Allergic Disease Update Sneezing, Wheezing, and Getting The Red Out: Clinical Classification and Outcome-Effective Pharmacotherapy
Authors: Michael Lynn, MD, Department of Emergency Medicine, Alameda County Medical Center, Highland General Hospital, Oakland, CA. Eric Snoey, MD, Residency Director, Department of Emergency Medicine, Alameda County Medical Center, Highland General Hospital, Oakland, CA. Gideon Bosker, MD, FACEP, Assistant Clinical Professor, Section of Emergency Services, Yale University School of Medicine, Associate Clinical Professor, Oregon Health Sciences University, Portland, OR.
Peer Reviewer: Corey Slovis, MD, Professor and Chairman, Department of Emergency Medicine, Vanderbilt University School of Medicine, Nashville, TN.
Editor’s NoteWhether the symptoms are mild or severe, the therapeutic mission statement is always the sameto get the red out. Most importantly, to get the red out quickly and to keep it out, with the hope of making misery a memory for the patient, preferably with medications that work rapidly and that produce as few side effects as possible. Although, except in the case of anaphylaxis, allergy-mediated diseases rarely produce life-threatening illness, the spectrum of conditions associated with allergic complaints frequently brings patients to their primary care physicians’ offices.
Among allergic conditions sending patients to their physicians are seasonal allergic rhinitis, perennial allergic rhinitis, acute and chronic urticaria, and anaphylaxis. Symptom-ameliorating measures will almost always include pharmacotherapeutic intervention, which can range from antihistamines, decongestants, and nasal steroids in less severe cases to epinephrine and systemic steroids in life-threatening cases. Outcomes will be optimized if physicians are able to distinguish among available medicationsin particular, by placing special emphasis on rapidity of onset of action, side effects, and efficacy of symptom relief.
Characterized by rhinorrhea, sneezing, and nasal congestion, allergic rhinitiswhether of the seasonal or perennial varietyrequires selecting medications that work as quickly as possible, have low discontinuation rates, make patients comfortable enough to resume or maintain their customary work, sleep, and recreational activities, and which are associated with minimal side effects. In the majority of cases, systemic oral therapy with second-generation H-1 receptor antagonists will constitute the primary bulwark of defense for initial treatment of acute symptoms; this may be followed by nasal corticosteroids for long-term suppression of symptoms. Patients with idiopathic urticaria require medications that reduce wheal and erythema, whereas individuals who present with anaphylaxis usually require multi-modal therapy linked to epinephrine and fluid administration as the cornerstone of treatment.
With these issues in focus, the following review presents a clinically useful classification of common allergic diseases encountered by the primary care practitioner. A detailed comparison-analysis of medications used for these conditions is provided, and strategies for optimizing outcomes are presented.
Ranging from mild nasal congestion and uncomfortable skin rashes to life-threatening anaphylaxis, allergic reactions have a dramatic effect on peoples’ lives. An allergic reaction is defined by a hypersensitive state acquired after exposure to a particular allergen.1 In broad clinical terms, allergic reactions include such conditions as rhinitis, urticaria, angioedema, and anaphylaxis. Allergic rhinitis has a prevalence rate ranging from 5-22% and is the sixth most common chronic condition in the United States, even outranking heart disease.2 Up to 30 million Americans suffer from the disorder, and, while the disease may begin at any age, children and adolescents are most commonly afflicted.2 An estimated 1.5 million school days and 3.4 million work days are lost each year due to allergic rhinitis. In addition, allergy sufferers who stay on the job report a 25% reduction in productivity secondary to the disease itself or sedation from drugs used to treat their symptoms.3,4 The combination of lost productivity, physician visits, and medication costs has an estimated economic impact of $1.8 billion per year.4 Clearly, allergic rhinitis has far-reaching implications.
Urticaria and angioedema also represent part of the spectrum of allergic reactions. In fact, up to 20% of the general population will develop urticaria or angioedema at some point in their lives.5 Although generally not life-threatening, urticaria and angioedema are distressing to patients and may be associated with significant morbidity. Anaphylaxis, on the other hand, is acutely life-threatening, often unpredictable, and demands immediate assessment and intervention.6-13
Clinical Categories. The term rhinitis refers to diseases characterized by inflammation of the nasal mucosa. Symptoms include variable periods of nasal discharge, congestion, and sneezing, that classically persist for at least one-half hour per day.14 Rhinitis can be broadly categorized based on infectious and non-infectious etiologies. Infectious rhinitis is best exemplified by the common cold, with its constellation of viral symptoms, including low-grade fever and cloudy nasal secretions. This review is limited to the non-infectious allergic variety of rhinitis. (See Table 1.)
