PRIMER

Allergic rhinitis
Jean Bousquet1,2,3,4 ✉, Josep M. Anto5,6,7,8, Claus Bachert9,10,11,12, Ilaria Baiardini13,
Sinthia Bosnic- Anticevich14,15, G. Walter Canonica13, Erik Melén16, Oscar Palomares17,
Glenis K. Scadding18, Alkis Togias19 and Sanna Toppila- Salmi20
Abstract | Allergic rhinitis (AR) is caused by immunoglobulin E (IgE)-m ediated reactions to
inhaled allergens and is one of the most common chronic conditions globally. AR often co-o
ccurs with asthma and conjunctivitis and is a global health problem causing major burden and
disability worldwide. Risk factors include inhalant and occupational allergens, as well as
genetic factors. AR impairs quality of life, affects social life, school and work, and is associated
with substantial economic costs. The Allergic Rhinitis and its Impact on Asthma (ARIA) initiative
classified AR into intermittent or persistent and mild or moderate/severe. The diagnosis is
based on the clinical history and, if needed in patients with uncontrolled rhinitis despite
medications or with long-l asting symptoms, on skin tests or the presence of serum-specific
IgE antibodies to allergens. The most frequently used pharmacological treatments include
oral, intranasal or ocular H1- antihistamines, intranasal corticosteroids or a fixed combination
of intranasal H1- antihistamines and corticosteroids. Allergen immunotherapy prescribed by a
specialist using high-q uality extracts in stratified patients is effective in patients with
persistent symptoms. Real- world data obtained by mobile technology offer new insights into
AR phenotypes and management. The outlook for AR includes a better understanding of novel
multimorbid phenotypes, health technology assessment and patient-c entred shared decision-
making.
✉e- mail: mucosal inflammation that is driven by The diagnosis of AR is made by medical
jean.bousquet@ type 2 cells1,2. AR seems to be the history and examination (physical
orange.fr
consequence of environmental exposures examination and, if needed, nasal
https://doi.org/
10.1038/ s41572-
acting on a predisposed genetic endoscopy) plus, in some patients, tests for
020-00227-0 background. AR is often co-m orbid with allergen- specific IgE (skin prick tests or
Allergic asthma and/or conjunctivitis. tests for serum- specific IgE). Available
rhinitis (AR) is AR is one of the most common chronic treatments include allergen avoidance,
characterized conditions in high- income countries, with pharmacotherapy with H1- antihistamines or
by sneezing, a prevalence of up to 50% in some intranasal corticosteroids (INCS) and
nasal countries3. By contrast, the prevalence is allergen-s pecific immunotherapy (AIT).
congestion, relatively low in low- income and middle- Many patients are dissatisfied with their
nasal itching income countries (LMICs), although treatment, for example, because
and prevalence is increasing steadily in these management does not take the patient’s
rhinorrhoea counties. AR is a global health problem needs into consideration, no cure is
(nasal that causes major burden and disability available, adherence to long-t erm therapy
discharge) and worldwide. Indeed, AR contributes to is poor and/or because the patient does not
is caused by missed or unproductive time at work4 and fully understand the condition. Real- world
immunoglobuli school, sleep problems and, in children, data obtained via mobile technology should
n E (IgE)- decreased involvement in outdoor offer new insights into the phenotypes and
mediated activities5. The economic effect of AR is management of AR.
reactions to often underestimated as indirect costs are This Primer discusses the epidemiology,
inhaled substantial, but the effect of AR on work risk factors and genetic background of AR.
allergens. productivity is estimated to cost €30 In addition, it reviews the mechanisms of
These immune billion to €50 billion per year in the disease, diagnosis, prevention and
reactions European Union4,6,7. management and the effect of AR on
involve quality of life (QOL).

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Epidemiology estimates, AR needs to be distinguished conducted from 1990 to 2010 in children
Prevalence from infectious rhinitis and non-a llergic (International Study of Asthma and Allergy
For accurate rhinitis. Two large multinational studies on in Childhood (ISAAC))8 and adults
prevalence the prevalence of allergic diseases were (European Community

Author addresses Melbourne

1
Charité – Universitätsmedizin Berlin, Humboldt-U niversität zu Berlin, (Australia)3. Of
Berlin, Germany. 2Berlin Institute of Health, Comprehensive Allergy note, AR is more
Center, Department of Dermatology and Allergy, Berlin, Germany. common in males
3
University Hospital Montpellier, Montpellier, France. before puberty,
4
MACVIA- France, Montpellier, France. whereas it is
5
ISGlobAL, Centre for Research in Environmental Epidemiology, more common in
Barcelona, Spain. females after
6
IMIM (Hospital del Mar Research Institute), Barcelona, Spain. puberty; these
7
Universitat Pompeu Fabra, Barcelona, Spain. differences are
8
CIBER Epidemiología y Salud Pública, Barcelona, Spain.
more pronounced
9
Upper Airways Research Laboratory, ENT Department, Ghent
in those with
University Hospital, Ghent, Belgium.
asthma and AR
concomitantly10.
10
Sun Yat-s en University, International Airway Research Center, First
In the US
Affiliated Hospital Guangzhou, Guangzhou, China.
National Health
11
Division of ENT Diseases, CLINTEC, Karolinska Institutet, Stockholm,
and Nutrition
Sweden.
Examination
12
Department of ENT Diseases, Karolinska University Hospital,
Survey III from
Stockholm, Sweden. 13Personalized Medicine Clinic Asthma & Allergy,
1988 to 1994, the
Humanitas University & Research Hospital-I RCCS, Rozzano, Milan,
prevalence of
Italy.
nasal symptoms
14
Woolcock Institute of Medical Research, University of Sydney,
during the
Glebe, NSW, Australia. 15Woolcock Emphysema Centre and Sydney
previous 12
Local Health District, Sydney, NSW, Australia.
months was
16
Institute of Environmental Medicine, Karolinska Institutet and Sachs’
highest (~30%)
Children’s Hospital, Stockholm, Sweden.
in individuals
17
Department of Biochemistry and Molecular Biology, School of
aged 17–29 years
Chemistry, Complutense University of Madrid, Madrid, Spain.
and lowest
18
The Royal National ENT Hospital, University College Hospitals,
(~10%) in those
London, UK. 19Division of Allergy, Immunology, and Transplantation
older than 60
(DAIT), National Institute of Allergy and Infectious Diseases, NIH,
years11.
Bethesda, MD, USA.
In general, the
20
Skin and Allergy Hospital, Karolinska Institutet, Helsinki University
prevalence of AR
Hospital and University of Helsinki, Helsinki, Finland.
has increased
Health Survey (ECRHS))3; however, worldwide since
more recent large studies have not the 1960s in
been undertaken. Collectively, these parallel to the
studies demonstrated that AR often increase in the
begins early in life, with a prevalence prevalence of
of more than 5% at 3 years of age. In atopy (that is, the
the ISAAC phase III study (consisting tendency to
of data from 236 centres in 98 produce IgE
countries), AR prevalence increased antibodies owing
from 8.5% in individuals aged 6–7 to genetic and/or
years to 14.6% in those aged 13–14 environmental
years8. Overall, AR in children and factors)12,13. The
adolescents was more prevalent in ISAAC also
high- income countries, but the evaluated the
prevalence of severe symptoms was change in
higher in LMICs9. In the ECRHS prevalence of
study (conducted in 35 centres in 15 allergic diseases
countries), the age-s tandardized and between 1994–
sex-standardized prevalence of AR in 1995 and 2002–
people aged 20–44 ranged from 11.8% 2003 (ref.8). For
in Oviedo (Spain) to 46.0% in the two age

