Alvin M. Sanico
Acute and chronic conditions attributed to allergy are among the most common afflictions encountered in medical practice. Indeed, recent studies suggest that the prevalence of allergen sensitivity has increased over the years (1). Allergy is a state of increased immunologic reactivity involving immunoglobulin E (IgE) antibodies against an otherwise innocuous foreign substance. Exposure of a susceptible individual to such an allergen leads to the release of chemical mediators that may cause clinical symptoms. The term atopy, which is sometimes used interchangeably with allergy, pertains to the genetic predisposition to develop IgE-mediated hypersensitivity.
A genetic basis for chronic allergic disease is supported by increased concordance rates in monozygotic versus dizygotic twins (2) and familial clustering. Children of parents with allergic disease are significantly more likely to develop the same illness compared with children whose parents are not affected. Indeed, the child's probability of developing an allergic disease increases as the number of affected parents increases from 0 to 2 (3).
The interaction between genetic and environmental factors further determines an individual's likelihood of developing an allergic disease. Changes in the environment associated with a Western life-style have been noted to correlate with the increasing prevalence of atopic disease in the United States and other industrialized nations. It is hypothesized that decreased exposure to microbial antigens due to excessive hygiene early in life promotes a shift in the phenotypes of helper T lymphocytes, from TH1 toward TH2 cells (4,5). TH1 cells produce interferon-γ, which suppresses the formation of IgE, while TH2 lymphocytes secrete interleukin-4 (IL-4) and other cytokines that induce the production of these antibodies (Fig. 30.1A).
In this chapter, conditions related to IgE-mediated hypersensitivity (except asthma, which is covered in Chapter 60) and similar disorders are discussed.
Pathophysiologic Basis for the Occurrence and Management of Allergic Disease
Allergens and Immunoglobulin E Antibodies
Most clinically relevant allergens are water-soluble proteins with a molecular weight of 10 to 40 kDs that are capable of inducing IgE production and binding to these antibodies. Examples of common environmental allergens include Amb a 1 from ragweed (Ambrosia artemisiifolia), Fel d 1 from cats (Felis domesticus), Can f 1 from dogs (Canis familiaris), Bla g 1 from cockroaches (Blattella germanica), and Der p 1 or Der f 1 from dust mites (Dermatophagoides pteronyssinus or D. farinae). Most of the animal-derived allergens belong to the lipocalin family
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of proteins and naturally function as proteases. Low-molelecular-weight substances such as penicillin may be allergenic by acting as haptens that bind covalently with serum proteins to form a complex that can then interact with IgE.
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FIGURE 30.1. Targets for the management of allergic disease. Sensitization to specific allergens series (A) occurs in an atopic individual, after which allergic inflammation series (B) can develop upon subsequent re-exposures. The interaction between genetic and environmental factors promotes the development of naïve helper T (TH0) lymphocytes into TH2 cells. TH2 lymphocytes interact with antigen presenting cells and consequently secrete cytokines such as interleukin-4 (IL-4), which induce B cells to mature into plasma cells and produce IgE antibodies. Allergic inflammation begins when multivalent allergens cross-link IgE bound to high affinity FcεRI receptors on tissue mast cells or peripheral blood basophils. This initiates a cascade of events leading to the release of granule and lipid membrane-derived products. These mediators, including histamine and leukotrienes, cause various clinical effects during the early and late phases of the allergic response. Various modes of management can be used to target components of this disease pathway. Identification and avoidance of relevant allergens is fundamental (Target 1). Pharmacotherapy can be directed toward amelioration of specific symptoms and/or control of the underlying inflammation. Rhinorrhea, nasal congestion, or bronchoconstriction can be specifically relieved by an anticholinergic, sympathomimetic, or β-agonist agent, respectively (Target 2). The effects of histamine or of leukotrienes can be attenuated by their respective receptor antagonists (Targets 3 and 4). The number of allergic inflammatory cells and the production of their mediators can be reduced by glucocorticoids (Target 5). The shift toward a TH2 phenotype of helper T cells and consequent production of IgE can be regulated by immunotherapy (Target 6). The effects of IgE can be inhibited by a newly developed monoclonal antibody that binds to it (Target 7). Other novel forms of treatment such as those directed against cytokines are still being investigated (Target 8). |
Under the influence of cytokines such as IL-4 from TH2 lymphocytes and other sources, B cells mature into plasma cells and secrete antigen-specific IgE. The presence of such antibodies is the principal basis for the development of allergic sensitivity.
Inflammatory Cells and Mediators
IgE binds to high-affinity FcεRI receptors on the surface of mast cells and basophils. Cross-linking of these receptor-bound IgE antibodies by multivalent allergens triggers a cascade of events leading to the release of mediators. These include preformed granule-associated products (e.g., histamine), newly synthesized products of arachidonic acid metabolism (e.g., leukotrienes), cytokines, and chemokines (e.g., IL-3, IL-4, and IL-5). Depending on which organ is affected, histamine may cause pruritus, sneezing, rhinorrhea, bronchoconstriction, and cutaneous wheal formation. These signs and symptoms develop within minutes of allergen exposure during the early phase of an allergic reaction.Leukotrienes are more potent than histamine in causing nasal congestion and bronchoconstriction. The various interleukins and tumor necrosis factor-α (TNF-α), among others, promote local tissue infiltration by cells such as eosinophils 6 to 12 hours after allergen exposure. During this period of the late phase response, manifestations of allergy such as nasal congestion and bronchoconstriction may recur (Fig. 30.2).
Pharmacotherapy
Various therapeutic agents may be used to block one or more components of the allergic inflammatory pathway (Fig. 30.1B). Limited symptomatic relief may be achieved by targeting specific end results such as rhinorrhea, nasal congestion, or bronchoconstriction. For example, anticho-linergic agents may be used to inhibit mucus secretions, sympathomimetic vasoconstrictors may reduce nasal congestion, whereas β-adrenergic agonists may reverse bronchoconstriction by activating adenylate cyclase with resultant increase in adenosine 3′,5′-monophosphate. Broader benefits may be attained with antagonists against receptors of mediators such as histamine or leukotrienes. More potent agents such as glucocorticoids have multiple effects, including the reduction of inflammatory cells and of the production or release of their mediators. A monoclonal antibody against IgE has been shown in clinical trials to be effective in ameliorating allergic airway disease (6). Cytokine-directed therapies such as antibodies against IL-5 have been developed, but so far they have not achieved significant clinical success (7).
Immunotherapy
Repeated administration of low concentrations of specific allergens has been shown to be highly effective in the management of patients with allergic airways disease or with insect venom hypersensitivity. Immunotherapy induces a shift from a TH2 to a TH1 profile of cytokine production with consequent reduction in levels of IgE (Fig. 30.1A), an increase in IgG antibodies that can block the effects of IgE (8), a decrease in allergen-induced release of mediators,
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and a reduction in the number of infiltrating allergic infla-mmatory cells (9).
