilia [87,88];
however, in moderate asthma, periostin failed to
associate with type-2 biomarkers even after stratifi-
cation for serum IgE [21]. Periostin is not associated
with asthma control and the ability to predict the
presence of eosinophilic asthma was modest com-
pared to blood eosinophils [89].
There are several factors continuously modulating
the disease endotype, from genetics and epigenetics to
anatomical factors, exposome and microbiome, met-
abolic pathways and psychological factor [9,90].
The dissociated effect with intraindividual
responses to a targeted approach was described sev-
eral years ago [6]. The meta-analysis of mepolizumab
trials confirmed this observation showing a good
effect of mepolizumab on exacerbations and FEV1
but no effect on rescue medication use and AHR [30].
Thus, the biomarker/endotype approach is not
always paralleling the outcome driven-approach.
The eligibility of patients for targeted treatment
in real life is yet to be proven given the low applica-
bility of the stringent criteria of randomized clinical
trials to the general population. In a real-life study,
0% of patients were eligible for mepolizumab, 31–
41% for omalizumab and 5% for reslizumab [91].
Precision medicine implies capacity to handle
vast amounts of data. These databases need to prove
clinical and research utility to justify investment.
Big data translation into clinical decision algorithms
and the integrative analysis of the exposome inter-
ference prove to be particularly difficult.
1528-4050 Copyright ß 2018 Wolters Kluwer Health, Inc. All rights reserved.
Endotypes in allergic diseases Agache and Rogozea
The present healthcare system is clearly not
ready for stratified medicine. A significant shift in
the doctor–patient relationship is expected with the
well-informed patient advocating for its own care
and connected in real time with the healthcare
provider that is provided with personalized infor-
mation from patient portals. Rapid learning systems
shape vast amounts of ‘real-world’ data unbiased by
any preselection criteria into real-time clinical deci-
sion support at the point of care leading to harmo-
nized care based on quality criteria. Upskilling the
healthcare providers and the bioinformaticians who
can ensure that the data are available, high quality
and well managed is further needed [92]. Regulatory
approval of the combinations of drugs and diagnos-
tic tests is also complicated.
CONCLUSION
The endotype-driven approach made some small but
decisive steps in the management of type-2 asthma,
atopic dermatitis and CRS. More research is urgently
needed for non type-2 asthma, allergic rhinitis, ana-
phylaxis, food and drug allergy and allergen immu-
notherapy. Addition of new targets such as the
epithelial barrier, the airway smooth muscle, the
innate immune cells and the epigenetic modifica-
tions will certainly prove rewarding in the near future.
Key-points for moving the field forward are
increased usage of the concept of multidimensional
endoyping to profile the complex endotypes/suben-
dotypes type-2 and nontype 2 allergic diseases com-
bined with a revised disease nomenclature based on
endotypes. The systems medicine approach comple-
mented by health-information technology is a must
although hampered at present by the difficulty in
translating big data.
Acknowledgements
I.A. prepared this review as part of the PN-II-RU-TE-
2014–4–2303 project.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED
READING
Papers of particular interest, published within the annual period of review, have
been highlighted as:
& of special interest
&& of outstanding interest
1. Collins FS, Varmus H. A new initiative on precision medicine. N Engl J Med
2015; 372:793–795.
www.co-allergy.com 181
Outcome measures
2. König IR, Fuchs O, Hansen G, et al. What is precision medicine? Eur Respir J
& 2017; 50:; pii: 1700391.
Provides a comprehensive definition of stratified medicine, targeted therapy and
deep phenotyping that focuses on precision medicine as a process.
3. Agache I, Akdis C, Jutel M, Virchow JC. Untangling asthma phenotypes and
endotypes. Allergy 2012; 67:835–846.
4. Muraro A, Lemanske RF Jr, Hellings PW, et al. Precision medicine in patients
with allergic diseases: airway diseases and atopic dermatitis-PRACTALL
document of the European Academy of Allergy and Clinical Immunology
and the American Academy of Allergy, Asthma & Immunology. J Allergy Clin
Immunol 2016; 137:1347–1358.
