Inflammatory Responses in Allergic Rhinitis: Traditional Approaches and Novel Treatment Strategies

Sadeq A. Quraishi; Michael J. Davies; Timothy J. Craig

Abstract

Allergic rhinitis (AR) is associated with decreased learning, performance and productivity at work and school, as well as a reduced quality of life. With a staggering annual economic impact between $6 billion and $8 billion, AR affects 20% of the adult population and up to 40% of children. Effective therapy for allergic rhinitis requires understanding the pathophysiology of the disease, as well as the role of various inflammatory mechanisms. As such, various classes of medication are at the physicians' disposal to treat patients with allergic rhinitis. Among these are second-generation antihistamines and anticholinergic agents, intranasal corticosteroids, and mast cell stabilizers. Recently, montelukast, a leukotriene receptor antagonist, has been added to the modes of therapy approved by the US Food and Drug Administration for allergic rhinitis. For patients refractive to standard pharmacologic intervention, immunotherapy has shown some promising results. As newer strategies emerge, treatment regimens for allergic rhinitis should continue to improve not only daytime symptoms, but also nighttime symptoms and sleep with the fewest possible adverse effects.

Allergic rhinitis (AR) is a common ailment, affecting 10% to 25% of the world's population.¹ In the United States, the prevalence of AR has increased during the past three decades; it is currently estimated at 20% in the general adult population and closer to 40% in children.^2,3 Reasons for this increase are not completely understood; however, pollution and indoor exposures—or even in some cases a lack of exposures—may play a role.⁴ One theory implicates a major shift in the gene pool, predisposing more individuals to excessive immunoglobulin E (IgE) production and thus, increased expression of AR.⁵

Irrespective of its cause, the annual economic impact of this pervasive disease is calculated to be $6.3 billion to $7.9 billion in direct and indirect costs.^6,7 This figure, however, does not account for the detrimental effects of AR on quality of life (QOL), which include fatigue, irritability, memory deficits, excessive daytime somnolence, and depression.^8,9 Quality of life is reduced in this patient population not only because of the disease symptoms (sneezing, nasal pruritus, rhinorrhea, and congestion), but also because its pathophysiology can disrupt normal sleep.^10,11 Therefore, effective therapy for AR must provide symptomatic relief and target the complex underlying inflammatory mechanisms.

This review provides a summary of the pathophysiology of AR, its relationship with asthma, and an analysis of the traditional modes of pharmacotherapy used in its management. This summary is followed by a review of emerging strategies and their rationale use in AR.

Pathophysiology of Allergic Rhinitis

Allergic rhinitis is characterized by a two-phase allergic reaction: an initial sensitization phase where allergen exposure results in IgE formation as well as induction of the humoral response, and subsequent clinical disease after repeated antigen exposure (Figure 1). The clinical phase can also be further subdivided into early- and late-phase responses.

Figure 1.

Pathophysiologic sequence of allergic rhinitis. (Sources: Young MC. Allergy Asthma Proc. 1998;19:211-218; Holgate ST et al. J Allergy Clin Immunol. 1996;98:1-13; and Naclerio RM. N Engl J Med. 1991;325:860-869.)

View Original | Slide (.ppt)

The early-phase inflammatory response is initiated within minutes of allergen exposure and is primarily due to the release by mast cells of mediators, including histamine, tryptase, cysteinyl leukotrienes (CysLTs), cytokines (interleukin-4 [IL-4], IL-5, IL-6, and tumor necrosis factor-α [TNF-α]), chemotactic factors, and enzymes (Figure 2). The net effect of these mediators is to produce the early symptoms of AR (primarily sneezing, itching, and rhinorrhea) and stimulate the production, adhesion, and infiltration into local tissue of circulating leukocytes, especially eosinophils.

Figure 2.

Reaction to allergen exposure in sensitized patients—mediators. (Sources: Young MC. Allergy Asthma Proc. 1998;19:211-218; 104. Kavuru MS et al. In: Diagnosis and Management of Rhinitis and Sinusitis. West Islip, NY: Professional Communications; 2001:19-24; and Ledford DK, Lockey RF. J Respir Dis. 1998;19:576-584.)

View Original | Slide (.ppt)

In contrast, the late-phase response begins 2 to 4 hours following allergen exposure and is essentially a cellular event^12-14 (Figure 3). Inflammatory cells become activated and release their mediators, promoting local edema and tissue damage and perpetuation of the overall inflammatory process.^12,13 Symptomatically, late-phase AR is characterized by nasal congestion and obstruction as opposed to sneezing and rhinorrhea, which are characteristic of the early phase response.¹⁵

Figure 3.

Reaction to allergen exposure in sensitized patients—inflammatory cells. (Sources: 106. Bascom R et al. Am Rev Respir Dis. 1988;138:406-412; Bascom R, et al. J Allergy Clin Immunol. 1988;81:580-589; and White M. J Allergy Clin Immunol. 1999;103:S378-S381.)

View Original | Slide (.ppt)

The role that various agents such as histamine play has been an area of intense study in the past. The role that CysLTs play as mediators of the inflammatory process has been more recently described, particularly as it relates to the pathophysiology of AR. Cysteinyl leukotrienes increase nasal airway resistance and airway obstruction and contribute to rhinorrhea via increased vascular permeability and mucus secretion.^14-17 They also function as chemoattractants for inflammatory cells, especially eosinophils, into the nasal tissues, which are then activated and secrete more inflammatory mediators, including CysLTs. This leads to augmented inflammation and congestion.^18,19

Other mediators, including prostaglandins (PGs), kinins, and neuropeptides, have been found to be important in AR. Prostaglandins, primarily PGD₂, cause congestion and rhinorrhea.^20,21 Kinins are released after allergen challenge; bradykinin elicits congestion, rhinorrhea, and sore throat.^22,23 Neuropeptides can induce vasodilation, thus causing congestion.^24-26

As noted, cytokine secretion is a major feature of the inflammatory process in AR, and these elements may play an important role in cellular adhesion. Cytokine release upregulates the expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin on the vascular endothelium, thereby enhancing the state of cell activation and prolonging the survival of eosinophils.^27-29 In addition, the endothelin-converting enzyme 1, which generates endothelin-1, is upregulated in AR.^30,31 This evidence points to an important underlying role for airway epithelial cells in initiating or maintaining local inflammation.

