Pathophysiology of Allergic and Nonallergic Rhinitis
Betul Sin1 and Alkis Togias2
1
Ankara University, School of Medicine, Ankara, Turkey; and 2National Institute of Allergy and Infectious Diseases, Bethesda, Maryland
Allergic and nonallergic rhinitis affect approximately 30% of the U.S.
population. Although allergic rhinitis has a clear definition and its
pathophysiology has been thoroughly investigated, nonallergic
rhinitis remains poorly defined and understood. There is consensus,
however, that nonallergic rhinitis consists of a variety of heteroge-
neous conditions. In allergic rhinitis, the process of allergen sen-
sitization involves the participation of antigen-presenting cells,
T lymphocytes, and B lymphocytes and depends on environmental
allergen exposure. Sensitization results in the generation of allergen-
specific IgE that circulates in the peripheral blood and attaches itself
on the surface of all mast cells and basophils including those that
home to the nasal mucosa. Subsequent nasal exposure to allergen
activates these cells and, through the release of the classic mediators
of the allergic reaction, produces acute nasal symptoms. Over a short
period of time, these symptoms become indolent, whereas inflam-
matory and immune cell infiltrate, including eosinophils, basophils,
neutrophils, T lymphocytes, and monocytes, characterizes the late
stages of the allergic response. In parallel, and probably as a result of
the development of mucosal inflammation, the nose becomes
primed to allergen and reacts more vigorously to subsequent
allergen exposure but also becomes hyperresponsive to irritants
and to changes in atmospheric conditions. In nonallergic rhinitis,
several conditions may have been identified that are of interest for
further research and phenotyping. These include a group of patients
with apparent hyperresponsiveness of the C-fiber sensory nerves
with no inflammatory changes in the nasal mucosa and a group with
mucosal eosinophilia who may have allergic sensitization to com-
mon aeroallergens that is, however, manifested only in the nasal
mucosa.
Keywords: allergic sensitization; nasal symptoms; hyperresponsiveness;
nasal inflammation; rhinopathy
Rhinitis is a term that describes the acute or chronic intermittent
or persistent presence of one or more nasal symptoms including
runny nose (nasal discharge), itching, sneezing, and stuffy nose
due to nasal congestion. These symptoms can also reflect the
noses natural responses to daily exogenous or endogenous stimuli
and may occasionally be experienced by everybody. In the clinical
setting, the presence of rhinitis becomes evident by the fact that
individuals having bothersome symptoms seek medical attention.
In epidemiological research, however, there is some difficulty
distinguishing people with rhinitis from normal individuals, and
one recognizes that the boundaries between health and disease
are blurred.
Although the term rhinitis implies inflammation of the nasal
mucous membranes, some rhinitis disorders are not associated
with inflammation. These include some forms of nonallergic,
irritant-induced rhinitis as well as some forms of rhinitis of un-
known etiology. For these conditions, the term rhinopathy may
be more appropriate.
(Received in original form August 27, 2010; accepted in final form September 9, 2010)
Correspondence and requests for reprints should be addressed to Alkis Togias,
M.D., Asthma and Inflammation, AAIB/DAIT/NIAID/NIH, 6610 Rockledge Drive,
Room 6417, Bethesda, MD 20892. E-mail: togiasa@niaid.nih.gov
Proc Am Thorac Soc Vol 8. pp 106114, 2011
DOI: 10.1513/pats.201008-057RN
Internet address: www.atsjournals.org
PHENOTYPES OF RHINITIS
The classification of rhinitis can be based on etiology and/or
the temporal pattern of symptoms. Unfortunately, there is no
widely accepted, scientifically valid classification of rhinitis,
mostly because of poor phenotyping of those forms that do
not fall under the allergic and the infectious categories. A
common classification is shown in Table 1.
Chronic rhinosinusitis with or without polyps, two possibly
distinct conditions that have not been included in this classifi-
cation are hypertrophic inflammatory states affecting the para-
nasal sinuses and the nasal mucosa that can affect allergic or
nonallergic individuals (1).
Traditionally, allergic rhinitis has been classified as seasonal
or perennial based on temporal patterns of symptoms. The
guidelines produced by the international working group ARIA
(Allergic Rhinitis and its Impact on Asthma) have reclassified
allergic rhinitis on the basis of the severity and duration of
symptoms; this helps in the classification of rhinitis when the
temporal patterns are not clear or are not globally applicable, and
allows harmonization with the classification of asthma. On the
basis of ARIA, patients with rhinitis are placed into one of four
categories: (1) mild intermittent, (2) mild persistent, (3) moder-
ate/severe intermittent, and (4) moderate/severe persistent (2).
GENERATION OF NASAL SYMPTOMS
Nasal symptoms represent exaggerated defensive and homeo-
static functions of the nasal mucosa. The nasal mucosa is lined
by pseudostratified squamous ciliated epithelium interspersed
with goblet cells and serous, mucous, and seromucous glands
capable of producing large amounts of mucus that traps large
particles in inhaled air (including infectious agents) and con-
tributes to inhaled air humidification (3, 4). Excessive production
of mucus generates rhinorrhea (runny nose) or, if drainage oc-
curs toward the nasopharynx, postnasal drip. A prominent sys-
tem of subepithelial capillary beds, capacitance vessels (venous
sinusoids), and arteriovenous anastomoses allows for large
amounts of blood to pool in the nasal submucosa and rapidly
engorge it (5, 6). This provides a wide surface for heat and water
exchange and supports the homeostatic functions of the nose
(air conditioning of inhaled air) (7). However, excessive blood
pooling causes a significant increase in nasal airway resistance
and is perceived as nasal congestion, blockage, or a stuffy
nose.
Nasal seromucous glands and blood vessels are highly
regulated by parasympathetic and adrenergic innervation de-
riving from the vidian (branch of the facial nerve) and other
nerves (8). Parasympathetic stimulation through acetylcholine
and possibly through vasoactive intestinal peptide results in
mucus production. Adrenergic nerve stimulation through nor-
adrenaline and possibly through neuropeptide Y has a primarily
nasal decongestant effect by constricting blood vessels, reducing
blood flow, and emptying the venous sinusoids (9, 10). Thus,
vascular engorgement is largely the result of reduced sympa-
thetic tone. The parasympathetic and sympathetic control of the
nasal glandular apparatus and vasculature is influenced by
extrinsic and possibly intrinsic stimuli that result in activation
of sensory nerves and the generation of central neural reflexes.