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groups evaluated as part of this study Classification
(6–7- year- olds and 13–14- year- Although historically AR has been
olds), the prevalence of AR increased categorized as seasonal and perennial, this
from the 1990s to the early years of distinction has not been well reproduced in
the first decade of the twenty- first epidemiological studies assessing molecular
century in many LMICs but decreased allergens as most patients are polysensitized
or had little change in western Europe. (sensitized to more than one allergen)27.
The reasons for the observed changes Accordingly, the organization Allergic
in prevalence are unclear8. Rhinitis and its Impact on Asthma (ARIA)
proposed replacing seasonality with
Risk factors intermittent and persistent rhinitis1.
Allergens associated with AR include pollens (tree, grass and The large
weed, including ragweed), moulds and indoor allergens (house number of risk
dust mites and animal allergens) and have a large geographical factors associated
variability within and between countries 14. Occupational AR with AR suggest
includes both IgE (vegetal and animal proteins as well as certain that the
chemicals) and non- IgE (isocyanates, persulfate salts and geographical
woods) mechanisms15. Risk factors for AR include antibiotic use, variations in
self- reported air pollution, exposure to farm animals (only in prevalence are
LMICs), exposure to cats and/or dogs, maternal and paternal due to a
smoking and vigorous physical activity in adolescents 16. Of note, constellation of
many of these risk factors are shared with asthma and atopic environmental
dermatitis16. Overweight and obesity are not associated with factors varying
AR17. Of note, many of these exposures and lifestyle risk factors between locations
have not been established as major risk factors for AR 18; for and time. These
example, ambient air pollution and passive smoking do not seem varying
to have a large effect on AR development, but pollution may be constellations of
associated with increased AR severity19. risk factors are
The proportion of rhinitis in general that is attributable to also a plausible
atopy is ~50% in the overall population 20. AR, asthma and atopic explanation for
dermatitis often coexist in the same individual, partially due to a the time and
shared genetic origin21,22. Indeed, data from genome- wide place distribution
association studies (GWAS) have demonstrated that allergic of allergic
diseases and traits share a large number of genetic susceptibility multimorbidity16.
loci, of which IL33, IL1RL1 (also known as IL33R), IL13– No biomarker
RAD50, C11orf30 (also known as EMSY)–LRRC32 and TSLP that can be used
seem to be important for multimorbid allergic diseases 18,23. In in clinical
addition, rhinitis was associated with TLR expression, whereas practice to
AR associated with asthma was associated with IL5 and IL33, predict the type
suggesting a different genetic cause for AR alone compared with (that is,
multimorbid AR24. Further research is warranted to explore phenotype or
transcriptomic signatures as biomarkers for single and endotype) and
multimorbid allergic diseases. severity of AR
Susceptibility loci for AR have various immune functions, and the
such as the inflammatory adhesion process for MRPL4 (19q13), development of
in the activation, development and maturation of B cells and its common co-m
epithelial barrier function/ regulatory T cell function for BCAP orbidities is
(also known as PIK3AP1; 10q24) and immune tolerance for available.
C11orf30– LRRC32 (11q13), whereas other loci have unknown
functions, such as FERD3L (7p21)23. In addition, data from one Multimorbidities
large GWAS and HLA fine- mapping study found 20 new loci and
that were associated with AR, many of which had immune sensitization
functions related to both innate and adaptive IgE- related Most patients
mechanisms25. In that study, the estimated proportion of AR with asthma have
attributable to the key identified AR- associated loci was 39%, multimorbid
which is a relatively high estimate for a complex disease. Other rhinitis (AR or
GWAS analyses have found common genetic mechanisms in AR non- allergic
and non- allergic rhinitis22,25,26. rhinitis), whereas
less than one-
third of patients
with AR have

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asthma associated with rhinitis1. The In addition, blood
Mechanisms of the Development of cells (such as
ALLergy (MeDALL) study, which basophils and
included 12 European birth cohorts, antigen- specific
demonstrated that the coexistence of T cells) and nasal
rhinitis with asthma and/or atopic mucosa tissue
dermatitis is more common than can be studied ex
expected by chance alone, both in the vivo42 using
presence and in the absence of IgE different stimuli
sensitization, suggesting that and
multimorbidity and IgE have different interventions.
genetic mechanisms28. In addition,
data from the MeDALL study The nasal epithelium
suggested that type 2 signalling The nasal mucosa is the primary air
pathways represent a relevant conditioner of the respiratory tract and the
multimorbidity mechanism of allergic first line of defence against airborne
diseases22. infectious agents. For these roles,
Many patients with AR also have maintaining and restoring epithelial
conjunctivitis, but rhinitis and integrity and the ability to initiate immune
rhinoconjunctivitis seem to be two responses are essential. In the presence of
separate diseases29–31 and should be conditions or factors that impair mucosal
differentiated. In addition, data from integrity, the epithelium releases alarmins
the mobile application MASK- air and other damage-a ssociated molecular
have identified an extreme pattern of patterns that initiate repair mechanisms but
uncontrolled multimorbidity can also induce protective inflammation. In
(uncontrolled rhinitis, conjunctivitis AR, the same mechanisms may be active in
and asthma during the same day) 32. inducing disease. For example, allergens
More recent classical epidemiological with protease activity (such as Der p 1 in
studies showed that ocular symptoms house dust mites) can directly compromise
are more common in polysensitized the epithelial barrier, whereas others (such
patients29 whether they have asthma or as Der p 2 in house dust mites) can activate
do not have asthma30, ocular symptoms pattern recognition receptors; in both cases
are associated with the severity of the epithelium can initiate innate immune
nasal symptoms33, ocular symptoms responses through the release of alarmins
are important to consider in severe such as IL-33, thymic stromal
asthma33 and the severity of allergic lymphopoietin (TSLP) or IL-25 (refs43–46).
diseases increases with the number of Alarmins can, in turn, activate group 2
allergic multimorbidities34. innate lymphoid cells (ILC2s), which
Monosensitization and rapidly produce in situ type 2 cytokines (IL-
polysensitization represent different 5, IL-13 and IL-4), therefore having a key
phenotypes of IgE- associated role in the initiation and maintenance of
disease35. Polysensitization is type 2 adaptive immune responses, leading
associated with an earlier onset of to IgE class switching and mucosal
allergy and with more severe inflammation. Additional environmental
symptoms compared with factors are probably involved in the
monosensitization. In addition, the pathophysiology of AR through their effects
multimorbidity polysensitization on the nasal epithelium. These include
phenotype seems to occur at various pollutants (diesel exhaust particles47 or other
ages and in various allergenic air pollutants48), irritants and infectious
environments and may be associated agents (Staphylococcus aureus49 or viruses).
with specific mechanisms of disease36. The exact mechanisms through which those
factors contribute to disease manifestation
Mechanisms/pathophysiology have not been elucidated.
Allergen exposure, either topically
intranasally or in an exposure Antigen presentation and sensitization The
chamber37, can be used to study nasal allergic immune response begins with a
allergic reactions, monitor symptoms sensitization phase when the patient is first
and collect nasal secretions and serum exposed to an allergen without experiencing
for mediator measurements in clinical symptoms (fig. 1). During this phase,
response to the allergen38 or nasal dendritic cells in the nasal mucosa take up
scrapings or biopsy from patients39–41. the allergen, process it and transport it to the
draining lymph node, in which the

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processed allergen is presented to naive CD4 T cells. Following
+
subsequent mast cell activation and
antigen presentation, naive CD4+ T cells are activated and degranulation. This leads to the release of
differentiate into allergen-s pecific type 2 T helper cells (T H2 prestored and newly synthesized mediators,
cells)50–55 that induce the activation of B cells and IgE class including histamine, sulfidopeptide
switching, which leads to B cell differentiation into plasma cells leukotrienes (leukotriene C4 and leukotriene
that produce allergen-s pecific IgE. IgE enters the circulation and D4), prostaglandin D2 and other products52
binds through its Cε3 domain to the high- affinity IgE receptor (fig. 1). These mediators interact with nasal
(FcεRI) on the surface of effector cells (for example, mast cells sensory nerves, vasculature and glands,
and basophils). These processes lead to the formation of a pool of resulting in acute AR symptoms.
memory allergen- specific TH2 cells and B cells. Although this In addition to
constitutes the first step in the development of allergy, it is also acute symptoms,
an ongoing process as the mucosa becomes exposed to various experimental
allergens on a chronic, seasonal or episodic basis. nasal exposure to
an allergen in an
Symptom generation and inflammation individual with
AR symptoms are caused by biochemical products released in the AR produces
nasal tissue during an allergic reaction. When a patient who has immediate signs
been sensitized by previous exposure to the allergen re- of inflammation,
encounters the causative such as plasma
exudation and the

