because its pathophysiology can disrupt

normal sleep.10,11 Therefore, effective

therapy for AR must provide symp-
Inflammatory Responses tomatic relief and target the complex
underlying inflammatory mechanisms.
in Allergic Rhinitis: Traditional This review provides a summary of
Approaches and Novel the pathophysiology of AR, its relation-
Treatment Strategies ship with asthma, and an analysis of the
traditional modes of pharmacotherapy
used in its management. This summary
Sadeq A. Quraishi, MHA is followed by a review of emerging
Michael J. Davies, MD strategies and their rationale use in AR.
Timothy J. Craig, DO
Pathophysiology of Allergic Rhinitis
Allergic rhinitis is characterized by a two-
phase allergic reaction: an initial sensiti-
zation phase where allergen exposure
Allergic rhinitis (AR) is associated with decreased learning, performance and results in IgE formation as well as induc-
productivity at work and school, as well as a reduced quality of life. With a stag- tion of the humoral response, and sub-
gering annual economic impact between $6 billion and $8 billion, AR affects sequent clinical disease after repeated
20% of the adult population and up to 40% of children. Effective therapy for antigen exposure (Figure 1). The clinical
allergic rhinitis requires understanding the pathophysiology of the disease, as phase can also be further subdivided into
well as the role of various inflammatory mechanisms. As such, various classes early- and late-phase responses.
of medication are at the physicians’ disposal to treat patients with allergic The early-phase inflammatory
rhinitis. Among these are second-generation antihistamines and anticholinergic response is initiated within minutes of
agents, intranasal corticosteroids, and mast cell stabilizers. Recently, mon- allergen exposure and is primarily due to
telukast, a leukotriene receptor antagonist, has been added to the modes of the release by mast cells of mediators,
therapy approved by the US Food and Drug Administration for allergic rhinitis. including histamine, tryptase, cysteinyl
For patients refractive to standard pharmacologic intervention, immunotherapy leukotrienes (CysLTs), cytokines (inter-
has shown some promising results. As newer strategies emerge, treatment reg- leukin-4 [IL-4], IL-5, IL-6, and tumor
imens for allergic rhinitis should continue to improve not only daytime symp- necrosis factor-
[TNF-
]), chemotactic
toms, but also nighttime symptoms and sleep with the fewest possible adverse factors, and enzymes (Figure 2). The net
effects. effect of these mediators is to produce
the early symptoms of AR (primarily
sneezing, itching, and rhinorrhea) and

A llergic rhinitis (AR) is a common

ailment, affecting 10% to 25% of
the world’s population.1 In the United
increase are not completely understood;
however, pollution and indoor expo-
sures—or even in some cases a lack of
stimulate the production, adhesion, and
infiltration into local tissue of circulating
leukocytes, especially eosinophils.
States, the prevalence of AR has exposures—may play a role. 4 One In contrast, the late-phase response
increased during the past three decades; theory implicates a major shift in the begins 2 to 4 hours following allergen
it is currently estimated at 20% in the gene pool, predisposing more individ- exposure and is essentially a cellular
general adult population and closer to uals to excessive immunoglobulin E event12-14 (Figure 3). Inflammatory cells
40% in children.2,3 Reasons for this (IgE) production and thus, increased become activated and release their medi-
expression of AR.5 ators, promoting local edema and tissue
Irrespective of its cause, the annual damage and perpetuation of the overall
DFrom the Department of Medicine, Section for economic impact of this pervasive dis- inflammatory process.12,13 Symptomati-
Pulmonary, Allergy, and Immunology, (Quraishi,
Davies, Craig), and the Department of Pediatrics ease is calculated to be $6.3 billion to $7.9 cally, late-phase AR is characterized by
(Craig) at Pennsylvania State University College billion in direct and indirect costs.6,7 This nasal congestion and obstruction as
of Medicine in Hershey; and the Department of figure, however, does not account for the opposed to sneezing and rhinorrhea,
Medicine, Division of Critical Care, Pulmonary,
Allergic, Immunologic Diseases at Thomas Jef- detrimental effects of AR on quality of which are characteristic of the early phase
ferson University, Jefferson Medical College in life (QOL), which include fatigue, irri- response.15
Philadelphia, Pa (Craig). tability, memory deficits, excessive day- The role that various agents such as
Address correspondence to Timothy J. Craig,
DO, Professor of Medicine and Pediatrics, Chief, time somnolence, and depression.8,9 histamine play has been an area of
Allergy Clinic, Pennsylvania State University College Quality of life is reduced in this patient intense study in the past. The role that
of Medicine, The Milton S. Hershey Medical Center, population not only because of the dis- CysLTs play as mediators of the inflam-
500 University Ave, H-041, Hershey, PA 17033-
0850. ease symptoms (sneezing, nasal pruritus, matory process has been more recently
E-mail: tcraig@[Link] rhinorrhea, and congestion), but also described, particularly as it relates to the

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 Sensitization

Antigen-presenting cells on various tissues, including

mucosal surfaces, endocytose inhaled allergen.