Furthermore, inducible nitric oxide (NO) synthase in the nasal mucosa has been shown to be upregulated in persistent AR with a concomitant reduction in the levels of NO after treatment with topical corticosteroids.³² Increased levels of exhaled NO have also been demonstrated during nasal and oral breathing in subjects with intermittent rhinitis.³³ A similar increase in NO has also been shown to accompany eosinophil recruitment during a clinically asymptomatic inflammatory response.³²

No clear correlation has yet been demonstrated between the amount of allergen-specific IgE present in serum and the nature or severity of allergic symptoms. This has raised the question of the possible role of non–IgE-mediated types of immune responses in AR, particularly of T-helper 2 (Th2) lymphocytes, which can generate IL-3, IL-4, IL-5, granulocyte-macrophage colony-stimulating factor (GM-CSF) and TNF-α.³⁴ After nasal allergen challenge, an increase in IL-4, IL-5, and GM-CSF has been described in association with a mucosal eosinophilia.³⁵ Nonetheless, a prerequisite for T-cell activation is the interaction with antigen-presenting cells, and recent evidence suggests that Langerhans' cells, as well as other dendritic cells, are found in the nasal mucosa, and the incidence of these cells increases during allergen provocation.³⁶

Asthma and Allergic Rhinitis

It is now recognized that asthma and AR do not necessarily constitute distinct disease entities, but rather represent a final common pathway of closely related pathologic processes in the respiratory tract, with variable expression of severity and response to treatment. The onset of AR and asthma also appear to be temporally related, with upper airway symptoms often preceding or appearing at the same time as asthma.³⁷

Although the prevalence of AR is as high as 89% and 94% in asthmatic adolescents and asthmatic adults, respectively, similarities and differences have been identified between these two conditions with regard to symptomatology, the role of inflammatory cells, T-cell activation, production of cytokines, cellular activity, the role of the airway epithelium, and response to treatment.^38,39 For example, both the nose and lower airways respond to neural stimulation by irritant substances. However, increased mucosal blood flow is the main contributor to exacerbations of nasal obstruction in AR in contrast to smooth muscle constriction as the major cause of lower airway narrowing in asthma.^40,41

And, although eosinophilia is a characteristic feature of both diseases, in AR the mucosal eosinophilic response is strongly related to the antigenic load as opposed to asthma, in which bronchial eosinophilia is prominent even in mild forms of the disease.^42-44 In both asthma and AR, there is evidence of epithelial accumulation of mast cells displaying allergen-induced activation, which results in the production of the pro-inflammatory mediators, including histamine, cytokines, prostaglandins, leukotrienes, tryptase, and kinins in the nose and the lower airways.^45-51

The role of T lymphocytes in the development and maintenance of AR has been previously discussed and recent confirmation of a predominant Th2-type CD4 positive T-cell profile has been obtained in studies of bronchoalveolar lavage in asthmatics.⁴¹ And although, there is evidence correlating the degree of T-cell activation with the severity of asthma, this correlation is yet to be convincingly demonstrated in AR.⁵² As such, it may be hypothesized that the crucial difference between asthma and AR could be the level of T-cell activation.

Adhesion mechanisms are also central to the pathogenesis of asthma and AR. Increased amounts of ICAM-1 and VCAM-1 have been demonstrated in chronic forms of both diseases and under conditions of allergenic stimulation, positive staining for adhesion molecules have been shown to increase in both the nose and lungs.^28,41,53 Interestingly, ICAM-1 is also a receptor for the vast majority of rhinoviruses, and it has been proposed that the induction of ICAM-1 on epithelial cells could be the primary event leading, through a concomitant rhinovirus infection, to asthma and nonspecific airway hyperreactivity.⁵⁴

Traditional Management of Allergic Rhinitis

Allergen avoidance and environmental control remain initial steps in managing AR. These interventions alone commonly provide insufficient relief. Therefore, manipulation of cytokine release from airway epithelial cells constitutes the next step in management. Topical corticosteroid applications and oral antihistamines are currently the two most important types of therapy and constitute the mainstay of the modern management of AR. Other agents in this area include oral and intranasal decongestants, oral corticosteroids, anticholinergic agents, leukotriene receptor antagonists, and mast cell stabilizers (Table).

Table:

Traditional Therapeutic Agents in Use for Allergic Rhinitis

Class	Mechanism of Action	Symptom Relief	Adverse Effects
Corticosteroids (intranasal, oral)	Bind to glucocorticoid receptors, affecting the production of various mediators	Sneezing, rhinorrhea, itching, congestion	Intranasal: irritation, bleeding Oral: Effects of long-term steroid use including potential growth suppression in children and osteoporosis
Mast cell stabilizers (intranasal)	Prevent mast cell degranulation	Sneezing, rhinorrhea, itching, congestion	Minimal
Antihistamine (intranasal, oral)	Antagonize histamine at the H₁ receptor	Sneezing, rhinorrhea, itching	First-generation: sedation, dry mouth, dry eyes, urinary retention Second-generation: minimal likelihood of sedation
Decongestants (intranasal, oral)	Stimulate α-adrenergic receptors, thereby inducing vasoconstriction	Congestion	Intranasal: rhinitis medicamentosa Oral: elevated blood pressure, tremor, tachycardia, loss of appetite, sleep disturbance
Anticholinergics (intranasal)	Muscarinic receptor blockade	Rhinorrhea	Minimal

View Large

Table:

Traditional Therapeutic Agents in Use for Allergic Rhinitis

Class	Mechanism of Action	Symptom Relief	Adverse Effects
Corticosteroids (intranasal, oral)	Bind to glucocorticoid receptors, affecting the production of various mediators	Sneezing, rhinorrhea, itching, congestion	Intranasal: irritation, bleeding Oral: Effects of long-term steroid use including potential growth suppression in children and osteoporosis
Mast cell stabilizers (intranasal)	Prevent mast cell degranulation	Sneezing, rhinorrhea, itching, congestion	Minimal
Antihistamine (intranasal, oral)	Antagonize histamine at the H₁ receptor	Sneezing, rhinorrhea, itching	First-generation: sedation, dry mouth, dry eyes, urinary retention Second-generation: minimal likelihood of sedation
Decongestants (intranasal, oral)	Stimulate α-adrenergic receptors, thereby inducing vasoconstriction	Congestion	Intranasal: rhinitis medicamentosa Oral: elevated blood pressure, tremor, tachycardia, loss of appetite, sleep disturbance
Anticholinergics (intranasal)	Muscarinic receptor blockade	Rhinorrhea	Minimal

