Allergic Rhinitis

ALLERGIC RHINITIS

ESSENTIALS OF DIAGNOSIS

1. Characterized by sneezing, itching, rhinorrhea, and congestion.
2. May be seasonal, perennial, or both.
3. Can be associated with other chronic conditions, including asthma, otitis media with effusion (OME), rhinosinusitis, and nasal polyposis.
4. Typical symptoms of sneezing, rhinorrhea, and nasal congestion can be associated with viral, bacterial, allergic, and nonallergic etiologies
5. Can have multiple triggers, both inhaled and in­gested.

General Considerations
Allergy is a clinical manifestation of an adverse immune response after repeated contact with usually harmless substances such as pollens, mold spores, animal dander, dust mites, foods, and stinging insects. Allergic rhinitis is an inflammation of the nasal mucous membranes caused by an IgE-mediated reaction to one or more allergens. The prevalence of allergic rhinitis can vary considerably among age groups and locales.

Allergic rhinitis is one of the most common allergic diseases in the United States, affecting between 20% and 25% of the population (approximately 40 million people). Allergic rhinitis may have its onset at any age, but the incidence of onset is greatest in adolescence, with a decreasing incidence with advancing age. Its peak prevalence is during the third and fourth decades (Figure 1).

Figure 1. Prevalence of allergic rhinitis by age group.

The economic costs of allergic rhinitis, both direct and indirect, are considerable. The largest portion of the direct costs is the expenditure for both prescription and nonprescription medications (approximately 4 bil­lion dollars annually). The largest indirect costs are from both the allergy itself and also from the negative side effects of allergy medication (primarily over-the-counter antihistamines).

Although allergic rhinitis is not life threatening, its symptomatic effects are considerable, resulting in a sig­nificantly diminished quality of life for many sufferers. A number of quality of life studies have shown that in almost every facet of daily life, including social and physical functionality, energy and fatigue levels, and a lack of sleep and mental health, patients with allergic rhinitis have a significant loss of the quality of life com­pared with nonallergic individuals. In fact, patients with allergic rhinitis have been shown to have a lower quality of life than many asthmatics. In addition, aller­gic rhinitis may contribute to sleep disorders, fatigue, and—of particular importance with children—learn­ing problems.

Pathogenesis
The allergic response is mediated primarily by a type I hypersensitivity reaction. This response involves the excess production of IgE antibodies and is termed an atopic reaction. In addition to allergic rhinitis, most cases of asthma and atopic dermatitis are considered to have an atopic cause.

In patients with an atopic disposition (a genetic trait), an allergic reaction begins with sensitization to a specific allergen (in allergic rhinitis, these are usually airborne), which induces IgE-antibody production. This occurs through a T-cell, B-cell, and plasma cell cascade. On subsequent exposure, the specific antigen attaches to two specific IgE antibodies attached to the surface of mast cells, which are prevalent in the submu-cosa of the respiratory and gastrointestinal tracts, the subconjunctiva of the eye, and the subcutaneous layer of the skin. Consequently, this IgE-mediated reaction causes degranulation of the mast cell, which then pro­vokes an inflammatory response with the release of mediators such as histamine, leukotrienes, cytokines, prostaglandins, and platelet-activating factor. This is referred to as the early-phase or humeral reaction and occurs within 10–15 minutes of allergen exposure; the release of histamine causes the symptoms of sneezing, rhinorrhea, itching, vascular permeability, vasodilata-tion, and glandular secretion.

The release of cytokines and leukotrienes subsequently causes an influx of inflammatory cells (mainly eosinophils) into the affected area (chemotaxis). This inflammatory response is called the late-phase or cellular reaction, which can begin 4–6 hours after the initial sensitization and may prolong and enhance the allergic cascade for as long as 48 hours. This response is the main cause of the symptoms of nasal congestion and postnasal drip in allergic rhinitis.
In addition, these mediators produce a hyperreac-tion to both specific allergens and nonspecific irritants such as tobacco smoke and chemical fumes, referred to as the priming effect.

Causes
The development of atopy may be influenced by the following:

1. Genetic susceptibility (ie, family history);
   
2. Environmental factors (eg, dust and mold exposure);
3. Exposure to allergens (eg, pollens, animal dander, and foods);
4. Passive exposure to tobacco smoke (especially in early childhood); and
   
5. Diesel exhaust particles (in urban areas)—among other factors.

In infancy and childhood, food allergens such as milk, eggs, soy, wheat, dust mites, and inhalant allergies such as pet dander are the major causes of allergic rhinitis and the comorbidities of atopic dermatitis, otitis media with effu­sion, and asthma. In older children and adolescents, pol­len allergens become more of a causative factor.