Non-infectious rhinitis can be further subdivided into seasonal allergic rhinitis and perennial allergic rhinitis. Patients with non-infectiousso-called allergic rhinitishave clear nasal discharge, often with large numbers of eosinophils.14 Fever typically is not present.15 Seasonal rhinitis and perennial allergic rhinitis are similar in their clinical manifestations. The fundamental difference is that perennial rhinitis has no seasonal variation. Although subtle differences in etiology and clinical manifestations exist, management of these disorders is similar.
Allergic Rhinitis. Allergic rhinitis may begin at any age, but it most often affects children and adolescents. An estimated 20-30% of adolescents suffer from this disorder.14 It is thought that infants are only rarely affected because a minimum of two seasons of exposure to new antigens are required before the disease can manifest itself. The need for prolonged, repeated exposure may also explain why patients without a history of allergic rhinitis may develop symptoms several years after moving to a new location that harbor different allergens. Allergic rhinitis afflicts men and women equally, and there is no ethnic or racial predominance. Once the disease begins, it tends to persist indefinitely, although spontaneous remissions have occurred.14
Etiology. The most common allergens implicated in seasonal allergic rhinitis are molds and pollens. Contrary to popular belief, plants that rely on insects for pollination (e.g., roses, dandelions) do not cause allergic rhinitis unless patients are continually in close contact with these plants. Rather, vegetation that depends on wind for cross-pollination (e.g., most grasses, trees, and weeds) are the more common precipitants of allergic rhinitis. In this regard, ragweed pollen appears in the northeastern and midwestern United States from mid-August through September. Sage brush is common in the western United States. Grass pollens occur throughout the nation in spring and summer months. These pollens contribute little, however, to symptoms of perennial allergic rhinitis. In perennial disease, house dust, animal dander, and molds are the most likely responsible allergens.14 This explains why perennial rhinitis generally does not vary with the seasons, although seasonal exacerbations may occur in patients with concomitant pollen allergy.
Pathophysiology. Allergic rhinitis requires two predisposing conditions to produce overt clinical disease: genetic predisposition and exposure to allergens.15 From a pathophysiological perspective, antigens such as pollens, molds, grains, and animal dander infiltrate the respiratory mucosa where Langerhans cells process and present them to T-lymphocytes. T-lymphocytes, in turn, release cytokines and granulocyte-macrophage colony-stimulating factor, which stimulate B-lymphocytes to produce IgE. IgE binds to receptors on mast cells in the nasal mucosa,16 and remains there until re-exposure to the allergen. At this point, the nasal mucosa is considered "sensitized" to that particular allergen. Interestingly, the nasal mucosa of people with allergic rhinitis has significantly more mast cells than that of non-affected people.17 Repeated exposure of IgE to the same allergen triggers an explosive release of a variety of vasoactive mediators from mast cells. This release is postulated to be the critical initiating event in the development of allergic symptoms. Mediators include histamine, leukotrienes, bradykinin, and prostaglandins. Histamine, which is the most important mediator, binds specifically to H-1 receptors in the nasal mucosa, inducing rhinorrhea, mucus production, and sneezing symptoms typical of allergic rhinitis.17
The mechanism of allergic rhinitis has been shown to involve both an immediate phase and a late phase. Immediate phase refers to the release from mast cells of preformed mediators such as histamine and leukotrienes that produce such clinical symptoms as rhinorrhea and sneezing within 30-60 minutes of exposure. Late-phase symptoms occur 4-24 hours after mast cell degranulation and are thought to be secondary to inflammatory cell infiltration of the nasal mucosa. The late phase differs from immediate phase in that nasal congestion and obstruction, rather than rhinorrhea, predominate.3 The distinction between immediate and late phase has significant therapeutic implications.