Antihistamines

Antihistamines are the oldest drugs used to treat allergic diseases. First-generation antihistamines (eg, chlorpheniramine maleate, diphenhydramine, promethazine hydrochloride, triprolidine hydrochloride) have an unfavorable riskbenefit ratio in most patients, with poor selectivity and a high rate of anticholinergic and sedative effects.⁵⁵ Although these agents may be useful at night and lead to better sleep, during the day, patients may be fatigued or sleepy. Furthermore, these agents have the potential to impair learning, especially in children. They have similar effects to those caused by alcohol, thus making skilled activities more difficult or dangerous.^56,57

Low-sedating or nonsedating, second-generation antihistamines (eg, cetirizine hydrochloride, loratadine, fexofenadine hydrochloride, desloratadine) have higher potency with prolonged durations of action. It has been shown that sedative effects of these antihistamines correlate with the level of antihistamine that crosses the blood-brain barrier. For example, fexofenadine, which does not cross the blood-brain barrier, tends to be less sedative than cetirizine, which occupies 30% of the histamine type 1 (H₁) receptors in the brain.⁵⁸ Because the second-generation antihistamines are less sedating or nonsedating, their impact on learning and drowsiness is similar to that of placebo.^56,57 These agents effectively reduce itching, sneezing, and watery rhinorrhea; however, nasal obstruction is not reduced significantly.^55,59

Topical antihistamines, delivered by nasal spray, avoid or minimize systemic adverse effects. Azelastine hydrochloride used topically has been shown to reduce rhinorrhea but failed to reduce congestion in one study, but not in another.^60,61 Thus, the debate on benefits of antihistamines on nasal congestion continues. Because antihistamines are not greatly effective in relieving congestion, they are often combined with a decongestant. However, because of the potential adverse effects of decongestants, caution should be used, especially with other over-the-counter combinations that contain a sedating first-generation antihistamine and a decongestant. Such combinations can cause insomnia and, subsequently, daytime fatigue. According to the Allergic Rhinitis and Its Impact on Asthma (ARIA) guidelines, these combinations should no longer be used.⁵⁵

Oral and Intranasal Decongestants

Intranasal or oral decongestants can effectively reduce nasal obstruction and congestion by their vasoconstrictive action on α-adrenergic receptors. Intranasal formulations act within 10 minutes, and many work up to 12 hours. Adverse effects may include nasal burning, dryness, or mucosal ulceration, and rarely, septal perforation. With oral formulations, activity starts within 30 minutes and lasts up to 6 hours, or for 8 to 24 hours with sustained-release formulas. Systemic effects can include irritability, dizziness, headache, tremor, tachycardia, and insomnia, which, in turn, can result in daytime somnolence. Tachyphylaxis and a rebound of symptoms (rhinitis medicamentosa) can result from prolonged use of a topical decongestant. Thus, long-term use of these agents is not recommended.⁵⁵

Oral and Intranasal Corticosteroids

Intranasal corticosteroids have proven efficacy in patients with AR, compared with placebo. Several studies have demonstrated that corticosteroids can attenuate the expression and release of pro-inflammatory cytokines from airway epithelial cells and that they are effective in reducing the number of epithelial Langerhans' cells, mast cells, eosinophils, IL-4 immunoreactive cells, and Th2 cells.^33,62-68 Clinically, they reduce congestion and improve sleep; furthermore, they reduce daytime sleepiness, daytime fatigue, and sleep problems.^69,70

Because of their topical application and low systemic bioavailability, intranasal corticosteroids are generally considered safe and have a minimal influence on adrenal suppression.^71,72 However, in treating concomitant diseases such as asthma, the amounts of nasal, inhaled, or oral steroids should be adjusted to avoid unwanted effects, including adrenal suppression.⁵⁵ Short courses of oral corticosteroids are particularly effective in severely symptomatic patients and when nasal blockage compromises the effective penetration of corticosteroid nasal sprays or drops.⁷³

Topical Anticholinergic Drugs

Parasympathetic stimulation of nasal glands results in vasodilation, resulting in watery secretion. Parasympathetic innervation is mediated through the autonomic transmitter acetylcholine. Therefore, muscarinic receptor blockade through anticholinergic drugs such as ipratropium bromide have antisecretory properties and a high safety profile with minimal crossing of the nasal and gastrointestinal mucosa as well as the blood-brain barrier.⁷⁴ When delivered locally to the nasal mucosa, anticholinergic drugs inhibit mucus secretion and the subsequent rhinorrhea in both adults and children with perennial AR.^75,76

In children with perennial AR, ipratropium given topically significantly improved rhinorrhea, congestion, and sneezing compared with baseline. Responses to QOL questionnaires showed also that after 6 months of treatment, ipratropium improved sleep by almost 50%.⁷⁷ However, because ipratropium does not relieve nasal congestion or sneezing associated with seasonal AR, the ARIA guidelines recommend it as first-line therapy only when rhinorrhea is the primary symptom.^55,74

Mast Cell Stabilizers

Sodium cromoglycate, with mast cell–stabilizing properties, is an effective strategy for controlling symptoms of AR with minimal associated adverse effects. However, its clinical effect is only for preventive purposes, and sodium cromoglycate is most likely to be useful if initiated before symptoms become severe.^78-81 It is effective in young children, but it has the disadvantage of having to be frequently administered (up to six times daily), with adherence to frequent dosing to achieve adequate prophylaxis.

New Agents Currently in Use

Although traditional agents provide relief for a large number of patients, their limitations and adverse effects have prompted further, more targeted research on the medical management of AR. Of particular use has been the ability to understand the similarities between the pathophysiology of asthma and that of AR, as well as the central role played by CysLTs in both diseases.