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FIGURE 30.2. Early and late phases of the allergic response. A: Within 10 minutes of experimental delivery of allergen (Ag) into the nose of subjects with allergic rhinitis, nasal congestion develops and then spontaneously subsides. In 40% to 60% of these individuals, nasal congestion recurs several hours thereafter, during the late phase of the allergic response. Series B: Similarly, inhalation of allergen causes an immediate but transient decrease in forced expiratory volume (FEV1) in subjects with allergic asthma. In the same proportion of individuals, narrowing of the lower airways may again develop several hours after allergen exposure. |
Allergic Rhinitis and Related Conditions
Allergic Rhinitis
Prevalence, Cost, and Comorbidities
Allergic rhinitis is the most common chronic atopic disease. It is estimated to affect up to 20% of the adult population and up to 40 million people in the United States (10). Its prevalence has been increasing, especially in industrialized countries. Direct and indirect costs associated with this condition amount to several billions of dollars annually (10,11). While direct costs are related to medications and clinic visits, indirect costs include reduced productivity and quality of life (12). Affected patients have been shown to have decreased cognitive ability, psychomotor speed, verbal learning, and memory during the allergy season (13). These may be due to the disease itself or the sedating effects of certain medications used (14). The impact of allergic rhinitis is further magnified by several comorbidities (15). For example, it may predispose a patient to develop recurrent sinusitis, due in part to impaired clearance of mucus secretions. Allergic inflammation leads to mucosal swelling with resultant obstruction of sinus openings at the ostiomeatal complex (16). Additionally, eosinophil-derived products such as major basic protein can disrupt normal ciliary activity (17). Given the close pathophysiologic relationship between the nasal passages and sinus cavities, the term rhinosinusitis has been introduced to represent this chronic inflammatory syndrome (18). In the same manner, uncontrolled allergic rhinitis may contribute to the development of recurrent eustachian tube dysfunction and otitis media in children (19).
Allergic conjunctivitis, commonly seen in conjunction with allergic rhinitis, is addressed later in this chapter.
Association with Asthma
Allergic rhinitis is closely associated with asthma, and together they are becoming more recognized as part of the same disease process. Such a condition of concomitant allergic rhinitis and asthma has been named allergic rhinobronchitis by some authors (20). This entity may perhaps be simply termed chronic allergic respiratory disease. Up to nine of ten patients with asthma have symptoms of rhinitis (21). Interestingly, even the few asthmatics who deny having upper airway symptoms may be shown to have subclinical evidence of allergic inflammation in nasal tissue biopsies (22). On the other hand, most patients with allergic rhinitis have no symptoms of asthma. This group may represent an earlier and/or milder form of chronic allergic respiratory disease. Of note, some individuals with allergic rhinitis and no apparent asthma exhibit bronchial hyper-responsiveness upon inhalational challenge with methacholine (23). Patients with allergic rhinitis have a significantly greater chance of subsequently developing overt asthma compared with individuals without a history of chronic nasal symptoms. Among asthmatics, those who have more severe allergic rhinitis tend to have worse outcomes. For example, they have more frequent asthma exacerbations and sleep disturbance (24). The effect of rhinitis on asthma may be because of several factors, such as mouth breathing because of significant nasal obstruction. This prevents warming, humidification, and filtering by the nasal passages of air inspired into the lower airways. Furthermore, exposure of the nasal mucosa to relevant allergens may lead to a widespread allergic inflammatory response. Indeed, localized allergen provocation of the nose induces inflammation not only in the nasal mucosa but also in bronchial tissue (25). Treatment with intranasal glucocorticoids improves both the nasal and chest symptoms of patients with concomitant allergic rhinitis and asthma (26) (Fig. 30.3). It is thus important to evaluate and manage both the upper and lower airways in such pa-tients (27).
Manifestations, Etiology, and Evaluation
The typical symptoms of allergic rhinitis include, in decreasing order of frequency, paroxysmal sneezing, nasal pruritus, nasal congestion, rhinorrhea, and postnasal drip. One or more of these symptoms may predominate and may be the focus of therapy. The temporal pattern and chronicity of symptoms, as well as pertinent exacerbating and alleviating factors, should be determined. Our survey of 412 individuals with allergic rhinitis showed that 17% experience symptoms year-round, 41% have strictly seasonal symptoms, and 42% reported perennial symptoms with seasonal exacerbations (Fig. 30.4). Seasonal symptoms during spring, summer, or fall may indicate sensitivity to tree, grass, or weed pollens, respectively. Perennial symptoms may be attributable to indoor sources of airborne allergens such as dust mites, fur-bearing pets, cockroaches, or rodents. In addition, irritants such as tobacco smoke and cold dry air can also trigger symptoms of rhinitis (28) (Table 30.1). This could be due to an exaggerated responsiveness of sensory nerves in the nasal mucosa in the setting of allergic inflammation (29).
In evaluating the patient, the temporal pattern of symptoms and details regarding environmental exposure at home and at work should be obtained. Physical examination may reveal boggy nasal turbinates and clear nasal secretions. The presence of any confounding anatomic abnormalities such as septal deviation should be evaluated at least by anterior rhinoscopy. If available, nasal endoscopy can provide illumination and direct visualization
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of the nasal passages and nasopharynx and help to localize polyps, purulent drainage, and other potential pathology (18).
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FIGURE 30.3. Improvement in asthma with treatment of allergic rhinitis. Asthma symptom scores of ragweed-sensitive individuals treated with placebo nasal sprays increase as the pollen count rises during the fall season. In contrast, active treatment of allergic rhinitis with beclomethasone or flunisolide nasal sprays not only improves nasal symptoms but also prevents allergen-induced exacerbation of asthma. (Adapted from Welsh P, Stricker W, Chu C, et al. Efficacy of beclomethasone nasal solution, flunisolide, and cromolyn in relieving symptoms of ragweed allergy. Mayo Clin Proc 1987;62:125. ) |
Management
The three main components of the management of allergic rhinitis are allergen avoidance, pharmacotherapy, and immunotherapy. Treatment options are chosen in a stepwise fashion based on the frequency and severity of symptoms (Fig. 30.5). Management of ocular symptoms is described later in this chapter.
Allergen Avoidance
Environmental control measures should be based on a careful assessment of allergen sensitivity. The presence of allergen-specific IgE antibodies may be established through skin testing in vivo or radioallergosorbent testing (RAST) of blood samples in vitro. During skin testing, small concentrations of various allergen extracts are introduced through superficial punctures or through intradermal injections on the arms or back. Skin testing provides immediate results and is generally more cost effective than in vitro testing. Results of these tests should be correlated with the patient's history to determine their clinical relevance. The temporal pattern of symptoms and of exposures should be clarified. For example, a positive skin test with dust mite allergen would be more relevant for an individual with perennial, rather than strictly seasonal, symptoms.
Dust Mites
Allergens of dust mites are contained in their fecal matter (30) and are mostly found in bedding. The use of dust mite-proof bedding covers can reduce the level of exposure to dust mite allergens, but as a single avoidance measure may not be enough to reduce symptoms of allergic
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rhinitis (31). Washing bedding with hot (>130°F [54.5°C) water every 1 to 2 weeks can kill dust mites on the surface and denature their allergens (32). Maintenance of relative humidity below 50% with a dehumidifier may also help reduce the dust mite population (33).
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FIGURE 30.4. Temporal patterns of allergic rhinitis. The temporal pattern of rhinitis symptoms may indicate the environmental allergens to which an individual is sensitive. Our survey of 412 individuals with allergic rhinitis shows that 17% have symptoms year-round, 41% have symptoms only during certain seasons, and 42% have year-round symptoms with seasonal exacerbations. |
Because dust mite particles are relatively large and thus do not remain constantly airborne, high efficiency particulate air filters are not effective in eliminating these allergens (34). For the same reason, so-called ion-charging devices would not have any significant impact on the allergen load inside the room (35). Application of so-called acaricides has not been proven to be consistently beneficial on a long-term basis (36).