Processing of allergen and copresentation (with HLA class II

molecules) to CD4 T cells.

Interleukin - 4 (IL- 4) and IL-13 stimulate T cells, which expand

to become IgE-secreting B cells.

Binding of allergen-specific IgE to receptors on mast cells

and basophils results in allergen priming.

Allergic Response in Sensitized Patients

Mediators (Figure 2) Inflammatory Cells (Figure 3)

Subsequent exposure of sensitized patient induces Inflammatory cells (eosinophils, basophils, monocytes,
allergic response. and lymphocytes) infiltrate nasal mucosa.

Allergen binds to IgE molecules on cell surface, activating Mediators released into nasal mucosa, triggering cellular
mast cells. processes.

Release of leukotrienes, interleukins, and cytokines by

Mast cells release granules (degranulation) containing mast cells promotes inflammatory processes and recruit-
preformed mediators. ment of inflammatory cells, particularly eosinophils.

Figure 1. Pathophysiologic sequence of allergic rhinitis.

Within minutes of exposure, activated mast cells begin to (Sources: Young MC. Allergy Asthma Proc. 1998;19:211-
synthesize and release new mediators. 218; Holgate ST et al. J Allergy Clin Immunol. 1996;98:1-13;
and Naclerio RM. N Engl J Med. 1991;325:860-869.)

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 Cytokine release upregulates the expres-
sion 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 persis-
tent AR with a concomitant reduction in
Figure 2. Reaction to allergen exposure in sensitized patients—mediators. (Sources: Young the levels of NO after treatment with top-
MC. Allergy Asthma Proc. 1998;19:211-218; 104. Kavuru MS et al. In: Diagnosis and Manage- ical corticosteroids.32 Increased levels of
ment of Rhinitis and Sinusitis. West Islip, NY: Professional Communications; 2001:19-24; and exhaled NO have also been demon-
Ledford DK, Lockey RF. J Respir Dis. 1998;19:576-584.) strated during nasal and oral breathing in
subjects with intermittent rhinitis.33 A
similar increase in NO has also been
shown to accompany eosinophil recruit-
ment 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, par-
ticularly of T-helper 2 (Th2) lymphocytes,
which can generate IL-3, IL-4, IL-5, gran-
ulocyte-macrophage colony-stimulating
factor (GM-CSF) and TNF-
.34 After
nasal allergen challenge, an increase in IL-
4, IL-5, and GM-CSF has been described
in association with a mucosal
Figure 3. Reaction to allergen exposure in sensitized patients—inflammatory cells. (Sources: eosinophilia.35 Nonetheless, a prerequisite
106. Bascom R et al. Am Rev Respir Dis. 1988;138:406-412; Bascom R, et al. J Allergy Clin for T-cell activation is the interaction with
Immunol. 1988;81:580-589; and White M. J Allergy Clin Immunol. 1999;103:S378-S381.) antigen-presenting cells, and recent evi-
dence suggests that Langerhans’ cells, as
pathophysiology of AR. Cysteinyl prostaglandins (PGs), kinins, and neu- well as other dendritic cells, are found
leukotrienes increase nasal airway resis- ropeptides, have been found to be impor- in the nasal mucosa, and the incidence of
tance and airway obstruction and con- tant in AR. Prostaglandins, primarily these cells increases during allergen
tribute to rhinorrhea via increased vas- PGD2, cause congestion and rhinor- provocation.36
cular permeability and mucus rhea.20,21 Kinins are released after allergen
secretion.14-17 They also function as challenge; bradykinin elicits congestion, Asthma and Allergic Rhinitis
chemoattractants for inflammatory cells, rhinorrhea, and sore throat.22,23 Neu- It is now recognized that asthma and AR
especially eosinophils, into the nasal tis- ropeptides can induce vasodilation, thus do not necessarily constitute distinct dis-
sues, which are then activated and secrete causing congestion.24-26 ease entities, but rather represent a final
more inflammatory mediators, including As noted, cytokine secretion is a common pathway of closely related
CysLTs. This leads to augmented inflam- major feature of the inflammatory pro- pathologic processes in the respiratory
mation and congestion.18,19 cess in AR, and these elements may play tract, with variable expression of severity
Other mediators, including an important role in cellular adhesion. and response to treatment. The onset of

