The allergic patient differs from nonallergic patients in several ways (Box 20-1). The cause is unknown, but these abnormalities clearly are associated with abnormal cytokine production (Table 20-1). The result of these abnormalities is that allergic persons suffer from diseases such as allergic rhinitis and allergic asthma.

Table 20-1 Cytokine Production Abnormalities and Effects in Allergic Patients

Cytokine	Effects
Increased production of IL-4	Enhanced IgE production
Increased production of IL-13	Enhanced IgE production
Increased production of IL-5	Enhanced eosinophil activity and prolongation of the life of eosinophils
Increased production of IL-9	Bronchial hyperreactivity

Ig, Immunoglobulin; IL, interleukin.

It must always be remembered, however, that these diseases are defined by their phenotype, and for each allergic disease, there is an almost identical phenotypic expression unrelated to allergy, including allergic and nonallergic (intrinsic) asthma, allergic and nonallergic rhinitis, and IgE-mediated and non–IgE-mediated anaphylactic events. Thus, when approaching the patient, the physician must always consider the mechanism of production of the symptoms because subtle differences may exist in treatment between allergic and nonallergic forms of disease, often with significant differences in prognosis.

The most important aspect of establishing the diagnosis of each of these illnesses is the history. The distinction between the allergic and nonallergic forms can only be conclusively determined by allergy testing. The most sensitive and least expensive (per test) means of assessing the presence of allergy is the allergy skin test. In vitro testing is often helpful, however, as a screening procedure.

The other important phenomenon to recognize is that the major allergic diseases (allergic rhinitis, allergic asthma, and anaphylaxis) are all increasing in incidence. The cause is unknown, but several hypotheses have been proposed. The hygiene hypothesis postulates that the rise in allergic disease is related to infection control in infants and children (e.g., through vaccination) and improved public health (e.g., through hygienic measures). Another hypothesis is that the allergic response is the same response used to defend against parasites. With a reduction in parasitic disease in more technically developed countries, a population has arisen that is free from exposure to parasites but still maintains a vigorous antiparasitic immune response that is aberrantly directed against the normally harmless organic substances such as pollen, animal dander, and food. Regardless of the mechanism, the burden of allergic disease in developed countries has increased rapidly since the 1970s.

Allergic Rhinitis

Allergic rhinitis is a symptom complex caused by airborne antigens. It occurs as seasonal rhinitis (hay fever) when pollens are in high concentration in the air. When it is intermittent or continuous without seasonal variation, it is termed perennial allergic rhinitis. Often occurring in families with an allergic history, perennial allergic rhinitis and mixed perennial and seasonal rhinitis were found to be twice as common as seasonal allergic rhinitis (Skoner, 2001).

Manifestations

In seasonal allergic rhinitis, exposure is followed by complaints of paroxysmal sneezing, a watery nasal discharge with congestion, and nasal pruritus. Conjunctival and pharyngeal itching often occurs. Less specific symptoms are postnasal drainage or fullness or aching in the frontal areas.

The patient might exhibit an allergic salute, an upward thrust of the palm against the nares to relieve itching and open the nasal airways and a gaping expression from mouth breathing. Allergic shiners or Dennie’s lines are wrinkles beneath the lower eyelid. Speech can have a nasal quality. In children, nasal irritation can result in nose picking and recurrent epistaxis. Sleep disruption is often associated with nasal obstruction and mouth breathing. Patients might have sleep apnea–like symptoms, including restless sleep, snoring, or nighttime coughing, associated with postnasal mucus drainage and mild hoarseness. The nasal mucosa is typically moist, with enlarged, pale turbinates and serous discharge. Because the sense of smell is impaired, appetite may be decreased. Maxillomandibular alignment problems (overbite or underbite) result from chronic symptoms.

In perennial allergic rhinitis, nasal congestion, itching, obstruction, and frequent sniffing may be associated with a loss of sense of taste or smell, with decreased hearing and a popping sensation in the ears. A lower sneezing threshold often occurs with altered autonomic reflexes in perennial allergic rhinitis. Paroxysms of sneezing and rhinorrhea can result from changes in ambient temperature, head movement, odors from perfume, tobacco smoke, irritants, alcohol, and exposure to small quantities of antigen. Exercise reverses nasal congestion temporarily, from minutes to hours.

The turbinates are usually swollen and edematous and may be mistaken for nasal polyps, which are pearl-gray gelatinous masses and unusual in uncomplicated allergic rhinitis. Below the turbinates, the floor of the nostril is often prominent as a result of mucosal edema. One third to one half of children with allergic rhinitis have eustachian tube obstruction and resultant serous otitis. Otoscopy reveals a retracted or bulging tympanic membrane, impaired mobility, or a fluid level. In patients with intact tympanic membranes, tympanometry to measure middle ear pressures provides an indirect measure of eustachian tube function (Lazo-Saenz et al., 2005). The edematous nasal mucosa can obstruct the ostia, resulting in congestion or sinusitis with pressure symptoms or headache that is particularly notable with bending forward. Up to one third of patients have a lower respiratory tract component, including exercise-induced and mild persistent asthma.

