ALLERGIC RHINITIS: NOTHING TO SNEEZE AT
From the 15th Annual Educational Meeting of the California Society of Allergy, Asthma, and Immunology
Eli O. Meltzer, MD, Clinical Professor, Department of Pediatrics, University of California, San Diego, School of
Medicine
| PATHOPHYSIOLOGY: IMPACT ON COMORBID CONDITIONS
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| Early-phase reaction: within minutes of exposure; involves de novo synthesis of newly generated mediators (cysteinyl
leukotrienes [CysLTs]; prostaglandins; platelet activating factor [PAF]; bradykinin; interleukins (ILs); tumor necrosis
factor alpha [TNF-α]; granulocyte-macrophage colony stimulating factor [GM-CSF]); early-phase reaction caused by receptors
on blood vessels, nerves, and glands
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| Late-phase reaction: release of cytokines and chemokines leads to activation of basophils, eosinophils, monocytes, and
lymphocytes (which in turn release more histamine, CysLTs, TNF-α, PAF, GM-CSF; and ILs); result is late-phase symptoms
of congestion, rhinorrhea, and sneezing
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| Inflammatory cells in nasal lavage samples: leukotriene (LT) synthetic proteins (eg, 5-lipoxygenase [5-LO], 5-lipoxygenase-activating
protein [FLAP], LTC4 synthase) in eosinophils, neutrophils, mast cells, and monocytes; CysTL
receptor on mast cells, neutrophils, eosinophils, and monocytes
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| AR symptoms: pathophysiology—histamine primary cause of pruritus and sneezing; CysTLs, prostaglandins, kinins,
neuropeptides known to cause rhinorrhea and also play role in development of congestion
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 | Ocular symptoms: itching; redness; chemosis; edema of eyelids; tearing; possible causative mechanisms—direct contact
of allergen with conjunctiva; ocular exposure to allergen via nasolacrimal duct (unlikely due to anatomic factors);
naso-ocular reflex (inflammatory mediators act on trigeminal nerve, causing release of neuropeptides that cause symptoms);
systemic reflex (presence of allergen in nerve causes parasympathetic stimulation that results in nasonasal reflex
and naso-ocular reflex); combination
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| Studies on ocular mechanism (Naclerio): involved unilateral nasal challenge; evaluation for nasonasal reflex in
contralateral nostril and evaluation for reflex changes in both eyes; collection of fluid to quantify amount of tears in
both eyes; in subsequent study, subjects treated with intranasal antihistamine before allergen challenge; findings—
nasal allergen challenge leads to ipsilateral and contralateral response, suggesting nasonasal reflex; responses reduced
by intranasal antihistamine; nasal allergen challenge also leads to ocular symptoms, suggesting eye symptoms induced
by naso-ocular reflex; these are also reduced by intranasal antihistamine
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| Effect of intranasal corticosteroids (ICS) on ocular symptoms: pretreatment with ICS (eg, flunisolide) reduces
amount of sneezing in early- and late-phase reactions; amounts of histamine, kinin, and vasoactive peptide also
reduced; by reducing nasal inflammation, ICS also reduce naso-ocular reflex; this is mechanism by which ICS reduce
symptoms of conjunctivitis; however, ICS cause only partial improvement in eye symptoms
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| Asthma associated with AR: incidence of asthma 2- to 3-fold greater (20%-30%) than in general population (10%);
possible causative mechanisms—activation of nasobronchial reflex; postnasal drainage of inflammatory material into
lower airway; shift from nasal to mouth breathing; systemic absorption of mediators and chemotactic factors from inflammatory
process in nose or sinuses, producing lower airway effects; evidence for nasobronchial reflex—in patients
with unilateral vagal nerve resection, bronchospasm produced when airway stimulated with silica on intact side, but not
on resected side; cold air in nose also causes bronchospasm
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| Nasal allergen provocation in patients with AR induces nasal and bronchial inflammation (study):
patients with AR (but nonasthmatic) compared to controls; both groups given nasal provocation by grass pollen; allergic patients
developed increased nasal symptoms; had reduced peak nasal inspiratory flow (PNIF); developed increased bronchial
symptoms; had decreased peak expiratory flow rate (PEFR); in addition, patients developed peripheral eosinophilia and increased