Classification

A. Seasonal Allergic Rhinitis
The symptoms of seasonal allergic rhinitis, as its name implies, occur or are increased during certain seasons, usually depending on the pollination of plants to which the patient is allergic. Trees pollinate in the spring, grasses in the late spring and summer, and weeds in the fall. In addition, molds may cause symptoms in the fall. Characteristic symptoms of seasonal allergies include sneezing, watery rhinorrhea, itching of the nose, eyes, ears, and throat, red and watering eyes, and nasal congestion. Symptoms are usually worse in the morning and are aggravated by dry, windy conditions when higher concen­trations of pollen are distributed over a wider area.

B. Perennial Allergic Rhinitis
The symptoms of perennial allergic rhinitis are usually constant, with little seasonal variation, although they may vary in intensity. Characteristic symptoms are pre­dominantly nasal congestion and blockage, and postna-sal drip. Rhinorrhea and sneezing are less common. Eye symptoms are less common, except with animal aller­gies. Seasonal pollen may cause the exacerbation of any of these symptoms.

Common allergens that cause perennial allergic rhi­nitis are indoor inhalants, predominantly dust mites, animal dander, mold spores, and cockroaches (in inner cities). Certain occupational allergens may also cause perennial allergic rhinitis; these are not usually constant because they depend on workplace exposure.

Food allergens may also contribute to perennial allergic rhinitis. In addition, food allergies are often associated with other symptoms, including gastrointes­tinal problems, urticaria, angioedema, and even ana-phylaxis after food is ingested.

Infections and nonspecific irritants may influence perennial allergic rhinitis. In children with allergies, there may be a higher incidence of respiratory tract infections, which in turn tend to aggravate allergic rhinitis and may lead to the development of complications, especially rhi-nosinusitis and otitis media with effusion. Other irritants such as tobacco smoke, chemical fumes, and air pollutants can also aggravate symptoms.

C. Other Classifications
Recently, other classifications of allergic rhinitis have been introduced. One of these is related to both the temporal incidence and the quality of life. Symptoms are classified as being intermittent (<> 4 d/wk or > 4 weeks’ duration) and by the intensity of the symptoms, with either minimal or moderate to severe changes in the quality of life. In another classification system, symptoms are based accord­ing to the type of symptom (eg, patients who experience sneezing and a runny nose or those who are congested) without a temporal relationship.

Clinical Findings

A. Patient History
The diagnosis of allergic rhinitis should determine whether the patient is atopic and, if so, what the caus­ative allergen is. To determine these, a basic clinical evaluation should be performed, which should consist of a patient history, a physical examination, and confir­matory tests.

A careful history provides important clues for the diagnostician. Genetic factors determine the likelihood of an individual becoming sensitized and producing IgE antibodies (ie, being atopic). A family history of aller­gies, eczema, or asthma increases this possibility. Chil­dren with parents who have allergies have been shown to have a > 50% chance of becoming allergic themselves. If only one parent or a sibling has allergies, this rate is lower but still significant.

A thorough allergy history should determine whether symptom patterns are seasonal or perennial. Symptoms may include clear and watery nasal discharge, nasal con­gestion, postnasal drip, and itching of the nose, throat, and eyes. Persistent symptoms are presumed to be due to exposure to an indoor allergen. Seasonal symptoms or symptoms that are reproducible from an inciting factor, such as cat exposure, are most likely to be allergic. If the use of medication, especially antihistamines (both pre­scription and nonprescription) or intranasal corticoster-oids improves symptoms, allergy is probable. This is not the case with either intranasal or oral decongestants, which affect both allergic and nonallergic symptoms. A history of an anaphylactic reaction following ingestion of a particular food or being stung by an insect usually indi­cates an atopic patient.

Patients should be questioned about the onset, dura­tion, type, progression, and severity of their symptoms. A relationship to the seasons is important, with seasonal symptoms usually indicating a pollen allergy or possibly a mold allergy, but temperate climates can blur these seasonal distinctions. Perennial symptoms usually mean an allergy to dust mites, mold, or animals. An increase in symptoms at night usually suggests an allergy to dust mites or pet dander.
Associated ocular, pharyngeal, and systemic symp­toms, including recurrent rhinosinusitis, ear infections, asthma flare-ups, gastrointestinal symptoms, and skin rashes and hives, are important facts to ascertain in the history taking.
The patient should always be questioned about the impact of the symptoms on the quality of his or her life, because the correct diagnosis and, ultimately, sympto­matic relief from the appropriate treatment will play a large part in the functional impact on the patient’s life.