Sin and Togias: Pathophysiology of Rhinitis
TABLE 1. CLASSIFICATION OF RHINITIS
I. Allergic (nonoccupational)
II. Infectious: Acute and chronic
a. Viral (common cold)
b. Bacterial
c. Fungal
III. Nonallergic, noninfectious rhinitis/rhinopathy
a. Idiopathic rhinitis (also termed vasomotor)
b. Nonallergic rhinitis with eosinophilia syndrome (NARES)
c. Estrogen-induced rhinitis (pregnancy, menstrual cycle related,
contraceptives)
d. Drug-induced rhinitis (topical a-adrenergic agonists, vasodilators)
e. Atrophic rhinitis (one form, ozena, is probably bacterial in origin)
f. Gustatory rhinitis (induced by spicy food)
g. Cold airinduced rhinitis (skiers nose)
h. Rhinitis due to anatomical abnormalities
i. Rhinitis associated with systemic conditions (vasculitis,
granulomatous diseases)
Nasal sensory nerve fibers are predominantly supplied by the
olfactory and trigeminal nerves. These fibers are mostly non-
myelinated C-fibers and myelinated Ad-fibers and can sense
noxious chemical and physical stimuli (11). In addition to the
generation of autonomic central reflexes, nasal sensory nerves
are the site of initiation of the sensation of nasal pruritus and of
sneezing, typical allergic rhinitis symptoms. Activation of C-
fibers is also believed to induce axon reflexes (antidromic
activation of collateral fibers), which result in the release of
a plethora of sensory neuropeptides in the nasal mucosa (e.g.,
the tachykinins substance P and neurokinin) with contribution
to tissue responses, including plasma leakage (12).
NASAL RESPONSIVENESS AND HYPERRESPONSIVENESS
Nasal responsiveness refers to the normal functional (not
immunologic) responses of the nasal mucosa to endogenous
or exogenous physical or chemical stimuli. An example of nasal
responsiveness is how the nose handles cold air. Cold air
induces significant water loss, especially under conditions of
hyperventilation. To preserve homeostasis and to avoid mucosal
dryness and damage, water is being constantly replenished by
107
passive transfer through the paracellular spaces of the nasal
airway epithelium. This process is not perceived as abnormal as
minimal rhinorrhea is produced (13).
The term nasal hyperresponsiveness describes the state of
exaggerated response to one or more endogenous or exogenous
stimuli. This may arise because of alterations in normal re-
sponsiveness as a result of pathological, or perhaps, genetic
factors affecting one or more structural or functional elements
of the nasal mucosa. Nasal mucosal inflammation represents
such a pathological factor. The example of the nasal response to
cold air can be used again to juxtapose normal responsiveness
and hyperresponsiveness: some individuals complain of exces-
sive symptoms when they are exposed to cold and windy
weather conditions; these can be either individuals with peren-
nial allergic rhinitis in whom allergic inflammation has up-
regulated the sensorineural apparatus (14) or people with some
defect that impairs homeostatic mechanisms for mucosal water
loss (15). In the first case, water loss from cold air breathing,
even if it results in only slight mucosal dryness, leads to
activation of sensory nerves and the induction of glandular
secretions and rhinorrhea through a reflex mechanism. In the
latter case, mucosal hypertonicity rapidly develops, leading to
sensorineural activation and, possibly, mast cell activation with
mediator release. In the first case, the stimulus is not excessive,
but the end-organ perceives it as such; in the latter case, the
stimulus becomes excessive because of inadequate homeostasis.
In both cases, exaggerated responses associated with nasal
symptoms are generated (Figure 1).
Hyperresponsiveness is not a single pathophysiological entity.
Theoretically, every functional element of the nasal mucosa that is
related to the generation of one or more symptoms may become
hyperresponsive. Therefore, to test for hyperresponsiveness with
the use of a provocative stimulus, one should be aware of the
characteristics of this stimulus. For example, methacholine can
only generate nasal secretions in the nose and, therefore, exagger-
ated secretory response to methacholine reflects glandular hyper-
responsiveness. On the other hand, histamine has multiple actions
including stimulation of nasal sensory nerves leading to sneezing,
itching, and reflex glandular activation, as well as direct effects on
the vasculature leading to increased nasal resistance (16).
Figure 1. Schematic diagram of hyperrespon-
siveness in comparison with normal nasal re-
sponsiveness. Normal responsiveness (left)
consists of defensive or homeostatic responses
to a stimulus or normal intensity and may or
may not produce mild nasal symptoms. Hyper-
responsiveness either manifests as an excessive
response to a stimulus of normal intensity,
which is secondary to alterations in the function
of nasal end-organs, or as a response to a stim-
ulus of normal intensity that, because of de-
fective homeostatic function, develops into an
excessive stimulus (e.g., cold air causing hyper-
tonicity; see text for details).
108
ALLERGIC RHINITIS
Allergic rhinitis is the most common form and a prototype of
IgE-mediated disease. The hallmark of allergic rhinitis is an IgE-
mediated, type 1 hypersensitivity reaction to an inciting inhaled
allergen. The result of this reaction is a cascade of immunolog-
ical and biochemical events leading to clinical expression of the
disease (Figure 2). Genetic predisposition and environmental
factors including allergen exposure and, perhaps, exposure to
environmental adjuvants or immune response suppressors prob-
ably exert important influences on the development of allergic
rhinitis.
Allergen Sensitization and IgE Synthesis and the Role of
Dendritic Cells and Lymphocytes
Allergens implicated in allergic rhinitis are in their vast majority
proteins that derive from airborne particles including pollens,
dust mite fecal particles, cockroach residue, and animal dander.
After inhalation of allergenic particles, allergens are eluted in
nasal mucus and subsequently diffuse into nasal tissues.
The sensitization process is initiated in nasal tissues when
antigen-presenting cells (APCs), which are primarily dendritic
cells, engulf allergens, break them into allergenic (antigenic)
peptides, and migrate to lymph nodes, where they present these
peptides to naive (never exposed to antigen) yet epitope-specific
CD41 T lymphocytes (T cells) (17, 18). CD41 lymphocyte acti-
vation requires the interaction of specific T-cell receptors on the
surface of T cells with allergen peptideMHC class II complexes
on the APCs and the ligation of costimulatory receptors of the
CD28 family on T cells by B7 family members of costimulatory
molecules (CD80 and CD86) on APCs (19). Naive helper T cells
are known as Th0 cells, because they produce a pattern of
cytokines that spans both the Th1 and Th2 phenotypes. If given
the proper stimulus, naive helper T cells can differentiate into the
biased Th1 or Th2 subset. In the case of allergy, the Th2 subset
plays a central role (20). In the development of Th2 cells, IL-4 is
a required stimulus.
Dendritic cells (DCs) form a network that is localized within
the epithelium and submucosa of the entire respiratory mucosa,
including the nasal mucosa (21). The number of both DCs
and T cells at the surface of the nasal epithelium is increased
in rhinitis. For example, increased numbers of CD1a1 and
CD11c1 DCs in the epithelium and lamina propria of the nasal
mucosa clustered with CD41 T lymphocytes and eosinophils
have been found in this disease (18). In addition to presenting
antigen, DCs can polarize naive T cells into either Th1 or Th2
cells according to their own phenotype and with signals received
from processed antigens and from the tissue microenvironment
during antigen presentation. For example, plasmacytoid DCs
matured by IL-3 and CD40 ligand engagement promote T cells
toward a Th2 phenotype, whereas cells that mature through
contact with a virus promote a Th1 phenotype (22). Other
signals affecting DCs and their influence on Th2 polarization of
T cells include prostaglandin E2 and thymic stromal lympho-
poietin released from epithelial cells, which switch the matura-
tion of myeloid DCs into Th2-promoting DCs, and lead to the
expression of OX40 ligand and inducible costimulatory ligand
on DCs (23).