Pets
Any fur-bearing animal potentially may cause allergic sensitization in a genetically predisposed individual. Cat allergy has been extensively studied in this regard. The allergenic proteins of cats mostly come from their sebaceous and salivary glands and are deposited onto the skin and fur (37). There may be significant variability in the levels of allergen shedding among cats (38). The most effective way to minimize exposure to such allergens in the home unfortunately entails complete removal of the pet. Confining the cat to parts of the home outside the patient's bedroom and using a high efficiency particulate air filter may reduce cat allergen levels, but may not be enough to produce any significant clinical improvement (39). This illustrates that even relatively low levels of allergens are sufficient to cause respiratory symptoms. Washing the cat may reduce levels of airborne allergens, but this effect is not sustained and its clinical benefit has not been proven (40). If and when patients comply with complete removal of the cat, they should be aware that residual allergens may persist for up to 6 months. Elimination of carpeting and thorough cleaning of the walls may facilitate the decline of allergen levels (41). Exposure to animal allergens may also occur outside the home, as shown by findings of significant levels of cat and dog allergens in school buildings (42). Cat allergens in particular tend to adhere to material surfaces and may be transported via clothing (43).
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TABLE 30.1 Reported Triggers of Allergic Rhinitis Symptoms |
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FIGURE 30.5. Stepwise management of allergic rhinitis. The modes of treatment are chosen based on the frequency and severity of rhinitis symptoms. The first step involves identification and avoidance of relevant allergens and other triggers. Relief of symptoms can be achieved with an antihistamine, decongestant, and/or anticholinergic agent as needed. For persistent disease, control of allergic inflammation can be attained with intranasal glucocorticoids or cromolyn. If these measures do not provide satisfactory improvement, allergen immunotherapy should be considered. |
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Pollens
Complete avoidance of outdoor allergens such as pollens is more difficult to achieve. Keeping the windows closed and using air-conditioning while indoors may help minimize exposure to tree, grass, and weed allergens that are typically prevalent during the spring, summer, and fall seasons, respectively. Multiple studies have documented exacerbation of symptoms among untreated patients in parallel with levels of pollen (26,44) (Fig. 30.6). A study on ragweed pollen counts showed that they begin to rise
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at 6:00 a.m. and peak at midday (45). Patients can check prevailing pollen counts that are regularly monitored across the United States and reported by the National Allergy Bureau (http://www.aaaai.org/nab).
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FIGURE 30.6. Long-term improvement of allergic rhinitis with immunotherapy. Symptom scores of control subjects with seasonal allergic rhinitis increased as grass pollen count rose during the summer season (A to D). In contrast, those who underwent immunotherapy experienced significantly decreased nasal symptoms within 1 year of treatment (A). Those who received continuous immunotherapy consistently had lower rhinitis symptom scores throughout the study (B to D). Interestingly, even those who stopped receiving immunotherapy after 3 to 4 years of treatment experienced extended relief of symptoms (B to D). (Adapted from Durham S, Walker S, Varga E, et al. Long-term clinical efficacy of grass-pollen immunotherapy. N Engl J Med 1999;341:468. ) |
Pharmacotherapy
For most patients with allergic rhinitis, complete allergen avoidance is unattainable or insufficiently effective, necessitating therapeutic intervention. Medications for this disease may be classified into two groups, rescue agents and controller agents (Table 30.2). Rescue medications are used as needed to provide immediate but transient relief of symptoms. These include antihistamines, decongestants, and anticholinergic agents. Controller medications are optimally used on a regular daily basis to mitigate the underlying pathology of allergic inflammation. These include topical glucocorticoids and cromolyn sodium. Antileukotrienes, which were originally approved for use in
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asthma, are now also indicated for controlling the symptoms of allergic rhinitis.
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TABLE 30.2 Types of Medications for Allergic Rhinitis |
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Histamine-1 Receptor Antagonists
Antihistamines significantly reduce symptoms of paroxysmal sneezing, pruritus, and rhinorrhea within 1 to 3 hours of dosing. Given this rapid onset of action, they are effectively used intermittently on an as-needed basis. Older generation antihistamines such as diphenhydramine were developed several decades ago and are now widely available as over the counter drugs. They are potent blockers of histamine receptors but also easily cross the blood–brain barrier, and commonly cause significant sedation, fatigue, and psychomotor impairment. It is important to note that impaired performance may occur even without the patient's awareness, as shown by a study in which individuals given diphenhydramine denied experiencing drowsiness but nonetheless performed poorly in a simulated driving test (46). These patients are more likely to be involved in motor vehicle accidents if medicated inappropriately. Older generation antihistamines should also be avoided by anyone operating machinery, because they have been associated with serious work accidents more than any other medication (47). The cost benefit of these agents should thus be weighed against the risk of serious psychomotor impairment and consequent injury. The newer generation antihistamines (Table 30.3) are comparatively more expensive but offer advantages over their older counterparts. They do not readily cross the blood–brain barrier and thus cause little or no central nervous system effects at regular doses (48). Two drugs in this class, terfenadine and astemizole which were associated with the development of cardiac dysrhythmias, particularly when used together with erythromycin or ketoconazole (49) were taken off the market in the United States.
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TABLE 30.3 Rescue Medications for Rhinitis |
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Most of the new antihistamines are derivatives of agents developed earlier. For example, cetirizine and fexofenadine are metabolites of hydroxyzine and terfenadine, respectively. The new antihistamines have significantly better safety profiles compared with their parent compounds (49), but are not necessarily more efficacious (50).
Decongestants
Antihistamines readily relieve rhinitis symptoms with the exception of nasal congestion. For this specific indication, oral sympathomimetic agents such as pseudoephed-rine may be considered. The common side effects of this medication include insomnia, anxiety, restlessness, and tachycardia. It should be avoided in patients with severe hypertension or coronary artery disease (CAD). Phenylpropanolamine, another decongestant that had been available for decades, was removed from the U.S. market after being implicated in several cases of hemorrhagic stroke (51). Combinations of an antihistamine and pseudoephed-rine (Table 30.3) may provide broader symptomatic relief than either agent alone.
Intranasal decongestant sprays such as naphazoline, oxymetazoline, and xylometazoline are available as
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over-the-counter medications. These should not be used for more than 3 to 5 days. Otherwise, rebound nasal congestion (rhinitis medicamentosa) may develop.
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TABLE 30.4 Controller Medications for Rhinitis |
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Intranasal Anticholinergic Agent
For patients with persistent rhinorrhea, ipratropium bromide 0.03% intranasal spray may be beneficial (Table 30.3). It can reduce the production of nasal secretions but does not significantly ameliorate other symptoms of rhinitis (52). Possible side effects include excessive nasal dryness and epistaxis.
Intranasal Glucocorticoids
Topical intranasal glucocorticoids are the most effective medications for persistent allergic rhinitis (53). Used prophylactically, they can attenuate the development of inflammation and of nasal symptoms during the early and late phases of the allergic response (54). Their onset of action may be evident within 1 day of treatment (55, 56, 57), and studies have demonstrated favorable results even if they are only used intermittently as needed (58). However, these medications are optimally effective when used on a regular daily basis. Although the various intranasal glucocorticoids are comparable in terms of clinical efficacy, they have significant differences in their bioavailability (53,59). Nonetheless, they do not cause any significant suppression of the hypothalamic–pituitary–adrenal axis when used at recommended doses (59). As in the case for any nasal spray, they may cause local irritation, particularly in the beginning of treatment when ongoing inflammation makes sensory nerves more sensitive to stimuli. To improve compliance, it may be best to give patients a choice of a preparation that they prefer, based on characteristics such as the medication's smell or taste, if any (Table 30.4). Some individuals may find liquid nasal sprays soothing, but others may find it more bothersome than dry sprays. Mild epistaxis may occur, especially when the nasal mucosa becomes too dry, in which case saline nasal sprays may be of benefit. Because anecdotal cases of septal perforation have been reported in association with intranasal sprays, patients should be monitored for the development of any mucosal erosion or incessant bleeding (60). Chronic use of intranasal glucocorticoids itself has not been associated with any detrimental histologic changes such as atrophy (61, 62, 63). Intranasal glucocorticoids do not have to be discontinued if the patient incidentally develops an upper respiratory infection, because these medications do not affect the course of such an infection (64).