5. Agusti A, Bel E, Thomas M, et al. Treatable traits: toward precision medicine of
chronic airway diseases. Eur Respir J 2016; 47:410–419.
6. Agache I. From phenotypes to endotypes to asthma treatment. Curr Opin
Allergy Clin Immunol 2013; 13:249–256.
7. Agache I, Sugita K, Morita H, et al. The complex type 2 endotype in allergy and
asthma: from laboratory to bedside. Curr Allergy Asthma Rep 2015; 15:29.
8. Agache I, Rogozea L. Asthma biomarkers: do they bring precision medicine
& closer to the clinic? Allergy Asthma Immunol Res 2017; 9:466–476.
The article offers an exhaustive characterization and critical appraisal of asthma
biomarkers in the advent of precision medicine.
9. Agache I, Akdis C. Endotypes of allergic diseases and asthma: an important
step in building blocks for the future of precision medicine. Allergol Int 2016;
65:243–252.
10. Kelly RS, Dahlin A, McGeachie MJ, et al. Asthma metabolomics and the
& potential for integrative omics in research and the clinic. Chest 2017;
151:262–277.
Review summarizing the 21 metabolomic studies of asthma in humans, all con-
cluding that individual metabolites and metabolomic profiles have high discrimi-
natory ability.
11. Kuo CS, Pavlidis S, Loza M, et al. T-helper cell type 2 (Th2) and non-Th2
& molecular phenotypes of asthma using sputum transcriptomics in U-
BIOPRED. Eur Respir J 2017; 49:; pii: 1602135.
Novel approach for moderate and severe asthma by analyzing sputum cell
transcriptomics. Three clusters are described: Th2-high eosinophilic, inflamma-
some-associated and activated metabolic/mitochondrial pathways.
12. McShane LM, Cavenagh MM, Lively TG, et al. Criteria for the use of omics-
based predictors in clinical trials. Nature 2013; 502:317–320.
13. Hinks TS, Brown T, Lau LC, et al. Multidimensional endotyping in patients with
severe asthma reveals inflammatory heterogeneity in matrix metalloproteinases
and chitinase 3-like protein 1. J Allergy Clin Immunol 2016; 138:61–75.
14. Agache I, Strasser DS, Pierlot GM, et al. Monitoring inflammatory hetero-
& geneity with multiple biomarkers for multidimensional endotyping of asthma. J
Allergy Clin Immunol 2018; 141:442–445.
The study argues in favor of multidimensional endotyping integrating visible
properties with biomarkers to characterize in depth both type-2 and nontype 2
asthma and highlights the pitfalls of using a low-cut off for blood eosinophils as a
selection criterion for type-2 targeted treatment.
15. Wang F, He XY, Baines KJ, et al. Different inflammatory phenotypes in adults
and children with acute asthma. Eur Respir J 2011; 38:567–574.
16. Aleman F, Lim HF, Nair P. Eosinophilic endotype of asthma. Immunol Allergy
Clin North Am 2016; 36:559–568.
17. Woodruff PG, Boushey HA, Dolganov GM, et al. Genome-wide profiling
identifies epithelial cell genes associated with asthma and with treatment
response to corticosteroids. Proc Nat Acad Sci USA 2007;
104:15858–15863.
18. Hekking PP, Loza MJ, Pavlidis S, et al. Pathway discovery using transcriptomic
profiles in adult-onset severe asthma. J Allergy Clin Immunol 2017; pii: S0091-
6749(17)31195-8. doi:10.1016/j.jaci.2017.06.037. [Epub ahead of print]
19. Sinha A, Desiraju K, Aggarwal K, et al. Exhaled breath condensate metabo-
lome clusters for endotype discovery in asthma. J Transl Med 2017; 15:262.
20. Xu W, Comhair SAA, Janocha AJ, et al. Arginine metabolic endotypes related
& to asthma severity. PLoS One 2017; 12:e0183066.
