OCM - ALLERGIC RHINITIS

Information
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A. Introduction

1.   Usually presents first in childhood or adolescence
2.   Often seasonal, spring and autumn
3.   Sneezing, rhinorrhea, nasal congestion, upper airway irritation
4.   Prevalence is ~10% of population
5.   Family history usually positive




B. Signs and Symptoms

1.   Nasal mucosa boggy, pale blue
a.   Clear discharge
b.   Thick yellow, yellow-green or brownish sputum suggests bacterial superinfection
c.   In allergic disease, eosinophils may be present on nasal smear


2.   Frequent sneezing
3.   Congestion apparent in patient's voice change
4.   Conjunctivitis (red eye) often present
5.   Sinus tenderness may be present
6.   Post-nasal drip may stimulate chronic cough
7.   Assess for wheezing and other signs of associated asthma




C. Pathophysiology [2,3]

1.   Allergic rhinitis is a Type I (IgE mediated) hypersensitivity reaction
2.   Aeroallergens are usually responsible
a.   Typically 5-70µm in diameter
b.   Dust mites and their droppings are probably the most important
c.   They live indoors in (older) bedding, carpets and upholstery
d.   However, reducing dust mite exposure in established allergic rhinitis did not improve clinical symptoms [21]
e.   Tree, grass and ragweed pollens are most common seasonal allergens
f.   Indoor and outdoor fungi
g.   Animal allergens including rat urine, cat dander, saliva and urine, and dog allergens


3.   Allergens inhaled through nose
a.   Processed by nasal mucosal macrophages, dendritic cells (antigen presenting cells, APC)
b.   Antigens expressed with class II MHC molecules on APC surface
c.   APC migrate to lymph nodes and present to T lymphocytes
d.   T lymphocytes are of the Th2 type and produce IL4, 5, 13 other cytokines
e.   These cytokines stimulate B lymphocytes to produce IgE
f.   IgE is major driver for allergic responses


4.   Tissue mast cells and blood borne basophils are activated by IgE
a.   IgE binds high affinity FcE receptors on these cells
b.   Mast cell degranulation is the initial "effector" event in allergic rhinitis
c.   Release of preformed mediators including histamine and bradykinin
d.   Histamine is responsible for ~50% of the symptoms
e.   Histamine also induces release of substance P from neurons, adding to symptoms
f.   Prostaglandins D2 and F2 as well as tryptase also released early
g.   Some leukotriene (LT) synthesis also takes place in the mast cells
h.   All of these molecules are proinflammatory, vasodilatory, and/or edema-inducing


5.   Other Effector Cells are Recruited
a.   Recruitment is mediated through specific cell-cell adhesion molecule interactions
b.   Expression of these cell adhesion molecules (CAM) induced by inflammatory mediators
c.   ICAM-1 and 2, VCAM, PECAM, and other CAMs are expressed on inflamed nasal mucosa
d.   Eosinophils, basophils and some neutrophils infiltrate mucosa
e.   Eosinophils release various cationic proteins and produce LT C4, D4 and E4
f.   Basophils release many of the same mediators as mast cells


6.   Effects are nasal inflammation, edema, pain, pruritus, erythema, congestion
7.   Chronic allergic rhinitis can lead to irreversible damage to tissues with fibrosis




D. Differential Diagnosis

1.   Allergic Rhinitis
2.   Eosinophilia Syndrome - may include anosmia
3.   Aspirin Sensitive Rhinosinusitis [17]
a.   Aspirin allergies often coexist in patients with asthma and/or sinusitis
b.   Aspirin allergies in setting of asthma, rhinosinusitis linked to elevated cysteinyl leukotriene receptor (CysLT1) expression
c.   Nasal polyps often with found
d.   Asthma, aspirin hypersensitivity, polyps often called "triad asthma"


4.   Nasal Polyps without aspirin sensitivity - uncommon
5.   Vasomotor rhinitis - congestion, rhinorrhea, anosmia, postnasal drip
6.   Sinusitis
7.   Nasal Decongestant Abuse - rebound with severe erythema of nasal passages




E. Diagnosis [8]

1.   Definitive diagnosis is not generally available
2.   Differential diagnosis should be considered initially based on history and physical
3.   Limited laboratory testing may be useful in differential diagnosis or severe cases
4.   Most patients should receive empiric treatment and assess response
5.   Most diagnostic tests for allergens have highly variable sensitivity and specificity
6.   Identify allergens with patient's skin testing or in vitro IgE specific antibody detection [3]
a.   Avoid the allergens identified
b.   Role of dust mites in perpetuating allergic asthma is unclear
c.   Allergen impermeable covers did not reduce asthma or allergic rhinitis in adults, including those with serum IgE to mite antigens [20,21]
d.   Therefore, most patients with allergic rhinitis should receive empiric treatment initially
e.   Allergen identity allows tailoring of immunotherapy