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 Table
Traditional Therapeutic Agents in Use for Allergic Rhinitis

Class Mechanism of Action Symptom Relief Adverse Effects

Corticosteroids Bind to glucocorticoid Sneezing, rhinorrhea, Intranasal: irritation,

(intranasal, oral) receptors, affecting the itching, congestion bleeding
production of various Oral: Effects of long-term
mediators steroid use including
potential growth
suppression in children
and osteoporosis

Mast cell stabilizers Prevent mast cell Sneezing, rhinorrhea, Minimal

(intranasal) degranulation itching, congestion

Antihistamine Antagonize histamine at Sneezing, rhinorrhea, First-generation: sedation,

(intranasal, oral) the H1 receptor itching dry mouth, dry eyes,
urinary retention
Second-generation: minimal
likelihood of sedation

Decongestants Stimulate
-adrenergic Congestion Intranasal: rhinitis

(intranasal, oral) receptors, thereby medicamentosa
inducing vasoconstriction Oral: elevated blood
pressure, tremor,
tachycardia, loss of
appetite, sleep disturbance

Anticholinergics Muscarinic receptor Rhinorrhea Minimal

(intranasal) blockade

AR and asthma also appear to be tem- forms of the disease.42-44 In both asthma conditions of allergenic stimulation, pos-
porally related, with upper airway symp- and AR, there is evidence of epithelial itive staining for adhesion molecules
toms often preceding or appearing at the accumulation of mast cells displaying have been shown to increase in both the
same time as asthma.37 allergen-induced activation, which results nose and lungs. 28,41,53 Interestingly,
Although the prevalence of AR is in the production of the pro-inflamma- ICAM-1 is also a receptor for the vast
as high as 89% and 94% in asthmatic ado- tory mediators, including histamine, majority of rhinoviruses, and it has been
lescents and asthmatic adults, respec- cytokines, prostaglandins, leukotrienes, proposed that the induction of ICAM-1
tively, similarities and differences have tryptase, and kinins in the nose and the on epithelial cells could be the primary
been identified between these two con- lower airways.45-51 event leading, through a concomitant
ditions with regard to symptomatology, The role of T lymphocytes in the rhinovirus infection, to asthma and non-
the role of inflammatory cells, T-cell acti- development and maintenance of AR specific airway hyperreactivity.54
vation, production of cytokines, cellular has been previously discussed and recent
activity, the role of the airway epithe- confirmation of a predominant Th2-type Traditional Management
lium, and response to treatment.38,39 For CD4 positive T-cell profile has been of Allergic Rhinitis
example, both the nose and lower air- obtained in studies of bronchoalveolar Allergen avoidance and environmental
ways respond to neural stimulation by lavage in asthmatics.41 And although, control remain initial steps in managing
irritant substances. However, increased there is evidence correlating the degree of AR. These interventions alone commonly
mucosal blood flow is the main contrib- T-cell activation with the severity of provide insufficient relief. Therefore,
utor to exacerbations of nasal obstruc- asthma, this correlation is yet to be con- manipulation of cytokine release from
tion in AR in contrast to smooth muscle vincingly demonstrated in AR.52 As such, airway epithelial cells constitutes the next
constriction as the major cause of lower it may be hypothesized that the crucial step in management. Topical corticoste-
airway narrowing in asthma.40,41 difference between asthma and AR could roid applications and oral antihistamines
And, although eosinophilia is a char- be the level of T-cell activation. are currently the two most important
acteristic feature of both diseases, in AR Adhesion mechanisms are also cen- types of therapy and constitute the main-
the mucosal eosinophilic response is tral to the pathogenesis of asthma and stay of the modern management of AR.
strongly related to the antigenic load as AR. Increased amounts of ICAM-1 and Other agents in this area include oral and
opposed to asthma, in which bronchial VCAM-1 have been demonstrated in intranasal decongestants, oral corticoste-
eosinophilia is prominent even in mild chronic forms of both diseases and under roids, anticholinergic agents, leukotriene