Clinical Symptoms and Signs. Rhinorrhea, nasal congestion, sneezing, and palatal itching are classic symptoms of allergic rhinitis. Sneezing may include paroxysms of as many as 10-20 sneezes, most commonly in the morning, when windborne pollens are released in greatest numbers.14 Rhinorrhea is often profuse and sustained and, usually, is thin and watery. Purulent rhinorrhea may indicate secondary bacterial infection. Swollen nasal turbinates frequently cause bothersome nasal congestion that, initially, is intermittent early in the season but often becomes constant as the allergy season progresses. Headache and earache may accompany nasal congestion, and sustained obstruction may even lead to alteration or loss of smell and taste. Persistent oropharyngeal drainage of nasal secretions causes an irritating sensation in the throat and, oftentimes, a chronic non-productive cough.14 Bronchial irritation may exacerbate reactive airway disease and present with typical symptoms of asthma.18 In fact, studies suggest that up to 38% of patients with allergic rhinitis have asthma, compared to 3-5 % in the general population.19
Once symptoms of allergic rhinitis develop, they usually recur at approximately the same time each year. Acutely sensitive patients develop symptoms early in the pollen season. As pollen concentrations increase, symptoms generally worsen. At the end of the season, symptoms gradually abate. Interestingly, in some individuals, symptoms may persist up to three weeks following the end of pollen season. This is thought to be secondary to a form of increased reactivity termed the "priming effect." Patients have a "primed" nose from a season of allergic symptoms and subsequently react to irritants that would not normally affect them. This "priming effect" generally abates within 2-3 weeks.14
On physical exam, a patient often has red, irritated skin in the area of the midface from rubbing or blowing the nose. Nasal turbinates are pale and edematous and may completely obstruct the nasal passages. Eyes usually demonstrate injected conjunctiva. Dark edematous circles under the eyes, common to atopic individuals, are the result of venous obstruction in the inferior orbital area due to nasal congestion. The posterior pharynx is usually normal, although lymphoid hyperplasia may be evident.15 Chest exam is unremarkable except in patients with concomitant reactive airway disease.
Drug Therapy for Allergic Rhinitis
Patients with allergic rhinitis should be treated in order to alleviate immediate symptoms and, with the objective of avoiding more problematic sequelae such as chronic sinusitis, inner-ear dysfunction, and sleep apnea. Not surprisingly, treatment options are variable and can be complex, and the physician is faced with a wide range of pharmacotherapeutic alternatives. (See Table 2 and Table 3.) In this regard, the type and etiology of allergic rhinitis, the patient’s age, occupation, and underlying co-morbid conditions will all affect management decisions. For example, sedating antihistamines must be used with caution in children as well as adults who cannot tolerate daytime sleepiness. Anticholinergic side effects may adversely affect urinary flow in men with benign prostatic hypertrophy. Drug-drug interactions are known to cause a fatal torsades des pointes in patients taking terfenadine or astemizole together with certain antimicrobial medications. Basic knowledge of the mechanism of pharmacologic agents used in allergic rhinitis clarifies the most suitable treatment options.
Antihistamines. Antihistamines have been available for 50 years but remain the most commonly used medication in the treatment of patients with allergic rhinitis. Currently, there are approximately 100 different antihistamines on the market, reflecting a wide range of pharmacological and clinical effects.3 When histamine is released from mast cells, it acts on three receptors: H-1, H-2, and H-3. H-1 receptor activation stimulates smooth muscle contraction and increases vascular permeability. Mucus production increases and sensory nerves are activated causing nasal pruritus and sneezing. H-2 receptor activation causes blood vessel dilation and gastric acid secretion. Finally, H-3 receptors, located in the brain, play a role in regulating the production and release of histamine from nerve tissue.2,6 Although histamine binds to all three receptors, only its effect on H-1 receptors is clinically important in allergic rhinitis. Antihistamine agents essentially work through competitive inhibition of these H-1 receptors.20 By blocking H-1 receptors, immediate phase symptoms are blunted. In contrast, H-2 antagonists, such as cimetidine and ranitidine, have little effect on H-1 receptors and, consequently, have not been shown to be clinically effective in the management of allergic rhinitis.2
First-generation antihistamines, such as diphenhydramine (Benadryl) and chlorpheniramine (Chlor-Trimeton), are highly lipophilic and penetrate the blood-brain barrier. This results in unacceptable sedation and disruption of motor skills in up to 25% of patients.20-22 Because of their sedation profile, several first-generation antihistamines are approved for use as sleeping medications.2 Due to sedation side effects, first-generation antihistamines usually are not recommended in school-aged patients nor should they be the daytime drugs of choice for adults who need to be truly alert (i.e., those who drive or operate heavy machinery.)21 These antihistamines can also produce profound anticholinergic side effects such as urinary retention, constipation, dry eyes, narrow-angle glaucoma,23 and tachycardia, which may preclude their use in the elderly or patients with comorbid conditions. Furthermore, first-generation antihistamines are contraindicated in pilots within 24 hours of flight because of sedation and changes in reflexes and depth perception.3