F. Treatment [2,3]

1.   Reduction of known allergens may be beneficial
2.   Intranasal Vasoconstrictors
a.   Not for chronic therapy due to tolerance buildup and rebound, which may be severe
b.   Use for exacerbations and/or until nasal glucocorticoids take effect
c.   Mainly alpha1-adrenergic agonists
d.   Long Acting - oxymetazoline (Afrin®), xylometazoline (Otrivin®)
e.   Intermediate Acting - naphazoline (Privine®), tetrahydrozoline (Tyzine®)
f.   Short Acting - phenylephrine (Neo-Synephrine®)
g.   Should not be used for more than 3-4 days, or rebound congestion may occur
h.   Rebound causes "rhinitis medica mentosa" and responds to nasal steroids
i.   Thus, combination of oxymetazoline and nasal steroids for acute treatment may be optimal therapy in persons with frequent attacks


3.   Intranasal Glucocorticoids [6,9,11]
a.   Probably most effective long term agent and well tolerated
b.   Intranasal glucocorticoids more effective than oral antihistamines
c.   First line for moderate to severe disease and very useful in mild allergic rhinitis
d.   Beclomethasone - Beconase® and Vancenase® (1-2 puffs/nostril bid-qid)
e.   Budesonide (Rhinocort®) - 2-4 puffs/nostril qd-bid
f.   Ciclesonide (Omnaris®) - 2 puffs per nostril qd [26]
g.   Flunisolide (Nasalide®) - 2 puffs/nostril bid
h.   Fluticasone (Flonase®, Veramyst®) - 2 puffs/nostril qd-bid
i.   Mometasone (Nasonex®) - 2 puffs/nostril qd
j.   Triamcinolone (Nasacort®) - 2 puffs/nostril qd-bid
k.   Combined with systemic antihistamines for most patients with moderate to severe rhinitis


4.   Intranasal Antihistamines
a.   Control symptoms well, but intranasal glucocorticoids are generally preferred
b.   Azelastine (Astelin®) - 0.1% nasal spray 1-2 puffs/nostril bid [6]
c.   Azelastine is absorbed systemically and may cause drowsiness
d.   Olopatadine (Patanase®) - 0.65 nasal spray 2 puffs/nostril bid [27]


5.   Ipratropium Bromide Nasal Spray (Atrovent®)
a.   Anti-cholinergic agent with efficacy in allergic rhinitis
b.   May be as effective as nasal glucocorticoids
c.   Dries nasal mucosa, reduces pruritic component


6.   Cromolyn Compounds
a.   Believed to be mast cell stabilizers
b.   Cromolyn Sodium (Nasalcrom®) may prevent symptoms of rhinitis
c.   Dose is 1 puff per nostril qid for 1 month, then reduce dose to tid or bid
d.   Ocular formulation (Crolom®) 4% solution is available for allergic conjunctivitis


7.   Systemic Antihistamines [5]
a.   Newer anti-H1 antagonists have less sedation activity and rapid onset of action
b.   They are more expensive (2-20 fold higher cost) than first generation agents
c.   Combination of antihistamines and decongestants are popular and effective


8.   First Generation Antihistamines [1,6]
a.   May cause somnolence, slowed cognition and reaction time, reduced work efficacy
b.   Also, urinary retention, dry mouth, tachycardia
c.   Prolonged QTc very uncommon
d.   Examples: Diphenhydramine (Benadryl®), Chlorpheniramine (Chlor-Trimeton®)
e.   Triprolidine (Actifed®), Hydroxizine (Atarax®, Vistaril®)


9.   Second Generation Antihistamines [1,6,18]
a.   Agents have minimal adverse CNS or anticholinergic effects
b.   Loratidine (Claritin®) - 10mg po qd; now available without prescription [18]
c.   Desloratidine (Clarinex®) - 5-20mg po qd; no QT prolongation [16]
d.   Fexofenadine (Allegra®) - 60mg po bid; onset <6 hours; no QT prolongation
e.   Cetirizine (Zyrtec®) - 5-10mg po qd; onset in 1-2 hours; no QT prolongation
f.   Levocetirizine (L-cetirizine, Xyzal®): 5mg qd; active cetirizine enantiomer [25]
g.   Fexofenadine appears to be most effective and safe at recommended doses overall [16]
h.   Fexofenadine free of sedation, even at high doses; loratadine nonsedating at standard doses; cetirizine more sedating than other second generation agents [25]


10.   Systemic Leukotriene Blockade [4,19,24]
a.   Leukotriene receptor antagonists montelukast, zafirlukast approved for use in asthma
b.   Montelukast (Singulair®) 10mg po qd approved for seasonal allergic rhinitis, age >2 years
c.   Very well tolerated but modest efficacy as single agents
d.   Appear less effective than intranasal glucocorticoids
e.   May be used in combination with other agents in patients with suboptimal responses


11.   Oral Decongestants
a.   Alpha1-agonists, often in combination with other agents such as antihistamines
b.   Pseudoephedrine (Sudafed®, others) - 30mg po qid or 60mg bid for long acting forms
c.   Phenylpropanolamine - associated with increased stroke risk in women; withdrawn from over-the-counter market [12]
d.   Loratidine/pseudoephedrine and other combinations are available