A distinct subtype of T cells, the so-called regulatory T cells
(Tregs), suppress immune responses (both Th2 and Th1)
through the secretion of inhibitory cytokines and cell surface
molecules including IL-10 and transforming growth factor-b,
cytotoxic T-lymphocyte antigen-4 (CTLA-4), and programmed
death-1 (PD-1). Tregs can also inhibit effector T cells via
a direct cellcell contact mechanism to induce apoptosis. In
addition, Tregs crosstalk with APCs to suppress T-cell activa-
PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL 8 2011
tion. Tregs are categorized as natural or adaptive (inducible,
Tr1). The former are characterized by the expression of high
levels of CD25 on their surface and by the transcription factor
forkhead box P3 (FoxP3) (24).
Both nonallergic and allergic individuals retain allergen-
specific IL-4producing effector T cells, IL-10producing Tr1
cells, and CD251 Tregs, but in different proportions. Thus, the
balance between Th2 and certain Treg populations may decide
whether clinical allergy will develop (25, 26). There is evidence
that CD251 regulatory T cells are defective in patients with
allergic rhinitis. For example, peripheral blood CD41CD251
cells have reduced ability to suppress T-cell proliferation during
the pollen season in patients with birch-induced allergic rhinitis
(27), and FoxP3 gene expression is reduced in nasal secretions
from patients with allergic rhinitis (28).
IgE, like all immunoglobulins, is synthesized by B lympho-
cytes (B cells) under the regulation of cytokines derived from
Th2 lymphocytes. Two signals are required. IL-4 or IL-13 pro-
vides the first essential signal that drives B cells to IgE prod-
uction by inducing e-germline gene transcription. In the case of
IgE-expressing memory B cells, these cytokines induce clonal
expansion. The second signal is a costimulatory interaction
between CD40 ligand on the T-cell surface and CD40 on the
B-cell surface. This signal promotes B-cell activation and switch
recombination for the production of IgE (29).
Once produced by B cells, IgE antibodies attach on tetra-
meric (abg2) high-affinity receptors (FceRI) on the surface of
mast cells and basophils, rendering them sensitized (30). IgE
can also bind to trimeric (ag2) FceRI on the surface of various
cells including dendritic cells (31), as well as on low-affinity IgE
receptors (CD23, FceRII) that are present on monocyte-
macrophages and on B lymphocytes (32, 33). However, it is
the IgEFceRI interaction on mast cells and basophils that
induces the classic allergic reaction at the cellular level. The
functions of the trimeric FceRI and of FceRII are not fully
elucidated. On the surface of DCs, FceRI binds to IgE and this
seems to facilitate allergen uptake by the DCs for processing
and presentation (31).
Allergic Reactions and Inflammatory Responses in the Nose
In presenting and discussing the inflammatory consequences of
allergic reactions in the nose and the role of the many biological
products, many assumptions are made. Information is obtained
from snapshot imaging of the nasal mucosa, from animal
models, and from basic knowledge about the in vitro activity
of various mediators, chemokines, cytokines, and so on. Yet,
little confirmatory information is available on the precise role of
these biological products in the in vivo setting, in allergic
rhinitis, as pharmacological or other inhibitory/blocking ap-
proaches do not exist or have failed to produce significant
clinical results.
The allergic reaction in the nose has early and late compo-
nents (early and late phases), both of which contribute to the
clinical presentation of allergic rhinitis. The early phase involves
the acute activation of allergy effector cells through IgE
allergen interaction and produces the entire spectrum of allergic
rhinitis symptoms. The late phase is characterized by the
recruitment and activation of inflammatory cells and the de-
velopment of nasal hyperresponsiveness with more indolent
symptoms.
Within minutes of contact of sensitized individuals with
allergens, the IgEallergen interaction takes place, leading to
mast cell and basophil degranulation and the release of
preformed mediators such as histamine and tryptase, and the
de novo generation of other mediators, including cysteinyl leu-
kotrienes (LTC4, LTD4, LTE4) and prostaglandins (primarily
Sin and Togias: Pathophysiology of Rhinitis 109

PGD2) (34, 35). Mast cells and basophils do not produce exactly nerve endings and causes sneezing, pruritus, and reflex secre-
the same array of mediators; for example, PGD2 is almost tory responses, but it also interacts with H1 and H2 receptors on
exclusively a mast cell product. The targets of these mediators mucosal blood vessels, leading to vascular engorgement (nasal
vary; for example, histamine activates H1 receptors on sensory congestion) and plasma leakage (36). Sulfidopeptide leukotri-
110 PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL 8 2011

b
Figure 2. The biology of allergic sensitization and of the allergic reaction in the nasal mucosa leading to the generation of symptoms and to
functional alterations such as nasal hyperresponsiveness. See text for details. Ach/VIP 5 acetylcholine/vasoactive intestinal peptide; CGRP 5
calcitonin gene-related peptide; ECP 5 eosinophil cationic protein; EPO 5 eosinophil peroxidase; FceR1 5 high-affinity Fc receptor for IgE; GM-
CSF 5 granulocyte-macrophage colony-stimulating factor; ICAM-1 5 intercellular adhesion molecule-1; LFA-1 5 lymphocyte functionassociated
antigen-1; MBP 5 major basic protein; MCP-1, -3, -4 5 monocyte chemotactic protein-1, -3, -4, respectively; MHC 5 major histocompatibility
complex; MIP-1a 5 macrophage inflammatory protein-1a; NKA 5 neurokinin A; PAF 5 platelet-activating factor; RANTES 5 regulated on
activation, normal T-cell expressed and secreted; sLT 5 sulfidoleukotriene; TARC 5 thymus and activation-regulated chemokine; TGF-b 5
transforming growth factor-b; Th1, Th2 5 helper T type 1 and type 2 cells, respectively; TNF-a 5 tumor necrosis factor-a; Treg 5 regulatory T cell;
TxA2 5 thromboxane A2; VCAM-1 5 vascular cell adhesion molecule-1; VLA-4 5 very late antigen-4.

enes, on the other hand, act directly on CysLT1 and CysLT2
receptors on blood vessels and glands, and can induce nasal
congestion and, to a lesser extent, mucus secretion (37). Ad-
ditional substances such as proteases (tryptase) and cytokines
(tumor necrosis factor-a) are released at this early stage of the
allergic reaction, but their role in the generation of acute
symptoms is unclear. Other mediators are produced through
indirect pathways; for example, bradykinin is generated when
kininogen leaks into the tissue from the peripheral circulation
and is cleaved by tissue kallikrein that is produced by serous
glands (38, 39).
The symptoms produced immediately after exposure to
allergen reach their peak within a few minutes and tend to
dissipate within 1 hour. Some individuals continue experiencing
symptoms for several hours; others enter a quiescent phase and
their symptoms recrudesce after several hours (40). The nature
of the late symptoms is somewhat different than that of the
acute symptoms in that sneezing and pruritus are not prom-
inent, whereas nasal congestion is. Overall, these late symptoms
occur in approximately 50% of people and, because their
relative indolence resembles the clinical presentation of chronic
rhinitis, the late phase is of particular scientific interest as
a model of chronic allergic disease.