B. Physical Examination
A physical examination should include inspection of the ears, throat, and nasal passages (including after decongesting with a topical decongestant). Typical findings in the nose in patients with seasonal allergic rhinitis include bluish, pale, boggy turbinates; wet, swollen mucosa; and nasal congestion with nasal obstruction. With perennial allergies, nasal congestion is the predominant sign, but the nasal examination may appear normal. Anatomic abnormalities, such as a devi­ated nasal septum, concha bullosa, and nasal polyps, may be present. It should be determined whether these abnormalities are the main cause or merely contributing factors to the patient’s symptoms. If nasal polyps are suspected, an endoscopic nasal exam is also warranted. Other possible physical findings include conjunctivitis, eczema, and, possibly, asthmatic wheezing.

In children, allergic “shiners” (dark circles under the eyes), facial grimacing, mouth breathing, and the “nasal salute” (constant rubbing of the tip of the nose with the hand) are common physical findings. In addition, in this age group, a concomitant otitis media with effusion is also a possibility.

C. Special Tests

1. Allergy testing—Allergy testing is performed to establish objective evidence of atopic disease. It also can determine the causative allergens responsible, which would then lead to specific therapeutic recommenda­tions. Two major types of testing are available for iden­tifying and quantifying allergen sensitivity: skin testing and in vitro serum assays.
2. Skin testing—Skin testing can be epicutaneous, intradermal, or a combination of both.
   a. Skin prick test—The skin prick test is the most common epicutaneous test used. In general, it is a quick, specific, safe, and economical test. With new multitest systems available, it is an easy and simple office procedure to perform and also allows for unifor­ mity in the testing procedure. When a test result is equivocal, it is often followed by an intradermal test.
   b. Intradermal testing—Intradermal testing, using quantitative 1:5 serial dilutions, is the skin testingmethod of choice for most otolaryngic allergists. This type of testing, termed intradermal dilutional testing (IDT) and formerly known as serial endpoint titration (SET), is an excellent quantifier of allergen sensitivity, and, as such, is of significant benefit in the preparation of safe and cost-efficient immunotherapy treatment. Today, many otolaryngologists use the skin prick multitest as a screening test prior to performing IDT.
   
3. In vitro testing—Allergen-specific serum IgE test­ing is an easy and accurate method for determining the presence of atopic allergy, and with newer in vitro tech­nology available, in vitro testing is at least equivalent to skin testing in efficacy. In vitro assays are safe, specific, cost-effective, and reproducible, and do not require the patient to be free of antihistamines and other medica­tions that may interfere with skin testing. They are also easy and quick and are therefore preferred, especially in children and in anxious patients.
   Although the original in vitro assay, the RAST test (radioallergosorbent test), is no longer performed, its name is still used today to generally describe IgE-spe-cific blood testing. However, not all in vitro assays available today are alike. The newer assays tend to be faster, more reliable, and more efficient than previous tests. The ImmunoCap is an excellent example of this newer technology. Not using a reliable assay may affect the diagnosis of atopy and therefore the prescribing of appropriate therapy (Figure 2).
   In vitro testing can be cost-effective if an initial, appro­priately chosen inhalant screening battery of 10–12 aller­gens consisting of the most prevalent pollens, molds, dust mites, and animals in the local environment is used. In chil­dren, common allergenic foods are substituted or added. No further testing is necessary if this battery is negative. If the screening battery is positive and if no immunotherapy is considered, additional allergy testing can be performed.
   

Figure 2. In vitro testing process.

Differential Diagnosis
The differential diagnoses of allergic rhinitis include the fol­lowing:

1. Infectious rhinitis (acute or chronic);
2. Peren­nial nonallergic rhinitis (eg, vasomotor rhinitis);
3. Pollut­ants and irritants;
4. Hormonal rhinitis (eg, pregnancy or hypothyroidism);
   
5. Medication-induced topical rhinitis (rhinitis medicamentosa);
6. Anatomic deformity (eg, a deviated septum, nasal polyps, or a concha bullosa); and
7. Tumors or foreign bodies.

Treatment
The appropriate management of these common respira­tory diseases differs substantially, particularly when allergy is a contributing component. The treatment of allergic rhinitis must consider the main symptoms, their severity, the patient’s quality of life, the cost of therapy, as well as the allergens involved in order to individualize the patient’s treatment options. In addition, in the treatment of nasal allergies, consideration must be given to both the patient’s desire for rapid long-lasting relief of symptoms without side effects and the relief of any particular idio­syncratic symptoms, such as persistent rhinorrhea.