Some of the second-generation antihistaminesamong them, terfenadine (Seldane), loratadine (Claritin), astemizole (Hismanal), cetirizine (Zyrtec), and fexofenadine (Allegra)have been available in either U.S. or non-U.S. markets for up to 10 years and represent a significant advance in the therapy of allergic rhinitis. (See Table 4.) In contrast to first-generation antihistamines, these drugs are far less sedating because they are more lipophobic20 and, therefore, are less likely to penetrate the blood brain barrier. Additionally, second-generation antihistamines have few, if any, anticholinergic side effects. A placebo-controlled, double-blinded study of 15 pediatric patients with allergic rhinitis found a significantly lower incidence of sedation and cognitive impairment in patients receiving terfenadine compared with the first-generation antihistamine chlorpheniramine.24 In a second study evaluating loratadine and diphenhydramine, 12 performance tests were administered that evaluated such skills as mathematical reasoning and memory before and after drug administration. The loratadine group performance was similar to placebo, but diphenhydramine lowered performance in two-thirds of the tests.18
The five low non- and/or minimally sedating second-generation antihistamines differ largely in terms of their half-lives, onset of action, and toxicity. Fexofenadine and terfenadine have a relatively short half-life and, therefore, require bid administration that may represent an inconvenience in a significant percentage of patients. Astemizole and loratadine have longer half-lives, permitting once-daily dosing, which may improve patient compliance. Cetirizine (Zyrtec) also has a long half-life similar to loratadine and astemizole, but its sedation profile is slightly different. Compared to the other previously mentioned second-generation antihistamines, which in placebo-controlled trials produce drowsiness in about 1-2% percent of patients, cetirizine produces symptoms such as drowsiness and/or sedation in an additional 7-8% of patients above the number of those reporting such symptoms in the placebo arm. (Overall, about 14% of patients taking cetirizine reported somnolence-related side effects in placebo-controlled studies.) From a clinical perspective, then, cetirizine, as compared to loratidine or fexofenadine, can be expected to produce drowsiness or sedation in only an additional six or seven patients out of 100 individuals receiving these medications.7-13 This difference must be weighed against the potential advantages demonstrated by cetirizine, in particular its rapid onset of action as compared to other agents, its lower cost among the second-generation antihistamine class, efficacy, and the fact that it has FDA approval for seasonal allergic rhinitis, perennial allergic rhinitis, and chronic urticaria.6-12
Multiple studies have compared the effectiveness of second-generation antihistamines to each other and to placebo. Two studies comparing loratadine, terfenadine, and placebo in patients with seasonal allergic rhinitis found a significant reduction of symptoms in the drug-treated group, with no difference in efficacy or side effects.26,27 A comparison study of cetirizine and terfenadine found both to be effective in reducing symptoms of perennial allergic rhinitis, but cetirizine caused slightly more sedation.28 Likewise, fexofenadine has been shown to be more effective than placebo, but there are no published studies comparing this antihistamine with other H-1 receptor antagonists.29-32
Although all second-generation antihistamines have similar efficacy, two have a rare but important side effect that, for all practical purposes, makes them less desirable than the others. Terfenadine and astemizole were recently linked to fatal cardiac arrhythmias, in particular torsades des pointes. A common pathway appears to be the prolongation of the Q-T interval.22,36 Independent risk factors are high serum drug levels,22 interactions with macrolide antibiotics and antifungals,29,33-35 liver disease, or intrinsic cardiac disease.15 Concomitant use of Type 1a antiarrhythmic agents, thioridazine, and the selective serotonin re-uptake inhibitors fluvoxamine (Luvox) and neferzodone (Serzone) has also been implicated.3 In addition, patients at risk for hypokalemia and hypomagnesemia should have other antihistamines prescribed for them, such as loratadine, fexofenadine, or cetirizine, all of which have no effect on the Q-T interval.22,26-28
Antihistamine Selection: Getting The Red Out. From a primary care perspective, one of the most important considerations when choosing an antihistamine for an acutely symptomatic patient is the onset of action of the drug and its efficacy. Comparing efficacy and rapidity of symptomatic relief requires head-to-head studies involving all available antihistamines that, until recently, have been lacking, especially for the newer, selective, peripheral histamine H-1-receptor antagonists. The lack of definitive studies comparing this class of medications has fueled considerable debate among emergency and primary care specialists as to which antihistamine is best-suited as initial therapy, especially for patients requiring definitive, prompt relief of discomforting or disabling symptoms caused by seasonal allergic or perennial allergic rhinitis.
Recently, however, an important study that attempted to rank such medications as cetirizine, loratidine, astemizole, and terfenadine according to their ability to produce relief of symptoms of allergic rhinitis has been published.36 In this well-designed investigation (financially supported, in part, by Nordic Merrell Dow, which markets terfenadine) that has important implications for initial selection of antihistamines, 111 ragweed-sensitive subjects were primed with pollen in an Environmental Exposure Unit. Individuals who were evaluated included those with sufficient symptoms produced over a three-hour exposure to 5000 ± 300 grains/m3 of ragweed pollen. When subjects had been sufficiently symptomatic after at least a 60-minute exposure, they were then given a single dose of either terfenadine (60 mg), astemizole (10 mg), cetirizine (10 mg), loratidine (10 mg), or placebo. During treatment, the allergen levels were maintained and the patients’ symptoms recorded every 30 minutes.
