Pathophysiology of Allergic and Nonallergic Rhinitis - ATS Journals

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 heterogeneous conditions. In allergic rhinitis, the process of allergen sensitization involves the participation of antigen-presenting cells, T lymphocytes, and B lymphocytes and depends on environmental allergen exposure. Sensitization results in the generation of allergenspecific 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 inflammatory 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 common 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 nose’s 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 unknown 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: [email protected] Proc Am Thorac Soc Vol 8. pp 106–114, 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 classification are hypertrophic inflammatory states affecting the paranasal 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) moderate/severe intermittent, and (4) moderate/severe persistent (2).

GENERATION OF NASAL SYMPTOMS Nasal symptoms represent exaggerated defensive and homeostatic 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 contributes to inhaled air humidification (3, 4). Excessive production of mucus generates rhinorrhea (runny nose) or, if drainage occurs toward the nasopharynx, postnasal drip. A prominent system 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 deriving 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 noradrenaline 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 sympathetic 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.

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TABLE 1. CLASSIFICATION OF RHINITIS

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 responsiveness 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 excessive symptoms when they are exposed to cold and windy weather conditions; these can be either individuals with perennial allergic rhinitis in whom allergic inflammation has upregulated 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, exaggerated secretory response to methacholine reflects glandular hyperresponsiveness. 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).

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 air–induced rhinitis (skier’s 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 nonmyelinated 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 Cfibers 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

Figure 1. Schematic diagram of hyperresponsiveness in comparison with normal nasal responsiveness. Normal responsiveness (left) consists of defensive or homeostatic responses to a stimulus or normal intensity and may or may not produce mild nasal symptoms. Hyperresponsiveness 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 stimulus of normal intensity that, because of defective homeostatic function, develops into an excessive stimulus (e.g., cold air causing hypertonicity; see text for details).

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ALLERGIC RHINITIS Allergic rhinitis is the most common form and a prototype of IgE-mediated disease. The hallmark of allergic rhinitis is an IgEmediated, type 1 hypersensitivity reaction to an inciting inhaled allergen. The result of this reaction is a cascade of immunological 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 probably 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 activation requires the interaction of specific T-cell receptors on the surface of T cells with allergen peptide–MHC 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 lymphopoietin released from epithelial cells, which switch the maturation 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 cell–cell contact mechanism to induce apoptosis. In addition, Tregs crosstalk with APCs to suppress T-cell activa-

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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 allergenspecific IL-4–producing effector T cells, IL-10–producing 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 lymphocytes (B cells) under the regulation of cytokines derived from Th2 lymphocytes. Two signals are required. IL-4 or IL-13 provides the first essential signal that drives B cells to IgE production 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 tetrameric (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 monocytemacrophages and on B lymphocytes (32, 33). However, it is the IgE–FceRI 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 approaches do not exist or have failed to produce significant clinical results. The allergic reaction in the nose has early and late components (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 development of nasal hyperresponsiveness with more indolent symptoms. Within minutes of contact of sensitized individuals with allergens, the IgE–allergen 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 leukotrienes (LTC4, LTD4, LTE4) and prostaglandins (primarily


PGD2) (34, 35). Mast cells and basophils do not produce exactly the same array of mediators; for example, PGD2 is almost exclusively a mast cell product. The targets of these mediators vary; for example, histamine activates H1 receptors on sensory

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nerve endings and causes sneezing, pruritus, and reflex secretory responses, but it also interacts with H1 and H2 receptors on mucosal blood vessels, leading to vascular engorgement (nasal congestion) and plasma leakage (36). Sulfidopeptide leukotri-

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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; GMCSF 5 granulocyte-macrophage colony-stimulating factor; ICAM-1 5 intercellular adhesion molecule-1; LFA-1 5 lymphocyte function–associated 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). Additional 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 prominent, 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 inflammatory cells and by alterations in nasal physiology, namely priming and hyperresponsiveness. Cells that migrate into the nasal mucosa include T cells, eosinophils, basophils, neutrophils, and monocytes (41–43). 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, H1–H4 (47), and the sulfidopeptide leukotrienes can attract and activate eosinophils. 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 eosinophils 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 [regulated 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 development of mucosal inflammation after allergen exposure. For example, 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 dendritic 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 production 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 plateletactivating 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 eosinophil 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) receptors, 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 implicated 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 regeneration and repair, perhaps because of its different embryological 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-


ness specific to the allergic reaction. Priming can be documented on natural allergen exposure. Connell was the first to describe the ‘‘priming effect’’ in the nose after allowing his study 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 permeability 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, providing evidence for the role of inflammation in this phenomenon (64, 65). Patients with allergic rhinitis, particularly those with perennial 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’’ (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 importantly, this increased responsiveness can be induced by allergen challenge (67). As discussed earlier, different stimuli act on different endorgans (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, hyperosmolar 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 hyperresponsiveness 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

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effect of glucocorticosteroids, it is believed that allergic inflammation is the culprit; the question remains, however, as to which element(s) of inflammation result(s) in end-organ hyperresponsiveness. In the case of sensorineural hyperresponsiveness, which is the only well-documented form, it has been postulated that nerve growth factor (NGF) or other neurotrophins 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 experimental allergen challenge, but not on challenge with histamine, suggesting a specific release pathway (70). The biological effects of NGF include changes in ongoing neuroterminal 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 encompassing 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 agreement 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. Individuals categorized as such are those who not only lack conventional 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 endocrine causes need to be ruled out. Their nasal symptoms 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). Surprisingly, the topical antihistamine azelastine has also shown moderate effectiveness (72), raising some interesting hypotheses as to the pathophysiology of this condition. Another important 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 pathophysiology 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 determine 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 following observations: (1) the nasal mucosa of such patients is indistinguishable from that of healthy control subjects lacking

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any evidence of inflammation or of a particular cell infiltrate (74); (2) nasal responsiveness to histamine, which is highly upregulated in perennial allergic rhinitis, is normal in this group of patients with nonallergic disease (75); (3) in contrast to histamine, 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 symptomatology, an observation that has been confirmed by several other European research teams (76–78); 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 sensitivity 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 sensitive 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.’’ 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 serumspecific IgE antibodies, these individuals develop nasal symptoms 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 released 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, excessive parasympathetic tone will produce rhinorrhea, whereas suppressed sympathetic activity can result in nasal congestion. A few studies have provided data indicating abnormal responses to autonomic tests in patients with nonallergic rhinitis. For example, heart rate variability according to various standard parameters was found to be higher in patients with idiopathic (vasomotor) rhinitis, without nasal eosinophilia, compared with nonrhinitic control subjects, indicative of increased parasympathetic activity (85). More generalized dysautonomia including both the parasympathetic and sympathetic nervous systems has been suggested by other studies (86–88). It remains to be seen whether dysautonomia characterizes a specific group of patients with idiopathic, nonallergic rhinitis and, if


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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.

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