Leukotriene Inhibitors

As noted previously, CysLTs are key mediators of AR symptoms, and of congestion in particular. Therefore, the use of antileukotrienes to alleviate both daytime and nighttime symptoms is a rational approach. For example, after allergen challenge in patients with AR, zileuton, a leukotriene synthesis inhibitor, significantly reduced congestion.⁸² Similarly, the leukotriene receptor antagonists provide effective symptomatic relief, compared with placebo. For example, pranlukast significantly reduced nasal mucosal swelling and zafirlukast significantly reduced congestion, rhinorrhea, and sneezing.^83,84

Montelukast, the only leukotriene receptor antagonist currently approved for treatment of AR in the United States, significantly improves nighttime symptoms (difficulty going to sleep, nighttime awakenings, and congestion on awakening), as well as daytime symptoms (congestion, rhinorrhea, pruritus, and sneezing), compared with placebo in patients with allergies in the spring and fall.^85-87 Furthermore, montelukast significantly reduces the number of peripheral blood eosinophils, suggesting that it reduces allergic inflammation systemically.⁸⁸ The combination of CystLTs (montelukast) with antihistamines (loratadine), however, has not demonstrated better symptom relief than therapy with single agents alone.⁸⁶

Immunotherapy

Immunotherapy has been shown to be effective in the treatment of seasonal and perennial rhinitis.^89-92 The proposed mechanisms for immunotherapy include blunting of elevations in IgE, decrease in serum neutrophil and eosinophil activity, reduction in the mast cell population as well as associated mediators, and the suppression of allergen-induced T-lymphocyte proliferative responses with an increase in the circulating numbers of allergen-specific CD8⁺ T lymphocytes^93-99 (Figure 4). Some evidence also suggests that these events may be mediated by an effect of immunotherapy on T lymphocytes with an alteration from a predominant “Th2” response to favor an additional “Th1” response, which eventually would lead to the attenuation of tissue eosinophilia and local IgE production.¹⁰⁰

Figure 4.

Omalizumab binds to free IgE, reducing cell-bound IgE. It reduces number of high-affinity receptors on the mast cells and basophils, reducing mediator release. This leads to a reduction in exacerbation of asthma and a reduction in symptoms.

View Original | Slide (.ppt)

Allergen-specific immunotherapy, administered under controlled conditions with immediate access to resuscitative equipment, has a prominent role in the treatment of severely symptomatic patients with allergic rhinitis who have failed to respond to conventional treatment with antihistamines, topical corticosteroids, or LRTAs, administerd singly or in combination. The advantage of immunotherapy is that the immune system is modified, and this modification may be permanent or at least persist for years after therapy is terminated.

Comment

Although numerous agents are available for the treatment of AR, it is crucial that allergen avoidance remains the cornerstone of therapy. Understandably, total avoidance may not be feasible or may provide only incomplete relief. As such, pharmacotherapy should be aimed at providing relief for specific symptoms. Recent investigations point to intranasal corticosteroids as the most cost-effective group of agents, but second-generation antihistamines and leukotriene receptor antagonists are also effective.^101-104 Immunotherapy, the only treatment that can modify the diseases, is indicated in patients with moderate to severe refractory AR.

1

Salib RJ, Drake-Lee A, Howarth PH. Allergic rhinitis: past, present and the future. Clin Otolaryngol.. (2003). ;28(4):291-303.

2

Dykewicz MS, Fineman S, Skoner DP, et al. Diagnosis and management of rhinitis: complete guidelines of the Joint Task Force on Practice Parameters in Allergy, Asthma and Immunology. Ann Allergy Asthma Immunol. 1998;81:478-518.

3

Fineman SM. The burden of allergic rhinitis: beyond dollars and cents. Ann Allergy Asthma Immunol.. (2002). ;88:S2-S7.

4

Passali D, Lauriello M, Mezzedimi C. Nasal allergy and atmospheric pollution. Int J Pediatr Otorhinolaryngol. 1999;49:S257-S260.

5

Howarth PH, Holmberg K. Allergic rhinitis: an increasing clinical problem. Allergy. 1995;50:4-5

6

IMS Health Retail 2000.

7

D'Alonzo GE Jr. Scope and impact of allergic rhinitis. J Am Osteopath Assoc. 2002;102:S2-S6.

8

Flemons WW, Tsai W. Quality of life consequences of sleep-disordered breathing. J Allergy Clin Immunol.. (1997). ;99:S750-S756.

9

Blaiss MS. Cognitive, social, and economic costs of allergic rhinitis. Allergy Asthma Proc.. (2000). ;21:7-13.

10

Lierl MB. Allergy of the upper respiratory tract. In: Lawlor GM Jr, Fischer TJ, Adelman DC, eds. Manual of Allergy and Immunology. rd ed. Boston, Mass: Little, Brown & Co;1995 : 94-111.

11

Lavie P, Gertner R, Zomer J, Podoshin L. Breathing disorders in sleep associated with “microarousals” in patients with allergic rhinitis. Acta Otolaryngol. 1981;92:529-533.

12

American Academy of Allergy, Asthma and Immunology. The Allergy Report. Overview of Allergic Diseases: Diagnosis, Management, and Barriers to Care. Volume I. Milwaukee, Wis: American Academy of Allergy, Asthma and Immunology, Inc;2000 : 1-97.

13

White M. Mediators of inflammation and the inflammatory process. J Allergy Clin Immunol. 1999;103:S378-S381.

14

Naclerio R. Clinical manifestations of the release of histamine and other inflammatory mediators. J Allergy Clin Immunol. 1999;103:S382-S385.

15

Bisgaard H, Olsson P, Bende M. Effect of leukotriene D4 on nasal mucosal blood flow, nasal airway resistance and nasal secretion in humans. Clin Allergy. 1986;16:289-297.

16

Miadonna A, Tedeschi A, Leggieri E, Lorini M, Folco G, Sala A, et al. Behavior and clinical relevance of histamine and leukotrienes C4 and B4 in grass pollen-induced rhinitis. Am Rev Respir Dis. 1987;136:357-362.

17

Okuda M, Watase T, Mezawa A, Liu CM. The role of leukotriene D4 in allergic rhinitis. Ann Allergy. 1988;60:537-540.

