Treatment of Allergic Rhinitis
`
`DENISE K. SUR, MD, and STEPHANIE SCANDALE, MD, David Geffen School of Medicine,
`University of California, Los Angeles, California
`
`Allergic rhinitis is a common chronic respiratory illness that affects
`quality of life, productivity, and other comorbid conditions, includ-
`ing asthma. Treatment should be based on the patient’s age and sever-
`ity of symptoms. Patients should be advised to avoid known allergens
`and be educated about their condition. Intranasal corticosteroids
`are the most effective treatment and should be first-line therapy for
`mild to moderate disease. Moderate to severe disease not respon-
`sive to intranasal corticosteroids should be treated with second-line
`therapies, including antihistamines, decongestants, cromolyn, leu-
`kotriene receptor antagonists, and nonpharmacologic therapies (e.g.,
`nasal irrigation). With the exception of cetirizine, second-generation
`antihistamines are less likely to cause sedation and impair perfor-
`mance. Immunotherapy should be considered in patients with a less
`than adequate response to usual treatments. Evidence does not sup-
`port the use of mite-proof impermeable covers, air filtration systems,
`or delayed exposure to solid foods in infancy. (Am Fam Physician.
`2010;81(12):1440-1446. Copyright © 2010 American Academy of
`Family Physicians.)
`
`ILLUSTRATION BY MARk LefkOwITz
`
`corticosteroids, oral and topical antihista-
`mines, decongestants, intranasal cromolyn
`(Nasalcrom),
`intranasal anticholinergics,
`and leukotriene receptor antagonists.4,5 The
`International Primary Care Respiratory
`Group, British Society for Allergy and Clini-
`cal Immunology, and American Academy of
`Allergy Asthma and Immunology recom-
`mend initiating therapy with an intranasal
`corticosteroid alone for mild to moderate
`disease and using second-line therapies for
`moderate to severe disease.4-7 Patients with
`moderate to severe disease not responding to
`oral or topical treatments should be referred
`for consideration of
`immunotherapy.3,8
`Table 2 gives a summary of pharmacologic
`treatments for allergic rhinitis.
`
`INTRANASAL CORTICOSTEROIDS
`
`▲ Patient information:
`A handout on this topic is
`available at http://
`familydoctor.org/083.xml.
`
`A
`
` llergic rhinitis is an immunoglobu-
`lin E–mediated disease, thought
`to occur after exposure to indoor
`and outdoor allergens such as
`dust mites, insects, animal danders, molds,
`and pollens. Symptoms include rhinorrhea,
`nasal congestion, obstruction, and pruritus.1
`Optimal treatment includes allergen avoid-
`ance, targeted symptom control, immunother-
`apy, and asthma evaluation, when appropriate.2
`In 2001, Allergic Rhinitis and Its Impact on
`Asthma guidelines were published in coopera-
`tion with the World Health Organization, sug-
`gesting that the treatment of allergic rhinitis
`make use of a combination of patient educa-
`tion, allergen avoidance, pharmacotherapy,
`and immunotherapy.3 In contrast with previ-
`ous guidelines, these recommendations are
`based on symptom severity and age, rather than
`the type or frequency of seasonal, perennial, or
`occupational exposures. Table 1 lists recom-
`mended treatments based on symptoms.
`
`Intranasal corticosteroids are the mainstay
`of treatment of allergic rhinitis. They act
`by decreasing the influx of inflammatory
`cells and inhibiting the release of cytokines,
`Pharmacotherapy
`thereby reducing inflammation of the nasal
`mucosa.3 Their onset of action is 30 minutes,
`treat-
`the
`for
`Pharmacologic options
`ment of allergic rhinitis include intranasal
`although peak effect may take several hours
`Exhibit 1071
`Volume 81, Number 12 ◆ June 15, 2010
`IPR2017-00807
`www.aafp.org/afp
`ARGENTUM
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`SORT: KEY RECOMMENDATIONS FOR PRACTICE
`
`Clinical recommendation
`
`Allergic Rhinitis
`
`Evidence
`rating
`
`References
`
`The initial treatment of mild to moderate allergic rhinitis should be an intranasal corticosteroid alone,
`with the use of second-line therapies for moderate to severe disease.