The study shows a novel endotype for persistent high FeNO asthma based on the
intensity of arginine metabolism in the airways and positions exhaled nitric oxide as
a biomarker of arginine metabolism, independent of the type-2 immune response.
21. Agache I, Strasser DS, Klenk A, et al. Serum IL-5 and IL-13 consistently serve
as the best predictors for the blood eosinophilia phenotype in adult asth-
matics. Allergy 2016; 71:1192–1202.
22. Seys SF, Scheers H, Van den Brande P, et al. Cluster analysis of sputum
cytokine-high profiles reveals diversity in T(h)2-high asthma patients. Respir
Res 2017; 18:39.
23. Hasegawa T, Uga H, Mori A, Kurata H. Increased serum IL-17A and Th2
cytokine levels in patients with severe uncontrolled asthma. Eur Cytokine
Netw 2017; 28:8–18.
24. Bhakta NR, Christenson SA, Nerella S, et al. IFN-stimulated gene expression,
& type 2 inflammation, and endoplasmic reticulum stress in asthma. Am J Respir
Crit Care Med 2018; 197:313–324.
The study dwells on nontype 2 pathways that contribute to asthma pathogenesis
describing the interferon-stimulated genes signature in mild asthma, independent
of the type-2 immune response.
25. Brown KR, Krouse RZ, Calatroni A, et al. Endotypes of difficult-to-control
asthma in inner-city African American children. PLoS One 2017;
12:e0180778.
182 www.co-allergy.com
26. Nachef Z, Krishnan A, Mashtare T, et al. Omalizumab versus mepolizumab as
add-on therapy in asthma patients not well controlled on at least an inhaled
corticosteroid: a network meta-analysis. J Asthma 2018; 55:89–100.
27. Mukherjee M, Paramo F, Kjarsgaard M, et al. Weight-adjusted intravenous
reslizumab in severe asthma with inadequate response to fixed-dose sub-
cutaneous mepolizumab. Am J Resp Crit Care Med 2018; 197:38–46.
28. Cabon Y, Molinari N, Marin G, et al. Comparison of antiinterleukin-5 therapies
& in patients with severe asthma: global and indirect meta-analyses of rando-
mized placebo-controlled trials. Clin Exp Allergy 2017; 47:129–138.
All randomized control trials with anti-IL5 treatments for patients with asthma over
the 1990–September 2015 period are reviewed. Similar patterns and rates of
adverse events and severe adverse events are reported with all anti-IL-5 drugs. The
data interpretations were not affected by the sensitivity analysis.
29. Farne HA, Wilson A, Powell C, et al. Anti-IL5 therapies for asthma. Cochrane
&& Database Syst Rev 2017; 9:CD010834.
Systematic review of 13 studies supporting the use of anti-IL-5 treatments as an
adjunct to standard of care in people with severe eosinophilic asthma and poor
control.
30. Wang FP, Liu T, Lan Z, et al. Efficacy and safety of anti-interleukin-5 therapy in
patients with asthma: a systematic review and meta-analysis. PLoS One
2016; 11:e0166833.
31. Tian BP, Zhang GS, Lou J, et al. Efficacy and safety of benralizumab for eosinophilic
asthma: a systematic review and meta-analysis of randomized controlled trials. J
Asthma 2017; 1–10; Doi:10.1080/02770903.2017.1379534. [Epub ahead of
print]
32. Lugogo N, Domingo C, Chanez P, et al. Long- term efficacy and safety of
mepolizumab in patients with severe eosinophilic asthma: a multicenter, open-
label, phase IIIb study. Clin Ther 2016; 38:2058–2070.
33. Albers FC, Price RG, Smith SG, Yancey SW. Mepolizumab efficacy in
patients with severe eosinophilic asthma receiving different controller thera-
pies. J Allergy Clin Immunol 2017; 140:1464–1466.
34. Murphy K, Jacobs J, Bjermer L, et al. Long-term safety and efficacy of
reslizumab in patients with eosinophilic asthma. J Allergy Clin Immunol Pract
2017; 5:1572–1581.