18

Meltzer EO. Role for cysteinyl leukotriene receptor antagonist therapy in asthma and their potential role in allergic rhinitis based on the concept of “one linked airway disease”. Ann Allergy Asthma Immunol. 2000;84:176-187.

19

Philip G, Malmstrom K, Hampel FC, Weinstein SF, LaForce CF, Ratner PH, et al. Montelukast for treating seasonal allergic rhinitis: a randomized, double-blind, placebo-controlled trial performed in the spring. Clin Exp Allergy. 2002;32:1020-1028.

20

Doyle WJ, Boehm S, Skoner DP. Physiologic responses to intranasal dose-response challenges with histamine, methacholine, bradykinin, and prostaglandin in adult volunteers with and without nasal allergy. J Allergy Clin Immunol. 1990;86:924-935.

21

Arimura A, Yasui K, Kishino J, Asanuma F, Hasegawa H, Kakudo S, et al. Prevention of allergic inflammation by a novel prostaglandin receptor antagonist, s-5751. J Pharmacol Exp Ther.. (2001). ;298:411-419.

22

Naclerio RM, Proud D, Togias AG, Adkinson NF Jr, Meyers DA, Kagey-Sobotka A, et al. Inflammatory mediators in late antigen-induced rhinitis. N Engl J Med.. (1985). ;313:65-70.

23

Proud D, Reynolds CJ, Lacapra S, Kagey-Sobotka A, Lichtenstein LM, Naclerio RM. Nasal provocation with bradykinin induces symptoms of rhinitis and a sore throat. Am Rev Respir Dis.. (1988). ;137:613-616.

24

Devillier P, Dessanges JF, Rakotosihanaka F, Ghaem A, Boushey HA, Lockhart A, et al. Nasal response to substance P and methacholine in subjects with and without allergic rhinitis. Eur Respir J.. (1988). ;1:356-361.

25

White MV, Kaliner MA. Mediators of allergic rhinitis. J Allergy Clin Immunol. 1992;90:699-704.

26

Howarth PH. Mediators of nasal blockage in allergic rhinitis. Allergy. 1997;52:12-18.

27

Klementsson H, Venge P, Andersson M, Pipkorn U. Allergen-induced changes in nasal secretory responsiveness and eosinophil granulocytes. Acta Otolaryngol. 1991;111:776-784.

28

Montefort S, Roche WR, Howarth PH, Djukanovic R, Gratziou C, Carroll M, et al. Intercellular adhesion molecule-1 (ICAM-1) and endothelial leucocyte adhesion molecule-1 (ELAM-1) expression in the bronchial mucosa of normal and asthmatic subjects. Eur Respir J.. (1992). ;5:815-823.

29

Wegner CD, Gundel RH, Reilly P, Haynes N, Letts LG, Rothlein R. Intercellular adhesion molecule-1 (ICAM-1) in the pathogenesis of asthma. Science. 1990;247:456-459.

30

Mullol J, Chowdhury BA, White MV, Ohkubo K, Rieves RD, Baraniuk J, et al. Endothelin in human nasal mucosa. Am J Respir Cell Mol Biol. 1993;8:393-402.

31

Furukawa K, Saleh D, Bayan F, Emoto N, Kaw S, Yanagisawa M, et al. Co-expression of endothelin-1 and endothelin-converting enzyme-1 in patients with chronic rhinitis. Am J Respir Cell Mol Biol.. (1996). ;14:248-253.

32

Hanazawa T, Antuni JD, Kharitonov SA, Barnes PJ. Intranasal administration of eotaxin increases nasal eosinophils and nitric oxide in patients with allergic rhinitis. J Allergy Clin Immunol. 2000;105:58-64.

33

Martin U, Bryden K, Devoy M, Howarth P. Increased levels of exhaled nitric oxide during nasal and oral breathing in subjects with seasonal rhinitis. J Allergy Clin Immunol. 1996;97:768-772.

34

Mosmann TR, Coffman RL. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol. 1989;7:145-173.

35

Durham SR, Ying S, Varney VA, Jacobson MR, Sudderick RM, Mackay IS, et al. Cytokine messenger RNA expression for IL-3, IL-4, IL-5, and granulocyte/macrophage-colony-stimulating factor in the nasal mucosa after local allergen provocation: relationship to tissue eosinophilia. J Immmunol. 1992;148:2390-2394.

36

Godthelp T, Fokkens WJ, Kleinjan A, Holm AF, Mulder PG, Prens EP, et al. Antigen presenting cells in the nasal mucosa of patients with allergic rhinitis during allergen provocation. Clin Exp Allergy. 1996;26:677-688.

37

Pedersen PA, Weeke ER. Asthma and allergic rhinitis in the same patients. Allergy. 1983;38:25-29.

38

Berger WE. Overview of allergic rhinitis. Ann Allergy Asthma Immunol. 2003;90:S7-S12.

39

Togias A. Rhinitis and asthma: evidence for respiratory system integration. J Allergy Clin Immunol. 2003;111:1171-1183.

40

Rowe-Jones JM. The link between the nose and lung, perennial rhinitis and asthma: is it the same disease? Allergy. 1997;52:20-28.

41

Djukanovic R, Wilson SJ, Howarth PH. Pathology of rhinitis and bronchial asthma. Clin Exp Allergy. 1996;26:44-51.

42

Bentley AM, Jacobson MR, Cumberworth V, Barkans JR, Moqbel R, Schwartz LB, et al. Immunohistology of the nasal mucosa in seasonal allergic rhinitis: increases in activated eosinophils and epithelial mast cells. J Allergy Clin Immunol. 1992;89:877-883.

43

Pipkorn U, Karlsson G, Enerback L. The cellular response of the human allergic mucosa to natural allergen exposure. J Allergy Clin Immunol. 1988;82:1046-1054.

44

Bentley AM, Cumberworth V, Varney VA, et al. Studies during the pollen season in understanding allergic rhinitis. Proceedings of the European Academy of Allergology and Clinical Immunology Congress, Paris. Adv Allergol Clin Immunol. 1992;457-464.

45

Lam S, al-Majed S, Chan H, Tse K, LeRiche JC, Chan-Yeung M. Differences in mediator release between allergic rhinitis and asthma. J Allergy Clin Immunol. 1991;87:842-849.