`Compared with first-generation antihistamines, second-generation antihistamines have a better adverse
`effect profile, including less sedation (with the exception of cetirizine [Zyrtec]).
`The adverse effects and higher cost of intranasal antihistamines, as well as their decreased effectiveness
`compared with intranasal corticosteroids, limit their use as first- or second-line therapy for allergic rhinitis.
`Although safe for general use, intranasal cromolyn (Nasalcrom) is not considered first-line therapy for
`allergic rhinitis because of its decreased effectiveness at relieving the symptoms of allergic rhinitis and
`its inconvenient dosing schedule.
`Nasal saline irrigation is beneficial in treating the symptoms of chronic rhinorrhea and may be used alone
`or as adjuvant therapy.
`Although dust mite allergies are common, studies have not found any benefit to using mite-proof
`impermeable mattress and pillow covers.
`Interventions without documented effectiveness in the prevention of allergic rhinitis include breastfeeding,
`delayed exposure to solid foods in infancy, and the use of air filtration systems.
`
`A
`
`A
`
`A
`
`C
`
`B
`
`A
`
`B
`
`4, 5, 7
`
`22
`
`28, 29
`
`1, 3
`
`53
`
`54-56
`
`57-61
`
`A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-
`oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to http://www.aafp.
`org/afpsort.xml.
`
`are a few studies that looked specifically at the effects of
`intranasal corticosteroids on skeletal growth and adre-
`nal activity. One RCT found the rate of skeletal growth
`unaffected in children using mometasone for one year.17
`Similarly, a well-designed prospective study did not
`show any difference in growth in children using nasal
`
`Table 1. Allergic Rhinitis Treatment Based on Symptoms
`
`to days, with maximum effectiveness usually noted after
`two to four weeks of use.9
`Many studies have demonstrated that nasal corticoste-
`roids are more effective than oral and intranasal antihis-
`tamines in the treatment of allergic rhinitis.4,5,10-12 One
`randomized controlled trial (RCT) looking at quality-
`of-life measures compared the antihistamine
`loratadine (Claritin) with the nasal corti-
`costeroid fluticasone (Flonase) in 88 adults
`over a four-week period.13 The study’s results
`showed that symptom scores were compara-
`ble, but quality-of-life scores were superior in
`the nasal corticosteroid group.
`Although there is no evidence that one
`intranasal corticosteroid
`is superior to
`another, many of the available products
`have different age indications from the U.S.
`Food and Drug Administration (FDA). Only
`budesonide (Rhinocort) carries the FDA
`pregnancy category B safety rating, and only
`mometasone (Nasonex) has a delivery device
`that received recognition from the National
`Arthritis Foundation for ease of use.14
`The adverse effects most commonly expe-
`rienced with the use of intranasal corti-
`costeroids are headache, throat irritation,
`epistaxis, stinging, burning, and nasal dry-
`ness.3,15 Although the use of intranasal cor-
`ticosteroids has raised concern for potential
`systemic adverse effects, including the sup-
`pression of the hypothalamic-pituitary axis,
`the products currently available have not
`been shown to have such effects.16 There
`
`Treatment type
`
`Intranasal
`corticosteroids
`
`Oral antihistamines
`
`Intranasal
`antihistamines
`
`Decongestants
`
`Intranasal
`cromolyn
`(Nasalcrom)
`
`Intranasal
`anticholinergics
`
`Leukotriene
`receptor
`antagonists
`
`Nasal saline
`irrigation
`
`Immunotherapy
`
`Ocular
`symptoms
`
`Nasopharyngeal
`itching
`
`Sneezing
`
`Rhinorrhea
`
`✔
`
`✔
`
`—
`
`✔
`
`—
`
`—
`
`✔
`
`—
`
`✔
`
`✔
`
`✔
`
`✔
`
`—
`
`✔
`
`—
`
`—
`
`—
`
`—
`
`✔
`
`✔
`
`✔
`
`—
`
`✔
`
`—
`
`—
`
`—
`
`✔
`
`✔
`
`✔
`
`✔
`
`✔
`
`✔
`
`✔
`
`✔
`
`✔
`
`✔
`
`NOTe: Listed in order of treatment preference.