35. Bel E, Wenzel S, Thompson P, et al. Oral glucocorticoid-sparing effect of
mepolizumab in eosinophilic asthma. N Engl J Med 2014; 371:1189–1197.
36. Sehmi R, Lim HF, Mukherjee M, et al. Benralizumab attenuates airway
eosinophilia in prednisone-dependent asthma. J Allergy Clin Immunol
2018. Jan 27. pii: S0091-6749(18)30129-5. doi: 10.1016/j.jaci.2018.
01.008.
37. Kelly EA, Esnault S, Liu LY, et al. Mepolizumab attenuates airway eosinophil
& numbers, but not their functional phenotype in asthma. Am J Respir Crit Care
Med 2017; 196:1385–1395.
Mepolizumab reduced airway eosinophil numbers but had a limited effect on airway
eosinophil activation markers, suggesting that these cells retain functionality. This
observation may explain why IL-5 neutralization reduces but does not completely
eradicate asthma exacerbations.
38. Korenblat P, Kerwin E, Leshchenko I, et al. Efficacy and safety of lebrikizumab
in adult patients with mild-to-moderate asthma not receiving inhaled corti-
costeroids. Respir Med 2018; 134:143–149.
39. Hanania NA, Korenblat P, Chapman KR, et al. Efficacy and safety of lebri-
kizumab in patients with uncontrolled asthma (LAVOLTA I and LAVOLTA II):
replicate, phase 3, randomised, double-blind, placebo-controlled trials. Lan-
cet Respir Med 2016; 4:781–796.
40. Brightling CE, Chanez P, Leigh R, et al. Efficacy and safety of tralokinumab in
patients with severe uncontrolled asthma: a randomised, double-blind, pla-
cebo-controlled, phase 2b trial. Lancet Respir Med 2015; 3:692–701.
41. Wenzel S, Castro M, Corren J, et al. Dupilumab efficacy and safety in adults
with uncontrolled persistent asthma despite use of medium-to-high-dose
inhaled corticosteroids plus a long-acting b2 agonist: a randomised dou-
ble-blind placebo-controlled pivotal phase 2b dose-ranging trial. Lancet
2016; 388:31–44.
42. Corren J, Parnes JR, Wang L, et al. Tezepelumab in adults with uncontrolled
& asthma. N Engl J Med 2017; 377:936–946.
The effect independent of blood eosinophils at baseline opens new perspectives
both for type-2 and nontype-2 asthma.
43. Bateman ED, Guerreros AG, Brockhaus F, et al. Fevipiprant, an oral pros-
taglandin DP2 receptor (CRTh2) antagonist, in allergic asthma uncontrolled
on low-dose inhaled corticosteroids. Eur Respir J 2017; 50:.
44. Mahmutovic Persson I, Menzel M, Ramu S, et al. IL-1b mediates lung
neutrophilia and IL-33 expression in a mouse model of viral-induced asthma
exacerbation. Respir Res 2018; 19:16.
45. Turan N, Edwards MJ, Bates S, et al. IL-6 pathway upregulation in subgroup of
& severe asthma is associated with neutrophilia and poor lung function. Clin Exp
Allergy 2018; Jan 6. doi: 10.1111/cea.13085. [Epub ahead of print]
Key proof-of-concept study arguing in favor of the inflammasone pathway sub-
endotype in nontype-2 asthma.
46. Evans MD, Esnault S, Denlinger LC, Jarjour NN. Sputum cell IL-1 receptor
& expression level is a marker of airway neutrophilia and airflow obstruction in
asthmatic patients. J Allergy Clin Immunol 2017. Dec 26. pii: S0091-
6749(17)31666-4.
One of the few studies evaluating the endotype of neutrohilic asthma and
positioning IL-1 receptor as a marker of neutrophilic inflammation and airflow
obstruction.