IL-5 in blood; increased eosinophils, IL-5, eotaxin cells, and adhesion molecules in nasal mucosa; and increased abnormalities
in bronchial mucosa; study showed crosstalk not only from upper to lower airway but from lower to upper
airway
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| Systemic propagation of inflammation (study): patients with AR (but nonasthmatic) compared to controls; both
groups given segmental bronchial grass pollen provocation; patients with AR developed increased nasal symptoms, obstruction
and reduced PNIF, bronchial symptoms, and decreased pulmonary function; also increased eosinophilia and IL-5
in blood and increased eosinophils, IL-5, and adhesion molecules in nasal mucosa and increased abnormalities in bronchial
mucosa
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| Systemic relationship between AR and asthma: local allergen exposure results in generalized inflammation; increased
production of mediators and inflammatory cells; absorption of mediators from local site, inducing release of eosinophils
from bone marrow; increased peripheral eosinophils migrate to site of allergen challenge and other areas;
recruitment to nasal and bronchial mucosa due to upregulation of adhesion molecules
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| Nasal allergen challenge increases bronchial hyperreactivity: series of Italian studies examining lower airway
(pulmonary function) in patients with perennial AR (PAR) or with seasonal AR (SAR); first study found 50% of patients
with SAR had increased bronchial hyperreactivity, although they remained asymptomatic; incidence even higher in patients
with PAR; in addition, 25% had decrease in forced expiratory flow rate (FEF 25-75); subsequent study with much larger
population again found increased bronchial hyperreactivity in 50% of patients with SAR and in >80% of those with PAR;
>50% of patients with increased hyperreactivity had abnormal FEF 25-75 (suggests FEF 25-75 could be marker of bronchial
impairment)
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| AR symptoms and asthma: patients with AR and asthma have more poorly controlled AR than those without asthma;
similarly, those with more severe nasal allergy tend to have less well controlled asthma, data show patients with no or
mild AR had better controlled asthma than those with more severe AR; also, incidence of hospitalizations and urgent
care/emergency department [ED] visits showed correlation between more severe allergic disease and more unstable
asthma
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| Patient Surveys: Burden of Rhinitis (2004)— survey questionnaire sent to 15,000 homes; identified 3800 individuals
thought to have AR and 3200 “nonsufferers” and compared them; Allergies in America (2006)—phone survey; 30,000
households systematically screened; ultimately focused on 2500 individuals who appeared to have AR
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| Morbidity associated with AR: in Burden of Rhinitis survey, 33% of participants with AR reported having mild disease,
50%, moderate disease, and 15%, severe disease; how bothersome were symptoms—75% of patients with stuffy
nose, 60% of those with runny nose, and 50% of patients with headache or itchy eyes claimed symptoms moderately or
extremely bothersome; impact on sleep—40% of patients with AR have difficulty falling asleep; 40% do not sleep
through night; 60% have nonrestorative sleep; study using Epworth sleepiness score found that AR leads to increased
daytime sleepiness; >80% in Allergies in America survey reported feeling tired; impact on mental status—>50% of patients
with AR say they are “miserable” or “irritable”; 25% to 35% report being depressed or embarrassed by their symptoms
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| Burden of AR: quality of life—85% of subjects felt AR interfered with daily life (40% to moderate or large degree);
>50% said disease caused them to miss work or interfered with performance; workforce productivity—survey comparing
1000 patients with AR and 1000 healthy individuals found correlation between increase in severity of allergy symptoms
and increase in limitation of ability to concentrate, to work without mistakes, and to handle workload;
comorbidities—in Burden of Rhinitis survey, 17% of patients with AR had comorbidities, in Allergies in America survey,
32%
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| Patients with AR often do not seek care for symptoms: in Burden of Rhinitis survey, >50% of patients with
severe disease had sought care (>40% did not get care); 70% of patients with moderate disease had not sought care;