Chronic or recurrent use of oral or parenteral glucocorticoids for allergic rhinitis is not advisable because of their potential systemic adverse effects.
Intranasal Cromolyn Sodium
Abatement of allergic inflammation may also be achieved with the use of intranasal cromolyn sodium. It typically has to be used up to four times daily to attain optimal benefit (Table 30.4).
Leukotriene Modifiers
Leukotriene receptor antagonists were originally approved for use in asthma but are now used also to treat seasonal and perennial allergic rhinitis (65,66). A study on montelukast showed reduction in allergic rhinitis symptoms by the second day of daily treatment (67).
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Immunotherapy
Immunotherapy should be considered for patients who do not satisfactorily respond to environmental control measures and pharmacotherapy, who do not tolerate or consistently comply with the use of medications, or who prefer long-term amelioration of their frequent symptoms of allergic rhinitis. The choice of specific allergens used for this mode of treatment should be tailored according to the individual's clinically relevant skin test or in vitro test results. Appropriately dosed allergen immunotherapy may be thoroughly effective alone or in combination with medications. Improvement is typically evident within 1 year of beginning treatment, which should then be continued for 3 to 5 years. Data from a long-term study has shown that clinical benefit may endure several years after discontinuation of immunotherapy (38) (Fig. 30.6). Anaphylactic reactions related to immunotherapy, albeit rare, may occur either during the build-up or maintenance phase. Most such reactions develop within 20 to 30 minutes of the allergen injection (68). This form of treatment should thus be administered only under the supervision of an appropriately trained physician, and patients should remain under observation for at least 20–30 minutes. Personnel, equipment, and medications required for the management of anaphylaxis (see Anaphylaxis and Anaphylactoid Reactions later in this chapter) should be readily available. Immunotherapy should not be administered to patients with ongoing cardiac or pulmonary instability. Alternative forms of treatment should also be considered in patients using β-blockers that may make them less responsive to epinephrine if needed for anaphylaxis. Dosing of allergen extracts should be adjusted accordingly if either systemic or large local reactions develop.
Novel Therapy
Immunomodulation to treat allergic respiratory diseases may also be achieved using novel agents such as omalizumab. This is a humanized monoclonal antibody that links to IgE, thereby preventing the binding of IgE to high-affinity FcεRI receptors on mast cells and basophils. Clinical trials have demonstrated its efficacy in rapidly reducing serum levels of free IgE and subsequently ameliorating symptoms of allergic rhinitis, but presently it is indicated only for moderate to severe allergic asthma that is not well-controlled with other forms of therapy (6).
Consultation with an Allergist
In the assessment and care of patients with allergic rhinitis, consultation with an allergist may be considered for several reasons:
Prognosis
A longitudinal study (69) showed that at followup after 23 years, about 23% of individuals with allergic rhinitis reported being symptom free, whereas 32% noted improvement in their disease. The condition was reported to be unchanged in 33%, worse in 9%, and in the remaining 3% of patients the data were not available. The probability of improvement tends to increase with younger age at onset of symptoms. There was improvement in 85% of individuals whose symptoms started at ages 1 to 5 years and in only 39% of those whose symptoms started at age greater than 20 years. The study also showed that patients with allergic rhinitis are about three times more likely to develop subsequent asthma (70). A separate study suggested that immunotherapy in children with allergic rhinitis may reduce the risk for future development of asthma (71).
Allergic Conjunctivitis
Evaluation
Ocular symptoms often accompany allergic rhinitis. Surveys indicate that up to 88% of patients with nasal symptoms also develop itchy, watery, red, teary, and/or swollen eyes. In parallel with rhinitis symptoms, these may occur on a seasonal or perennial basis. Studies in children indicate that it is also possible to have allergic conjunctivitis as the single manifestation of atopy. On physical examination, hyperemia and edema of the conjunctivae, termed chemosis, may be noted bilaterally.
Management
As in rhinitis, the first step in the management of allergic conjunctivitis is the identification and avoidance of offending factors. Cold compresses may provide symptomatic relief. The application of preservative-free artificial tears may help clear the eyes of allergens. For more persistent symptoms, pharmacotherapy with various ophthalmic solutions may provide benefit. These include antihistamines that reduce ocular itching, topical decongestants that reduce redness and swelling, and mast cell stabilizers and other similar agents that ameliorate the underlying inflammation (Table 30.5). As in allergic rhinitis, immunotherapy has likewise been shown to significantly ameliorate symptoms of allergic conjunctivitis (72).
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TABLE 30.5 Medications for Allergic Conjunctivitis |
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Nonallergic Rhinitis
Description
Recurrent nasal symptoms may occur independent of IgE mediation, in which case tests for sensitivity to suspected allergens are negative. Various studies in different clinical settings indicate that 17% to 52% of chronic rhinitis cases have a nonallergic etiology (73). It is difficult to predict whether or not an individual's nasal complaints are IgE mediated simply based on their triggers. Of note, allergic rhinitis symptoms may be triggered not only by allergens but also by nonallergenic irritants such as tobacco smoke and cold dry air (28) (Table 30.1). On the other hand, the age at onset of symptoms may help predict whether a patient has allergic or nonallergic rhinitis. The likelihood of obtaining a positive allergy skin test is greater than 90% if the symptoms began before age 10 years but is less than 40% after age 40 (74). Other details in the history may help differentiate allergic rhinitis from nonallergic rhinitis. Symptoms of nonallergic rhinitis typically occur year-round, whereas the pattern for allergic rhinitis may be perennial, seasonal, or perennial with seasonal exacerbation (Fig. 30.4). In contrast to allergic rhinitis, nonallergic rhinitis is less frequently associated with pruritus, ocular symptoms, concomitant asthma, or a family history of atopy. Gender may also be a risk factor for nonallergic rhinitis, as one study showed that 71% of patients with nonallergic rhinitis are female compared with 55% in a group with allergic rhinitis (73).
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TABLE 30.6 Possible Causes of Nonallergic Rhinitis Symptoms |
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In most cases of nonallergic rhinitis, the exact pathophysiology is difficult to establish. The commonly used term vasomotor rhinitis may be a misnomer because it suggests an established disease mechanism. Research studies indicate that 15% to 33% of patients with nonallergic rhinitis have more than 10% eosinophilia in nasal smears and/or elevated eosinophil cationic protein in nasal fluids and are thus diagnosed with nonallergic rhinitis with eosinophilia syndrome (NARES) (73).