46

Bradding P, Roberts JA, Britten KM, Montefort S, Djukanovic R, Mueller R, et al. Interleukin-4, -5, and -6 and tumor necrosis factor-alpha in normal and asthmatic airways: evidence for the human mast cell as a source of these cytokines. Am J Respir Cell Mol Biol.. (1994). ;10:471-480.

47

Castells M, Schwartz LB. Tryptase levels in nasallavage fluid as an indicator of the immediate allergic response. J Allergy Clin Immunol. 1988;82:348-355.

48

Naclerio RM, Creticos PS, Norman PS, Lichtenstein LM. Mediator release after nasal airway challenge with allergen. Am Rev Respir Dis. 1986;134:1102 .

49

Liu MC, Hubbard WC, Proud D, Stealey BA, Galli SJ, Kagey-Sobotka A, et al. Immediate and late inflammatory responses to ragweed antigen challenge of the peripheral airways in allergic asthmatics. Cellular, mediator, and permeability changes. Am Rev Respir Dis.. (1991). ;144:51-58.

50

Creticos PS, Adkinson NF Jr, Kagey-Sobotka A, Proud D, Meier HL, Naclerio RM, et al. Nasal challenge with ragweed pollen in hay fever patients. Effect of immunotherapy. J Clin Invest. 1985;76:2247-2253. Erratum in: J Clin Invest. 1986;78:1421.

51

Bradding P, Feather IH, Wilson S, Bardin PG, Heusser CH, Holgate ST, et al. Immunolocalization of cytokines in the nasal mucosa of normal and perennial rhinitic subjects. The mast cell as a source of IL-4, IL-5, and IL-6 in human allergic mucosal inflammation. J Immmunol. 1993;151:3853-3865.

52

Vrugt B, Djukanovic R, Bron A, Aalbers R. New insights into the pathogenesis of severe corticosteroid dependent asthma. J Allergy Clin Immunol. 1996;98:522-526.

53

Montefort S, Gratziou C, Goulding D, Polosa R, Haskard DO, Howarth PH, et al. Bronchial biopsy evidence for leukocyte infiltration and upregulation of leukocyte-endothelial cell adhesion molecules 6 hours after local allergen challenge of sensitized asthmatic airways. J Clin Invest. 1994;93:1411-1421.

54

Canonica GW, Ciprandi G, Pesce GP, Buscaglia S, Paolieri F, Bagnasco M. ICAM-1 on epithelial cells in allergic subjects: a hallmark of allergic inflammation. Int Arch Allergy Immunol. 1995;107:99-102.

55

Bousquet J, van Cauwenberge P, Khaltaev N. Allergic rhinitis and its impact on asthma. J Allergy Clin Immunol. 2001;108:S147-S334.

56

Weiler JM, Bloomfield JR, Woodworth GG, Grant AR, Layton TA, Brown TL, et al. Effects of fexofenadine, diphenhydramine, and alcohol on driving performance. A randomized, placebo-controlled trial in the Iowa driving simulator. Ann Intern Med.. (2000). ;132:354-363.

57

Vuurman EF, van Veggel LM, Uiterwijk MM, Leutner D, O'Hanlon JF. Seasonal allergic rhinitis and antihistamine effects on children's learning. Ann Allergy. 1993;71:121-126.

58

Tashiro M, Mochizuki H, Iwabuchi K, Sakurada Y, Itoh M, Watanabe T, et al. Roles of histamine in regulation of arousal and cognition: functional neuroimaging of histamine H1 receptors in human brain. Life Sci. 2002;72:409-414.

59

Nayak AS, Schenkel E. Desloratadine reduces nasal congestion in patients with intermittent allergic rhinitis. Allergy. 2001;56:1077-1080.

60

Saengpanich S, Assanasen P, de Tineo M, Haney L, Naclerio RM, Baroody FM. Effects of intranasal azelastine on the response to nasal allergen challenge. Laryngoscope. 2002;112:47-52.

61

Golden S, Teets SJ, Lehman EB, Mauger EA, Chinchilli V, Berlin JM, et al. Effect of topical nasal azelastine on the symptoms of rhinitis, sleep, and daytime somnolence in perennial allergic rhinitis. Ann Allergy Asthma Immunol. 2000;85:53-57,

62

Wang JH, Devalia JL, Xia C, Sapsford RJ, Davies RJ. Expression of RANTES by human bronchial epithelial cells in vitro and in vivo and the effect of corticosteroids. Am J Respir Cell Mol Biol.. (1996). ;14:27-35.

63

Trigg CJ, Manolitsas ND, Wang J, Calderon MA, McAuley A, Jordon SE, et al. Placebo-controlled immunopathologic study of four months of inhaled corticosteroids in asthma. Am J Respir Crit Care Med. 1994;150:17-22.

64

Baroody FM, Cruz AA, Lichtenstein LM, Kagey-Sobotka A, Proud D, Naclerio RM. Intranasal beclomethasone inhibits antigen-induced nasal hyperresponsiveness to histamine. J Allergy Clin Immunol. 1992;90:373-376.

65

Holm AF, Fokkens WJ, Godthelp T, Mulder PG, Vroom TM, Rijntjes E. Effect of 3 months' nasal steroid therapy on nasal T cells and Langerhans cells in patients suffering from allergic rhinitis. Allergy. 1995;50:204-209.

66

de Graaf-in't Veld C, Garrelds IM, Jansen AP, Van Toorenenbergen AW, Mulder PG, Meeuwis J, et al. Effect of intranasal fluticasone proprionate on the immediate and late allergic reaction and nasal hyperreactivity in patients with a house dust mite allergy. Clin Exp Allergy. 1995;25:966-973.

67

Baraniuk JN. Mechanisms of rhinitis. Allergy Asthma Proc. 1998;19:343-347

68

Baraniuk JN. Pathogenesis of allergic rhinitis. J Allergy Clin Immunol. 1997;99:S763-S772.

69

Craig TJ, Teets S, Lehman EB, Chinchilli VM, Zwillich C. Nasal congestion secondary to allergic rhinitis as a cause of sleep disturbance and daytime fatigue and the response to topical nasal corticosteroids. J Allergy Clin Immunol. 1998;101:633-637.