Fig. 1 | Pathophysiology of allergic rhinitis. During the sensitization phase, allergens are taken up by dendritic cells in
the nasal mucosa and induce a series of events leading to the generation of plasma cells that produce allergen-s pecific
immunoglobulin E (IgE) that binds to mast cells and basophils and to a pool of memory allergen-s pecific type 2 T
helper cells (TH2 cells) and IgE+ B cells. In individuals who are sensitized to the allergen, subsequent allergen exposure
activates basophils and mast cells in the nasal mucosa, triggering the release of allergic mediators (including histamine
and sulfidopeptide leukotrienes), leading to the acute symptoms of allergic rhinitis. Subsequent cytokine production by
memory allergen-s pecific TH2 cells induces an inflammatory infiltrate (eosinophil recruitment) within a few hours,
leading to more symptoms and changes in the functional aspects of the nasal mucosa that mimic chronic rhinitis. ILC2,
group 2 innate lymphoid cell; LTD4, leukotriene D4; LTE4, leukotriene E4; MHC-I I, class II major histocompatibility
complex; PGD2; prostaglandin D2; TCR, T cell receptor; TSLP, thymic stromal lymphopoietin. Adapted with permission
from ref.51, Wiley.

development of a
allergen, the allergen binds to allergen- specific IgE on mast cells type 2
in the nasal mucosa, resulting in IgE and FcεRI crosslinking and inflammatory

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infiltrate characterized by eosinophils, esponsiveness, where the nasal response
neutrophils and basophils and by a (sneezing, rhinorrhoea and so on) to a
mononuclear infiltrate (primarily TH2 stimulus that is not an allergen (for
cells)56. Indeed, classic type 2 example, histamine) can be augmented by a
cytokines — such as IL-4, IL-5 and prior allergen challenge. In the natural
IL-13 — can be detected in tissue and history of AR, this phenomenon may
measured in nasal secretions several explain the high sensitivity of patients to
hours after allergen exposure57,58 (fig. 1). irritants and to environmental changes61.
In the natural presentation of AR, the Nasal priming
histopathology is quite similar to that may be caused by
after experimental allergen exposure, the increased
and activation of allergen- specific accumulation of
memory TH2 cells by dendritic cells mast cells or
and other antigen- presenting cells basophils —
such as B cells via mechanisms which is a
partially depending on IgE- facilitated consequence of
allergen presentation is believed to repeated allergen
play a critical role49,50. Activated exposure — at
allergen- specific TH2 cells produce the site of the
large amounts of IL-4, IL-5 and IL-13 allergic reaction
that contribute to vascular in the nose62, in
permeability, the infiltration of addition to the
eosinophils and other inflammatory induction of non-
cells into the nasal mucosa, local IgE specific hyper-
production, increased mucus responsiveness at
production, vascular leakage and the ‘end- organ’
expansion, and activation and (nose) level. In
differentiation of different subsets of addition, late-p
TH2 cells40,42,43. Of particular interest hase reactions
are antigen- specific TH2 peripheral and chronicity
blood cells that display markers such might also
as CRTH2, CD161 and CCR4 with depend on the
very little expression of CD27. These perpetuation of
cells, also known as TH2α cells, are allergen- specific
associated with AR severity and are adaptive immune
characteristically suppressed by responses.
allergen immunotherapy57. Although Indeed, persistent
the histology of AR shows a typical symptoms
type 2 inflammation, there is little following
evidence of mucosal remodelling in allergen
contradistinction with asthma46,52. challenge could
Although patients with AR experience acute symptoms on be mediated
exposure to a known allergen, the natural symptomatic state can mainly by the
be chronic with relatively low fluctuations and frequently accumulation of
includes non- allergen triggers such as irritants and changes in allergic mediators
environmental conditions. Experimental allergen provocations in the nasal
(nasal challenges), whether conducted by direct instillation of an mucosa but also
allergen into the nasal cavities or through an environmental by the activation
exposure unit, help identify a number of pathophysiological of allergen-s
phenomena that offer better understanding of the overall clinical pecific memory
picture of AR. Acute symptoms are reduced within minutes but TH2 cells by
can persist at lower levels for hours after allergen exposure or dendritic cells
can recrudesce in a phenomenon known as the ‘late- phase’ and other
reaction59. Late- phase reactions may explain why, after sudden antigen-
exposure to a large amount of an allergen, a patient with AR may presenting cells
remain symptomatic for prolonged periods. Repetitive allergen such as B cells
exposure leads to another phenomenon, whereby progressively via mechanisms
lower amounts of the allergen are required to elicit symptoms; partially
this has been termed ‘priming’ 60. Nasal priming may explain depending on
why, towards the end of a pollen season, patients with AR tend to IgE-f acilitated
become symptomatic even when exposed to very low levels of allergen
pollen. A third phenomenon is the induction of nasal hyper-r presentation63,64.

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Activated TH2 cells produce large is released on
amounts of type 2 cytokines that nasal allergen
contribute to enhance all the local provocation69 and
pathophysiological mechanisms can be found in
described above, including the nasal glandular
enhanced and sustained activation not epithelial cells
only of tissue- resident mast cells but and eosinophils
also of basophils infiltrating the nasal in the nasal
mucosa, which also might well mucosa70.
contribute to the clinical symptoms
after allergen- induced IgE Diagnosis, screening and prevention
crosslinking and subsequent release of AR is often under- recognized owing to
mediators50–52 (fig. 1). Nasal late-p hase poor public awareness, limited access to
reactions, priming and non- specific allergologists and confounding diagnoses,
hyper- responsiveness are such as the common cold71. The diagnosis
inflammation dependent and can be of AR is made by considering a detailed
suppressed by nasal corticosteroids. history that is supported by examination
However, the specific molecular and findings (physical examination and, if
cellular events underlying these needed, nasal endoscopy) and, if necessary,
phenomena are not yet fully testing for allergen-s pecific IgE. Other tests
understood. such as nasal allergen challenge, CT scans,
evaluation of nasal nitric oxide and ciliary
Role of nasal nerves beat frequency, nasal smears, nasal cultures
The nervous system has a key role in and analysis of nasal fluid for β- transferrin)
the nasal symptoms of AR. The nasal may be required to include or exclude
mucosa is densely innervated by different forms of rhinitis72. The ARIA
adrenergic and cholinergic nerve guidelines propose classifying AR as
fibres, and the epithelium is innervated intermittent or persistent depending on the
by interdigitating sensory nerve duration of symptoms, with persistent
endings, mostly nociceptors (receptors rhinitis occurring for more than 4 days for 4
that respond to noxious stimuli)65. In weeks at a time, and as mild or moderate to
addition, nasal chemosensory cells that severe, depending on whether sleep and
express bitter taste receptors may daily activities are affected or whether
reflect a specialized sensory nerve symptoms are troublesome73 (fig. 1). In
system that reacts to noxious stimuli addition, AR can also be classified as mild,
and bacterial products66. Cholinergic moderate or severe74.
and adrenergic nerve fibres are
activated through central reflexes Clinical history
initiated at the nasal mucosa by
The clinical history should note symptoms,
sensory nerves, including nociceptor C
particularly those that cause major
fibres. Nasal C fibres and other
problems, where and when they occur, and
sensory nerves express receptors for
any exacerbating and relieving factors.
some mediators of the allergic
Other symptoms in the chest, ears, throat,
response (such as histamine and
gut or skin, in addition to whether there is a
bradykinin), and also express several
patient history or a family history of allergic
transient receptor potential ion
disease and/or immune problems, together
channels that are activated by noxious
with a review of treatments previously tried,
physical or chemical stimuli, such as
those currently being taken and their
low pH, high or low temperatures,
efficacy, should all be noted.
CO2 and hypertonicity. These fibres
All individuals are familiar with rhinitis
may also have a local effector function
because of the common cold. Rhinitis is
as they produce and release
defined clinically as having two or more of
neuropeptides via axonal, antidromic
the following symptoms for more than 1
reflexes67. However, the mechanism
hour per day: nasal running, blocking,
and clinical role are unclear. Nasal
itching or sneezing. The diagnosis is made
hyper-r esponsiveness seems to have a
by an accurate history but can be missed
strong neural component68. Indeed,
owing to misperceptions such as symptoms
changes in the density and
being ascribed to frequent colds, mouth-
neuropeptide content of sensory
breathing children having enlarged adenoids
nerves have been found in the nose of
and secretions being missed when they pass
patients with AR. A putative mediator
posteriorly. Questioning patients with
of these changes, nerve growth factor,