There are several possible etiologic or contributory factors for chronic recurrent nasal symptoms in a nonatopic individual (Table 30.6). Rhinorrhea induced by eating spicy foods is termed gustatory rhinitis, which is a reflex response likely involving capsaicin-sensitive and vagal nerve fibers. Nasal obstruction may be related to structural changes due to septal deformities, nasal polyps, granulomatous diseases such as sarcoidosis or Wegener granulomatosis, and benign or malignant tumors of the nasopharynx. Radiographic studies such as sinus computed tomography may be useful in evaluating these possibilities when strongly suspected. Referral to an otorhinolaryngologist is warranted if any of these conditions is discovered. Pregnancy may also produce nonallergic rhinitis symptoms, which typically increase during the early and late gestational periods and decline postpartum. These may develop in association with physiologic hormonal or vascular changes. Rhinitis symptoms commonly occur due to upper respiratory infection, which may be characterized by mucopurulent discharge and painful sinuses (see Chapter 33). These are usually self-limited if it is viral or otherwise responsive to appropriate antibiotics if it is bacterial in origin.
Recurrent rhinorrhea or nasal congestion may also be associated with over-the-counter and prescription drugs (Table 30.7). For example, prolonged use of intranasal decongestant sprays may lead to rebound congestion and rhinitis medicamentosa. This condition is characterized by a hyperemic and edematous nasal mucosa that becomes
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progressively unresponsive to vasoconstricting agents. Recalcitrant rhinitis symptoms such as nasal irritation and congestion may also be due to the use of illicit drugs such as snorted cocaine.
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TABLE 30.7 Examples of Medications Reported to Cause Symptoms of Rhinitis |
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Management
The presence of any etiologic or contributory factor for nonallergic rhinitis must be addressed. Avoiding exposure to known triggers, particularly irritants such as tobacco smoke at home and in the workplace, may help ameliorate the patient's condition. Empirical use of intranasal glucocorticoids (Table 30.4), such as those used for allergic rhinitis, is the usual mode of treatment. The efficacy of topical steroids, however, tends to be less consistent in nonallergic rhinitis compared with allergic rhinitis. Patients with NARES tend to respond more favorably to intranasal glucocorticoids compared with those with other forms of nonallergic rhinitis (73). However, the evaluation of nasal smears to detect eosinophilia and diagnose NARES is unnecessary, because patients alternatively may be given a trial of intranasal glucocorticoids. Azelastine nasal spray also has an indication for use in nonallergic rhinitis. For patients with severe rhinitis medicamentosa, a short course of oral glucocorticoids (prednisone 30 mg/day for 5 to 7 days) minimizes the rebound phenomenon as the decongestant spray is tapered and discontinued. Oral decongestants and/or anticholinergic agents (Table 30.3) may also be used for symptom-directed treatment of nonallergic rhinitis. Immunotherapy is not a consideration in these cases because they are not IgE mediated.
Generalized Allergic and Pseudoallergic Conditions
Anaphylaxis and Anaphylactoid Reactions
Description
Anaphylaxis is a rapidly evolving systemic allergic reaction that may be life threatening. Although most of these reactions develop at home (75), they also occur in the hospital setting. It is estimated to affect 1 of every 3,000 inpatients in the United States with a 1% risk of a fatal outcome (76). A study in Great Britain indicated that approximately half of fatal anaphylactic reactions are iatrogenic (77).
Anaphylaxis involves IgE-mediated release of cellular products such as histamine and leukotrienes from mast cells and basophils upon exposure of a previously sensitized person to a foreign substance. Such products may affect multiple organs, resulting in cutaneous, respiratory, cardiovascular, or gastrointestinal (GI) manifestations. Table 30.8 lists the frequency of occurrence of these signs and symptoms recorded in a case series of anaphylaxis (78). Respiratory distress may be due to upper airway obstruction and/or bronchoconstriction. Hypotension may be due to vasodilatation or increased vascular permeability. These developments typically occur within minutes of exposure to the offending agent but may develop up to an hour later. The more rapid reactions tend to be more severe. Up to one-quarter of affected patients exhibit a biphasic pattern in which signs and symptoms again develop 1 to 8 hours after they initially resolve (75,79). It is thus important to keep affected patients under close observation during this period.
Anaphylactic reactions may be triggered by minute amounts of an allergenic substance. The most commonly
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implicated triggers are certain drugs and foods. Other causes of anaphylaxis include stinging insect venoms and latex. The evaluation and management of allergy to these specific elements are discussed separately later in this chapter. About 6% to 20% of cases have no identifiable cause and are thus termed idiopathic anaphylaxis (75,80).
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TABLE 30.8 Signs and Symptoms of Anaphylaxis |
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The term anaphylactoid reaction denotes the same clinical picture produced by anaphylaxis but by definition is not mediated by IgE antibodies. Nonetheless, these so-called pseudoallergic reactions may similarly involve bioactive mediators released by mast cells and basophils. These cells can be directly activated, independent of IgE, by opiates (81) or by hyperosmolar agents (82). Other possible mechanisms include activation of the complement cascade and production of anaphylatoxins such as C3a and C5a that trigger mediator release (83). In contrast to anaphylaxis, these pseudoallergic reactions do not require previous exposure.
Depending on the patient's clinical presentation, the differential diagnosis may include vasovagal reaction, acute ischemia, asthma exacerbation, hyperventilation syndrome, carcinoid syndrome, and systemic mastocytosis. The diagnosis of anaphylaxis is strongly supported by the demonstration of elevated serum histamine or tryptase. However, this may be difficult to demonstrate because of the short half-lives of these mediators. If possible, histamine should be measured within 10 minutes to 1 hour, and tryptase within 1 to 2 hours, of the anaphylactic reaction (84).
Management
Because acute anaphylactic or anaphylactoid reactions are potentially fatal, the patient's cardiopulmonary status and the need for timely intervention must be quickly addressed. Most anaphylaxis deaths due to food allergy are associated with respiratory arrest, whereas those due to drugs and stinging insect venoms are associated with cardiovascular collapse. The median time to respiratory or cardiac arrest has been found to be 30 minutes for fatal anaphylactic reactions to foods, 15 minutes for insect venom, and 5 minutes for drugs (77).
Epinephrine is the drug of choice for the acute treatment of life-threatening anaphylaxis because of its combined α- and β-agonist properties. The α component increases peripheral vascular resistance and ameliorates hypotension, urticaria, and angioedema, and the β component has inotropic and bronchodilatory effects. The adult dose is 0.2 to 0.5 mL of a 1:1,000 solution (0.2 to 0.5 mg epine-phrine) given subcutaneously or intramuscularly (Table 30.9). The recommended route is intramuscular injection into the thigh as it has been shown to produce faster systemic absorption and higher peak levels of the drug (85). Dosing may be repeated every 10 to 15 minutes as needed for up to three doses. A retrospective study has shown that more than one dose of epinephrine is required in 36% of cases of anaphylaxis (86).
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TABLE 30.9 Medications for the Acute Management of Anaphylaxis |
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Antihistamines help to reduce the effects of histamine released from mast cells and basophils. Diphenhydramine is given intramuscularly or intravenously at an initial dose of 1 to 2 mg/kg, and then 25 to 50 mg intravenously, intramuscularly, or orally every 4 to 6 hours to relieve recurrent signs and symptoms (Table 30.9). Additional treatment with an H2 blocker such as ranitidine or cimetidine may provide further benefit (87).
Bronchodilator therapy with nebulized albuterol should be given if bronchospasm occurs as part of the anaphylactic reaction, especially in asthmatic patients. Intubation or tracheotomy to allow ventilatory support may be required in severe cases of respiratory distress.
Glucocorticoids are not first-line agents for the treatment of anaphylaxis but are commonly used, putatively to attenuate any late-phase reaction. Methylprednisolone is given at a dose of 1 to 2 mg/kg intravenously (Table 30.9).