The percentage of patients who demonstrated clinically important relief (defined as "marked relief" or "complete relief" at three consecutive time points) were greatest in the cetirizine group (69.6%), followed by terfenadine (54.5%), loratidine (50.0%), astemizole (40.9%), and placebo (31.8%), but these differences were not different among the treatment groups (P = 0.119). Analysis, however, did demonstrate that cetirizine was different from placebo (P = 0.025). Interestingly, while the antihistamines did not differ significantly with respect to clinically important relief, when investigators examined the times to onset of relief and the proportion of individuals who achieved definitive relief of symptoms caused by allergic rhinitis, significant differences were detected among the four treatment groups tested with the second-generation antihistamines. Definitive relief, which represents a clinically desirable extension of "marked relief," was defined as "marked relief" or "complete relief" without being followed by such subsequent patient assessments as "moderate, slight, or no relief" on the effectiveness scale.
The percentage of patients reporting definitive relief in the various treatment groups were: 65.2% in the cetirizine group; 45.5% in the terfenadine group; 31.8% in the loratidine group; 27.3% in the placebo group; and 22.7% in the astemizole group (P = 0.023). These differences were statistically significant. In addition, the times to onset of definitive relief for seasonal allergic rhinitis were statistically significant among the five groups (P = 0.010). The ranking from quickest to slowest was cetirizine, terfenadine , loratidine, astemizole, respectively. Finally, a "global" evaluation, in which the patients express their willingness to take the study medication again, yielded the following percentages: cetirizine (82.6%), terfenadine (66.7%), astemizole (63.6%), loratidine (40.9%), and placebo (36.4%) (P = 0.036). Based on these studies, the investigators concluded that cetirizine and terfenadine continuously ranked higher in terms of onset of action and efficacy, while loratidine and astemizole ranked lower.
Unfortunately, fexofenadine was not evaluated in this study, and therefore, head-to-head comparisons between this drug and others are not available. However, based on these study results, and the ongoing concern over drug interactions with terfenadine (which the FDA has recommended removing from the market), it would appear as if cetirizine currently represents an excellent initial antihistamine of choice for allergic or perennial rhinitis patients encountered in the primary care setting. It should be stressed that because of the rapid onset of action of cetirizine, some patientsespecially those with unpredictably waxing and waning symptomsmay be able to achieve adequate relief by taking the medication on a once-daily, "as-needed" basis and the drug may be especially attractive in cost-conscious managed care settings. This approach can substantially reduce overall costs of antihistamine therapy. Finally, if patients on cetirizine subsequently complain of drowsiness or sedation, they can be switched to another second-generation antihistamine.36
Very few other side effects have been found with second-generation antihistamines. Several reports of mechanical upper gastrointestinal tract obstruction in patients taking a loratadine/decongestant combination (Claritin-D 24 hour) suggest caution in prescribing this medicine to patients with known dysphagia or gastrointestinal anatomic abnormalities.37 Patients taking astemizole have reported weight gain.38 The single overall drawback of second-generation antihistamines is their expense. Loratadine, for example, has a wholesale cost of $58.08 for a one-month supply, compared to $2.03 for diphenhydramine.39
Decongestants. Because numerous non-histaminergic mediators also are involved, antihistamines alone may not adequately control symptoms of allergic rhinitis.18 For example, late-phase symptoms of allergic rhinitis, such as nasal congestion and construction, may be attenuated by decongestants.3,18,20,23 Decongestants are sympathomimetics that produce clinical relief by stimulating alpha receptors in the nasal mucosa, causing a reduction in edema and blood flow.22 Topically administered decongestants control symptoms more rapidly and selectively than orally administered ones, with few systemic side effects.2 Common topical agents include phenylephrine (Neosynephrine) and oxymetazoline (Afrin), both of which are equally effective and have a duration of action between one and eight hours, respectively.22 Importantly, topical agents can only be used safely for a maximum of five days before risking "rhinitis medicamentosa," a form of rebound nasal congestion.20,22 This prospect significantly limits the role of these agents to intermittent, PRN use; accordingly, prolonged use is ill-advised.
Oral decongestants (e.g., pseudoephedrine [Sudafed], and phenylpropanolamine) are commonly combined with antihistamines to enhance control of both nasal congestion and rhinorrhea. Combinations of pseudoephedrine with loratadine (Claritin-D) or terfenadine (Seldane-D) are typical examples. A randomized, triple-blinded study comparing loratadine/pseudoephedrine with chlorpheniramine/pseudoephedrine demonstrated symptomatic improvement in both groups. However, there were significantly fewer complaints of sedation and dry mouth in the loratadine/pseudoephedrine group.40 Unfortunately, all forms of oral decongestants may be associated with systemic side effects such as tachycardia, irritability, and "agitated sedation."3,20,22 These side effects can be significant. Interestingly, the sense of agitated sedation may occur even when oral decongestants are combined with sedating first-generation antihistamines such as chlorpheniramine.3 Cautious use of phenylpropanolamine-containing compounds is mandatory, especially in patients with hypertension. Consequently, combination agents are generally not advised as first-time therapy, unless non-combination agents fail to produce desired clinical effects.