Volume 18  Number 3  June 2018

47. Vroman H, Bergen IM, van Hulst JAC, et al. TNF-a-induced protein 3 levels in
lung dendritic cells instruct TH2 or TH17 cell differentiation in eosinophilic or
neutrophilic asthma. J Allergy Clin Immunol 2017; Sep 6. pii: S0091-
6749(17)31422-7. doi: 10.1016/j.jaci.2017.08.012. [Epub ahead of print]
48. Qiu YY, Zhou XY, Qian XF, et al. 1,25-dihydroxyvitamin D3 reduces mouse
airway inflammation of neutrophilic asthma by transcriptional modulation of
interleukin-17A. Am J Transl Res 2017; 9:5411–5421.
49. Panda L, Gheware A, Rehman R, et al. Linoleic acid metabolite leads to
steroid resistant asthma features partially through NF-kB. Sci Rep 2017;
7:9565.
50. Lee TH, Chang HS, Bae DJ, et al. Role of S100A9 in the development of
neutrophilic inflammation in asthmatics and in a murine model. Clin Immunol
2017; 183:158–166.
51. Gibson PG, Yang IA, Upham JW, et al. Effect of azithromycin on asthma
& exacerbations and quality of life in adults with persistent uncontrolled asthma
(AMAZES): a randomised, double-blind, placebo-controlled trial. Lancet
2017; 390:659–668.
The study consolidates the value of azithromycinin reducing exacerbations in
persistent symptomatic asthma.
52. Brusselle GG, Vanderstichele C, Jordens P, et al. Azithromycin for prevention
of exacerbations in severe asthma (AZISAST): a multicentre randomised
double-blind placebo-controlled trial. Thorax 2013; 68:322–329.
53. Zhang F, Su X, Huang G, et al. sRAGE alleviates neutrophilic asthma by
blocking HMGB1/RAGE signalling in airway dendritic cells. Sci Rep 2017;
7:14268.
54. Chen Z, Bai FF, Han L, et al. Targeting neutrophils in severe asthma via siglec-
9. Int Arch Allergy Immunol 2018; 175:5–15.
55. Peters SP, Kunselman SJ, Icitovic N, et al. Tiotropium bromide step-up therapy
for adults with uncontrolled asthma. N Engl J Med 2010; 363:1715–1726.
56. Szefler SJ, Murphy K, Harper 3rd T, et al. A phase III randomized controlled
trial of tiotropium add-on therapy in children with severe symptomatic asthma.
J Allergy Clin Immunol 2017; 140:1277–1287.
57. Hoshino M, Ohtawa J, Akitsu K. Effects of the addition of tiotropium on airway
dimensions in symptomatic asthma. Allergy Asthma Proc 2016;
37:147–153.
58. Hamelmann E, Bernstein JA, Vandewalker M, et al. A randomised controlled
trial of tiotropium in adolescents with severe symptomatic asthma. Eur Respir
J 2017; 49:.
59. Lee L, Kerwin E, Collison K, et al. The effect of umeclidinium on lung function
and symptoms in patients with fixed airflow obstruction and reversibility to
salbutamol: a randomised, 3-phase study. Respir Med 2017; 131:148–157.
60. Lee LA, Briggs A, Edwards LD, et al. A randomized, three-period crossover
study of umeclidinium as monotherapy in adult patients with asthma. Respir
Med 2015; 109:63–73.
61. Facciolongo N, Di Stefano A, Pietrini V, et al. Nerve ablation after bronchial
thermoplasty and sustained improvement in severe asthma. BMC Pulm Med
2018; 18:29.
62. Chupp G, Laviolette M, Cohn L, et al. Long-term outcomes of bronchial
thermoplasty in subjects with severe asthma: a comparison of 3-year follow-
up results from two prospective multicentre studies. Eur Respir J 2017; 50:.
63. Steelant B, Farré R, Wawrzyniak P, et al. Impaired barrier function in patients
with house dust mite-induced allergic rhinitis is accompanied by decreased
occludin and zonula occludens-1 expression. J Allergy Clin Immunol 2016;
137:1043–1053.