In general, three options are available for the manage­ment of allergic rhinitis:
(1) avoidance and environmental controls,
(2) pharmacotherapy, and
(3) immunotherapy.

A. Environmental Controls
Even if environmental controls are not complete, reduc­ing the allergic load may significantly decrease symp­toms. Methods of minimizing exposure to pollen are to avoid outdoor activities during relevant pollen seasons (eg, mowing the lawn and gardening), to keep home and car windows closed, and to use air conditioning when possible. To control dust mites, mold, and pet dander, the following practices should be used:
(1) reduce house­hold humidity to below 50%;
(2) wash bed linens in hot water;
(3) remove carpets and pets from the most often used living areas, especially bedrooms;
(4) encase pillows, mattresses, and box springs in hypoallergenic coverings (for dust mite protection); and
(5) in poor and urban set­tings, eliminate cockroaches (Table 1). For airborne allergens (eg, animal dander), air purifiers can be used.

B. Pharmacotherapeutic Measures
When selecting a pharmacologic treatment for allergic rhinitis, consideration must be given to the patient’s underlying condition, the likely pathophysiology, the dominant symptoms, the patient’s age and condition, the coexistence of related airway disorders, the patient’s preference, and the patient’s compliance history. In addition, before initiating any pharmacotherapy, the patient’s use and response to previous treatment should be considered (Table 2).

1. Antihistamines—Antihistamines are frequently used as a first-line therapy; many are available without a prescription. They block H1 receptor sites and pre­vent histamine-induced reactions, including inhibiting increased vascular permeability, smooth muscle con­traction, increased mucus production, and pruritus. Antihistamines also inhibit the “wheal and flare” response of the skin and therefore they affect skin testing unless withdrawn a few days before skin testing. They do not affect in vitro testing. Antihistamines are effective in early-phase reaction and therefore reduce sneezing, rhinorrhea, and itching. They have little effect on nasal congestion, a late-phase phenomenon.
   Nonprescription, first-generation antihistamines can cause sedation and impair performance and have been associated with a higher risk of both automobile and work-related accidents, decreased work performance and productivity, and impaired learning and academic performance. These side effects can be significantly exacerbated by alcohol, sedatives, antidepressants, and hypnotics. Many have anticholinergic effects and cause dry mouth. These include diphenhydramine (eg, Benadryl), hydroxyzine (eg, Atarax), chlorpheniramine, and brompheniramine. The latter two are found in most nonprescription cold remedies.
   Second-generation antihistamines have an antihista-mine activity comparable to that of first-generation antihistamines but have a better safety profile with lit­tle, if any, sedation as they have little affinity for central H1 receptors. They have no anticholinergic activity and are well absorbed, with a rapid onset of action and symptom relief usually within 1 hour. Second-genera­tion antihistamines are typically dosed once daily and are rarely associated with drug tolerance with prolonged use. Those available orally in the United States are fex-ofenadine (eg, Allegra), loratadine (eg, Claritin), deslor-atadine (eg, Clarinex), and cetirizine (eg, Zyrtec). A sec­ond-generation intranasal antihistamine, azelastine (eg, Astelin), is also available.
2. Intranasal corticosteroids—Intranasal corticoster-oids may be the most effective medications for the over­all control of allergic rhinitis symptoms. They relieve sneezing, itching, and rhinorrhea, and also nasal con­gestion. Maximal effect may take from 1 to 2 weeks after the onset of their use. Their effectiveness depends applica­tion. They act on the late-phase reaction and therefore prevent a significant influx of inflammatory cells. The newer formulations (mentioned below) have minimal systemic absorption with no systemic side effects, and they have been approved for use in children. They have no systemic side effects with regard to HPA axis sup­pression and do not affect long-bone growth in chil­dren. In young adults and children, they are considered the drugs of choice in the treatment of allergic rhinitis. Local side effects, such as dryness and epistaxis, can be reduced by careful patient instruction on their use and also the regular, concomitant use of intranasal saline. Commonly available intranasal corticosteroids in the United States include triamcinolone (eg, Nasacort), budesonide (eg, Rhinocort), fluticasone (eg, Flonase), and mometasone (eg, Nasonex).
   Table 1. Environmental control of indoor aeroallergens.
   