A detailed history should be taken to identify any causative agent so preventive measures may be implemented. Referral to an allergist may be considered for further evaluation and management. Skin testing or in vitro tests may detect specific IgE against suspected agents. If future re-exposure is anticipated, desensitization against suspect drugs or immunotherapy against insect venom may be indicated, as discussed later in this chapter.
Patient Education
Patients should be educated about the early recognition of anaphylaxis and the need for immediate action. They should always carry epinephrine for self-administration in case of future life-threatening allergic reaction. A survey has shown that a large percentage of patients with a history of anaphylaxis do not carry epinephrine (78). This should be addressed, because failure to promptly administer this drug increases the risk for fatal anaphylaxis (79). EpiPen Auto-Injector, a device that delivers 0.3 mL of 1:1,000 epinephrine (0.3 mg) intramuscularly through a spring-activated concealed needle, may be used for this
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purpose. For small children, the EpiPen Jr. Auto-Injector device delivers 0.3 mL of 1:2,000 epinephrine (0.15 mg). The patient should be instructed about the proper use of this device to avoid mistakes that lead to ineffective delivery of the drug (88). Epinephrine should be used only in the event of actual or impending cardiovascular or respiratory compromise. In such cases, the patient should seek emergency medical care because additional treatment could be required. Periodic followup should be made to ensure that unused epinephrine is replaced before its expiration date (89).
Prognosis
A longitudinal study has shown that at followup after an average of 2.5 years, 60% of patients with recurrent idiopathic anaphylaxis report resolution of this problem. In 26% of cases, the frequency of anaphylactic episodes decreased, and it increased in 6% (90). The prognosis among patients with allergic reactions to known causes such as foods, drugs, or insect venom is discussed under Specific Allergic and Pseudoallergic Conditions.
Urticaria and Angioedema
It is estimated that 16% to 24% of the U.S. population will develop urticaria at least once in a lifetime (91). Affected individuals present with pruritic, erythematous, circumscribed superficial wheals or “hives” that may be coalescent. The individual skin lesions usually resolve within 24 hours, but others may develop at additional sites. The hives, which are largely due to local plasma extravasation, typically appear on the trunk and extremities but may arise anywhere on the body. Angioedema is swelling of deeper subcutaneous or submucosal tissue that is less circumscribed than urticaria. Unlike other forms of edema, these are often asymmetrically distributed and have no predilection for dependent areas. Urticaria and angioedema occur together in 49% of cases. About 40% of affected patients develop urticaria alone, whereas 11% develop angioedema without hives (91).
Urticaria and angioedema are arbitrarily classified as acute if they occur over a period of less than 6 weeks or chronic if they last longer. For acute urticaria and/or angioedema an apparent cause may be found, whereas chronic cases rarely have an identifiable cause.
Evaluation
Acute Urticaria and Angioedema
Possible causes of acute urticaria and/or angioedema that may be gleaned from the history include drugs, foods, insect bites or stings, physical elements, infections, and topical irritants. Of note, only some of these cases have demonstrable involvement of IgE-mediated allergy. It is helpful if a temporal relationship between the onset of symptoms and a particular trigger factor can be established. For example, a history of food ingestion or insect sting minutes before the development of urticaria or angioedema strongly suggests an allergic reaction. Several nonallergic causes may also be identified. A history of exercise or heat exposure preceding the appearance of pinpoint hives suggests cholinergic urticaria, a nonallergic state. Other physical elements that can trigger urticaria and/or angioedema include pressure, vibration, and cold temperature (92). Urticaria and angioedema may also be associated with infections, for example, hepatitis viruses or Helicobacter pylori, although reports have been conflicting (91,93,94).
If allergen sensitivity is suspected as a cause of recurrent acute urticaria or angioedema, appropriate skin testing or in vitro tests by an allergist may be useful. If physical elements are suspected, diagnostic provocation can be performed. For example, an ice cube may be applied for 5 to 10 minutes on the forearm of a patient with a history of cold-induced urticaria to verify such diagnosis (95). If no specific cause can be identified, a limited workup may be considered to screen for any underlying systemic condition based on findings in the history and physical examination.
Chronic Urticaria and/or Angioedema
For patients with chronic urticaria and/or angioedema, differential diagnoses to consider include connective tissue disease or vasculitis, complement-related disorders, presence of autoantibodies, lymphoproliferative diseases, or mastocytosis with urticaria pigmentosa. A thorough review of systems and physical examination should be performed to evaluate the possibility of these conditions.
The cutaneous lesions associated with urticarial vasculitis are different from benign urticaria in that they are purpuric, persist longer than 24 hours, are painful rather than pruritic, and typically leave residual skin pigmentation. Cutaneous vasculitis accounts for less than 1% of all cases of chronic urticaria (96).
Angioedema, specifically if it is not accompanied by urticaria, may be due to a C1 esterase inhibitor deficiency. This condition may be hereditary or acquired. Laryngeal or gastrointestinal tissue swelling can cause airway obstruction or abdominal discomfort, respectively. Gastrointestinal symptoms may be the sole manifestation of this disease and can lead to unnecessary exploratory laparotomy (97).Hereditary angioedema (HAE) is an autosomal dominant disorder due to several possible defects in the C1 esterase inhibitor gene (98).Acquired angioedema has been associated with connective tissue diseases, lymphoproliferative disorders, malignancies, or autoantibodies against the C1 esterase inhibitor protein (99). For patients with chronic angioedema without urticaria, complement C4 levels should be measured. These are persistently low
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during and between attacks of angioedema because of C1 esterase inhibitor deficiency. In contrast, levels of C2 are low only during episodes of active disease, and C3 levels are unaffected. The diagnosis is established by demonstrating low quantitative and/or functional levels of C1 esterase inhibitor. Its quantity is low in type 1 HAE, which accounts for 85% of cases. In the 15% of cases with type 2 HAE, C1 esterase inhibitor is normal in quantity but is functionally impaired (100). To distinguish between hereditary and acquired angioedema, C1q level should be measured. Levels of C1q are normal in HAE but are low in acquired angioedema (99). Resultant elevations in C2 kinin and bradykinin are believed to be the cause of tissue swelling in these patients (99,101). Elevation in bradykinin, which increases vascular permeability, also has been implicated in angioedema associated with angiotensin-converting enzyme (ACE) inhibitors. Angiotensin II receptor blockers (ARBs) can also induce angioedema, especially in patients with a prior history of developing the same problem following treatment with an ACE inhibitor (102).
Some studies suggest that autoimmunity may play a role in subgroups of patients with chronic idiopathic urticaria or angioedema. Autoantibodies against thyroid peroxidase or thyroglobulin (103) and against IgE or the α chain of the IgE receptor have been implicated (92,104,105). However, the exact role of autoantibodies in the pathogenesis of chronic urticaria and angioedema remains unclear, and routine measurement of their levels is not recommended. In refractory cases of urticaria or when vasculitis is suspected, skin biopsy should be considered (96).