Allergen exposure also results in nasal mucosal inflammation
characterized by the influx and activation of a variety of in-
flammatory cells and by alterations in nasal physiology, namely
priming and hyperresponsiveness. Cells that migrate into the
nasal mucosa include T cells, eosinophils, basophils, neutro-
phils, and monocytes (4143). Also, mast cells are increased in
number in the submucosa and infiltrate the epithelium after
allergen exposure or during pollen season (44, 45). In biopsies
obtained hours after nasal allergen provocation on individuals
with allergic rhinitis, T cells predominate in the tissue infiltrate.
In nasal secretions, the total number of leukocytes increases by
many fold over several hours and the majority of leukocytes are
neutrophils and eosinophils (42, 46). It is likely that cell
migration is due to the chemokines and cytokines released by
the primary effector cells, mast cells, and basophils, acutely and
over several hours after allergen exposure. Interestingly, some
of the acutely released mediators may have cytokine-like
effects. For example, histamine regulates dendritic cells and T
cells via its four distinct histamine receptors, H1H4 (47), and
the sulfidopeptide leukotrienes can attract and activate eosin-
ophils. A reduction in eosinophil accumulation in nasal tissues is
observed with CysLT1 receptor antagonists (48). Some of the
products of the acute allergic reaction affect the vascular
endothelium and up-regulate adhesion molecules, some of which
have relative cellular specificity (e.g., vascular cell adhesion
molecule-1 expression is important in the recruitment of eosin-
ophils as it interacts with very late antigen-4 on the eosinophil
surface [49]). Other effector cell products can activate structural
cells in the nasal mucosa, such as epithelial cells and fibroblasts,
to release additional chemokines (e.g., eotaxin, RANTES [reg-
ulated on activation normal T cell expressed and secreted], and
thymus and activation regulated chemokine [TARC]) that facil-
itate cell influx from the peripheral blood (50). Furthermore, the
cells that arrive at the site of allergic inflammation become
activated in situ and release additional cytokines and chemokines,
resulting in the perpetuation of inflammation.
Th2 cytokines probably play a central role in the develop-
ment of mucosal inflammation after allergen exposure. For ex-
ample, IL-5 is central in the recruitment of eosinophils (51) and
IL-4 is important in the recruitment of both eosinophils and
basophils (52). IL-13, which derives from basophils, mast cells,
and Th2 cells, induces the expression of several chemokines that
are thought to selectively recruit Th2 cells, namely TARC and
monocyte-derived chemokine (53). IL-13 can also recruit den-
dritic cells to the site of allergen exposure via the induction of
matrix metalloproteinase-9 and TARC. Most importantly, as
discussed earlier, Th2 cytokines deriving from T cells and other
cells perpetuate allergy by promoting continuous IgE produc-
tion by B cells.
The role of the eosinophil needs to be emphasized. These
cells arrive rapidly in the nasal mucosa after allergen exposure.
Eosinophils produce several important cytokines such as IL-5,
which has strong chemoattractant properties and acts in an
autocrine fashion to promote eosinophil survival and activation
(54, 55). Most importantly, eosinophils serve as a major source
of lipid mediators such as LTC4, thromboxane A2, and platelet-
activating factor (56). The influx of activated eosinophils results
in the release of toxic granule products, particularly major basic
protein (MBP), eosinophil cationic protein (ECP), and eosino-
phil peroxidase (EPO), which can damage nasal epithelial cells
(57). Even at low concentrations, MBP can reduce ciliary beat
frequency in vitro. MBP has also been shown in animals to alter
neuronal function by interfering with muscarinic (M2) recep-
tors, allowing increased release of acetylcholine at neuronal
junctions or endplates (58). These effects may contribute to the
inflammatory features of the late-phase response and to nasal
hyperresponsiveness.
In asthma, it is believed that chronic inflammation leads to
airway remodeling, but the concept of remodeling in allergic
rhinitis is controversial as studies have reported conflicting
findings on epithelial damage or thickening of the reticular
basement membrane (59). Growth factors that have been im-
plicated in lower airways remodeling have also been detected in
the nasal mucosa of individuals with allergic rhinitis. It appears
that alterations of mucosal structural elements are far less
extensive in the nasal mucosa compared with the lower airways,
even though the nasal mucosa is more exposed to allergens and
environmental toxins. One could speculate that the nasal
mucosa may have a much higher capacity for epithelial re-
generation and repair, perhaps because of its different embry-
ological origin (60).
Functional Consequences of Allergic Inflammation: Priming
to Allergen and Nasal Hyperresponsiveness
Priming to allergen refers to the phenomenon of increased nasal
responsiveness to allergen with repeated allergen exposure.
One can argue that priming is a form of nasal hyperresponsive-
Sin and Togias: Pathophysiology of Rhinitis
ness specific to the allergic reaction. Priming can be docu-
mented on natural allergen exposure. Connell was the first to
describe the priming effect in the nose after allowing his study which element(s) of inflammation result(s) in end-organ hyper-
volunteers to spend time outdoors on consecutive days in the
middle of the pollen season (61). Also, Norman demonstrated
that nasal symptoms are higher at the end of the pollen season,
compared with the beginning, despite equal levels of ragweed
pollen in the air (62). In the clinical research setting, where
a high dose of allergen is administered as a challenge over a short
period of time, priming can be demonstrated within a few hours
(63, 64).
The mechanism of priming is believed to involve several
factors. First, increased numbers of mast cells in the epithelium
and the influx of basophils provide many more targets for IgE
allergen interaction and mediator release. There is more
evidence supporting the role of basophils in this mechanism
because increased levels of histamine, but not PGD2, a mast cell
marker, are found in nasal fluids after an allergen challenge that
shows the priming effect (64). Second, the inflammation that
develops after allergen exposure can result in increased perme-
ability of the epithelium and easier allergen penetration to
IgE-bearing cells. Third, again because of inflammation, the
responses of the nasal end-organs may become exaggerated; this
mechanism would be the same as that of nonspecific nasal
hyperresponsiveness (see below). Nasal allergen priming is
ablated by oral or topical glucocorticosteroid treatment, pro-
viding evidence for the role of inflammation in this phenome-
non (64, 65).
Patients with allergic rhinitis, particularly those with peren-
nial disease, experience symptoms on exposure to several
nonallergic stimuli such as smoke, strong odors, and other
irritants. Because these clinical sensitivities are similar to those
reported by patients with nonallergic rhinitis, some clinicians
consider this a distinct clinical phenotype, mixed rhinitis endocrine causes need to be ruled out. Their nasal symptoms
(allergic and nonallergic) (66). However, the prevalence of
these clinical sensitivities in individuals with perennial allergic
rhinitis is so high that it is cogent to consider the nonallergic
symptom triggers a phenotypic component of allergic disease.
Furthermore, there is enough experimental evidence in allergic
rhinitis for increased responsiveness of the nasal mucosa to
a variety of stimuli that are not allergens and, even more im-
portantly, this increased responsiveness can be induced by
allergen challenge (67).