`
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`Allergic Rhinitis
`Table 2. Summary of Treatments for Allergic Rhinitis
`
`Pregnancy
`category
`
`Minimum
`age
`
`Mechanism and onset
`of action
`
`Adverse effects
`
`Six years
`Six years
`Six years
`Six years
`Two years
`12 years
`Two years
`12 years
`
`Six months
`Six months
`Six months
`12 years
`Two years
`
`Five years
`Six years
`
`12 years
`
`Two years
`
`Inhibits the influx of
`inflammatory cells;
`onset of action is less
`than 30 minutes
`
`Bitter aftertaste, burning, epistaxis,
`headache, nasal dryness, potential
`risk of systemic absorption, rhinitis
`medicamentosa, stinging, throat
`irritation
`
`Blocks H1 receptors; onset of
`action is 15 to 30 minutes
`
`Dry mouth, sedation at higher than
`recommended doses
`
`Blocks H1 receptors; onset of
`action is 15 minutes
`
`Bitter aftertaste, epistaxis, headache,
`nasal irritation, sedation
`
`Vasoconstriction; onset of
`action is 15 to 30 minutes
`
`Arrhythmias, dizziness, headache,
`hypertension, insomnia, nervousness,
`tremor, urinary retention
`
`Inhibits histamine release;
`results typically noted in one
`week, but may take two to
`four weeks for full effect
`
`epistaxis, nasal irritation, sneezing
`
`Six years
`
`Blocks acetylcholine receptors;
`onset of action is 15 minutes
`
`epistaxis, headache, nasal dryness
`
`Six months
`
`Blocks leukotriene receptors;
`onset of action is two hours
`
`elevated levels of alanine transaminase,
`aspartate transaminase, and bilirubin
`
`Treatment
`
`Intranasal corticosteroids
`Beclomethasone (Beconase)
`Budesonide (Rhinocort)
`Ciclesonide (Omnaris)
`Flunisolide
`Fluticasone furoate (Veramyst)
`Fluticasone propionate (Flonase)
`Mometasone (Nasonex)
`Triamcinolone (Nasacort)
`Oral antihistamines
`Cetirizine (Zyrtec)
`Desloratadine (Clarinex)
`Fexofenadine (Allegra)
`Levocetirizine (Xyzal)
`Loratadine (Claritin)
`Intranasal antihistamines
`Azelastine (Astelin)
`Olopatadine (Patanase)
`Oral decongestants
`Pseudoephedrine
`
`Intranasal cromolyn
`Cromolyn (Nasalcrom)
`
`Intranasal anticholinergics
`Ipratropium (Atrovent)
`
`B
`C
`C
`C
`C
`C
`C
`C
`
`B
`C
`C
`B
`B
`
`C
`C
`
`C
`
`B
`
`B
`
`Leukotriene receptor antagonists
`Montelukast (Singulair)
`B
`
`NOTe: Listed in order of treatment preference.
`
`corticosteroids for at least three years.18 However, one
`randomized trial of 90 children (six to nine years of
`age) who were treated with beclomethasone (Beconase)
`or placebo for one year showed suppressed growth rates
`in the group taking beclomethasone compared with the
`placebo group.19 Although nasal fluticasone has been
`shown to reduce endogenous cortisol excretion in one
`study, its impact on growth is unknown.20 Despite the
`data, all intranasal corticosteroids carry a warning that
`long-term use may restrict growth in children.
`
`ORAL ANTIHISTAMINES
`
`Histamine is the most studied mediator in early allergic
`response. It causes smooth muscle constriction, mucus
`secretion, vascular permeability, and sensory nerve stim-
`ulation, resulting in the symptoms of allergic rhinitis.21
`
`The first-generation antihistamines include brompheni-
`ramine, chlorpheniramine, clemastine, and diphenhydr-
`amine (Benadryl). They may cause substantial adverse
`effects, including sedation, fatigue, and impaired mental
`status. These adverse effects occur because the older anti-
`histamines are more lipid soluble and more readily cross
`the blood-brain barrier than second-generation antihis-
`tamines. The use of first-generation antihistamines has
`been associated with poor school performance, impaired
`driving, and an increase in automobile collisions and
`work injuries.22-25 Although one RCT of 63 children eight
`to 10 years of age did not show that the short-term use of
`first- or second-generation antihistamines caused drowsi-
`ness or impaired school performance, the children in this
`study were only treated for three days, and the sample size
`was small.26
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`

`Allergic Rhinitis
`
`Compared with first-generation antihistamines,
`second-generation antihistamines have a better adverse-
`effect profile and cause less sedation, with the exception
`of cetirizine (Zyrtec).21,22 The second-generation oral
`antihistamines include desloratadine (Clarinex), levoce-
`tirizine (Xyzal), fexofenadine (Allegra), and loratadine.