>40% of patients with moderate to severe disease not taking medicine; patients who took medicine most commonly
used over-the-counter preparations; only 45% took prescription medicine
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| Perceived control of nasal symptoms over past 4 wk: only 13% of patients with severe disease and 25% with
moderate disease said symptoms well controlled or completely controlled; ocular symptoms also not well controlled
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New Pharmacologic Interventions
| Antihistamine-antileukotriene combination: 1997 study—compared treatment with 10 mg montelukast, 10 mg
loratadine, or placebo vs combination of loratadine and montelukast; patients who received combination therapy showed
significantly greater improvement in daytime nasal symptoms and trend toward greater improvement in nighttime nasal
symptoms and daytime eye symptoms; combined analysis of 3 studies (1997-99)—found treatment with montelukast or
loratadine alone significantly better than placebo, but loratadine/montelukast combination better than monotherapy; 12-
wk study (2004)—looked at treatment with montelukast, cetirizine, placebo or combination of both medications; combination
more effective than placebo and more effective than either drug alone in reducing congestion, rhinorrhea, sneezing,
and nasal and eye itching; also, level of marker for eosinophilic activity (eosinophil cationic protein) significantly
increased in all groups except those who received combination therapy
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| Intranasal antihistamines: available for >10 yr; azelastine best known; study of olopatadine (0.4% and 0.6% formulations
as nasal spray) vs placebo for treatment of SAR showed greater improvement in total nasal symptom score (TNSS)
with intranasal olopatadine (superior to placebo for individual symptoms of runny nose, itchy nose, sneezing, and congestion);
study at speaker’s institution—also found intranasal olopatadine superior to placebo reflectively and at end of
dosing interval; 0.4% and 0.6% preparations both effective, but 0.6% “worked somewhat better”; did not show greater
improvement in nasal congestion; however, in all 7 Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) domains,
0.6% olopatadine proved superior to placebo; incidence of bitter taste less than with azelastine
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| Intranasal antihistamine and/or ICS: study looked at treatment with intranasal antihistamine (azelastine) or ICS
(fluticasone propionate [FP]) alone vs combination; conclusions—combination of antihistamine and ICS more efficacious
than monotherapy with either component and provided 40% improvement in symptom relief (TNSS) over either
agent alone; individual symptoms of nasal congestion, itchy nose, rhinorrhea, and sneezing all showed significantly
greater improvement; 48% greater improvement of congestion (single most bothersome symptom) than with FP alone
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New ICS
| Ciclesonide: prodrug (on-site activation); has first-pass metabolism (low bioavailability in gut); high protein binding so
less bioavailability outside nasal airway; reduced adverse event profile; lipid conjugation enables symptom relief over 24
hr; unique hypotonic formulation allows greater adherence to cells and longer time in nasal tissue; study of ciclesonide
for treatment of SAR showed significant improvement in TNSS; patients better within 24 hr, and improvement sustained
over 4-wk study period; also studied for treatment of PAR (magnitude of improvement similar to that seen in SAR study)
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| Fluticasone furoate (FF): properties different from those of FP; has high glucocorticosteroid receptor binding in cytoplasm;
once bound to receptor, has more rapid translocation to cell nucleus than FP or dexamethasone (presumably facilitates
clinical efficacy); clinical study (SAR in adults)—FF showed improvement in TNSS reflectively over first 24 hr
and statistically significant improvement over 2-wk period; also showed improvement in ocular symptoms; markedly
better than placebo in all RQLQ domains; trials in children 2 to 11 yr of age—found 55-µg dose (1 spray/nostril) and
110-µg dose (2 sprays/nostril) produced greater degree of improvement than placebo; however, in SAR trial, only children
receiving 110 µg showed statistically significant improvement, while in trials for treatment of PAR, children who received
55 µg showed better improvement than those who got 110 µg dose; start child on 1 spray/nostril and increase to 2