Management
Management of Urticaria or Angioedema without a Known Cause
Management of idiopathic urticaria and angioedema is mainly directed toward amelioration of symptoms. For this purpose, various combinations of antihistamines can provide benefit. Older generation antihistamines are quite effective, but they often cause significant psychomotor impairment in contrast to newer agents (Table 30.3). Addition of H2 receptor antagonists such as cimetidine or ranitidine to treat persistent cases may provide further benefit (106). Tricyclic antidepressants such as doxepin have potent H1- and H2-blocking capabilities and may thus play a therapeutic role. However, their use could be limited by side effects such as sedation and psychomotor impairment (107). Chronic use of oral or parenteral glucocorticoids is not advised in view of their known adverse affects. However, brief courses of oral glucocorticoids may be needed occasionally for severe exacerbations. The use of aspirin and similar nonsteroidal anti-inflammatory drugs (NSAIDs) should be discouraged because they can induce exacerbations of chronic idiopathic urticaria and angioedema (108).
Management of Urticaria or Angioedema with a Known Cause
For nonidiopathic cases when a specific cause such as a food or drug has been identified, avoidance measures should be implemented. For patients diagnosed with C1 esterase inhibitor deficiency, prophylactic management with anabolic steroids such as stanozolol or danazol can prevent recurrence of life-threatening angioedema. The dosage should be cautiously reduced to the lowest effective level possible. The patient's liver function, serum cholesterol, and iron profile should be monitored. Adverse effects in women may include signs of virilization such as hoarseness, acne, irregular menses, and changes in hair pattern (109). If available, infusion of vapor-heated C1 esterase inhibitor concentrate can be used to treat acute episodes of angioedema (110).
For patients with chronic urticaria and thyroid autoantibodies, treatment with thyroid hormone has been reported to provide benefit in some individuals (103), but this effect is neither consistent nor predictable.
Prognosis
A study of patients with chronic idiopathic urticaria or angioedema showed that after 1 year, 38% of those with urticaria alone, 20% with angioedema alone, and 60% with combined urticaria and angioedema were symptom free (111). Another study indicated that up to 20% of patients with chronic idiopathic urticaria continue to be affected after 20 years (92).
Specific Allergic and Pseudoallergic Conditions
Drug Allergy
About 10% to 20% of hospitalized patients in the United States experience some form of adverse drug reaction (112), with fatal outcomes in an estimated 100,000 cases a year (113). Although most of these reactions are not IgE-mediated, approximately 6% to 10% may have an allergic or immunologic basis (114). Systematic data about adverse drug reactions in the outpatient setting are lacking, but this problem is nonetheless an important consideration in ambulatory care.
β-Lactam Antibiotics
Penicillin is the most common cause of drug-related fatal anaphylaxis. It is estimated that anaphylactic reactions occur in 0.004% to 0.015% of all courses of penicillin (115). Such reactions tend to occur more frequently when penicillin is given parenterally rather than orally (116).
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Although most cases involve middle-aged adults, elderly patients tend to have more fatal outcomes, probably due to underlying cardiovascular insufficiency. The risk of allergic reaction to penicillin may be higher among patients with a history of similar adverse reactions to other drugs such as sulfonamide antibiotics (117).
If patients who give a history of a penicillin-induced allergic reaction require treatment with this drug, skin testing should be done first to identify those at risk for anaphylaxis. If the anaphylactic reaction occurred recently, skin testing should be deferred for 1 to 2 weeks; otherwise, the result could be unreliable (118). Skin testing should be performed using major and minor antigenic determinants of this drug. Benzylpenicilloyl polylysine (Pre-Pen) is considered the major determinant because it represents 95% of haptenated penicillin. The minor determinants include benzylpenicillin (penicillin G), which is commercially available, and benzylpenicilloate and benzylpenniloate, which are available only in certain medical centers. It is believed that the minor determinants are responsible for more severe hypersensitivity reactions. Of note, skin testing does not predict adverse effects that are not IgE-mediated such as delayed cutaneous rash, erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Skin testing is not required if there is no personal history of adverse reaction to this drug, even if there is a family history of penicillin allergy. At present, there is no reliable in vitro test for hypersensitivity to this anti-biotic.
Only 10% to 20% of patients who give a history of reaction to penicillin are truly allergic to this drug based on skin testing (116). About 97% to 99% of patients with negative skin tests using the major and minor determinants will tolerate penicillin. On the other hand, patients with a positive history and positive skin test have at least a 50% probability of developing an immediate hypersensitivity reaction if they receive penicillin (119). Alternative antibiotics should therefore be used in these cases. If administration of penicillin is mandatory, the patient should first undergo desensitization. This entails administration of incremental doses of the drug in a carefully monitored setting until therapeutic levels are reached to achieve immunologic tolerance.
About 98% of patients with a history of penicillin allergy will tolerate treatment with cephalosporins, especially the second and third generations of this class of antibiotics. However, the 2% who do react will likely have life-threatening anaphylaxis. There is no validated skin test available for cephalosporins, because their antigenic determinants remain to be established. For these reasons, patients with a history of anaphylactic reaction to penicillin and a positive penicillin skin test should either avoid cephalosporins or undergo desensitization (112,120).
Carbapenems such as imipenem can be cross-reactive with penicillin and should be avoided by penicillin-allergic patients (121). In contrast, the monobactam aztreonam rarely cross-reacts with penicillin (122).
Ampicillin and amoxicillin are known to cause morbilliform rashes, which are not life threatening, in 5% to 10% of patients. These effects are not IgE mediated, so skin testing is not warranted.
Although some patients maintain their hypersensitivity for long periods of time, in the majority the penicillin skin test becomes negative within 10 years (123). This may partially explain why 80% to 90% of patients who give a past history of allergy to penicillin have no evidence of sensitivity to this drug upon testing. Repeat skin testing before each subsequent course of β-lactam antibiotics is not needed because the risk of resensitization is low (124).
Aspirin and Nonsteroidal Anti-inflammatory Drugs
Aspirin ranks second to penicillin as a frequent cause of adverse drug reactions. Affected patients typically experience exacerbation of their pre-existing rhinoconjunctivitis, asthma, urticaria, and/or angioedema. However, these side effects are largely unrelated to IgE-mediated mechanisms. In addition to aspirin sensitivity, some patients can have concurrent asthma and nasal polyposis. These three conditions constitute the so-called Samter triad.
Patients with sensitivity to aspirin similarly develop adverse reactions to NSAIDs such as those listed in Table 30.10. Furthermore, a study has shown that up to 34%
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of aspirin-sensitive asthmatic patients can have mild reactions to acetaminophen at high doses of 1000 mg or greater (125). As such, patients with aspirin sensitivity should avoid both NSAIDs and high doses of acetaminophen. However, these individuals can tolerate lower doses of acetaminophen.
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TABLE 30.10 NSAIDs That Should Be Avoided by Patients with Aspirin Sensitivity |
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There is no skin test or in vitro test for the diagnosis of aspirin or NSAID intolerance. An oral challenge with aspirin is the only definitive way to establish the presence of sensitivity to this medication.
Desensitization should be considered if the benefit outweighs the risk of an adverse reaction. One example is the use of aspirin in patients with myocardial infarction (MI) (126). Patients who successfully undergo aspirin desensitization are also expected to tolerate NSAIDs. Once tolerance is achieved, administration of therapeutic doses of the drug should be continued on a daily basis. Otherwise, full sensitization may recur if the medication is discontinued for up to 7 days.
Radiographic Contrast Material
The incidence of adverse reactions to radiocontrast material is estimated to be 5% to 8%. These may occur with intravascular administration or during hysterosalpingograms, myelograms, and retrograde pyelograms. Although these effects are believed to be unrelated to IgE-mediated hypersensitivity, the reaction is clinically similar to anaphylaxis. Contrary to common belief, shellfish allergy is not a risk factor for the development of adverse effects from radiocontrast dye. The acute treatment of anaphylactoid reactions to radiocontrast media is similar to the management of anaphylaxis.