As discussed earlier, different stimuli act on different end-
organs (glands, blood vessels, nerves) and some stimuli act on
multiple end-organs simultaneously. Hyperresponsiveness may
exist in one end-organ but not another. For example, hyper-
osmolar saline induces a secretory response, which is believed
to be secondary to C-fiber activation. In perennial allergic
rhinitis, the nasal secretory response to hyperosmolar saline
was found to be augmented compared with healthy control
subjects, but a question was raised concerning whether this
represents hyperresponsiveness of C-fibers or of the glandular
apparatus (68). However, in the same study it was shown that
the secretory response to methacholine, which stimulates only
the glands, was not different in the subjects with perennial
allergic rhinitis compared with the control subjects; this was
a convincing demonstration that the sensorineural apparatus is
in a hyperresponsive state in allergic rhinitis. Other stimuli
demonstrating hyperresponsiveness in perennial or seasonal
allergic rhinitis include histamine, bradykinin, capsaicin, and
cold air. Allergen challenge has been shown to induce hyper-
responsiveness to histamine and this phenomenon can be
blocked by topical steroid pretreatment (67).
The pathways leading to end-organ hyperresponsiveness in
allergic rhinitis are not understood. Because of the inhibitory
111
effect of glucocorticosteroids, it is believed that allergic in-
flammation is the culprit; the question remains, however, as to
responsiveness. In the case of sensorineural hyperresponsive-
ness, which is the only well-documented form, it has been
postulated that nerve growth factor (NGF) or other neuro-
trophins may play a role. NGF is abundant inside nasal
glandular epithelial cells and in the majority of eosinophils
(69). Interestingly, NGF is released in nasal secretions on ex-
perimental allergen challenge, but not on challenge with
histamine, suggesting a specific release pathway (70). The
biological effects of NGF include changes in ongoing neuro-
terminal function, as well as C-fiber sprouting. These effects
could render nociceptor nerves more responsive due to either
lower firing thresholds or to increased numbers of C-fibers.
NONALLERGIC RHINITIS
As discussed earlier, nonallergic rhinitis is a broad term en-
compassing a number of nasal conditions, the only common
denominator of which is the lack of systemic allergic sensitization
(negative skin testing and/or lack of serum-specific IgE) to the
aeroallergens implicated in allergic rhinitis (Table 1). Because
of such definition, these conditions are heterogeneous and of
widely diverse pathophysiology. Moreover, the lack of agree-
ment on clinical phenotypes and the lack of strict diagnostic
criteria have made most of these conditions difficult to study.
The most common form of nonallergic rhinitis is the
idiopathic condition also known as vasomotor rhinitis. Individ-
uals categorized as such are those who not only lack conven-
tional evidence of allergic disease, but are also devoid of any
evidence of sinusitis/nasal polyposis, anatomic abnormalities, or
a known infection. In addition, pharmacological (iatrogenic) or
are chronic, without a seasonal pattern (although cases of
seasonal symptomatology have been described), and are more
likely to include nasal congestion and clear rhinorrhea and less
likely sneezing and pruritus. Patients with idiopathic/vasomotor
rhinitis report a family history of rhinitis less frequently than
patients with allergic disease. Clinical sensitivity to irritants and
to changes in atmospheric conditions is common, but it is not
known whether it is more common than in patients with
perennial allergic rhinitis. These patients are characterized by
relatively modest responses to nasal corticosteroids (71). Sur-
prisingly, the topical antihistamine azelastine has also shown
moderate effectiveness (72), raising some interesting hypothe-
ses as to the pathophysiology of this condition. Another im-
portant observation is that up to one-quarter of these patients, if
reevaluated at a later stage, may show evidence of allergic
sensitization and may be reclassified into the allergic rhinitis
category (73). Although adequate research in the pathophysi-
ology of idiopathic rhinitis is lacking, some observations raise
the possibility that this condition may indeed encompass
a number of distinct entities. In the following sections, we
present information about three conditions with potentially
distinct pathophysiology that require further exploration for
nosological confirmation and more in-depth research to de-
termine mechanisms and optimal treatment.
Nonallergic, Neurogenic Rhinopathy?
A series of studies conducted primarily in the Netherlands led
to the hypothesis that, in a subgroup of patients with nonallergic
rhinitis, neural function abnormalities may be responsible for
their symptoms. The Dutch investigators have made the fol-
lowing observations: (1) the nasal mucosa of such patients is
indistinguishable from that of healthy control subjects lacking
112
any evidence of inflammation or of a particular cell infiltrate
(74); (2) nasal responsiveness to histamine, which is highly up-
regulated in perennial allergic rhinitis, is normal in this group of
patients with nonallergic disease (75); (3) in contrast to hista-
mine, these patients appear to be hyperresponsive to cold air
provocation in the nose (75); (4) repetitive nasal application
of capsaicin, which is meant to defunctionalize nasal nociceptor
C-fibers, leads to prolonged (up to 6 mo) improvement in symp-
tomatology, an observation that has been confirmed by several
other European research teams (7678); and (5) improvement
of this condition by capsaicin is accompanied by reduction in
nasal responsiveness to cold air (76). Taken together, these
observations suggest a sensorineural dysregulation in which
capsaicin-sensitive nerve fibers play a central role. The sensi-
tivity to cold air can be explained by the fact that the primary
stimulus in a cold air challenge may be hyperosmolarity and
that the capsaicin receptor TRPV1 on nerve fibers is also sen-
sitive to hypertonicity. Stimulation of nasal secretory responses
by hypertonic saline can be reduced by capsaicin pretreatment
(68). The lack of mucosal inflammation justifies the term
rhinopathy as opposed to rhinitis. 5. Watanabe K, Watanabe I. The ultrastructural characteristics of the
Local Allergic Rhinitis?
British researchers and, more recently, researchers from Spain
have published a series of interesting observations raising the
hypothesis that another subgroup of patients with idiopathic
rhinitis suffers from a form of localized allergic disease. In
contrast to the neurogenic rhinopathy group, these patients
show evidence of inflammation in their nasal mucosa, primarily
eosinophilia and, perhaps, increased mast cell numbers (79). In
fact, it may not be surprising if these are the same patients as
those that have been classified for 3 decades as having NARES
(nonallergic rhinitis with eosinophilia syndrome) (80) (Table 1).
Despite having negative skin tests and no detectable serum-
specific IgE antibodies, these individuals develop nasal symp-
toms on nasal provocation with various allergens (including
house dust mite, grass, and olive pollen) (81, 82). In addition to
the symptoms, inflammatory mediators indicative of mast cell
activation (tryptase) and eosinophil activation (ECP) are re-
leased in nasal secretions at early and late phases after allergen
challenge, respectively (82, 83). In the absence of experimental
allergen exposure, nasal secretions of some of these patients
contain specific IgE antibodies against the allergens to which
they react locally. What has not been demonstrated yet is the
presence of IgE-producing B cells in the nasal mucosa of these
individuals and the ability of nasal mucosal explants to produce
IgE ex vivo, on allergen exposure, as has been demonstrated in
patients with allergic rhinitis (84).
Dysautonomic Rhinopathy?
Even less characterized, compared with the groups described
previously, are patients with nonallergic rhinitis who present
evidence of systemic autonomic dysfunction. Theoretically, ex-
cessive parasympathetic tone will produce rhinorrhea, whereas
suppressed sympathetic activity can result in nasal congestion.