Diagnosis

A seasonal history or an association with an inhaled allergen is helpful. It is often difficult to associate specific allergens with perennial rhinitis, although late-evening or early-morning symptoms may be seen with dust allergy. Occasionally, improvement of symptoms with a change in environment, such as a vacation, indicates the presence of environmental allergens. A nasal smear, stained with Hansel’s stain to identify eosinophils, can support a diagnosis of nasal allergy, but it is not itself diagnostic. An elevated peripheral eosinophil count may be helpful; however, marked allergic symptoms can occur in the absence of blood eosinophilia.

Treatment

Nasal Polyps

Key Points

• Nasal polyps may be associated with aspirin sensitivity.

• Nasal polyps can aggravate sinus disease.

• Topical glucocorticoids are important in long-term treatment.

• Polyps can recur after polypectomy.

Perennial allergic rhinitis may be associated with nasal polyps, but usually only when it is complicated by sinus infection. In adults, polyps may be associated with sensitivity to aspirin manifested by aggravation of rhinitis, asthma, and even shock.

Nasal polyps often develop in the absence of or only coincidentally with allergy. Polyps arise from diseased ethmoid and maxillary sinuses and are easily visible in the nasal cavity. Nasal polyps can cause obstruction and aggravate the preexisting sinus disease. The size of nasal polyps may be reduced by brief treatment with systemic glucocorticoids and by daily use of topical glucocorticoids for longer periods.

If sinus infection or the underlying allergic factors are not appropriately controlled, polypectomy may be necessary. Unfortunately, polyps tend to recur without sinus surgery.

Nonallergic Rhinitis

Key Points

• Symptoms of nonallergic rhinitis include chronic nasal obstruction and eosinophils on nasal smear, in the absence of allergy.

• Topical glucocorticoid steroid therapy is useful in treatment of NARES.

• Aggravating factors include physical changes or irritants for vasomotor rhinitis.

• Ipratropium bromide is best for controlling symptoms of vasomotor rhinitis.

Some patients with perennial rhinitis are not atopic by history or skin testing. Chronic nasal obstruction is the predominant symptom, and the condition may be associated with sinus disease and nasal polyps. Although there is no evidence of allergy by skin testing, numerous eosinophils are present, and the diagnosis is readily made by examining the nasal secretions for eosinophils and eosinophilic cationic protein (Kramer et al., 2004). The condition is also called nonallergic rhinitis with eosinophilia (NARES). A substantial number of patients have chronic rhinitis with rhinorrhea, postnasal drainage, and chronic or intermittent nasal obstruction. Symptoms are aggravated by many physical or irritant factors, such as cold air, odors, and smoke. Skin tests are negative, and no eosinophils are present in the tissue or secretions.

Topical glucocorticoid therapy is much more effective than antihistamines or decongestants for NARES. As with asthmatic patients, patients with associated sinus disease and nasal polyps are at risk for adverse reactions to aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs). Patients with NARES are also at risk for obstructive sleep apnea (Wallace et al., 2008). Ipratropium bromide (0.03%) spray solution, fluticasone, and azelastine nasal sprays have all been shown to be effective treatment. Some patients benefit from antihistamine-decongestant combinations. The regular use of buffered saline lavage can also provide satisfactory symptomatic relief.

Allergy in the Eye

Key Points

• Symptoms of eye allergy include pruritus, erythema, and lacrimation.

• Treatment includes oral antihistamines plus topical medications such as mast cell stabilizers or H₁ blockers.

Conjunctivitis is the usual ocular reaction to airborne allergens. As in other forms of allergic inflammation, the mast cell plays a key role. Itching is the first symptom and may be associated with lacrimation. Dilation of the conjunctival blood vessels produces a “red” eye. Transudation of fluid through vessel walls results in edema of the conjunctiva, and exuded cells with increased glandular mucus secretions result in ocular discharge. In most atopic patients, conjunctivitis and allergic rhinitis occur together, but some patients are bothered only by eye symptoms. In contrast to other forms of conjunctivitis, the secretions contain eosinophils.

Vernal conjunctivitis is so called because of its occurrence in spring and summer. It is characterized by a bilateral recurrent inflammation of the conjunctiva. Vernal conjunctivitis typically occurs between ages 5 and 20 years. It often spontaneously resolves in 10 years. More than 50% of children with vernal conjunctivitis also have an atopic disorder such as allergic rhinitis, eczema, or asthma. Signs and symptoms include acute itching, tearing, photophobia, and excess mucus production. The patient often has a sense of a foreign body in the eye.