Topical Corticosteroids. In patients who can tolerate them, nasal steroids have become a cornerstone of treatment for allergic rhinitis.3,10,16 (See Table 5.) These agents decrease nasal mast cell density,17 inhibit multiple steps in the inflammatory process, and decrease capillary permeability.22 In contrast to many antihistamines and decongestants, nasal steroids act on both immediate (e.g., rhinorrhea) and late (e.g., nasal congestion) phase reactions. This permits control of all aspects of allergic rhinitis.23 An estimated 90% of patients with allergic rhinitis have significant symptomatic relief when treated with nasal steroids;2 the efficacy of these agents has been shown in multiple studies.2,41,42 Comparison studies of steroids with placebo demonstrate significant improvement in symptoms and fewer lost days from work.42
Nasal steroids are non-sedating and can be combined with antihistamines/decongestants in patients who have symptoms that are difficult to control. Adverse effects are usually minimal and include nasal irritation and mild epistaxis, the most commonly reported problems. Nasal Candida albicans has not been reported.22 Adverse systemic effects of nasal steroids are controversial but may include reversible open-angle glaucoma in patients over age 60 and cataract formation.23 A recent Canadian study, however, did not find any association between glaucoma and extended use of nasal steroids.43 It is prudent, however, for the primary care physician to suggest glaucoma and cataract screening within three months of beginning steroid therapy.23
An important drawback to these agents is the need for at least three days of regular use before a noticeable clinical response, which is in contrast to the rapid onset of antihistamines such as cetirizine. Since allergen exposure typically is unanticipated, patients often require "rescue" from their misery with a short course of antihistamines until the nasal steroids take effect.3
Systemic therapy with steroids is rarely indicated in the treatment of allergic rhinitis. Their use should be limited to patients with complete nasal obstruction refractory to decongestant and antihistamine therapy, since these patients may progress to develop inner-ear disorders or sleep apnea. A short 10-day tapering regimen course is suggested.2
Cromolyn Sodium. Cromolyn nasal preparations are effective in reducing symptoms of allergic rhinitis through suppression of mast cell degranulation. Like antihistamines, cromolyn is more effective in alleviating immediate-phase symptoms such as sneezing, rhinorrhea, and nasal pruritus but does not attenuate nasal congestion or other late-phase symptoms.44 Cromolyn requires prophylactic administration, 4-6 times per day, and may take from 1-4 weeks before producing symptomatic relief.3,22 In some patients, cromolyn may be ineffective if started after onset of symptoms. Due to its very favorable side-effect profile, it is especially suitable for children and the elderly, although compliance with its frequent use may be a limiting factor.
Anticholinergics. In 1996, ipatropium bromide (Atrovent) nasal spray became available for use in the treatment of allergic rhinitis. Although it has yet to gain widespread use, this anticholinergic medicine effectively controls rhinorrhea. Ipatropium bromide reduces the volume of nasal secretions by inhibiting parasympathetic stimulation of nasal tissue. At therapeutic levels, rhinorrhea has been shown to decrease significantly. It has no effect on sneezing and nasal pruritus, nor does it relieve nasal congestion.22,23 Ipatropium bromide does not cross the blood-brain barrier, and it has no systemic anticholinergic effects.45 Similarly, long-term adverse effects, as well as tolerance to its therapeutic effects, do not occur. Epistaxis and nasal dryness are the most commonly reported side effects.22,46
Immunotherapy. Patients may inquire about "allergy shots." The principal behind this therapeutic option is to repeatedly inject tiny amounts of a specific allergen in order to gradually reduce the body’s immunologic response to this allergen. Symptom relief takes between three months and two years, and therapy must be continued for several years after the cessation of symptoms. Immunotherapy may help allergic symptoms to a specific allergen, but it will not affect concomitant allergies to other allergens. Thus, continued use of adjunctive pharmacotherapy is often necessary. Finally, immunotherapy poses a small but significant risk of anaphylactic reaction to the injected allergen. It should only be administered by specialists with resuscitative equipment at hand. Immunotherapy is contraindicated in patients on beta-blockers (which may render the patient refractory to standard anaphylactic treatment), severe asthma, or severe atopic dermatitis. Despite the risks, immunotherapy may be useful in patients who cannot avoid allergens (e.g., veterinarians who develop animal dander allergies) or who prove refractory to standard pharmacotherapy.3,47
Clinical Background. Urticaria and angioedema affect up to 20% of the population at some point in their lives.48 These disorders are usually acute and self-limited, although chronic forms do exist. Both disorders represent cutaneous or subcutaneous manifestations of mediators released from cells that have been stimulated by allergens. Urticaria is characterized by erythematous, well-circumscribed edematous lesions that are often evanescent and pruritic. The distribution of urticarial lesions is highly variable but most commonly involves the trunk.48 Angioedema represents a similar pathological reaction to urticaria, but the reaction is located in the deep dermis and subcutaneous tissue rather than in the superficial skin layers, where there are few sensory nerve endings, the lesions tend to be non-pruritic and the skin itself may appear normal.5 Angioedema most often involves the face, eyelids, and tongue, where it may produce findings ranging from mild edema to massive lingual and pharyngeal swelling. Angioedema co-exists with urticaria in approximately 50% of patients.5 It is unclear why some patients develop urticaria, some develop angioedema, and others manifest both.