A few studies have provided data indicating abnormal re-
sponses to autonomic tests in patients with nonallergic rhinitis.
For example, heart rate variability according to various stan-
dard parameters was found to be higher in patients with
idiopathic (vasomotor) rhinitis, without nasal eosinophilia,
compared with nonrhinitic control subjects, indicative of in-
creased parasympathetic activity (85). More generalized dysau-
tonomia including both the parasympathetic and sympathetic
nervous systems has been suggested by other studies (8688). It
remains to be seen whether dysautonomia characterizes a spe-
cific group of patients with idiopathic, nonallergic rhinitis and, if
PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL 8 2011
so, what the clinical attributes of these patients are. Furthermore,
it remains to be seen whether dysautonomia can be a predictor
of a therapeutic response to particular forms of treatment such
as nasal ipratropium, which is indicated for patients with
difficult-to-control rhinorrhea as their primary complaint.
Author Disclosure: B.S. does not have a financial relationship with a commercial
entity that has an interest in the subject of this manuscript. A.T. is employed by
the National Institutes of Health.
References
1. Tan BK, Schleimer RP, Kern RC. Perspectives on the etiology of
chronic rhinosinusitis. Curr Opin Otolaryngol Head Neck Surg 2010;
18:2126.
2. Bousquet J, Van Cauwenberge P, Khaltaev N. Allergic rhinitis and its
impact on asthma. J Allergy Clin Immunol 2001;108:S147S334.
3. Tos M. Goblet cells and glands in the nose and paranasal sinuses. In:
Proctor DF, Andersen IB, editors. The nose: upper airway physiology
and the atmospheric environment. Amsterdam: Elsevier Biomedical
Press; 1982. pp. 99144.
4. Kaliner M, Marom Z, Patow C, Shelhamer J. Human respiratory mucus.
J Allergy Clin Immunol 1984;73:318323.
capillary walls in human nasal mucosa. Rhinology 1980;18:183195.
6. Burnham HH. An anatomical investigation of blood vessels of the lateral
nasal wall and their relation to turbinates and sinuses. J Laryngol Otol
1935;50:569593.
7. Hanna L, Scherer P. Regional control of local airway heat and water
vapor losses. J Appl Physiol 1986;61:624632.
8. Cauna N, Cauna D, Hinderer K. Innervation of human nasal glands.
J Neurocytol 1972;I:4960.
9. Figueroa JM, Mansilla E, Suburo AM. Innervation of nasal turbinate
blood vessels in rhinitic and nonrhinitic children. Am J Respir Crit
Care Med 1998;157:19591966.
10. Baraniuk JN, Silver PB, Kaliner MA, Barnes PJ. Neuropeptide Y is
a vasoconstrictor in human nasal mucosa. J Appl Physiol 1992;73:
18671872.
11. Sarin S, Undem B, Sanico A, Togias A. The role of the nervous system
in rhinitis. J Allergy Clin Immunol 2006;118:9991014.
12. Barnes P, Baraniuk J, Belvisi M. Neuropeptides in the respiratory tract.
Am Rev Respir Dis 1991;144:13911399.
13. Togias A, Naclerio RM. Cold airinduced rhinitis. Clin Allergy Immunol
2007;19:267281.
14. Hanes L, Issa E, Proud D, Togias A. Stronger nasal responsiveness to
cold air in individuals with rhinitis and asthma, compared with rhinitis
alone. Clin Exp Allergy 2005;36:2631.
15. Cruz AA, Naclerio RM, Proud D, Togias A. Epithelial shedding is
associated with nasal reactions to cold, dry air. J Allergy Clin
Immunol 2006;117:13511358.
16. Nathan R, Eccles R, Howarth P, Steinsvag S, Togias A. Objective
monitoring of nasal patency and nasal physiology in rhinitis. J Allergy
Clin Immunol 2005;115:S442S459.
17. Godthelp T, Fokkens WJ, Kleinjan A, Holm AF, Mulder PG, Prens EP,
Rijntes E. Antigen presenting cells in the nasal mucosa of patients
with allergic rhinitis during allergen provocation. Clin Exp Allergy
1996;26:677688.
18. KleinJan A, Willart M, van Rijt LS, Braunstahl GJ, Leman K, Jung S,
Hoogsteden HC, Lambrecht BN. An essential role for dendritic cells
in human and experimental allergic rhinitis. J Allergy Clin Immunol
2006;118:11171125.
19. Bugeon L, Dallman M. Costimulation of T cells. Am J Respir Crit Care
Med 2000;162:S164S168.
20. Georas S, Guo J, Fanis U, Casolaro V. T-helper cell type-2 regulation in
allergic disease. Eur Respir J 2005;26:11191137.
21. Hartmann E, Graefe H, Hopert A, Pries R, Rothenfusser S, Poeck H,
Mack B, Endres S, Hartmann G, Wollenberg B. Analysis of plasma-
cytoid and myeloid dendritic cells in nasal epithelium. Clin Vaccine
Immunol 2006;13:12781286.
22. Liu YJ. IPC: professional type 1 interferon-producing cells and plasma-
cytoid dendritic cell precursors. Annu Rev Immunol 2005;23:275306.
23. Bharadwaj AS, Bewtra AK, Agrawal DK. Dendritic cells in allergic
airway inflammation. Can J Physiol Pharmacol 2007;85:686699.
24. Maloy K, Powrie F. Regulatory T cells in the control of immune
pathology. Nat Immunol 2001;2:816822.
Sin and Togias: Pathophysiology of Rhinitis
25. Akdis M, Verhagen J, Taylor A, Karamloo F, Karagiannidis C, Crameri
R, Thunberg S, Deniz G, Valenta R, Fiebig H, et al. Immune
responses in healthy and allergic individuals are characterized by
a fine balance between allergen-specific T regulatory 1 and T helper
2 cells. J Exp Med 2004;199:15671575.
26. Maggi L, Santarlasci V, Liotta F, Frosali F, Angeli R, Cosmi L, Maggi
E, Romagnani S, Annunziato F. Demonstration of circulating
allergen-specific CD41CD25highFoxP31 T-regulatory cells in both
nonatopic and atopic individuals. J Allergy Clin Immunol 2007;120:
429436.
27. Grindebacke H, Wing K, Andersson AC, Suri-Payer E, Rak S, Rudin
A. Defective suppression of Th2 cytokines by CD4CD25 regulatory
T cells in birch allergics during birch pollen season. Clin Exp Allergy
2004;34:13641372.
28. Lee SM, Gao B, Dahl M, Calhoun K, Fang D. Decreased FoxP3 gene
expression in the nasal secretions from patients with allergic rhinitis.
Otolaryngol Head Neck Surg 2009;140:197201.
29. Geha R. Regulation of IgE synthesis in humans. J Allergy Clin Immunol
1992;90:143150.
30. Henry AJ, Cook JP, McDonnell JM, Mackay GA, Shi J, Sutton BJ,
Gould HJ. Participation of the N-terminal region of Ce3 in the
binding of human IgE to its high-affinity receptor FceRI. Biochemistry
1997;36:1556815578.