sprays/ nostril if child not doing well
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| Immunotherapy (IT): practiced since early 1900s; classic study looked at patients who received 3 to 4 yr of grass pollen
subcutaneous IT (SIT); patients then randomized to receive monthly maintenance therapy or placebo for additional
3 yr; 15 newly recruited untreated patients added to observe natural course of disease; findings—in first 3 to 4 yr, patients
on SIT showed greater improvement in symptoms, medication use, and visual analog score; patients who continued
with therapy and patients who discontinued therapy both did better than those on placebo
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| IT with ragweed-toll-like receptor 9 agonist vaccine for AR: patients who were ragweed sensitive randomized to receive
either placebo or ragweed conjugated to immunostimulatory sequence of DNA (purpose to increase activity of toll-like
receptor 9, with the goal of making patients more immunologically responsive; immunostimulatory sequence called
absorbed immunologic chemical [AIC]); treatment given before ragweed season, and patients followed; patients who
received AIC improved by their own perception and on visual analog scale in categories of daily symptoms, quality of
life, eye symptoms, and sleep; immunologically, patients had greater increase in Amb a1-specific IgG antibody; decrease
in Amb a1-specific IgE antibody; greater decrease in intradermal skin test and greater decrease in number of IL-
4-positive basophils; without giving further doses, in second year, patients on AIC found to do better on visual analog
scale and used less medication
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| SIT with anti-IgE monoclonal antibody treatment: patients given SIT with grass pollen allergen plus omalizumab,
SIT with grass pollen allergen alone; omalizumab alone, or SIT with unrelated allergen (eg, birch); patients who
received SIT plus anti-IgE monoclonal antibody showed greater improvement in ocular and nasal symptoms, compared
to those who received either therapy alone (patients who received SIT with unrelated allergen did not do as well); combination
seemed to do better, as measured by symptom relief and medication use
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Suggested Reading
Berger W et al: Impact of azelastine nasal spray on symptoms and quality of life compared with cetirizine oral tablets in
patients with seasonal allergic rhinitis. Ann Allergy Asthma Immunol 97:375, 2006; Braunstahl GJ et al: Nasal allergen
provocation induces adhesion molecule expression and tissue eosinophilia in upper and lower airways. J Allergy Clin Immunol
107:469, 2001; Braunstahl GJ et al: Segmental bronchial provocation induces nasal inflammation in allergic
rhinitis patients. Am J Respir Crit Care Med 161:2051, 2000; Ciprandi G et al: Bronchial hyperreactivity and spirometric
impairment in patients with seasonal allergic rhinitis. Respir Med 98:826, 2004; Ciprandi G et al: Role of FEF25-75
as an early marker of bronchial impairment in patients with seasonal allergic rhinitis. Am J Rhinol 20:641, 2006; Creticos
PS et al: Immune Tolerance Network Group. Immunotherapy with a ragweed-toll-like receptor 9 agonist vaccine for allergic
rhinitis. N Engl J Med 355:1445, 2006; Durham SR et al: Long-term clinical efficacy of grass-pollen immunotherapy.
N Engl J Med 341:468, 1999; Fokkens WJ et al: Once daily fluticasone furoate nasal spray is effective in
seasonal allergic rhinitis caused by grass pollen. Allergy 62:1078, 2007; Hampel FC Jr et al: Improved quality of life
among seasonal allergic rhinitis patients treated with olopatadine HCl nasal spray 0.4% and olopatadine HCl nasal spray
0.6% compared with vehicle placebo. Allergy Asthma Proc 27:202, 2006; Hansen I et al: Mediators of inflammation in
the early and the late phase of allergic rhinitis. Curr Opin Allergy Clin Immunol 4:159, 2004; Kaiser HB et al: Fluticasone
furoate nasal spray: a single treatment option for the symptoms of seasonal allergic rhinitis. J Allergy Clin Immunol
119:1430, 2007; Lamb CE et al: Economic impact of workplace productivity losses due to allergic rhinitis compared
with select medical conditions in the United States from an employer perspective. Curr Med Res Opin 22:1203, 2006;
Meltzer EO: Allergic rhinitis: managing the pediatric spectrum. Allergy Asthma Proc 27:2, 2006; Meltzer EO: Clinical
evidence for antileukotriene therapy in the management of allergic rhinitis. Ann Allergy Asthma Immunol (4 Suppl
1):23, 2002; Meltzer EO: Formulation considerations of intranasal corticosteroids for the treatment of allergic rhinitis.