Individuals who have a history of reactions to radiocontrast media have a greater risk of experiencing adverse effects upon re-exposure. The reported probability of a recurrent anaphylactoid reaction upon repeat exposure ranges from 16% to 44%. This risk can be lowered to approximately 1% by pretreating the affected patient with glucocorticoids and antihistamines. Prophylaxis can be provided with prednisone given at a dose of 50 mg at 13 hours, 7 hours, and 1 hour before the procedure. An oral antihistamine (Table 30.3) is then given 1 hour before the administration of radiocontrast material (127). The use of radiocontrast media with low osmolality can likewise reduce the risk of anaphylactoid reactions (128).
Food Allergy
Epidemiology
Food allergy affects approximately 2% of the adult population in the United States (129). Anaphylactic reactions to food requiring treatment in the emergency department are estimated to occur about 1,000 times a year, with a number of cases resulting in death (130). More than 90% of fatal cases of food allergy have been attributed to peanuts and tree nuts (131). A significant portion of the population is at risk, as 3 million Americans have been determined to have peanut and/or tree nut allergy. Notably, about half the members of this group have never sought medical evaluation, and only a few have epinephrine available for emergency use (132).
Relatively few foods account for the vast majority of food allergy. Milk, eggs, peanuts, soy, and wheat account for 90% of food hypersensitivity in children, but in adults, peanuts, fish, shellfish, and tree nuts are responsible for 85% of food-related reactions. It is rare for an individual to be allergic to more than three foods (129).
Evaluation
A detailed history is important in evaluating the possibility of IgE-mediated sensitivity to food. When they occur, allergic reactions to food typically develop from a few minutes to an hour after ingestion. The absence of a close temporal relationship between exposure and the development of signs and symptoms should prompt a search for other explanations. The manifestations of allergic reactions to food can range from nausea, vomiting, and abdominal cramping to generalized urticaria and respiratory distress.
Some reported cases of anaphylactic reactions to food have been associated with factors such as exercise after a meal (133). Other case reports suggest that in highly sensitized patients, reactions can be triggered by skin contact or inhalational exposure to food particles (134).
For diagnostic purposes, tests for food-specific IgE antibodies or food challenges may be applicable. Although puncture skin testing and in vitro assays have low specificity and positive predictive values, they have excellent sensitivity and negative predictive accuracy. Only about 50% of patients with positive skin tests to food will have a reaction to double-blind placebo-controlled food challenge. On the other hand, negative skin tests virtually rule out IgE-mediated food sensitivity. For in vitro evaluation, cut-off levels of IgE that provide positive and negative predictive values of 95% and 90%, respectively, have been determined for egg, milk, peanuts, and fish (135).
Patient history regarding possible food allergy is not always reliable. Only about 40% of cases can be verified as true food-induced allergic reactions through double-blind placebo-controlled food challenges. This office-based procedure can be considered if no specific item is identified as the cause of an allergic reaction, but certain foods remain strongly suspected. It can be performed under close medical supervision by starting with minute amounts of the suspected food and stopping as soon as symptoms such as oral itching or nausea develop (136).
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Management
Once a food item is identified as a possible cause of hypersensitivity reactions, it should be vigilantly eliminated from the patient's diet. Those with a history of severe allergic reaction should be prescribed epinephrine to be self-administered in case of cardiovascular or respiratory compromise due to anaphylaxis (see details in preceding section Anaphylaxis and Anaphylactoid Reactions, Patient Education). Patients and their caregivers can obtain further support and useful updates from the Food Allergy and Anaphylaxis Network (http://www.foodallergy.org). A study of the use of anti-IgE in patients with peanut allergy had favorable results and opened the possibility of a disease-modifying treatment in the future (137).
Prognosis
About one-third of adults with food allergy will lose their clinical reactivity after 1 to 2 years of allergen avoidance. However, neither skin tests nor in vitro tests can predict which patients will experience resolution of their food hypersensitivity (138).
Insect Venom Allergy
Evaluation
Anaphylactic reactions to insect venom account for about 50 deaths annually in the United States (139), and it is possible that additional cases are undiagnosed and unreported. Stinging insects that cause such IgE-mediated reactions include yellow jackets, hornets, wasps, honeybees, and imported fire ants. Yellow jackets dwell in the ground, whereas hornets build nests in trees and shrubs. Both can be quite aggressive and often sting with minimal provocation. Wasps build honeycomb nests in dark areas, whereas honeybees can be wild or domesticated. Imported fire ants dwell in mounds of soil mostly in the southern states, and their habitat is expanding (140).
Most insect stings typically cause localized swelling, erythema, pain, and pruritus, which are largely due to histamine, serotonin, and kinins contained in the venom. Such limited reactions are not life threatening, but potentially fatal anaphylaxis can also develop in susceptible individuals. The signs and symptoms of such serious reactions can include any combination of generalized urticaria, angioedema, and cardiovascular and/or pulmonary dis-tress.
Localized reactions are not associated with increased risk of subsequent anaphylaxis and thus do not require any long-term intervention. Systemic allergic reactions, however, merit further evaluation and management. Skin testing and/or in vitro tests should be done to demonstrate the presence of IgE antibodies specific for the suspected insect venom.
Management
Adult patients with a confirmed history of systemic allergic reaction to insect venom have a 30% to 60% risk of developing anaphylaxis again in reaction to subsequent stings. Insect venom immunotherapy is thus indicated because it reduces the risk of a subsequent systemic allergic reaction to approximately 2% (141). In children, immunotherapy reduces the risk of a systemic reaction from about 17% to 3% (142). As in any case of anaphylactic reactions, patients should carry epinephrine that can be self-administered as needed. Unfortunately, this important measure is often overlooked (143).
Prognosis
Prospective studies indicate that insect venom immuno-therapy can be discontinued after 5 years of treatment. Data from followup evaluation over the next 5 to 10 years show that the residual risk of a systemic reaction to an insect sting is 5% to 15%. Patients who experienced a life-threatening reaction may opt to continue their treatment indefinitely (141).
Latex Allergy
The prevalence of latex hypersensitivity in the general population is less than 1%. However, certain groups have a significantly higher risk of developing this condition. For example, latex allergy is estimated to affect 24% to 60% of patients with spina bifida and genitourinary abnormalities who have undergone multiple surgeries and to affect 5% to 15% of health care workers (144). This increased risk can be attributed to a higher rate of exposure to latex gloves among these individuals.
Several proteins in the sap of the rubber tree (Hevea brasiliensis) have been identified as latex allergens. Exposure can occur by direct contact, parenteral administration, or inhalation of aerosolized particles. Powdered latex gloves are common sources of the latter, because latex allergens are absorbed by cornstarch powder. Individuals with latex allergy may experience similar hypersensitivity reactions to avocado, banana, chestnut, or kiwi because these foods may have cross-reactivity with latex allergens (145). IgE antibodies against latex allergens can be demonstrated by skin testing or by in vitro tests.
Avoidance of latex products is the only means of preventing serious allergic reactions in a sensitized individual. Primary prevention of latex allergy through the institution of latex-free environments should be encouraged. In the hospital setting, for example, only nonlatex gloves should be allowed to minimize sensitization of high-risk individuals and to avoid adverse reactions among those who are already sensitized. Affected patients should always carry epinephrine that can be self-administered in case of a life-threatening allergic reaction.
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Specific References*
For annotated General References and resources related to this chapter, visit http://www.hopkinsbayview.org/PAMreferences.
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