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asthma regarding nasal function (such as the ability to breathe can also occur
through the nose and to smell) should be undertaken as most with cocaine
patients with asthma have rhinitis or rhinosinusitis73. abuse and
The clinical history may also provide a clue to the inciting vasculitides.
allergen or allergens. Of note, long-t erm allergen exposure is Asthma
harder to diagnose than short- term exposure as the major should always be
symptom is often nasal blockage and postnasal discharge, with assessed in
fewer obvious symptoms such as nasal itching, running and patients with AR
sneezing. Nasal inflammation can also cause non-s pecific nasal by asking
hyper-reactivity to non- allergic stimuli75 and a poor sense of patients about
smell, among other multimorbidities76. Some pollen-s ensitive wheezing,
individuals with AR may present with oral symptoms of pollen shortness of
food syndrome, such as itchy mouth and throat after ingestion of breath and sleep
the food77. disturbance plus,
if needed, an
Examination objective
An examination of the whole patient is measurement
necessary as rhinitis has important co- such as
morbidities76. Children should have spirometry80 and
their growth assessed, as severe vice versa in
airway problems are associated with patients with
reduced growth, and the combined use asthma owing to
of INCS and inhaled corticosteroids the frequent co-
may reduce height at high doses78. The occurrence of
presence of facial features such as these disorders.
conjunctivitis, nasal allergic crease, Patients should
allergic salute or double creases also undergo ear
beneath the eyes (Dennie–Morgan inspection as
lines) all suggest that the patient has otitis media with
an allergic diathesis. effusion (also
Nasal examination is needed in known as glue
patients with moderate to severe AR or ear) may be a co-
in those with uncontrolled symptoms m orbidity in
despite optimal treatment. This children with
examination should include rhinitis and in
assessment of the external appearance adults with
followed by internal examination, severe forms of
preferably with a nasendoscope. An rhinosinusitis81.
otoscope may suffice to examine the The general
nose in children. The position of the examination
nasal septum, as well as the size and needs to also
colour of the inferior turbinates, include skin
should be noted, together with the examination for
appearance of the mucosa and the atopic dermatitis,
presence and nature of any secretions, and, in patients
polyps, bleeding, tumours, crusting or with obstructive
foreign bodies. The classic appearance rhinitis,
of the nasal cavity in patients with AR assessment of
is swollen pale bluish inferior thyroid function
turbinates with copious clear by checking for
secretions; however, the nose may slow relaxation
look normal, and these features are not after the ankle
restricted to AR. Of note, the mucosa jerk and for eye
may be slightly reddened in patients signs such as
using INCS72. Referral to an ear, nose puffiness, redness
and throat specialist is advised for and/or bulging, as
patients with nasal polyps, bleeding, hypothyroidism.
unilateral disease, high crusting and
septal perforations79. High crusting and Tests
septal perforations most commonly Whether further
result from previous septal surgery but diagnostic testing
for AR is

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required in all patients is disputed. results are not concordant, to monitor the
Some clinicians do not recommend progress of AIT and in research studies 90.
further testing in those with a clear Local AR might be an independent rhinitis
history of nasal symptoms that are phenotype, although it is treated in the same
provoked by allergen exposure82. This way as AR91.
occurs in most northern hemisphere Patients with rhinitis who have negative
patients allergic to pollen and with results on tests for allergy have non- allergic
intermittent exposure to animal or rhinitis, which can be caused by several
occupational allergens but is not factors that can broadly be divided into
possible with long-t erm exposure, as infectious and non- infectious factors. Tests
with pollens in most tropical climates to identify these factors are detailed in an
or indoor allergens such as house dust EAACI position paper72.
mites. By contrast, other clinicians
recommend further testing in all Box 1 | Managing patients with AR during
patients with symptoms suggestive of the COVID-19 pandemic
AR. Testing for allergen- specific IgE
using skin prick or blood tests72 to The global spread of COVID-19 has caused
identity the allergen can be performed sudden and dramatic changes in society and
to support the diagnosis and is health care, including management of allergic
mandatory when AIT is being rhinitis (AR). Severe acute respiratory
considered as part of the treatment. Of syndrome coronavirus 2 (SARS-C oV-2) particles
note, the results from IgE testing need that are inhaled though the nose or the mouth
to be interpreted in the light of the bind to upper respiratory tract cells, and the
clinical history, as both false-p ositive nose is the first organ to be invaded203. In
and false-negative results can occur 83. addition, SARS-C oV-2 binds to angiotensin-
In one meta- analysis of skin prick converting enzyme 2 (ACE2), and expression of
tests, the sensitivity ranged from 68% ACE2 is lower in patients with allergic diseases,
to 100% and the specificity ranged suggesting that they may be less prone to
from 70% to 91% (ref.84). SARS-C oV-2 infection204,205. The effect of AR on
Component- resolved diagnosis (that is, using purified native COVID-19 is still a matter of debate, and no
or recombinant allergens to identify IgE sensitivity to individual firm conclusion can be drawn206. Smell
allergens) is not yet routine in AR diagnosis but may provide dysfunction and anosmia are common COVID-
important information. For example, the detection of serum IgE 19 symptoms207.
antibodies to specific molecules (Phl p 1, Phl p 5, Bet v 1 or Pru The allergy and immunology communities
p 3) could be used as a biomarker to predict AR persistence and have quickly responded by mobilizing practice
the future onset of multimorbidities, such as asthma and/or pollen adjustments and embracing new paradigms of
food syndrome85–87. Moreover, component- resolved diagnosis care to protect patients and staff from severe
may be useful in understanding cross- sensitizations and in SARS- CoV-2 exposure208–211 using telehealth212.
proposing AIT where specific molecular sensitization can guide Some recommendations regarding the
the content of the vaccine86. treatment of AR in patients with COVID-19
have been made. For example, although oral
Other diagnostic tests may be required to verify the diagnosis
corticosteroids are contraindicated in patients
of AR or to make an alternative diagnosis. Additional tests
with COVID-19, they can be used without
include nasal allergen challenge, nasal cytology, nasal nitric
restriction in patients with AR and COVID-19
oxide measurements and ciliary beat frequency analysis 72. Nasal
(ref.213). Practical recommendations were made
smear cytology is practised in some centres. The presence of a
to organize an allergy clinic208. In addition,
high number of eosinophils (although the necessary percentage of
Allergic Rhinitis and its Impact on Asthma
cells is debatable) suggests an inflammatory process but not
(ARIA) and EAACI recommend stopping all
necessarily AR (AR or non-a llergic rhinitis with eosinophilia),
forms of allergen-s pecific immunotherapy in
which is likely to be corticosteroid responsive. Unilateral
patients with AR who have COVID-19 and
eosinophilia can occur so bilateral samples must be taken 88. Nasal
continuing allergen-s pecific immunotherapy in
nitric oxide measurement is a simple and rapid test to
patients with AR who do not have COVID-19
discriminate AR, non-a llergic rhinitis, and subgroups with
(refs214–216). The possibility of expanding
acceptable sensitivity and specificity, but it can be done only in
highly specialized centres89. injection intervals in the continuation phase
should be checked and may be beneficial. On
the other hand, face masks may reduce the
Testing for local AR
severity of AR symptoms217.
Some patients with rhinitis who do not have systemic IgE As for any other chronic disease, is clear that
sensitization identified via a skin prick test and serum allergen- the COVID-19 pandemic will profoundly change
specific IgE show nasal reactivity on a nasal allergen provocation AR management owing to the infectivity of
test (whereby an allergen is entered into the nose). Nasal allergen
provocation tests can be used when the history and systemic IgE

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allergic patients, probable changes in management and major changes of the correct use of intranasal sprays to
in health- care systems. ensure they correctly adhere to the therapy.