70

Hughes K, Glass C, Ripchinski M, Gurevich F, Weaver TE, Lehman E, et al. Efficacy of the topical nasal steroid budesonide on improving sleep and daytime somnolence in patients with perennial allergic rhinitis. Allergy. 2003;58:380-385.

71

Nguyen KL, Lauver D, Kim I, Aresery M. The effect of a steroid “burst” and long-term, inhaled fluticasone propionate on adrenal reserve. Ann Allergy Asthma Immunol. 2003;91:38-43.

72

Wilson AM, Sims EJ, McFarlane LC, Lipworth BJ. Effects of intranasal corticosteroids on adrenal, bone, and blood markers of systemic activity in allergic rhinitis. J Allergy Clin Immunol. 1998;102:598-604.

73

Durham SR. Mechanisms and treatment of allergic rhinitis. In: Mackay IS, Bull TR, eds. Scott-Brown's Otolaryngology. th ed. Oxford, England: Butterworth-Heinemann; 1997;1-16.

74

Wood C, Fireman P, Grossman J, Wecker M, MacGregor T. Product characteristics and pharmacokinetics of intranasal ipratropium bromide. J Allergy Clin Immunol. 1995;95(5 Pt 2):1111-1116.

75

Meltzer EO, Orgel HA, Bronsky EA, Findlay SR, Georgitis JW, Grossman J, et al. Ipratropium bromide aqueous nasal spray for patients with perennial allergic rhinitis: a study of its effect on their symptoms, quality of life, and nasal cytology. J Allergy Clin Immunol. 1992;90:242-249.

76

Meltzer EO, Orgel HA, Biondi R, Georgitis J, Milgrom H, Munk Z, et al. Ipratropium nasal spray in children with perennial rhinitis. Ann Allergy Asthma Immunol. 1997;78:485-491.

77

Milgrom H, Biondi R, Georgitis JW, Meltzer EO, Munk ZM, Drda K, et al. Comparison of ipratropium bromide 0.03% with beclomethasone dipropionate in the treatment of perennial rhinitis in children. Ann Allergy Asthma Immunol. 1999;83:105-111.

78

Druce HM, Goldstein S, Melamed J, Grossman J, Moss BA, Townley RG. Multicenter placebo-controlled study of nedocromil sodium 1% nasal solution in ragweed seasonal allergic rhinitis. Ann Allergy. 1990;65:212-216.

79

Orgel HA, Meltzer EO, Kemp JP, Ostrom NK, Welch MJ. Comparison of intranasal cromolyn sodium, 4%, and oral terfenadine for allergic rhinitis: symptoms, nasal cytology, nasal ciliary clearance, and rhinomanometry. Ann Allergy. 1991;66:237-244.

80

Dykewicz MS, Fineman S, Nicklas R, Lee R, Blessing-Moore J, Li JT. Joint Task Force Algorithm and Annotations for Diagnosis and Management of Rhinitis. Ann Allergy Asthma Immunol. 1998;81:469-473.

81

Mabry RL. Topical pharmacotherapy for allergic rhinitis: nedocromil. Am J Otolaryngol. 1993;14:379-381.

82

Knapp HR. Reduced allergen-induced nasal congestion and leukotriene synthesis with an orally active 5-lipoxygenase inhibitor. N Engl J Med. 1990;323:1745-1748.

83

Numata T, Konno A, Yamakoshi T, Hanazawa T, Terada N, Nagata H. Comparative role of peptide leukotrienes and histamine in the development of nasal mucosal swelling in nasal allergy. Ann Otol Rhinol Laryngol. 1999;108:467-473.

84

Donnelly AL, Glass M, Minkwitz MC, Casale TB. The leukotriene D4-receptor antagonist, ICI 204,219, relieves symptoms of acute seasonal allergic rhinitis. Am J Respir Crit Care Med.. (1995). ;151:1734-1739.

85

van Adelsberg J, Philip G, LaForce CF, Weinstein SF, Menten J, Malice MP, et al. Randomized controlled trial evaluating the clinical benefit of montelukast for treating spring seasonal allergic rhinitis. Ann Allergy Asthma Immunol. 2003;90:214-222.

86

Nayak AS, Philip G, Lu S, Malice MP, Reiss TF. Efficacy and tolerability of montelukast alone or in combination with loratadine in seasonal allergic rhinitis: a multicenter, randomized, double-blind, placebo-controlled trial performed in the fall. Ann Allergy Asthma Immunol. 2002;88:592-600.

87

Juniper EF. Rhinitis management: the patient's perspective. Clin Exp Allergy. 1998;28:S34-S38.

88

Philip G, Malmstrom K, Hampel FC, Weinstein SF, LaForce CF, Ratner PH, et al. Montelukast for treating seasonal allergic rhinitis: a randomized, double-blind, placebo-controlled trial performed in the spring. Clin Exp Allergy. 2002;32:1020-1028.

89

Bousquet J, Hejjaoui A, Soussana M, Michael FB. Double-blind, placebo-controlled immunotherapy with mixed grass-pollen allergoids. IV. Comparison of the safety and efficacy of two dosages of a high-molecular-weight allergoid. J Allergy Clin Immunol. 1990;85:490-497.

90

Varney VA, Gaga M, Frew AJ, Aber VR, Kay AB, Durham SR. Usefulness of immunotherapy in patients with severe summer hay fever uncontrolled by antiallergic drugs. BMJ. 1991;302:265-269.

91

Chervinsky P, Casale T, Townley R, Tripathy I, Hedgecock S, Fowler-Taylor A, et al. Omalizumab, an anti-IgE antibody, in the treatment of adults and adolescents with perennial allergic rhinitis. Ann Allergy Asthma Immunol. 2003;91:160-167.

92

Casale TB, Condemi J, LaForce C, Nayak A, Rowe M, Watrous M, et al. Omalizumab Seasonal Allergic Rhinitis Trail Group. Effect of omalizumab on symptoms of seasonal allergic rhinitis: a randomized controlled trial. JAMA. 2001;286:2956-2967.

93

Lichtenstein LM, Ishizaka K, Norman PS, Sobotka AK, Hill BM. IgE antibody measurements in ragweed hay fever. Relationship to clinical severity and the results of immunotherapy. J Clin Invest. 1973;52:472-482.