Ann Allergy Asthma Immunol 98:12, 2007; Meltzer EO: The relationships of rhinitis and asthma. Allergy Asthma Proc
26:336, 2005; Meltzer EO et al: Efficacy and safety of ciclesonide, 200 microg once daily, for the treatment of perennial
allergic rhinitis. Ann Allergy Asthma Immunol 98:175, 2007; Meltzer EO et al: Safety and efficacy of olopatadine
hydrochloride nasal spray for the treatment of seasonal allergic rhinitis. Ann Allergy Asthma Immunol 95:600, 2005; Parks
KW, Casale TB: Anti-immunoglobulin E monoclonal antibody administered with immunotherapy. Allergy Asthma
Proc 27(2 Suppl 1):S33, 2006; Ratner PH et al: Efficacy and safety of ciclesonide nasal spray for the treatment of seasonal
allergic rhinitis. J Allergy Clin Immunol 118:1142, 2006; Rolinck-Werninghaus C et al: Omalizumab Rhinitis
Study Group. The co-seasonal application of anti-IgE after preseasonal specific immunotherapy decreases ocular and nasal
symptom scores and rescue medication use in grass pollen allergic children. Allergy 59:973, 2004; Spector SL: Overview
of comorbid associations of allergic rhinitis. J Allergy Clin Immunol 99:S773, 1997.
Educational Objectives
| The goal of this program is to improve the treatment of allergic rhinitis (AR), focusing on the pathophysiology of the disease
and its impact on comorbid conditions and on emerging therapies for treatment. After hearing and assimilating this
program, the clinician will be better able to:
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| 1. Discuss the components that contribute to the pathogenesis of AR.
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| 2. Describe the possible causative mechanisms of the interrelationships between AR and asthma.
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| 3. Examine the effect of AR on quality of life.
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| 4. Explain the additional treatment benefits of oral antihistamine–antileukotriene combinations, intranasal antihistamine
–corticosteroid combinations, and newer intranasal corticosteroids.
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| 5. Describe some of the recent modifications of subcutaneous immunotherapy.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty members to disclose relevant
financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified conflicts
were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial
interest. For this program, the following has been disclosed: Dr. Meltzer has received grants/research support from,
been on the Speaker’s Bureaus for, and/or served as a consultant for Abbott, Adelphi, Alcon, Allux, Altana, Amgen, AstraZeneca,
Capnia, Clay-Park, Critical Therapeutics, Dey, Evolutec, Genentech, GlaxoSmithKline, Greer, Inspire, Hoffmann-
LaRoche, KOS, MediciNova, MedPointe, Merck, Novartis, Pharmaxis, Pfizer, Rigel, Sanofi-Aventis, Schering-Plough,
Shionogi, Teva, Verus, and Wyeth.
Acknowledgements
Dr. Meltzer was recorded at A Midsummer Night’s Wheeze, the 15th Annual Educational Meeting of the California Society
of Allergy, Asthma, and Immunology, held July 27-29, 2007, in San Francisco, CA, and sponsored by the Office of Continuing
Medical Education, Keck School of Medicine of the University of Southern California and the California Society of Allergy,
Asthma, and Immunology. The Audio-Digest Foundation thanks Dr. Meltzer and the sponsors for their cooperation
in the production of this program.
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