64. Steelant B, Seys SF, Van Gerven L, et al. Histamine and T helper cytokine-
driven epithelial barrier dysfunction in allergic rhinitis. J Allergy Clin Immunol
2017; Oct 23. pii: S0091-6749(17)31622-6. doi: 10.1016/
j.jaci.2017.08.039. [Epub ahead of print]
65. Weinstein SF, Katial R, Jayawardena S, et al. Efficacy and safety of dupilumab in
perennial allergic rhinitis and comorbid asthma. J Allergy Clin Immunol 2018. Jan
17. pii: S0091-6749(18)30077-0. doi: 10.1016/j.jaci.2017.11.051.
66. Kortekaas Krohn I, Callebaut I, Alpizar YA, et al. MP29-02 reduces nasal
& hyperreactivity and nasal mediators in patients with house dust mite-allergic
rhinitis. Allergy 2017; Nov 9. doi: 10.1111/all.13349. [Epub ahead of print]
One of the few mechanistic studies in allergic rhinitis showing the effect of the
topical application of a steroid and an antihistamine on barrier and neurogenic
dysfunction and on eosinophilic inflammation
67. Tomassen P, Vandeplas G, Van Zele T, et al. Inflammatory endotypes of
chronic rhinosinusitis based on cluster analysis of biomarkers. J Allergy Clin
Immunol 2016; 137:1449–1456.
68. Kortekaas Krohn I, Bobic S, Dooley J, et al. Programmed cell death-1
expression correlates with disease severity and IL-5 in chronic rhinosinusitis
with nasal polyps. Allergy 2017; 72:985–993.
69. Wang X, Zhang N, Bo M, et al. Diversity of TH cytokine profiles in patients with
chronic rhinosinusitis: a multicenter study in Europe, Asia, and Oceania. J
Allergy Clin Immunol 2016; 138:1344–1353.
1528-4050 Copyright ß 2018 Wolters Kluwer Health, Inc. All rights reserved.
Endotypes in allergic diseases Agache and Rogozea
70. Tsybikov NN, Egorova EV, Kuznik BI, et al. Anticytokine autoantibodies in
chronic rhinosinusitis. Allergy Asthma Proc 2015; 36:473–480.
71. Maxfield AZ, Landegger LD, Brook CD, et al. Periostin as a biomarker for nasal
polyps in chronic rhinosinusitis. Otolaryngol Head Neck Surg 2018;
158:181–186.
72. Asano T, Kanemitsu Y, Takemura M, et al. Serum periostin as a biomarker for
comorbid chronic rhinosinusitis in patients with asthma. Ann Am Thorac Soc
2017; 14:667–675.
73. Brescia G, Barion U, Zanotti C, et al. Blood eosinophil-to-basophil ratio in
patients with sinonasal polyps: does it have a clinical role? Ann Allergy
Asthma Immunol 2017; 119:223–226.
74. Czarnowicki T, Esaki H, Gonzalez J, et al. Early pediatric atopic dermatitis
shows only a cutaneous lymphocyte antigen (CLA)(þ) TH2/TH1 cell imbal-
ance, whereas adults acquire CLA(þ) TH22/TC22 cell subsets. J Allergy Clin
Immunol 2015; 136:941–951.
75. Czarnowicki T, Gonzalez J, Shemer A, et al. Severe atopic dermatitis is
characterized by selective expansion of circulating TH2/TC2 and TH22/
TC22, but not TH17/TC17, cells within the skin-homing T-cell population.
J Allergy Clin Immunol 2015; 136:104–115.
76. Bager P, Wohlfahrt J, Boyd H, et al. The role of filaggrin mutations during
pregnancy and postpartum: atopic dermatitis and genital skin diseases.
Allergy 2016; 71:724–727.
77. Thijs JL, Strickland I, Bruijnzeel-Koomen CAFM, et al. Moving toward en-
dotypes in atopic dermatitis: identification of patient clusters based on serum
biomarker analysis. J Allergy Clin Immunol 2017; 140:730–737.