   Allergen	Environmental Control
   House dust mites	• Encase mattress, box spring, and pillows in occlusive covers • Wash all bedding in water > 130° F weekly • Dehumidify (<> • Remove reservoirs (especially carpeting)
   Pets	• Remove pet from home or at least from patient’s bedroom • Remove reservoirs (carpeting, stuffed furniture), if feasible • Wash animal frequent

3. Systemic corticosteroids—Systemic corticosteroids may be necessary for severe, intractable symptoms. They can be administered either by intramuscular injection or orally. With the latter, a tapering dose is usually given over 3–7 days. Systemic corticosteroids act on inflammation and significantly reduce all the symptoms of allergic rhinitis. The repeated use of these agents can cause serious side effects, such as HPA axis suppression, as well as other common side effects of steroid use.
   Table 2. Pharmacologic agents in the management of allergic rhinitis.
   

   Class	Mechanism of Action
   Antihistamines	Antagonize the H1 receptor–mediated effects of histamine
   Decongestants	Act predominantly on α-adrenergic recep­tors of the mucosa of the respiratory tract
   Intranasal and oral corticosteroids	Exert a wide range of effects on multiple cell types and mediators
   Mast cell stabilizers	Inhibit the release of mediators from mast cells
   Anticholinergic agents	Antagonize the action of acetylcholine at muscarinic receptors
   Leukotriene modifiers	Antagonize the action of leukotriene re­ceptors or inhibit 5-lipoxygenase and the formation of leukotrienes

   
   
4. Decongestants—Decongestants act on α-adrener-gic receptors of the nasal mucosa, producing vasocon-striction and thus reducing turbinate congestion. They improve nasal patency but do not relieve rhinorrhea, pruritus, and sneezing. These preparations are found mostly in nonprescription cold medicines and should be used with care in patients with cardiac problems and hypertension. Intranasal decongestants (eg, oxymetazoline) can cause rebound nasal congestion and cause dependency if used for more than 3–4 days (rhinitis medicamentosa).
5. Intranasal anticholinergics—These agents tend to control only rhinorrhea and have no other effects on allergy symptoms. One of the most commonly used intranasal anticholinergics is ipratropium bromide (eg, Atrovent). These agents can be combined with other allergic medications to control rhinorrhea in perennial allergic rhinitis.
6. Intranasal cromolyn—Intranasal cromolyn (eg, Nasalcrom) must be used before the onset of symptoms to be effective. This medication must be used through­out the entire exposure; it is considered to be very safe. The recommended dosage is four times daily.
7. Leukotriene inhibitors—Montelukast “Singulair” is a newer medication for the treatment of allergic rhi­nitis. To date, clinical studies have shown its efficacy to be greater than that of placebo, but less effective than antihistamines and intranasal steroids in the treatment of allergic rhinitis (Table 2).
   

C. Immunotherapy
Immunotherapy attempts to increase the threshold level of the appearance of symptoms after aeroallergen expo­sure. The exact mechanism of how immunotherapy works is still unclear; it may be the production of so-called “blocking” antibodies, as well as regulation of the immune cascade that causes allergic reactions.

Indications for immunotherapy include long-term pharmacotherapy for prolonged periods of time, the inadequacy or intolerability of drug therapy, and signif­icant allergen sensitivities. Before beginning immuno-therapy, the physician must first confirm the atopic diagnosis by testing IgE specific to the offending aller­gen (or allergens).

Most immunotherapy administered in the United States today is through a gradual increase in the dose of the antigen(s) given until either a mild systemic symptom or a large local reaction at the subcutaneous injection site occurs (optimal dose therapy). In some centers, sublingual immunotherapy is the method of choice. This is more common in Europe and tends to be easy and safe to administer at home by the patients themselves.

There is no adequate test available to indicate to the patient how long immunotherapy must be continued. Therefore, a clinical response with a reduction in symp­toms dictates the duration of specific treatment. A mini­mum of 2–3 years is usually given to avoid a rapid recur­rence of symptoms in uncomplicated allergic rhinitis.

D. Other Treatment Considerations
The first aspect of treating patients who have not responded well to therapeutic measures, including immunotherapy, is determining to what degree thera­peutic compliance has occurred. The next steps are to adjust drug dosages, try one or two other agents, and consider combination therapy. In addition, the physi­cian should determine whether allergy exposure has increased and should also review the environmental control measures. Finally, it may be necessary to recon­sider the diagnosis and reevaluate the patient.

Table 4. Pharmacotherapies for allergic rhinitis.

Agent	Inflammation	Congestion	Rhinorrhea	Sneezing	Nasal Itch	Ocular Symptoms
Antihistamines 1st generation 2nd generation	±	-	+ +	+ +	+ +	+ +
Topical antihistamines	±	±	+	+	+	±
Decongestants	-	+	-	-	-	-
Intranasal steroids	+	+	+	+	±	±
Oral steroids	+	+	+	+	±	+
Intranasal cromolyn	±	±	±	±	±	±