`Second-generation antihistamines have more complex
`chemical structures that decrease their movement across
`the blood-brain barrier, reducing central nervous system
`adverse effects such as sedation. Although cetirizine is
`a second-generation antihistamine and a more potent
`histamine antagonist, it does not have the benefit of
`decreased sedation. As a group, the second-generation
`oral antihistamines are thought to stabilize and control
`some of the nasal and ocular symptoms, but have little
`effect on nasal congestion.21
`In general, first- and second-generation antihista-
`mines have been shown to be effective at relieving the
`histamine-mediated symptoms associated with aller-
`gic rhinitis (e.g., sneezing, pruritus, rhinorrhea, ocular
`symptoms), but are less effective than intranasal cortico-
`steroids at treating nasal congestion. Because their onset
`of action is typically within 15 to 30 minutes and they
`are considered safe for children older than six months,
`antihistamines are useful for many patients with mild
`symptoms requiring “as needed” treatment.27
`
`INTRANASAL ANTIHISTAMINES
`
`Compared with oral antihistamines, intranasal anti-
`histamines offer the advantage of delivering a higher
`concentration of medication to a specific targeted area,
`resulting in fewer adverse effects.3 Currently, azelastine
`(Astelin; approved for ages five years and older) and
`olopatadine (Patanase; approved for ages six years and
`older) are the two FDA-approved intranasal antihista-
`mine preparations for the treatment of allergic rhinitis.
`As a class, their onset of action occurs within 15 min-
`utes and lasts up to four hours. Adverse effects include
`a bitter aftertaste, headache, nasal irritation, epistaxis,
`and sedation. Although intranasal antihistamines are
`an option in patients whose symptoms did not improve
`with second-generation oral antihistamines, their use as
`first- or second-line therapy is limited by their adverse
`effects and cost compared with second-generation oral
`antihistamines, and by their decreased effectiveness
`compared with intranasal corticosteroids.28,29
`
`DECONGESTANTS
`
`Oral and topical decongestants improve the nasal con-
`gestion associated with allergic rhinitis by acting on
`adrenergic receptors, which causes vasoconstriction in
`
`the nasal mucosa, resulting in decreased inflammation.3-5
`Although the most commonly available decongestants
`are phenylephrine, oxymetazoline (Afrin), and pseu-
`doephedrine, the abuse potential for pseudoephedrine
`should be weighed against its benefits.
`Common adverse effects that occur with the use of
`intranasal decongestants are sneezing and nasal dryness.