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 receptor antagonists, and mast cell sta- with other over-the-counter combina- adjusted to avoid unwanted effects,
bilizers (Table). tions that contain a sedating first-gener- including adrenal suppression.55 Short
ation antihistamine and a decongestant. courses of oral corticosteroids are par-
Antihistamines Such combinations can cause insomnia ticularly effective in severely symp-
Antihistamines are the oldest drugs used and, subsequently, daytime fatigue. tomatic patients and when nasal blockage
to treat allergic diseases. First-generation According to the Allergic Rhinitis and compromises the effective penetration
antihistamines (eg, chlorpheniramine Its Impact on Asthma (ARIA) guidelines, of corticosteroid nasal sprays or drops.73
maleate, diphenhydramine, promet- these combinations should no longer be
hazine hydrochloride, triprolidine used.55 Topical Anticholinergic Drugs
hydrochloride) have an unfavorable risk- Parasympathetic stimulation of nasal
benefit ratio in most patients, with poor Oral and Intranasal Decongestants glands results in vasodilation, resulting in
selectivity and a high rate of anticholin- Intranasal or oral decongestants can effec- watery secretion. Parasympathetic inner-
ergic and sedative effects.55 Although tively reduce nasal obstruction and con- vation is mediated through the auto-
these agents may be useful at night and gestion by their vasoconstrictive action on nomic transmitter acetylcholine. There-
lead to better sleep, during the day,
-adrenergic receptors. Intranasal for- fore, muscarinic receptor blockade
patients may be fatigued or sleepy. Fur- mulations act within 10 minutes, and through anticholinergic drugs such as
thermore, these agents have the potential many work up to 12 hours. Adverse ipratropium bromide have antisecretory
to impair learning, especially in children. effects may include nasal burning, dry- properties and a high safety profile with
They have similar effects to those caused ness, or mucosal ulceration, and rarely, minimal crossing of the nasal and gas-
by alcohol, thus making skilled activi- septal perforation. With oral formula- trointestinal mucosa as well as the blood-
ties more difficult or dangerous.56,57 tions, activity starts within 30 minutes brain barrier.74 When delivered locally
Low-sedating or nonsedating, and lasts up to 6 hours, or for 8 to 24 to the nasal mucosa, anticholinergic
second-generation antihistamines (eg, hours with sustained-release formulas. drugs inhibit mucus secretion and the
cetirizine hydrochloride, loratadine, fex- Systemic effects can include irritability, subsequent rhinorrhea in both adults and
ofenadine hydrochloride, desloratadine) dizziness, headache, tremor, tachycardia, children with perennial AR.75,76
have higher potency with prolonged and insomnia, which, in turn, can result In children with perennial AR, ipra-
durations of action. It has been shown in daytime somnolence. Tachyphylaxis tropium given topically significantly
that sedative effects of these antihis- and a rebound of symptoms (rhinitis improved rhinorrhea, congestion, and
tamines correlate with the level of anti- medicamentosa) can result from pro- sneezing compared with baseline.
histamine that crosses the blood-brain longed use of a topical decongestant. Responses to QOL questionnaires
barrier. For example, fexofenadine, which Thus, long-term use of these agents is showed also that after 6 months of treat-
does not cross the blood-brain barrier, not recommended.55 ment, ipratropium improved sleep by
tends to be less sedative than cetirizine, almost 50%.77 However, because ipratro-
which occupies 30% of the histamine Oral and Intranasal pium does not relieve nasal congestion or
type 1 (H1) receptors in the brain.58 Corticosteroids sneezing associated with seasonal AR,
Because the second-generation antihis- Intranasal corticosteroids have proven the ARIA guidelines recommend it as
tamines are less sedating or nonsedating, efficacy in patients with AR, compared first-line therapy only when rhinorrhea is
their impact on learning and drowsiness with placebo. Several studies have the primary symptom.55,74
is similar to that of placebo.56,57 These demonstrated that corticosteroids can
agents effectively reduce itching, attenuate the expression and release of Mast Cell Stabilizers
sneezing, and watery rhinorrhea; how- pro-inflammatory cytokines from airway Sodium cromoglycate, with mast cell–sta-
ever, nasal obstruction is not reduced epithelial cells and that they are effective bilizing properties, is an effective strategy
significantly.55,59 in reducing the number of epithelial for controlling symptoms of AR with
Topical antihistamines, delivered by Langerhans’ cells, mast cells, eosinophils, minimal associated adverse effects. How-
nasal spray, avoid or minimize systemic IL-4 immunoreactive cells, and Th2 ever, its clinical effect is only for preven-
adverse effects. Azelastine hydrochlo- cells.33,62-68 Clinically, they reduce con- tive purposes, and sodium cromoglycate
ride used topically has been shown to gestion and improve sleep; furthermore, is most likely to be useful if initiated
reduce rhinorrhea but failed to reduce they reduce daytime sleepiness, daytime before symptoms become severe.78-81 It is
congestion in one study, but not in fatigue, and sleep problems.69,70 effective in young children, but it has the
another.60,61 Thus, the debate on benefits Because of their topical application disadvantage of having to be frequently
of antihistamines on nasal congestion and low systemic bioavailability, administered (up to six times daily), with
continues. Because antihistamines are intranasal corticosteroids are generally adherence to frequent dosing to achieve
not greatly effective in relieving conges- considered safe and have a minimal adequate prophylaxis.
tion, they are often combined with a influence on adrenal suppression.71,72
decongestant. However, because of the However, in treating concomitant dis- New Agents Currently in Use
potential adverse effects of deconges- eases such as asthma, the amounts of Although traditional agents provide relief
tants, caution should be used, especially nasal, inhaled, or oral steroids should be for a large number of patients, their lim-