Pathogenesis. The pathogenesis of urticaria and angioedema involve multiple mediators and pathways, some of which remain poorly understood. The most important mechanism is similar to that of allergic rhinitis: an allergen stimulates production of IgE, which then binds to mast cells (and other cells as well). Histamine and other mediators (e.g., leukotrienes) are released from mast-cell granules. These mediators cause vasodilation (erythema) and increased vascular permeability (edema). A second pathway involves the complement cascade. Specifically, C3a, C4a, and C5a interact directly with the mast-cell surface to induce histamine release. Another pathway involves activation of Hageman factor that, via the coagulation cascade, initiates the formation of mediators such as kallikrein and bradykinin.5
Etiology. The etiology of urticaria and angioedema is often idiopathic.41 (See Table 6.) In general, allergens that have been ingested or are in direct contact with skin are most likely to be the responsible agents. This is in contrast with inhaled allergens, which are more likely to cause nasal or respiratory symptoms.5 Of the identifiable causes of urticaria and angioedema, drugs are most commonly responsible.48 Virtually any drug may induce an allergic reaction, but several medicines are uniquely capable of directly activating mast cells. These drugs include morphine, codeine, vancomycin, and radiocontrast agents, among others. Penicillin is also well-known for causing urticaria, although through an IgE-mediated mechanism rather than direct mast-cell stimulation. Angiotensin-converting enzyme (ACE) inhibitors cause angioedema through a mechanism that is thought to involve production of bradykinin.49 Likewise, foods such as nuts and shellfish are frequently implicated in allergic reactions. Insect bites and stings, exercise, latex gloves, and even semen are known to induce urticaria and angioedema.50-53 Uncommon and poorly defined syndromes related to cholinergic sensitivity, cold, sun, water, and dermatographism have also been described.5
There also are chronic and hereditary forms of these disorders. Chronic urticaria is arbitrarily defined as a reaction that lasts longer than six weeks. It is usually idiopathic, although autoimmune disorders such as systemic lupus erythematosus (SLE) and rheumatoid arthritis may occasionally be responsible. Seven percent of patients with SLE develop hives at some point in their illness.48 Other systemic disorders such as infection, malignancy, and endocrine dysfunction may also involve chronic urticaria.48 Hereditary angioedema is caused by a deficiency in C-1 esterase inhibitor, which results in repeated episodes of idiopathic angioedema.49 Attacks are typically mild and infrequent but can, in rare patients, become a daily, debilitating event.54 Interestingly, inciting allergens or events leading to attacks of hereditary angioedema often cannot be identified. A family history of angioedema is suggestive of this disorder.
Signs and Symptoms. Patients with acute urticaria will complain of intense pruritus; hives typically will be evident on physical exam. Individuals with chronic urticaria generally have less pruritus, and hives may be less prominent. Patients with angioedema generally have non-pruritic edema of the affected area. Edema usually is moderate and self-limited, but lingual and pharyngeal swelling is massive at times and may result in airway obstruction. Stridor, hoarseness, dysphagia, and drooling are typical signs of impending airway compromise.