Allergen avoidance
Mobile health
When possible, avoiding or minimizing
Mobile health tools use algorithms
exposure to the causative allergens should
created using advanced statistics
be the first management step for AR.
(neural networks) on data including
Although allergen avoidance may reduce
medical diagnoses and questionnaire
symptoms of AR, it should never isolate
answers92. Very large numbers of
individuals from social interactions. Data
patients can be studied with data
regarding the benefits of house dust mite
obtained by mobile phones, and, in the
avoidance in asthma are conflicting, and
future, mobile health added to
interventions designed to reduce house dust
machine learning may be useful for
mites have unknown effectiveness101. For
the screening of undiagnosed patients
patients who are polysensitized, avoidance
with AR in the general population.
strategies are often challenging as it is
difficult to eliminate all causative allergens
Prevention
or triggers18. Some classical, but often
Many different attempts have been
unproven allergen avoidance measures for
made to prevent allergic diseases,
AR include use of bed covers for house dust
although most of these attempts have
mite allergy, removing pets from the home,
been unsuccessful. However, farm
changing profession for occupational
animal exposure in early life is a
allergens or wearing masks for pollen
protective factor for allergic diseases
allergy. An innovative approach is to feed
in high- income countries93 and also
cats with a cat food containing antibodies
possibly in some LMICs, although the
against Fel d 1 to reduce allergenicity of the
mechanisms are unclear94. In addition,
cat102.
early-l ife exposure to cats and dogs
may prevent the development of
allergy but results are not consistent 95. Pharmacotherapy
The use of probiotics or prebiotics Many pharmacological treatment options
prenatally and postnatally has failed to are available for the management of AR
reduce AR96,97. Moreover, the use of (TaBle 1). Oral and/or intranasal H1-
pharmacological therapies before antihistamines, INCS and the fixed
allergen exposure cannot prevent the combination of INCS and H1-
onset of symptoms in AR98. antihistamines are all considered first-l ine
treatments depending on the severity or
burden of symptoms.
Management
Treatments for AR include education,
H1-a ntihistamines. H1-a ntihistamines for
allergen avoidance, pharmacotherapy
AR treatment are available in oral,
and AIT1,79,99. Pharmacotherapy is
intranasal and ocular formulations and are
effective in most patients and, when
first-l ine treatments for patients with mild
properly implemented, improves
symptoms or those who do not want to use
QOL; however, many patients do not
an INCS treatment. H1- antihistamines
follow prescriptions and are poorly
block the action of histamine by acting as
adherent to pharmacotherapy.
neutral receptor antagonists or inverse
No biologic has been approved for
agonists of the histamine H1 receptor103.
AR except omalizumab in Japan for
Different H1‐antihistamines have different
Cryptomeria japonica allergy100, and,
chemical structures, pharmacokinetics and
owing to their costs and the prevalence
potential for drug–drug and drug–food
of AR, newly developed biologics may
interactions, and they are classified into
be restricted to highly stratified
non- sedating, less- sedating and sedating
patients with severe AR. Of note, some
groups on the basis of brain H 1 receptor
changes to the management of AR
occupancy103. The less- sedating second-
have occurred owing to the COVID-19
generation oral H1-a ntihistamines (such as
pandemic (Box 1).
desloratadine, loratadine, cetirizine,
levocetirizine and rupatadine) and the non-
Education
sedating H1- antihistamines (such as
As AR is a chronic condition that is caused by specific allergens, fexofenadine and bilastine) are well
it is important for patients to try to identify allergens and/or tolerated, safe and effective104. First-
environmental agents that may precipitate their AR. In addition, generation oral H1- antihistamines should be
it is important for clinicians to inform patients of the importance

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avoided owing to adverse effects, in particular sedation, and are than H1-
not recommended for AR treatment103,105. First- generation H1- antihistamines
antihistamines have not been optimally studied as most trials of and leukotriene
these therapies do not meet appropriate standards in terms of receptor
study design, meaning their relative efficacy is unknown106. antagonists,
particularly for

Table 1 | Treatment options for allergic rhinitis

Treatment Rhinorrhoea Sneezing Nasal Nasal Ocular Onset of
itch obstruction symptoms action
Oral H1- antihistamine ++ ++ + + + 1–3 hours
Intranasal H1- antihistamine ++ ++ + + 0 <30 minutes
Ocular H1 antihistamine 0 0 0 0 +++ 15 minutes
Intranasal corticosteroid +++ +++ +++ +++ + to ++ 6–48 hours
Intranasal corticosteroid plus ++++ ++++ ++++ ++++ +++ 10–60
intranasal H1- antihistamine minutes
Nasal decongestant 0 0 0 +++ 0 15 minutes
Intranasal chromone + + + + 0 15 minutes
Ocular chromone 0 0 0 0 ++ 15 minutes
Leukotriene receptor + + + + 0 1 hour
antagonist
Intranasal anti- cholinergic ++ 0 0 0 0 1 hour
agent
0, no evidence of efficacy;+ to ++++, increasing levels of evidence of efficacy.
nasal congestion,
In general, the advantages of oral H1- antihistamines are once- although their
a -day administration, rapid and effective action and low cost. efficacy requires
However, they are less effective than INCS, particularly for nasal several hours or
congestion (which is a common symptom of AR). Oral H1- days104,110 (TaBle
antihistamines are often sufficient for the treatment of mild AR, 1). The
and many patients prefer oral drugs to other formulations. Some mechanism of
oral H1- antihistamines may, with caution, be used in pregnancy action of INCS is
or in women who are breastfeeding (for example, cetirizine, related to the
levocetirizine and loratadine107). local anti-
Topically administered H1- antihistamines (alcaftadine, inflammatory
azelastine, bepotastine, cetirizine, epinastine, ketotifen, and effect on nasal
olopatadine (as eye drops) and azelastine and olopatadine (as mucosal cells. As
nasal sprays)) are suitable for patients with mild AR or ocular with intranasal
symptoms. These medicines may have a bitter taste in 15–20% of formulations of
patients. The effect begins 1–3 hours after administration 104,108. other drugs, all
Mild uncommon adverse effects include dry mouth, drug- patients should
induced rash and swelling of the salivary glands. As previously be educated on
mentioned, patients should be educated on the correct way to the correct way
administer intranasal H1- antihistamines. to administer
intranasal
Intranasal corticosteroids. INCS such products.
as beclomethasone, budesonide, INCS are not
ciclesonide, fluticasone propionate, systemically
fluticasone furoate, mometasone absorbed;
furoate and triamcinolone acetonide therefore, there
are first- line therapeutic options for are no systemic
patients with persistent or moderate to adverse effects.
severe symptoms. INCS effectively The most
control the four major symptoms of common INCS
AR (TaBle 1), and some INCS (such as adverse effects
intranasally administered fluticasone are local,
furoate) can reduce ocular including nasal
symptoms109. INCS are more effective irritation,

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stinging and epistaxis111, and can and the
usually be prevented by aiming the fluticasone
spray slightly away from the nasal propionate–
septum. Long- term INCS use does not azelastine fixed
damage nasal mucosa or induce combination125.
glaucoma112, and growth effects in Cetirizine is
children seem to be minimal78. Some approved at 6
INCS, such as budesonide, can be months of age in
safely used during pregnancy at the some countries.
recommended therapeutic dose after a In addition, INCS
thorough medical evaluation113. can be prescribed
in preschool
INCS and intranasal H1- antihistamine fixed combination. children, H1-
Fixed- dose combinations of INCS and intranasal H 1- antihistamines
antihistamine for treatment of AR and rhinoconjunctivitis include are suitable for
fluticasone propionate–azelastine114 and mometasone– persons older
olopatadine, which was approved in Australia in 2019 (ref.115). than 1 year, and
These medications are more effective than the individual cromoglycate or
compounds administered separately, are well tolerated (except antihistamine eye
for some bitter taste in a few patients) and are effective within drops are suitable
minutes (fluticasone propionate–azelastine)116 or within 1 hour for patients older
(mometasone–olopatadine)117 (TaBle 1). These therapies are than 3 years.
typically used in patients who failed to benefit from INCS
treatment alone and have been suggested for use in non- adherent AR
patients who treat their symptoms intermittently. Combining oral pharmacotherap
H1-a ntihistamines and INCS does not seem to increase the y in elderly
efficacy of INCS118,119. patients. In most
elderly patients,
rhinitis
Other drugs. Leukotriene receptor antagonists, montelukast and
symptoms,
zafirlukast, are used in the treatment of AR. Their effect is close
diagnosis and
to that of oral H 1- antihistamines104. In Europe, leukotriene
treatment are the
receptor antagonists have been approved by the EMA only for
same as for other
patients with co-m orbid asthma and AR. Other AR therapies,
adult age groups.
such as chromones and ipratropium bromide, are effective for
However, elderly
only some symptoms. For example, chromones (disodium
patients often
cromoglycate) can mostly be self- administered and tried in
have mixed AR
patients with mild local ocular symptoms 104. Chromones are safe,
and non-a llergic
but their effectiveness is usually quite modest. The ipratropium
rhinitis with
bromide nasal spray is well tolerated but is effective only for
multiple triggers
nasal secretion104. Decongestants include intranasal sprays (for up
and have higher
to 7 days), such as oxymetazoline or phenylephrine sprays, and
levels of mucosal
H1- antihistamines combined with decongestant
dryness than
sympathomimetic tablets or capsules (for up to 10 days), such as
younger
acrivastine, cetirizine hydrochloride or desloratadine plus
patients126.
pseudoephedrine104, and are indicated only in those with severe
Rhinitis
nasal obstruction and should not be used long term to avoid
symptoms in
rhinitis medicamentosa (for intranasal preparations). Saline
elderly patients
irrigation may reduce patient- reported disease severity in adults
may include
and children with AR, with no reported adverse effects 120,121.
profuse
Herbal products, homeopathy and acupuncture are still largely
rhinorrhoea
used for treatment of AR but lack clear evidence, and herbal
without itching,
medicine can cause adverse effects such as contact dermatitis,
isolated nasal
headache, itchy eyes and gastrointestinal symptoms122.
obstruction
usually when
AR pharmacotherapy and children. lying down, and
Few studies have evaluated AR nasal crusting in
pharmacotherapy in preschool winter or in
children99. The therapies with patients treated
demonstrated efficacy are rupatadine123 with diuretics.
and, in school- aged children, INCS, oral H1-
cetirizine124, azelastine hydrochloride antihistamines,