`Duration of use for more than three to five days is usually
`not recommended, because patients may develop rhini-
`tis medicamentosa or have rebound or recurring conges-
`tion.3 However, a study of 35 patients found no rebound
`when oxymetazoline was used for 10 days.30 Because oral
`decongestants may cause headache, elevated blood pres-
`sure, tremor, urinary retention, dizziness, tachycardia,
`and insomnia, patients with underlying cardiovascular
`conditions, glaucoma, or hyperthyroidism should only
`use these medications with close monitoring.3-5 A study
`of 25 patients with controlled hypertension provides
`some reassurance about the use of oral decongestants;
`compared with placebo, this randomized crossover
`study found minimal effect on blood pressure with pseu-
`doephedrine use.31
`
`INTRANASAL CROMOLYN
`
`Intranasal cromolyn is available over the counter and is
`thought to act by inhibiting the degranulation of mast
`cells.1 Although safe for general use, it is not consid-
`ered first-line therapy for allergic rhinitis because of its
`decreased effectiveness at relieving symptoms compared
`with antihistamines or intranasal corticosteroids, and
`its inconvenient dosing schedule of three or four times
`daily.1,3
`
`INTRANASAL ANTICHOLINERGICS
`
`Ipratropium (Atrovent) has been shown to provide relief
`only for excessive rhinorrhea. Advantages include that
`it does not cross the blood-brain barrier and is not sys-
`temically absorbed.1 Adverse effects include dryness of
`the nasal mucosa, epistaxis, and headache. Compliance
`is also an issue because it needs to be administered two
`or three times daily.1
`
`LEUKOTRIENE RECEPTOR ANTAGONISTS
`Although the leukotriene LTD4 receptor antagonist
`montelukast (Singulair) is FDA approved for the treat-
`ment of allergic rhinitis, a systematic review of 20 trials
`involving adults treated with montelukast for allergic
`rhinitis showed only minimal improvement (which was
`not clinically relevant) in the symptom of nasal con-
`gestion.32 Another RCT involving 58 adults compar-
`ing montelukast with pseudoephedrine for two weeks
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`Allergic Rhinitis
`
`showed no difference between the two therapies.33
`In addition, two large, independent meta-analyses con-
`cluded that although montelukast is better than pla-
`cebo, it is not as effective as intranasal corticosteroids
`or antihistamines and should only be considered as
`second- or third-line therapy.32,34
`
`COMBINATION THERAPY
`
`Although many studies have looked at the combination
`of an intranasal corticosteroid with an antihistamine
`or leukotriene receptor antagonist, most have con-
`cluded that combination therapy is no more effective
`than monotherapy with intranasal corticosteroids.11,35-37
`However, one study looking at the combination of fluti-
`casone and azelastine found this treatment combina-
`tion to be superior to either treatment alone in patients
`with moderate to severe allergic rhinitis.38 Therefore,
`although patients should not have therapy initiated with
`more than one agent, combination therapy is an option
`for patients with severe or persistent symptoms.
`
`rhinosinusitis symptoms, medication use, and skin sen-
`sitivities when compared with placebo.43
`Omalizumab (Xolair), an anti-immunoglobulin E
`antibody, has been shown to be effective in reducing
`nasal symptoms and improving quality-of-life scores in
`patients with allergic rhinitis.44 The main limitations of
`its current use are its high cost (average wholesale price
`is $679 to $3,395 per month45) and lack of FDA approval
`for home use.
`
`Nonpharmacologic Therapies
`ACUPUNCTURE
`Although the precise mechanism by which acupunc-
`ture works is unclear, proponents suggest that it releases
`neurochemicals such as beta-endorphins, enkephalins,
`and serotonin, which in turn mediate the inflammatory
`pathways involved in allergic rhinitis. Based on RCTs
`looking at acupuncture as a treatment for allergic rhini-
`tis in adults and children, there is insufficient evidence
`to support or refute its use.46-49
`
`Immunotherapy
`Immunotherapy should be considered for
`patients with moderate or severe persis-
`tent allergic rhinitis that is not responsive
`to usual treatments.8 Targeted immuno-
`therapy is the only treatment that changes
`the natural course of allergic rhinitis,
`preventing exacerbation.39 It consists of
`a small amount of allergen extract given
`sublingually or subcutaneously over the
`course of a few years, with maintenance
`periods typically lasting between three
`to five years. The greatest risk associated
`with
`immunotherapy
`is anaphylaxis.