31. Novak N, Kraft S, Bieber T. Unraveling the mission of FceRI on
antigen-presenting cells. J Allergy Clin Immunol 2003;111:3844.
32. Tsicopoulos A, Joseph M. The role of CD23 in allergic disease. Clin Exp
Allergy 2000;30:602605.
33. Horiguchi S, Okamoto Y, Chazono H, Sakurai D, Kobayashi K.
Expression of membrane-bound CD23 in nasal mucosal B cells from
patients with perennial allergic rhinitis. Ann Allergy Asthma Immunol
2005;94:286291.
34. Naclerio R, Meier H, Kagey-Sobotka A, Adkinson N, Meyers D,
Norman P, Lichtenstein L. Mediator release after nasal airway
challenge with allergen. Am Rev Respir Dis 1983;128:597602.
35. Creticos P, Peters S, Adkinson N, Naclerio R, Hayes E, Norman P,
Lichtenstein L. Peptide leukotriene release after antigen challenge in
patients sensitive to ragweed. N Engl J Med 1984;310:16261630.
36. Togias A. H1-receptors: localization and role in airway physiology and in
immune functions. J Allergy Clin Immunol 2003;112:S60S68.
37. Peters-Golden M, Gleason MM, Togias A. Cysteinyl leukotrienes: multi-
functional mediators in allergic rhinitis. Clin Exp Allergy 2006;36:
689703.
38. Baumgarten C, Nichols R, Naclerio R, Proud D. Concentrations of
glandular kallikrein in human nasal secretions increase during ex-
perimentally induced allergic rhinitis. J Immunol 1986;137:13231328.
39. Proud D, Togias A, Naclerio R, Crush S, Norman P, Lichtenstein L.
Kinins are generated in vivo following nasal airway challenge of
allergic individuals with allergen. J Clin Invest 1983;72:16781685.
40. Naclerio R, Proud D, Togias A, Adkinson N, Meyers D, Kagey-Sobotka
A, Plaut M, Norman P, Lichtenstein L. Inflammatory mediators in
late antigeninduced rhinitis. N Engl J Med 1985;313:6570.
41. Varney V, Jacobson M, Sudderick R, Robinson D, Irani A, Schwartz L,
Mackay I, Kay A, Durham S. Immunohistology of the nasal mucosa
following allergen-induced rhinitis. Am Rev Respir Dis 1992;146:
170176.
42. Lim M, Taylor R, Naclerio R. The histology of allergic rhinitis and its
comparison to cellular changes in nasal lavages. Am J Respir Crit Care
Med 1995;151:136144.
43. Bascom R, Wachs M, Naclerio R, Pipkorn U, Galli S, Lichtenstein L.
Basophil influx occurs after nasal antigen challenge: effects of topical
corticosteroid pretreatment. J Allergy Clin Immunol 1988;81:580589.
44. Bentley A, Jacobson M, Cumberworth V, Barkans J, Moqbel R, Schwartz
L, Irani A, Kay A, Durham S. Immunohistology of the nasal mucosa
in seasonal allergic rhinitis: increases in activated eosinophils and
epithelial mast cells. J Allergy Clin Immunol 1992;89:877883.
45. Fokkens W, Godthelp T, Holm A, Blom H, Mulder P, Vrooms T,
Rijntjes E. Dynamics of mast cells in the nasal mucosa of patients
with allergic rhinitis and non-allergic controls: a biopsy study. Clin
Exp Allergy 1992;22:701710.
46. Bascom R, Pipkorn U, Lichtenstein L, Naclerio R. The influx of
inflammatory cells into nasal washings during the late response to
antigen challenge: effect of steroid pretreatment. Am Rev Respir Dis
1988;138:406412.
47. Jutel M, Akdis M, Akdis CA. Histamine, histamine receptors and their
role in immune pathology. Clin Exp Allergy 2009;39:17861800.
113
48. Ueda T, Takeno S, Furukido K, Hirakawa K, Yajin K. Leukotriene
receptor antagonist pranlukast suppresses eosinophil infiltration and
cytokine production in human nasal mucosa of perennial allergic
rhinitis. Ann Otol Rhinol Laryngol 2003;112:955961.
49. Dobrina A, Menegazzi R, Carlos T, Nardon E, Cramer R, Zacchi T,
Harlan J, Patriarca P. Mechanisms of eosinophil adherence to
cultured vascular endothelial cells: eosinophils bind to the cytokine-
induced endothelial ligand vascular cell adhesion molecule-1 via the
very late activation antigen-4 integrin receptor. J Clin Invest 1991;88:
2026.
50. Plewako H, Holmberg K, Oancea I, Gotlib T, Samolinski B, Rak S. A
follow-up study of immunotherapy-treated birch-allergic patients:
effect on the expression of chemokines in the nasal mucosa. Clin
Exp Allergy 2008;38:11241131.
51. Flood-Page PT, Menzies-Gow AN, Kay B, Robinson D. Eosinophils
role remains uncertain as anti-interleukin-5 only partially depletes
numbers in asthmatic airway. Am J Respir Crit Care Med 2003;167:
199204.
52. Schleimer R, Sterbinsky S, Kaiser J, Bickel C, Klunk D, Tomioka
K, Newman W, Luscinskas F, Gimbrone M, McIntyre B, et al.
Interleukin-4 induces adherence of human eosinophils and basophils
but not neutrophils to endothelium: association with expression of
VCAM-1. J Immunol 1992;148:10861092.
53. Terada N, Nomura T, Kim W, Otsuka Y, Takahashi R, Kishi H,
Yamashita T, Sugawara N, Fukuda S, Ikeda-Ito T, et al. Expression
of CC chemokine TARC in human nasal mucosa and its regulation
by cytokines. Clin Exp Allergy 2001;31:19231931.
54. Walsh G, Hartnell A, Wardlaw A, Kurihara K, Sanderson C, Kay A. Il-5
enhances the in vitro adhesion of human eosinophils, but not the
neutrophils, in a leukocyte integrin (CD11/18)dependent manner.
Immunology 1990;71:258265.
55. Tomaki M, Zhao L-L, Lundahl J, Sjostrand M, Jordana M, Linden A,
OByrne P, Lotvall J. Eosinophilopoiesis in a murine model of allergic
airway eosinophilia: involvement of bone marrow IL-5 and IL-5
receptor a. J Immunol 2000;165:40404050.
56. Weller P, Lee C, Foster D, Corey E, Austen K, Lewis R. Generation and
metabolism of 5-lipoxygenase pathway leukotrienes by human eosin-
ophils: predominant production of leukotriene C4. Proc Natl Acad Sci
USA 1983;80:76267630.
57. Ayers G, Altman L, McManus M, Agosti J, Baker C, Luchtel D,
Loegering D, Gleich G. Injurious effect of the eosinophil peroxi-
dasehydrogen peroxidasehalide system and major basic protein on
human nasal epithelium in vitro. Am Rev Respir Dis 1989;140:125131.
58. Jacoby D, Gleich G, Fryer A. Human eosinophil major basic protein is
an endogenous allosteric antagonist at the inhibitory muscarinic M2
receptor. J Clin Invest 1993;91:13141318.