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intranasal H1- antihistamines and the patients with AR self-m edicate or use over-
azelastine hydrochloride– fluticasone the- counter medications, placing the
propionate fixed combination are first- pharmacist at the forefront of treatment 130.
line therapeutic options in elderly Patients consulting primary care physicians
patients127. Of note, ageing can affect usually have uncontrolled symptoms despite
the nasal mucosa by increasing use of multiple medications. Adherence to
cholinergic treatment is a major issue131, as many
patients do not seek advice from physicians,
do not follow the physician’s prescriptions
Table 2 | Next-g eneration ARIA
and self-m edicate to control their
guidelines
symptoms often using over- the- counter
activity and atrophy126; thus, the dose of topically administered medications130. Surprisingly, the use of
therapies may need to be reduced in elderly patients. In addition, multiple medications is associated with
some therapies can cause specific adverse effects in elderly poor rhinitis control132.
individuals. Indeed, oral decongestants or systemic Some recommendations for AR
glucocorticosteroids are not recommended in elderly patients treatment are based on the Grading of
owing to adverse effects127. Oral decongestants can cause, for Recommendations, Assessment,
example, palpitations, insomnia, nervousness, irritability, trouble Development and Evaluation (GRADE)
with urination and reduced appetite, whereas guidelines104,118,119,133. Next- generation
glucocorticosteroids can induce glaucoma, cataract, osteoporosis guidelines134 were subsequently developed
and diabetes mellitus. Moreover, first- generation H1- using existing GRADE- based guidelines
antihistamines are strongly discouraged in elderly individuals and real-w orld evidence including data
owing to sedation and anticholinergic effects128,129. Caution from randomized controlled trials, real-w
should be exercised in patients with co- existing diseases, orld data provided by mobile
polymedication and organ (such as renal or liver) dysfunctions127. technology131,132 and data from additive
studies, such as allergen chamber studies
Real-l ife data and next- generation guidelines. Real-l ife assessing the speed of onset of
observational studies using mobile health have found that most medications116,117 (TaBle 2). Real- life data

Guideline GRADE evidence (RCT) Real- world evidence

Oral H1- antihistamines are less potent than INCS V RCT and RWD
Many patients prefer oral drugs None None
Intranasal H1- antihistamines are less effective than INCS V RCT and RWD
Intranasal H1- antihistamines are effective within minutes None Chamber studies
INCS are potent medications, first- line therapy in moderate V RCT and RWD
to severe AR
INCS need a few hours to 1–2 days to be effective (except V Chamber studies
ciclesonide)
The combination of INCS and oral H1- antihistamines does not V RCT and RWD
offer advantage over INCS
INCS and intranasal H1- antihistamines are more potent than INCS With restriction RCT and RWD
in moderate to severe AR
INCS and intranasal H1- antihistamines are effective between None Chamber studies
10 and 60 minutes
Adapted with permission from ref.134, Elsevier. AR, allergic rhinitis; ARIA, Allergic Rhinitis and its Impact on Asthma;
GRADE, Grading of Recommendations, Assessment, Development and Evaluation; INCS, intranasal corticosteroids; RCT,
randomized controlled trial; RWD, real-w orld data using mobile technology.

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Nutrition or physical activity

Behavioural science Patient with

rhinitis and/or
asthma symptoms
Patient participation, Symptom
health literacy and monitoring
self-care through
technology-assisted Self-care
‘patient activation’
Medication
monitoring
• Air pollution ARIA in the pharmacy Pharmacist Biodiversity
• Aerobiology Guided
self-management
with mHealth
General practitioner AR action
plan
Next-generation
GRADE guidelines
Specialist
Interactive
care with HCP
guidance
Emergency care
(asthma)

Planetary health

Fig. 2 | Care pathways for allergic rhinitis. The MASK- air study is conducted in 27 countries across the world. The
MASK- air good practice was recognized by the Directorate-G eneral for Health and Food Safety of the European
Commission as a digital tool for citizen empowerment and for person-c entred care. It proposes a stepwise care
pathway for allergic rhinitis (AR). Patients with rhinitis symptoms typically use self-c are. Patients typically then consult
a pharmacist (in many but not all countries), then their general practitioner and then, if needed, specialists. Patients
attend emergency care facilities in cases of severe asthma exacerbation. The next-g eneration care pathway approach
for AR management proposes strategies to improve the stepwise approach using guided self-m anagement with
mobile health technology (mHealth). Non- pharmacological treatment (allergen and environmental pollutant
avoidance, nasal saline douching exercise, nutrition and increasing biodiversity) needs to be included in the care
pathway to sustain both patient and planetary health. ARIA, Allergic Rhinitis and its Impact on Asthma; GRADE,
Grading of Recommendations Assessment, Development and Evaluation; HCP, health-c are professional. Adapted from
ref.135, CC BY 4.0.

clearly indicate that patients prefer as-n eeded websites (fig. 3), following which patients should be
treatment to continuous treatment, and this should be referred to physicians. Mobile technology could
reflected in future guidelines. reduce the time between the first symptoms and
referral of patients with uncontrolled symptoms to
Care pathways for a digitally enabled, patient- specialists, as primary care physicians can have an
centred approach. AR treatment should be objective assessment after the first allergy season
individualized according to the symptom profile, (pollen or indoor allergens), including adherence to
severity and duration, the patient’s preference of oral treatment and control of rhinitis and asthma.
versus intranasal administration, and the availability
and affordability of medications. Mobile technology Allergen-s pecific immunotherapy
can improve shared decision- making, and one AIT is indicated for AR, allergic rhinoconjunctivitis
example has been recognized as a Good Practice by and/or asthma when symptoms remain uncontrolled
the Directorate-G eneral for Health and Food Safety of with avoidance measures and appropriate
the European Commission for digital health in AR 135 pharmacotherapy in adherent patients138.
and for change management136 (fig. 2). The aim of AIT is to induce tolerance to the
Multistakeholder care pathways should be allergens and, therefore, to reduce the symptoms of
established in each country or region as health- care allergic diseases. For a sustained effect, AIT should be
systems differ135,137. As many patients with AR self- applied for a minimum of 3 years, either continuously
medicate and have poor symptomatic control, there is or preseasonally139. The induction of tolerance by AIT
a great need to improve self- management for patients leads to changes in allergen- specific memory T cell
with AR, which can be aided by mobile health. In this and B cell responses and in the allergen-s pecific IgE
scenario, patient counselling is first done by and IgG antibody levels, and modifies the activation
pharmacists with the help of allergy guides and