`Although the usefulness of sublingual
`immunotherapy in adults with allergic
`rhinitis has been supported by several
`large trials, studies in children have met
`with mixed results, and the FDA has yet
`to approve a commercial product for sub-
`lingual use.8,40-42
`Recombinant DNA technology has
`also played a role in immunotherapy,
`allowing for the development of allergen-
`specific vaccines. In a multicenter RCT
`involving 134 adults receiving a recom-
`binant birch pollen vaccine for 12 con-
`secutive weeks followed by monthly
`injections for 15 months, patients noted
`statistically significant improvements in
`
`Treatment of Allergic Rhinitis
`
`Allergic rhinitis
`
`Allergen avoidance and patient education
`
`Mild intermittent
`symptoms
`
`Mild to moderate
`persistent symptoms
`
`Severe persistent
`symptoms
`
`Second-generation
`oral or intranasal
`antihistamine, as
`needed
`
`Intranasal corticosteroids
`alone as first-line treatment
`
`Consider nasal irrigation or
`decongestants for nasal
`congestion*
`Consider ipratropium
`(Atrovent) or intranasal
`antihistamines for rhinorrhea
`Consider oral or intranasal
`antihistamine for persistent
`nasal ocular symptoms
`
`Intranasal corticosteroids
`plus oral or intranasal
`antihistamine, oral
`leukotriene receptor
`antagonist, or intranasal
`cromolyn (Nasalcrom)
`
`Symptoms persist
`
`Consider immunotherapy
`referral or alternative
`treatments (e.g., allergen
`avoidance, nasal irrigation,
`acupuncture, probiotics,
`herbal preparations)
`
`*—Use of nasal decongestants for longer than three days is cautioned because of risk of
`rebound congestion.
`
`Figure 1. Algorithm for the treatment of allergic rhinitis.
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`Allergic Rhinitis
`
`PROBIOTICS
`Based on the limited data to date, probiotics cannot be
`endorsed as a useful alternative therapy for allergic rhini-
`tis. Studies of probiotics gave mixed results and included
`12 RCTs and one study looking at prenatal treatment.50,51
`
`HERBAL PREPARATIONS
`
`Many herb and plant-extract compounds have been
`studied with respect to allergic rhinitis treatment, but
`the effectiveness and safety of these compounds have not
`been established.52
`
`OTHER
`
`Patients with allergic rhinitis should avoid exposure to
`cigarette smoke, pets, and allergens to which they have
`a known sensitivity. Nasal irrigation is beneficial in the
`treatment of chronic rhinorrhea and may be used alone
`or as adjuvant therapy.53 Irrigation using a neti pot is
`superior to saline sprays; it may also be done with a low-
`pressure squeeze bottle.53
`Prevention has been a large focus in the study of aller-
`gic rhinitis, but few interventions have proven effective.
`Although dust mite allergies are common, studies have
`not found any benefit to using mite-proof imperme-
`able mattress and pillow covers.54-56 Other examples of
`proposed interventions without documented effective-
`ness include breastfeeding, delayed exposure to solid
`foods in infancy, and use of air filtration systems.57-61
`Figure 1 provides an algorithm for the treatment of
`allergic rhinitis with pharmacologic and nonpharma-
`cologic therapies.
`
`The Authors
`DENISE K. SUR, MD, is clinical professor, vice chair for education, and resi-
`dency director in the Department of Family Medicine at the David Geffen
`School of Medicine, University of California, Los Angeles.
`
`STEPHANIE SCANDALE, MD, is an assistant clinical professor in the
`Department of Family Medicine at the David Geffen School of Medicine.
`
`Address correspondence to Denise K. Sur, MD, UCLA Family Health
`Center, Department of Family Medicine, 1920 Colorado Ave., Santa
`Monica, CA 90404 (e-mail: dsur@mednet.ucla.edu). Reprints are not
`available from the authors.
`
`Author disclosure: Nothing to disclose.
`
`REFERENCES
`
`1. Nelson HS, Rachelefsky GS, Bernick J. The Allergy Report. Milwaukee,
`Wis.: American Academy of Allergy, Asthma & Immunology; 2000.
`2. Bousquet J, Khaltaev N, Cruz AA, et al. Allergic Rhinitis and its Impact
`on Asthma (ARIA) 2008 update (in collaboration with the World
`Health Organization, GA(2)LeN and AllerGen). Allergy. 2008;63(suppl
`86):8-160.
`
`3. Bousquet J, Van Cauwenberge P, Khaltaev N; ARIA Workshop Group;
`World Health Organization. Allergic rhinitis and its impact on asthma.
`J Allergy Clin Immunol. 2001;108(5 suppl):S147-S334.
`4. Price D, Bond C, Bouchard J, et al. International Primary Care Respira-
`tory Group (IPCRG) Guidelines: management of allergic rhinitis. Prim
`Care Respir J. 2006;15(1):58-70.
`5. Scadding GK, Durham SR, Mirakian R, et al.; British Society for Allergy
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