59. Salib RJ, Howarth PH. Remodelling of the upper airways in allergic
rhinitis: is it a feature of the disease? Clin Exp Allergy 2003;33:
16291633.
60. Bousquet J, Jacquot W, Vignola A, Bachert C, van Cauwenberge P.
Allergic rhinitis: a disease remodeling the upper airways? J Allergy
Clin Immunol 2004;113:4349.
61. Connell J. Quantitative intranasal pollen challenges. III. The priming
effect in allergic rhinitis. J Allergy 1969;43:3344.
62. Norman PS. A rational approach to desensitization. J Allergy 1969;44:
129145.
63. Wachs M, Proud D, Lichtenstein L, Kagey-Sobotka A, Norman P,
Naclerio R. Observations on the pathogenesis of nasal priming.
J Allergy Clin Immunol 1989;84:492501.
64. Pipkorn U, Proud D, Lichtenstein L, Schleimer R, Peters S, Adkinson
N, Kagey-Sobotka A, Norman P, Naclerio R. Effect of short-term
systemic glucocorticoid treatment on human nasal mediator release
after antigen challenge. J Clin Invest 1987;80:957961.
65. Pipkorn U, Proud D, Lichtenstein L, Kagey-Sobotka A, Norman P,
Naclerio R. Inhibition of mediator release in allergic rhinitis by
pretreatment with topical glucocorticoids. N Engl J Med 1987;316:
15061510.
66. Nassef M, Shapiro G, Casale TB. Identifying and managing rhinitis and
its subtypes: allergic and nonallergic componentsa consensus report
and materials from the Respiratory and Allergic Disease Foundation.
Curr Med Res Opin 2006;22:25412548.
67. Baroody F, Cruz A, Lichtenstein L, Kagey-Sobotka A, Proud D, Naclerio
R. Intranasal beclomethasone inhibits antigen-induced nasal hyper-
responsiveness to histamine. J Allergy Clin Immunol 1992;90:373376.
114
68. Sanico AM, Philip G, Lai G, Togias A. Hyperosmolar saline induces
reflex nasal secretions, evincing neural hyperresponsiveness in allergic
rhinitis. J Appl Physiol 1999;86:12021210.
69. Wu X, Myers AC, Goldstone AC, Togias A, Sanico AM. Localization of
nerve growth factor and its receptors in the human nasal mucosa.
J Allergy Clin Immunol 2006;118:428433.
70. Sanico AM, Stanisz A, Gleeson TD, Bora S, Proud D, Bienenstock J,
Koliatsos V, Togias A. Nerve growth factor expression and release in
allergic inflammatory disease of the upper airways. Am J Respir Crit
Care Med 2000;161:16311635.
71. Jacobs R, Lieberman P, Kent E, Silvey M, Locantore N, Philpot EE.
Weather/temperature-sensitive vasomotor rhinitis may be refractory
to intranasal corticosteroid treatment. Allergy Asthma Proc 2009;30:
120127.
72. Banov C, Lieberman P. Efficacy of azelastine nasal spray in the
treatment of vasomotor (perennial nonallergic) rhinitis. Ann Allergy
Asthma Immunol 2001;86:2835.
73. Rondon C, Dona I, Torres MJ, Campo P, Blanca M. Evolution of
patients with nonallergic rhinitis supports conversion to allergic
rhinitis. J Allergy Clin Immunol 2009;123:10981102.
74. van Rijswijk J, Blom H, KleinJan A, Mulder P, Rijntjes E, Fokkens W.
Inflammatory cells seem not to be involved in idiopathic rhinitis.
Rhinology 2002;40:16.
75. Braat J, Mulder P, Fokkens W, van Wijk R, Rijntjes E. Intranasal cold
dry air is superior to histamine challenge in determining the presence
and degree of nasal hyperreactivity in nonallergic noninfectious
perennial rhinitis. Am J Respir Crit Care Med 1998;157:17481755.
76. van Rijswijk J, Boeke E, Keizer J, Mulder P, Blom H, Fokkens W.
Intranasal capsaicin reduces nasal hyperreactivity in idiopathic rhini-
tis: a double-blind randomized application regimen study. Allergy
2003;58:754761.
77. Lacroix J, Buvelot J, Polla B, Lundberg J. Improvement of symptoms of
non-allergic chronic rhinitis by local treatment with capsaicin. Clin
Exp Allergy 1991;21:595600.
78. Blom H, Van Rijswijk J, Garrelds I, Mulder P, Timmermans T, Van
Wijk R. Intranasal capsaicin is efficacious in non-allergic, non-
PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL 8 2011
infectious perennial rhinitis: a placebo-controlled study. Clin Exp
Allergy 1997;27:796801.
79. Powe D, Huskisson R, Carney A, Jenkins D, Jones N. Evidence for an
inflammatory pathophysiology in idiopathic rhinitis. Clin Exp Allergy
2001;31:864872.
80. Jacobs R, Freedman P, Boswell R. Nonallergic rhinitis with eosinophilia
(NARES syndrome). J Allergy Clin Immunol 1981;67:253262.
81. Carney AS, Powe DG, Huskisson RS, Jones NS. Atypical nasal challenges
in patients with idiopathic rhinitis: more evidence for the existence of
allergy in the absence of atopy? Clin Exp Allergy 2002;32:14361440.
82. Rondon C, Romero JJ, Lopez S, Antunez C, Martn-Casanez E, Torres
MJ, Mayorga C, R-Pena R, Blanca M. Local IgE production and
positive nasal provocation test in patients with persistent nonallergic
rhinitis. J Allergy Clin Immunol 2007;119:899905.
83. Rondon C, Fernandez J, Lopez S, Campo P, Dona I, Torres MJ,
Mayorga C, Blanca M. Nasal inflammatory mediators and specific
IgE production after nasal challenge with grass pollen in local allergic
rhinitis. J Allergy Clin Immunol 2009;124:10051011.e1.
84. Cameron L, Gounni A, Frenkiel S, Lavigne F, Vercelli D, Hamid Q.
SeSm and SeSg switch circles in human nasal mucosa following ex vivo
allergen challenge: evidence for direct as well as sequential class
switch recombination. J Immunol 2003;171:38163822.
85. Vayisoglu Y, Ozcan C, Pekdemir H, Gorur K, Pata YS, Camsari A.
Autonomic nervous system evaluation using heart rate variability para-
meters in vasomotor rhinitis patients. J Otolaryngol 2006;35:338342.
86. Wilde D, Cook JA, Jones AS. The nasal response to axillary pressure in
non-eosinophilic intrinsic rhinitis. Clin Otolaryngol Allied Sci 1997;22:
219221.
87. Jaradeh S, Smith T, Torrico L, Prieto T, Loehrl T, Darling R, Toohill R.
Autonomic nervous system evaluation of patients with vasomotor
rhinitis. Laryngoscope 2000;110:18281831.
88. Elsheikh MN, Badran HM. Dysautonomia rhinitis: associated otolaryn-
gological manifestations and characterization based on autonomic
function tests. Acta Otolaryngol 2006;126:12061212.