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thresholds for mast cells, basophils and dendritic mobile health may be of great interest. The symptom–
cells140. Of note, the levels of allergen-s pecific nasal medication score, grading symptoms and medication
and serum IgG4 antibodies correlate closely with the use on a daily basis, still remains the most reliable
clinical response to AIT in patients with AR141. parameter of success in daily practice.
Selecting allergens that have a clinical effect on the Adverse effects of AIT are relatively common but
patient is paramount to the success of AIT. These are rarely severe138. Local reactions include redness
causative allergens can be identified through clinical and swelling at the injection site that occurs
history taking, component- resolved diagnosis and, if immediately or several hours after injection. Other
indicated and necessary, nasal provocation testing. The adverse effects, such as sneezing, nasal congestion or
use of prescription databases has indicated that the hives, indicate systemic reactions. Serious reactions
product- specific efficacy demonstrated in double- such as swelling of lips and tongue, laryngeal oedema,
blind, placebo- controlled, randomized trials translates shortness of breath and chest tightness (asthma) in
into real life142. Evidence of efficacy of AIT has been response to injections are very rare but require
demonstrated for grass, birch (covering the immediate medical attention and upfront preparations,
homologous group of Betulaceae tree pollen), ragweed such as availability of equipment and medications, and
and Cryptomeria japonica pollen143,144, as well as house training of the personnel. Symptoms of an
dust mites145, whereas less evidence is available for anaphylactic reaction typically include swelling in the
other types of pollen, animal dander or moulds. Only throat, wheezing or tightness in the chest, nausea and
regulated, standardized allergen extracts that have dizziness and should be immediately treated with
demonstrated efficacy and safety should be used for adrenaline (auto- injector) and preparation of an
AIT138,146,147. However, efficacy can be assumed for intravenous access. As most serious reactions develop
allergens within homologous groups, including several within 30 minutes after injection, it is recommended
pollen and house dust mite extracts as defined by that patients are supervised in the physician’s office for
respective EMA guidelines for allergen products 138. at least 30 minutes before leaving. Allergen drops or
There is no evidence that mixing different allergens is tablets have a more favourable safety profile than
effective in AIT, as this may result in underdosing and injections. The first sublingual therapy dose should be
a potential degradation of specific allergens. administered under the supervision of a physician, but
AIT can be applied via the subcutaneous or the subsequent doses can be administered at home. Most
sublingual routes, as tablets or drops, following the adverse events are local (mouth itching, lip swelling
same indications and contraindications148. Natural and nausea) and spontaneously subside with further
allergens or chemically modified allergens (known as administration.
allergoids) may be used, with the aim of reducing the
risk of adverse events but maintaining efficacy or Quality of life
enabling an increased dosage138,149. International and Health- related QOL (HRQOL) is the most frequently
national guidelines are available104,150–152 and are patient- reported outcome in AR (TaBle 3). The ARIA
updated on a regular basis. recommendations73 have proposed grading AR
Owing to the need for long- term use and the cost severity by taking into account the effect of AR on
in most countries, only selected patients should receive HRQOL. Moreover, regulatory authorities such as the
AIT, which should be prescribed by allergists (fig. 4). FDA154 and the EMA155 have provided guidance to the
However, no validated biomarkers for predicting or industry on how to use patient-r eported outcomes to
monitoring the efficacy of AIT at an individual patient support labelling claims and routinely consider
level are available in clinical practice 153, although patient- reported outcomes as a tool used for data
collection. In addition,
Symptoms of allergic rhinitis

• VAS (nose)
• Patient preference (oral vs intranasal treatment)

VAS score <50 VAS score ≥ 50

• Avoidance of • Nasal saline • INCS • INCS
known allergens • Intranasal H1-antihistamine • Other • INCS and intranasal H
1-antihistamine
and pollutants • Oral H1-antihistamine (if VAS score2)≤ treatment • Other treatment

Review symptomatic patient after 5–10 days

VAS score <20 VAS score ≥ 50

• Consider stopping treatment if outside allergy VAS score 20–50 • Step up (according to ARIA guidelines)
season • Continue if possible, or consider referral to
• Continue treatment if during allergy season treatment specialist physician

Fig. 3 | Care pathway for the management of allergic rhinitis in the pharmacy. A simple algorithm to help the
pharmacist diagnose allergic rhinitis and dispense over-t he- counter medications is required. Use of a visual analogue
scale (VAS) to determine symptom severity is simple and accurate. The patient’s symptoms need to be reassessed
regularly
NATURE REVIEWS | DISEASE PRIMERS if not daily
| Article citation ID: to propose stopping the treatment, to continue use of over-t he- counter medications or to send15
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the patient to a physician. ARIA, Allergic Rhinitis and its Impact on Asthma; INCS, intranasal corticosteroids. Adapted
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patient preferences and values are introduced as of HRQOL in clinical practice, which is encouraged
cornerstones in GRADE, which is the best option for owing to the potential to optimize disease
grading clinical evidence and developing management168,169, remains limited. In the next few
recommendations for diagnostic and therapeutic years, the questionnaires for assessing and monitoring
interventions156. Although patient-r eported outcomes AR HRQOL in individual patients need to be
are not explicitly included in the definition of validated170 and introduced into routine care.
personalized medicine, they represent a real
opportunity for involving patients in each step of Outlook
disease management157. Mobile health
The availability of validated questionnaires for AR Multimorbidity in allergic airway diseases is well
has permitted the evaluation of the effect of this known76, but a mobile application (MASK- air)
disease in adults, children and adolescents. The use of created to assess how multimorbidity affects
generic tools, which are applicable to all health symptoms and severity has provided further findings32.
conditions, has underlined that adults with AR who Indeed, data from this mobile application have
have HRQOL scores significantly lower than those of revealed that AR and rhinoconjunctivitis do not seem
the general population have HRQOL scores that are to be the same disease and have identified a pattern of
lower than those of patients with asthma158. In uncontrolled multimorbidity in some patients
addition, children and adolescents with AR had lower (uncontrolled rhinitis, conjunctivitis and asthma on the
HRQOL scores than healthy peers159. The effect of AR same day)32. Data from such mobile applications are
on the physical domain of QOL was comparable in generating hypotheses that need confirmation in
teenagers with AR and in those with asthma160. epidemiological studies. In this regard, differences
The aspects of HRQOL that are relevant for between AR alone and AR associated with
patients with AR have been identified by disease- conjunctivitis were previously known29 but
specific questionnaires161,162. A rich literature shows epidemiological studies using data from mobile
how the presence and severity of symptoms negatively applications demonstrated that ocular symptoms are
affect daily activities, performance, sleep, physical and more common in patients with polysensitization 30, are
emotional status and social functioning at all ages163; associated with nasal symptom severity 33 and are
the effect of AR and multimorbid asthma 164–166; the important to consider in severe asthma33. Moreover,
possibility to minimize or delete AR impact 164; and the the severity of allergic diseases increases with the
effect of symptomatic treatments167 or specific number of allergic multimorbidities34. This is the first
immunotherapy. Of note, AR impairs QOL to a greater example of a discovery of novel allergic phenotypes
extent than moderate asthma158 and significantly using a mobile health application confirmed by classic
impairs work productivity4. epidemiological studies. Other mobile tools have been
Interest in the patients’ perspective is continuously proposed171 but few have been tested172. There is an
growing in AR research. Nonetheless, the routine use urgent need to replicate existing data and to optimize
mobile health for

Patient with moderate to severe symptoms of before AIT can be performed, including a
rhinitis or rhinoconjunctivitis, with or without asthma correct allergy diagnosis, the assessment of
adherence to medications and the
demonstration of an uncontrolled disease
Symptoms on exposure to relevant aeroallergens during the allergen exposure despite optimal
medications. IgE, immunoglobulin E; sIgE,
Confirmation of IgE sensitization (skin tests and/or serum- specific immunoglobulin E. Adapted
sIgE) to relevant allergen with permission from ref.138, Wiley.
AR management in the digital
Treat with appropriate pharmacotherapy according
transformation of health and care173. An
to guidelines and avoidance measures where possible interesting approach will be to propose
alerts for pollen174, pollution or asthma
exacerbations175.
Evaluate control and adherence during • Rhinitis may follow the
allergen exposure proposed algorithm
Mechanisms
• Asthma: consider lack and multimorbidity
of control in As
patients
previously mentioned, allergic diseases
Demonstrated insufficient control and good adherence treated with are
inhaled
heterogeneous; some patients have AR
corticosteroids
Patient’s and/or alone, whereas others have AR and asthma
• For safety reasons,
caregiver’s views AIT should not (with
be or without other allergic
manifestations), although few patients have
initiated if asthma
Consider AIT is not stable asthma alone. In addition, there are
probably common genes associated with
Fig. 4 | Stratification of patients for AIT. Only some patients with asthma and AR and specific genes
allergic rhinitis need allergen immunotherapy (AIT), such as patients associated with AR alone. Combining big
who respond poorly to optimal treatment. Several steps are required data analyses (such as from the MASK-a ir