94

McHugh SM, Ewan PW. Reduction of increased serum neutrophil chemotactic activity following effective hyposensitization in house dust mite allergy. Clin Exp Allergy. 1989;19:327-334.

95

Rak S, Lowhagen O, Venge P. The effect of immunotherapy on bronchial hyperresponsiveness and eosinophil cationic protein in pollen-allergic patients. J Allergy Clin Immunol. 1988;82:470-480.

96

Otsuka H, Mezawa A, Ohnishi M, Okubo K, Seki H, Okudo M. Changes in nasal metachromatic cells during allergen immunotherapy. Clin Exp Allergy. 1991;21:115-119.

97

Varney VA, Hamid QA, Gaga M, Ying S, Jacobson M, Frew AJ, et al. Influence of grass pollen immunotherapy on cellular infiltration and cytokine mRNA expression during allergen-induced late-phase cutaneous responses. J Clin Invest. 1993;92:644-651.

98

Creticos PS, Adkinson NF Jr, Kagey-Sobotka A, Proud D, Meier HL, Naclerio RM, et al. Nasal challenge with ragweed pollen in hay fever patients. Effect of immunotherapy. J Clin Invest. 1985;76:2247-2253.

99

Rocklin RE, Sheffer AL, Greineder DK, Melmon KL. Generation of antigen-specific suppressor cells during allergy desensitization. N Engl J Med. 1980;302:1213-1219.

100

Durham SR. New insights into the mechanisms of immunotherapy. Eur Arch Otorhinolaryngol. 1995;252:S64-S67.

101

Lee TA, Divers CH, Leibman CW. Evaluating the efficiency of treatment in the allergic rhinitis market. J Manag Care Pharm. 2004;10:S3-S8.

102

Sullivan PW, Follin SL, Nichol MB. Transitioning the second-generation antihistamines to over-the-counter status: a cost-effectiveness analysis. Med Care. 2003;41:1382-1395.

103

Waddell AN, Patel SK, Toma AG, Maw AR. Intranasal steroid sprays in the treatment of rhinitis: is one better than another? J Laryngol Otol. 2003;117:843-855.

104

Reissman D, Price T, Leibman CW. Cost efficiency of intranasal corticosteroid prescribing patterns in the management of allergic rhinitis. J Manag Care Pharm. 2004;10(1 suppl):S9-S13.

Figure 1.

Pathophysiologic sequence of allergic rhinitis. (Sources: Young MC. Allergy Asthma Proc. 1998;19:211-218; Holgate ST et al. J Allergy Clin Immunol. 1996;98:1-13; and Naclerio RM. N Engl J Med. 1991;325:860-869.)

View Original | Slide (.ppt)

Figure 2.

Reaction to allergen exposure in sensitized patients—mediators. (Sources: Young MC. Allergy Asthma Proc. 1998;19:211-218; 104. Kavuru MS et al. In: Diagnosis and Management of Rhinitis and Sinusitis. West Islip, NY: Professional Communications; 2001:19-24; and Ledford DK, Lockey RF. J Respir Dis. 1998;19:576-584.)

View Original | Slide (.ppt)

Figure 3.

Reaction to allergen exposure in sensitized patients—inflammatory cells. (Sources: 106. Bascom R et al. Am Rev Respir Dis. 1988;138:406-412; Bascom R, et al. J Allergy Clin Immunol. 1988;81:580-589; and White M. J Allergy Clin Immunol. 1999;103:S378-S381.)

View Original | Slide (.ppt)

Figure 4.

Omalizumab binds to free IgE, reducing cell-bound IgE. It reduces number of high-affinity receptors on the mast cells and basophils, reducing mediator release. This leads to a reduction in exacerbation of asthma and a reduction in symptoms.

View Original | Slide (.ppt)

Table:

Traditional Therapeutic Agents in Use for Allergic Rhinitis

Class	Mechanism of Action	Symptom Relief	Adverse Effects
Corticosteroids (intranasal, oral)	Bind to glucocorticoid receptors, affecting the production of various mediators	Sneezing, rhinorrhea, itching, congestion	Intranasal: irritation, bleeding Oral: Effects of long-term steroid use including potential growth suppression in children and osteoporosis
Mast cell stabilizers (intranasal)	Prevent mast cell degranulation	Sneezing, rhinorrhea, itching, congestion	Minimal
Antihistamine (intranasal, oral)	Antagonize histamine at the H₁ receptor	Sneezing, rhinorrhea, itching	First-generation: sedation, dry mouth, dry eyes, urinary retention Second-generation: minimal likelihood of sedation
Decongestants (intranasal, oral)	Stimulate α-adrenergic receptors, thereby inducing vasoconstriction	Congestion	Intranasal: rhinitis medicamentosa Oral: elevated blood pressure, tremor, tachycardia, loss of appetite, sleep disturbance
Anticholinergics (intranasal)	Muscarinic receptor blockade	Rhinorrhea	Minimal

View Large

Table:

Traditional Therapeutic Agents in Use for Allergic Rhinitis

Class	Mechanism of Action	Symptom Relief	Adverse Effects
Corticosteroids (intranasal, oral)	Bind to glucocorticoid receptors, affecting the production of various mediators	Sneezing, rhinorrhea, itching, congestion	Intranasal: irritation, bleeding Oral: Effects of long-term steroid use including potential growth suppression in children and osteoporosis
Mast cell stabilizers (intranasal)	Prevent mast cell degranulation	Sneezing, rhinorrhea, itching, congestion	Minimal
Antihistamine (intranasal, oral)	Antagonize histamine at the H₁ receptor	Sneezing, rhinorrhea, itching	First-generation: sedation, dry mouth, dry eyes, urinary retention Second-generation: minimal likelihood of sedation
Decongestants (intranasal, oral)	Stimulate α-adrenergic receptors, thereby inducing vasoconstriction	Congestion	Intranasal: rhinitis medicamentosa Oral: elevated blood pressure, tremor, tachycardia, loss of appetite, sleep disturbance
Anticholinergics (intranasal)	Muscarinic receptor blockade	Rhinorrhea	Minimal

Inflammatory Responses in Allergic Rhinitis: Traditional Approaches and Novel Treatment Strategies

Related content

Related Topics