12.   Anti-IgE Immunotherapy [13,14,22]
a.   Monoclonal antibody omalizumab specifically binds to human IgE
b.   Omalizumab binds more than 95% of free serum IgE
c.   Reduction in serum IgE causes reduction in IgE (FcE) receptors on mast cells, basophils
d.   Given weekly, reduces symptoms of rhinitis during ragweed allergy season
e.   Omalizumab also reduces symptoms in severe allergic asthma [15,22]


13.   Immunotherapy [2]
a.   Goals: convert IgE to an IgG response and reduce hypersensitivity symptoms
b.   Requires skin testing or radioallergen tests (RAST) to determine offending agent
c.   Open ended trial of weekly injections of small amounts of agents are given
d.   ~85% of patients obtain long term symptom relief
e.   After 4-6 seasons, immunotherapy can usually be discontinued


14.   Immunotherapy with Ragweek-TLR-9 Agonist Vaccine [10]
a.   Toll-like receptor 9 (TLR-9) stimulates Th1 cytokines
b.   Amb a 1, ragweek-pollen allergen, conjugated to a TLR-9 stimulator
c.   Six weekly injections of conjugate vaccine versus placebo
d.   Vaccine reduced peak-seaon rhinitis scores and daily nasal symptoms
e.   Vaccine also prevented usual seasonal increase in ragweed specific IgE response
f.   Generally well tolerated


15.   Systemic glucocorticoids may be used in very severe and resistant cases




F. Treatment of Allergic Conjunctivits [7]

1.   Conjunctivitis, severe redness in eyes with pruritis, is frequent with allergic rhinitis
2.   Topical agents of various classes are usually used
a.   NSAIDs
b.   Antihistamines
c.   Mast cell stabilizers


3.   Caution in patients with glaucoma
4.   Ocular Ketorolac (Acular®) - NSAID with good efficacy, use limited to 7-14 days
5.   Ocular Antihistamines
a.   Levocabastine (Livostin®) - new ocular anti-H1-histamine, with rapid efficacy
b.   Olopatadine (Patanol®) - 0.1%; selective H1-antagonist and mast cell stabilizer
c.   Epinastine (Elestat®) - 0.05%; selective H1-antagonist and mast cell stabilizer [23]


6.   Ocular Mast Cell Stabilizers
a.   Lodoxamide (Alomide®) - ocular mast cell stabilizer, 0.1%, use limited to 3 months
b.   Cromolyn Sodium (Crolom®) - mast cell stabilizer, 4% solution is available


7.   Unless otherwise indicated, use agents for 2-12 weeks


References
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1.   Kay AB. 2001. NEJM. 344(1):30 
2.   Kay AB. 2001. NEJM. 344(2):109 
3.   Plaut M and Valentine MD. 2005. NEJM. 353918):1935
4.   WIlson AM, O'Byrne PM, Parameswaran K. 2004. Am J Med. 116(5):338 
5.   Antihistamines. 1996. Med Let. 38(970):21 
6.   Azelastine. 1997. Med Let. 39(1000):47 
7.   Allergic Conjunctivitis. 1997. Med Let. 39(1014):108 
8.   Gendo K and Larson EB. 2004. Ann Intern Med. 140(4):278 
9.   Fluticasone for Allergic Rhinitis. 2007. Med Let. 49(1273):90 
10.   Creticos PS, Schroeder JT, Hamilton RG, et al. 2006. NEJM. 355(14):1445 
11.   Mometasone. 1999. Med Let. 41(1046):16 
12.   Phenylpropanolamine. 2000. Med Let. 42(1094):113 
13.   Plaut M. 2001. JAMA. 286(23):3005 
14.   Casale TB, Condemi J, LaForce C, et al. 2001. JAMA. 286(23):2956 
15.   Busse W, Corren J, Lanier BQ, et al. 2001. J Allergy Clin Immunol. 108:184 
16.   Desloratidine. 2002. Med Let. 44(1126):27 
17.   Sousa AR, Parikh A, Scadding G, et al. 2002. NEJM. 347(19):1493 
18.   Loratidine OTC. 2003. Med Let. 45(1147):3 
19.   Montelukast for Allergic Rhinitis. 2003. Med Let. 45(1152):21 
20.   Woodcock A, Forster L, Mathhews E, et al. 2003. NEJM. 349(3):225 
21.   Terreehorst I, Hak E, Oosting AJ, et al. 2003. NEJM. 349(3):237 
22.   Omalizumab. 2003. Med Let. 45(1163):67 
23.   Epinastine. 2004. Med Let. 46(1181):35 
24.   Montelukast for Allergic Rhinitis. 2005. Med Let. 47(1220):85 
25.   Levocetirizine. 2007. Med Let. 49(1275):97 
26.   Ciclesonide. 2008. Med Let. 50(1285):33 
27.   Olopatadine. 2008. Med Let. 50(1289):51 

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