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application ), classical epidemiological studies, in silico
135
Novel cost-e
analysis, transcriptomics using microarray data (as exemplified ffective
in MeDALL22,24,35) or RNA sequencing176 has led to the pharmacologic
reclassification of the mechanisms of allergic diseases. For al treatments
example, polysensitization and multimorbidity represent the Despite AR
extreme allergic phenotype, starting early in life, and are being one of the
associated with IL5 and IL33 activation. Notably, several of these most prevalent
and other genes associated with allergic multimorbidity point diseases in the
towards type 2 inflammation177 and eosinophil activation24. By world with a
contrast, rhinitis alone is associated with Toll-l ike receptor high economic
pathways, which have a key role in the innate immune system. burden, no big
Assessing these mechanisms in more detail may allow better pharmaceutical
understanding of the mechanisms of allergy and provide novel companies are
insights for prevention and treatment. Although it is well developing
established that novel

Table 3 | Questionnaires for the assessment of HRQOL in patients with rhinitis

Questionnaire Number of Population Ref.
items
196
Rhinoconjuctivitis Quality of Life Questionnaire (RQLQ) 28 Adults
197
raciborskiMini Rhinoconjunctivitis Quality of Life Questionnaire (Mini-R QLQ) 14 Adults
198
Nocturnal Rhinoconjunctivitis Quality of Life questionnaire (NRQLQ) 16 Adults
199
RHINASTHMA 30 Adults
170
RhinAsthma Patient Perspective (RAPP) 10 Adults
200
Adolescent Rhinoconjunctivitis Quality of Life Questionnaire 25 Adolescents
166
RHINASTHMA Adolescents 20 Adolescents
201
Pediatric Rhinoconjunctivitis Quality of Life Questionnaire (PRQLQ) 23 6–12 years
165
RHINASTHMA children 17 6–11 years
202
RhinAsthma Patient Perspective children (RAPP) 5 6–11 years
treatments. The
HRQOL, health-r elated quality of life. reasons for this
paradox are
complex but
rhinitis can lead to asthma, the exact phenotype of AR prone to can be
developing asthma is still unclear. It is possible that summarized as
polysensitized individuals can more commonly develop asthma. follows:
overall, low-
New treatments cost
As many patients do not experience medications are
full relief from AR symptoms with effective in
available treatments, knowledge gaps most patients if
undermine the development of new they are used
pharmacological and biological appropriately,
interventions to improve and, in many
management. One important area of countries, they
research is the identification of novel are given over
reliable biomarkers to phenotype or the counter with
endotype patients with AR to predict no cost for the
treatment response and management payers; AR is
strategies. Other areas of research not a life-
include the elucidation of novel threatening
molecular mechanisms involved in disease and
allergen- specific response payers
perpetuation in the nasal mucosa and prioritize life-s
translational integration of genomics, aving
transcriptomics, proteomics and medications, for
metabolomics into health care. example, for

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 Primer
cancer, rare diseases and COVID-19; medications possible to control their
developing medications with an disease. Accordingly, there is an urgent
efficacy substantially higher than that need to propose shared decision- making
of those currently on the market may using mobile health tools to optimize AR
be difficult; and, owing to the number treatment. In addition, drug repurposing
of patients with AR, only low- cost could be useful for treatment
medications may eventually be
reimbursed if patients with AR are
not stratified, and therefore the cost
of the development of an AR
treatment largely surpasses potential
revenues and very few trials are
ongoing178.
In addition, although monoclonal
anti- IgE or anti- IL-4/IL-13 is
effective in AR179,180 and some of the
available biologics (or those in the
pipeline) for asthma may be suitable
for patients with severe, multimorbid
allergic conditions or stratified
patients with very severe AR, there
are only a few repurposing attempts
for asthma medications. One example
is montelukast, which, in Europe, is
indicated only for asthma with AR
multimorbidity as there was a request
from the payers to lower the price of
the asthma drug if the medication was
also approved for AR alone. In
addition, monoclonal antibodies to
allergens may be of interest in those
with AR caused by a single major
allergen driving the allergic reaction.
Patient stratification is needed to find a group of patients that
are unresponsive to the current medications and to obtain indirect
costs incurred by these patients. The estimated cost of AR in
Europe owing to presenteeism ranges from €25 billion to €50
billion6. A novel model of reimbursement of medications should
be developed with, for example, enterprises paying for a potential
new treatment with a precise cost-e ffectiveness analysis showing
potential benefits. Mobile health can have a role in the cost-e
ffectiveness analysis.

Improved treatment
Increasing safety while maintaining or even increasing efficacy
are the main goals of research for novel vaccine development and
improvement of treatment schemes in AIT. Perspectives in AIT
are well established181, and many new products are in
development182–185. However, the vast majority of previous
attempts failed because safety issues or lack of efficacy was
observed. Future directions for conventional AIT include use of
adjuvants, including vitamin D, Toll- like receptor ligand
agonists, biologics186 or probiotics187. Several attempts have been
made to increase tolerance and efficacy using molecular allergy
vaccines acting on B cells or T cells but none has produced
convincing results188.
Treatment of AR could also be improved by the use of shared
decision- making, a process whereby both the patient and the
physician contribute to the medical decision- making process. In
AR, data from mobile technology have revealed that patients are
not adherent to treatment and self- medicate using as many

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 Primer
1. of AR and could be aided by mobile health . 135,189,190
Authorities should be supported for the transformation
Bousquet, J.
et al. Value- added medicine can help address unmet patient of health and care towards integrated care with
needs and could improve treatment-a ssociated QOL. organizational health literacy for allergic
diseases135,173,194 A global allergy simple solution should
The global allergy solution provide the framework to digitally transform the
The delivery of cost-e ffective modern health care is prevention and control of allergic diseases in a cost-
effective manner. Mobile health could be used
challenging for the management of chronic diseases
optimize an accessible and affordable treatment in
and in particular for allergic diseases191, as
stratified and participatory patients with allergic
management, which is often dependent on specialist
diseases to provide change management195.
and supporting services, is becoming unaffordable.
Accordingly, innovative solutions often based on Published online xx xx xxxx
mobile health are required192,193.
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paper of the German ARIA GroupA in Disclaimer
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Allergology (GPA)F in cooperation with Nature Reviews Disease Primers thanks F.
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Author contributions
Introduction (G.W.C.); Epidemiology (J.M.A.);
Mechanisms/ pathophysiology (J.B., A.T. and
O.P.); Genetics (E.M.); Diagnosis, screening and
prevention (G.K.S.); Management (S.T.- S, S.B.-
A and C.B.); Quality of life (G.W.C. and I.B.);
Outlook (J.B.); Overview of Primer (J.B.).

Competing interests
J.B. reports personal fees from Chiesi,
Cipla, Hikma, Menarini, Mundipharma, Mylan,
Novartis, Purina, Sanofi-A ventis, Takeda,
Teva and Uriach and other fees from KYomed-
Innov and MASK- air outside the submitted
work. S.B.- A. reports grants from TEVA and
personal fees from AstraZeneca, Boehringer
Ingelheim, GlaxoSmithKline, Mylan, Sanofi
and TEVA outside the submitted work. C.B.
reports personal fees from ALK, Mylan,
GlaxoSmithKline, Sanofi, Novartis and
AstraZeneca. G.W.C. reports having received
research grants as well as being a lecturer
or having received advisory board fees from
A.Menarini, ALK- Abelló, Allergy
Therapeutics, AstraZeneca, Boehringer
Ingelheim, Chiesi Farmaceutici, Genentech,
Guidotti-M alesci, GlaxoSmithKline, Hal
Allergy, Mylan, Merck, Merck Sharp &
Dohme Mundipharma, Novartis, Regeneron,
Roche, Sanofi- Aventis, Sanofi- Genzyme,
Stallergenes- Greer, UCB Pharma, Uriach
Pharma, Valeas and Vibor-P harma. I.B
reports personal fees from Menarini,
Mundipharma, Novartis, GlaxoSmithKline,
Sanofi-G enzyme, AstraZeneca and Boehringer
Ingelheim outside the submitted work. E.M.
reports personal fees from AstraZeneca,
Chiesi, Novartis and Sanofi outside the
submitted work. O.P. reports research grants
from Inmunotek S.L. and Novartis and fees for
giving scientific lectures from Allergy
Therapeutics, Amgen, AstraZeneca, Diater,
GlaxoSmithKline S.A., Inmunotek S.L.,
Novartis, Sanofi- Genzyme and Stallergenes,
and has participated in advisory boards for
Novartis and Sanofi-G enzyme. G.K.S. reports
personal fees from ALK, Bayer,

24 | Article citation ID: (2020) 6:95 www.nature.com/nrdp

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