78. Dyjack N, Goleva E, Rios C, et al. Minimally invasive skin tape strip RNA
sequencing identifies novel characteristics of the type 2-high atopic dermatitis
disease endotype. J Allergy Clin Immunol 2018; Jan 6. pii: S0091-
6749(18)30001-0. doi: 10.1016/j.jaci.2017.10.046. [Epub ahead of print]
79. Szabó K, Gáspár K, Dajnoki Z, et al. Expansion of circulating follicular T helper
cells associates with disease severity in childhood atopic dermatitis. Immunol
Lett 2017; 189:101–108.
80. Staudacher A, Hinz T, Novak N, et al. Exaggerated IDO1 expression and
activity in Langerhans cells from patients with atopic dermatitis upon viral
stimulation: a potential predictive biomarker for high risk of eczema herpe-
ticum. Allergy 2015; 70:1432–1439.
81. Simpson EL, Bieber T, Guttman-Yassky E, et al. Two phase 3 trials of
dupilumab versus placebo in atopic dermatitis. N Engl J Med 2016;
375:2335–2348.
82. Blauvelt A, de Bruin-Weller M, Gooderham M, et al. Long-term management
of moderate-to-severe atopic dermatitis with dupilumab and concomitant
topical corticosteroids (LIBERTY AD CHRONOS): a 1-year, randomised,
double-blinded, placebo-controlled, phase 3 trial. Lancet 2017;
389:2287–2303.
83. de Bruin-Weller M, Thaçi D, Smith CH, et al. Dupilumab with concomitant
topical corticosteroids in adult patients with atopic dermatitis who are not
adequately controlled with or are intolerant to ciclosporin A, or when this
treatment is medically inadvisable: a placebo-controlled, randomized phase 3
clinical trial (LIBERTY AD CAFÉ). Br J Dermatol 2017; Nov 28. doi: 10.1111/
bjd.16156. [Epub ahead of print]
84. Snast I, Reiter O, Hodak E, et al. Are biologics efficacious in atopic dermatitis?
A systematic review and meta-analysis. Am J Clin Dermatol 2017; Nov 2. doi:
10.1007/s40257-017-0324-7.
85. Pan Y, Xu L, Qiao J, Fang H. A systematic review of ustekinumab in the
treatment of atopic dermatitis. J Dermatolog Treat 2018; Feb 5:1-3. doi:
10.1080/09546634.2017.1406894. [Epub ahead of print]
86. Harris JM, Maciuca R, Bradley MS, et al. A randomized trial of the efficacy and
safety of quilizumab in adults with inadequately controlled allergic asthma.
Respir Res 2016; 17:29.
87. Jia G, Erickson RW, Choy DF, et al. Periostin is a systemic biomarker of
eosinophilic airway inflammation in asthmatic patients. J Allergy Clin Immunol
2012; 130:647–654.
88. Kanemitsu Y, Matsumoto H, Izuhara K, et al. Increased periostin associates
with greater airflow limitation in patients receiving inhaled corticosteroids. J
Allergy Clin Immunol 2013; 132:305–312.
89. Simpson JL, Yang IA, Upham JW, et al. Periostin levels and eosinophilic
inflammation in poorly-controlled asthma. BMC Pulm Med 2016; 16:67.
90. Durack J, Lynch SV, Nariya S, et al. Features of the bronchial bacterial
microbiome associated with atopy, asthma, and responsiveness to inhaled
corticosteroid treatment. J Allergy Clin Immunol 2017; 140:63–75.
91. Albers FC, M€ ullerová H, Gunsoy NB, et al. Biologic treatment eligibility for
real-world patients with severe asthma: the IDEAL study. J Asthma 2018;
55:152–160.
92. Chambers DA, Feero WG, Khoury MJ, et al. Convergence of implementation
science, precision medicine, and the learning healthcare system: a new model
for biomedical research. JAMA 2016; 315:1941–1942.
www.co-allergy.com 183