The topical conjunctival appearance establishes the diagnosis, which is confirmed by cytologic smears showing numerous eosinophils. In the tarsal (palpebral) form, there are flat-top cobblestone papillae; in the limbal form, there may be gelatinous hypertrophy and limbal papillary hypertrophy often associated with white dots (Trantas’ dots). Although vernal conjunctivitis is usually self-limiting, corneal complications can occur, and ophthalmology consultation should be obtained. Although conjunctivitis is typically seasonal and common in atopic patients, no allergens have been identified as causal or aggravating factors.

The usual therapy for allergic conjunctivitis is an oral antihistamine with a topical medication (Table 20-3). Cromolyn (Opticrom) and lodoxamide 0.1% (Alomide) are mast cell stabilizers. Topical H₁ histamine blockers are also effective for treating allergic conjunctivitis. Ophthalmic histamine blocker solutions include emedastine (Emadine) and levocabastine (Livostin). Azelastine (Optivar), epinastine (Elestat), ketotifen (Zaditor, Claritin Eye, Zyrtec Itchy Eye) and olopatadine (Patanol, Pataday) are dual-acting drugs, preventing mast cell release and exerting antihistamine activity as well. Ketorolac (Acular) is a NSAID. Regular daily use is necessary to obtain maximum positive results with all topical agents. In severe cases and in vernal conjunctivitis, a soluble steroid such as fluorometholone ophthalmic solution (0.1%) is effective. The dose should be titrated to the minimum required to control symptoms. Use should be intermittent because glucocorticoids can lead to the development of cataracts, potentiate a secondary bacterial infection or a herpes simplex keratitis, and increase intraocular pressure. Steroid eyedrops should always be used under supervision by an ophthalmologist.

Table 20-3 Ophthalmic Solutions Useful in the Treatment of Allergic Conjunctivitis

Drug (Brand)	Formulation	Dosage
Mast Cell Stabilizers
Cromolyn (Opticrom)	4%	1-2 gtt OU every 4-6 hr daily
Lodoxamide (Alomide)	0.1%	1 gtt OU qid
H₁ Histamine Blockers
Emedastine (Emadine)	0.05%	1 gtt OU qid
Levocabastine (Livostin)	0.5 mg/mL	1 gtt OU bid
Combination Stabilizers/Blockers
Ketotifen (Zaditor)	0.025%	1 gtt OU bid 8-12 hr apart
(Zyrtec Itchy Eye)	0.025%	1 gtt OU bid 8-12 hr apart
(Claritin Eye)	0.025%	1 gtt OU bid 8-12 hr apart
Epinastine (Elestat)	0.05%	1 gtt OU bid
Olopatadine (Patanol)	0.1%	1 gtt OU bid 6-8 hr apart
(Pataday)	0.2%	1 gtt OU qd
Azelastine (Optivar)	0.05%	1 gtt OU bid
Nonsteroidal Anti-Inflammatory Drugs
Ketorolac (Acular)	0.5%	1 gtt OU qid

OU, Each eye; gtt, drops; qid, four times daily; bid, twice daily; qd, once daily.

Asthma

The definition of asthma has undergone many changes over the years, but three elements are key to the diagnosis: reversible airway obstruction, airway inflammation, and increased airway responsiveness to a variety of stimuli. Physicians must remember that not all wheezing is asthma, and not all asthma has wheezing. Asthma is a chronic inflammatory disorder of the airways in which many different cells play a role. In patients with asthma, this inflammation causes breathlessness, chest tightness, recurrent episodes of wheezing, and cough, particularly at night. These symptoms are usually associated with variable airflow limitation that is partly reversible with treatment or sometimes spontaneously. This inflammation causes an associated increase in airway responsiveness to a variety of stimuli (Busse et al., 2007). Data from the Centers for Disease Control and Prevention (CDC) have shown an increase in the prevalence of asthma in the United States from 1980 to 2001. However, there has been no increase in mortality and hospitalization rates since 1997 (cdc.gov/asthma; see also Chapter 20).

Diagnosis

Because of the lack of any specific symptom or sign to define asthma by history or physical examination, some patients are mistakenly thought to have asthma. Numerous other diseases must be considered in the differential diagnosis of asthma (Box 20-2). Although parental history of asthma is present in half of children with asthma, the positive predictive value of this history ranges from 11% to 37% (Burke et al., 2003). The diagnosis of asthma should occur in three stages. First, suggestive symptoms referable to the chest with precipitating factors should raise the possibility of asthma. Second, further testing should be performed to confirm the diagnosis. Third, the patient should have symptomatic improvement with the appropriate asthma therapy (see Classification). When all the stages have been performed and meet the criteria, the diagnosis of asthma can be made.