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 Reduces
mediator release
B lymphocytes
Allergy inflammation:
Allergic eosinophils and
mediators lymphocytes
ε-switch

Plasma cell
Release
of IgE
Reduces asthma
Omalizumab exacerbations and
Allergens
symptoms

Binds to free
IgE, reducing
cell-bound IgE
Reduces
high-affinity
receptors

Mast cells
Basophils

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.

itations and adverse effects have significantly improves nighttime symp- bers of allergen-specific CD8 T lym-
prompted further, more targeted research toms (difficulty going to sleep, nighttime phocytes93-99 (Figure 4). Some evidence
on the medical management of AR. Of awakenings, and congestion on awak- also suggests that these events may be
particular use has been the ability to ening), as well as daytime symptoms mediated by an effect of immunotherapy
understand the similarities between the (congestion, rhinorrhea, pruritus, and on T lymphocytes with an alteration from
pathophysiology of asthma and that of sneezing), compared with placebo in a predominant “Th2” response to favor
AR, as well as the central role played by patients with allergies in the spring and an additional “Th1” response, which
CysLTs in both diseases. fall.85-87 Furthermore, montelukast sig- eventually would lead to the attenuation
nificantly reduces the number of periph- of tissue eosinophilia and local IgE pro-
Leukotriene Inhibitors eral blood eosinophils, suggesting that duction.100
As noted previously, CysLTs are key it reduces allergic inflammation system- Allergen-specific immunotherapy,
mediators of AR symptoms, and of con- ically.88 The combination of CystLTs administered under controlled condi-
gestion in particular. Therefore, the use of (montelukast) with antihistamines tions with immediate access to resusci-
antileukotrienes to alleviate both day- (loratadine), however, has not demon- tative equipment, has a prominent role in
time and nighttime symptoms is a strated better symptom relief than the treatment of severely symptomatic
rational approach. For example, after therapy with single agents alone.86 patients with allergic rhinitis who have
allergen challenge in patients with AR, failed to respond to conventional treat-
zileuton, a leukotriene synthesis inhibitor, Immunotherapy ment with antihistamines, topical cortico-
significantly reduced congestion.82 Sim- Immunotherapy has been shown to be steroids, or LRTAs, administerd singly
ilarly, the leukotriene receptor antago- effective in the treatment of seasonal and or in combination. The advantage of
nists provide effective symptomatic relief, perennial rhinitis.89-92 The proposed immunotherapy is that the immune
compared with placebo. For example, mechanisms for immunotherapy include system is modified, and this modifica-
pranlukast significantly reduced nasal blunting of elevations in IgE, decrease tion may be permanent or at least persist
mucosal swelling and zafirlukast signif- in serum neutrophil and eosinophil for years after therapy is terminated.
icantly reduced congestion, rhinorrhea, activity, reduction in the mast cell pop-
and sneezing.83,84 ulation as well as associated mediators, Comment
Montelukast, the only leukotriene and the suppression of allergen-induced Although numerous agents are available
receptor antagonist currently approved T-lymphocyte proliferative responses for the treatment of AR, it is crucial that
for treatment of AR in the United States, with an increase in the circulating num- allergen avoidance remains the corner-

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