Laboratory Work-up and Treatment. Unless an underlying illness is suspected, laboratory tests play no role in the acute management of urticaria and angioedema. Treatment of these disorders ideally involves avoidance of the inciting allergen. However, since allergens usually are unknown or have already caused symptoms, drug therapy plays a key role. Antihistamines are a mainstay of therapy. In acute urticaria, a short course will block histamine-mediated effects such as pruritus. Patients with chronic urticaria benefit from taking antihistamines prophylactically. In mild reactions or chronic forms of these disorders, oral antihistamines are given. The second-generation cetirizine, which is approved for use in patients with chronic urticaria, has the advantage of rapid onset of action time (usually, within 60 minutes) and less sedation than such classically used agents as hydroxyzine (Atarax) and diphenhydramine (Benadryl). No difference in efficacy has been found in clinical trials comparing first- and second-generation antihistamines to each other.55,56 Patients with severe urticaria or angioedema should receive SQ epinephrine and parenteral diphenhydramine (1 mg/kg up to 50 mg). Non-sedating antihistamines are not available in parenteral form.
H-2 blockers such as cimetidine (Tagamet) and ranitidine (Zantac) can be particularly useful in urticaria, especially when combined with H-1 blockers.5 The rationale for use of H-2 blockers reflects the presence of a small number of H-2 receptors in skin, in addition to large numbers of H-1 receptors located there. By blocking both receptors, antihistamines potentially have a greater effect. H-2 blockers have also been proposed for use in treating acute angioedema, but clinical trials have not shown improved outcomes.
Steroid creams and ointments are not beneficial in the management of either urticaria or angioedema. Oral and IV steroids, however, are effective in reducing oropharyngeal inflammation in angioedema or urticaria,49 although clinical effects may take several hours to become apparent. In a prospective, randomized, double-blinded study of patients with acute urticaria, patients who received prednisone for four days improved more rapidly than those who received placebo.57 Similarly, patients with oropharyngeal angioedema should receive a short tapering course of oral steroids as outpatients.
Patients who have signs or symptoms of airway obstruction should be treated similarly to patients with systemic anaphylaxis. They should receive incremental doses of epinephrine 0.3 mg SQ q 20 minutes.5,58 In addition, nebulized racemic epinephrine should also be considered. Patients in extremis may require IV epinephrine. For reasons that are unclear, patients with hereditary angioedema or ACE-inhibitor induced angioedema may be less responsive to epinephrine, H-1 and H-2 blockers, and steroids.54,59 Definitive airway management with endotracheal intubation or crichothyroidotomy may be necessary.
True anaphylaxis represents a life-threatening allergic reaction demanding immediate action. This section offers a brief review, with emphasis on management techniques.
The first fatal anaphylactic reaction was described over 4000 years ago following a Hymenoptera sting. In the modern era, however, iatrogenic causes have eclipsed Hymenoptera stings as causes of severe or fatal anaphylactic reactions.60-67 Horse serum used in diphtheria and tetanus antitoxins was an early culprit. In hospitalized patients today, radiocontrast dyes and beta-lactam antibiotics account for an estimated 500 fatalities annually.67 Penicillin, which became widely available after World War II, caused its first-reported anaphylactic death in 1949.61 Anaphylactic reactions to beta-lactam antibiotics occur in 1-5 per 10,000 administrations. About 10% of these are life-threatening, and 1% are fatal. Importantly, the vast majority of these reactions stem from intravenous or intramuscular administrations rather than oral therapy.60 Hymenoptera venom (yellow jackets, hornets, honeybees, bumblebees, wasps, and fire ants) causes an estimated 50 deaths per year in the United States,63,64 far outnumbering deaths from snake bites. Interestingly, only 9-25% of fatal stings report previous hymenoptera allergy.65 Anaphylactic reactions to foods, such as shellfish, nuts, and eggs, can also occur.
The pathophysiology of anaphylaxis involves an IgE-mediated hypersensitivity reaction. First, IgE, formed in response to a specific allergen, binds to mast cells. Upon re-exposure to the allergen, the IgE cross stimulates the release of preformed mediators such as histamine. In contrast, anaphylactoid reactions are non-IgE mediated but are clinically indistinguishable from true anaphylaxis. Importantly, while anaphylaxis requires previous exposure to the allergen, anaphylactoid reactions require no immunologic memory; in this case, degranulation of mast cells thus may occur on first exposure to the allergen.60
Clinical Features. Patients vary greatly in terms of the presentation, onset, and course of anaphylaxis, but clinical manifestations usually occur within seconds to minutes.61 A small subset of patients may remain relatively asymptomatic for an hour or more before developing severe symptoms.68 Most patients have a predictable, uniphasic course where they develop signs and symptoms of anaphylaxis early, respond to therapy, and remain asymptomatic thereafter.60 About 20% of patients, however, have biphasic reactions characterized by a second episode of anaphylaxis up to eight hours following apparent recovery from the initial event.61,69 Rarely, anaphylaxis will be protracted, with symptoms persisting up to three weeks.68 Unfortunately, no particular test or spectrum of clinical symptoms allows prediction of which patients will have biphasic or protracted responses.
Airway obstruction and cardiovascular collapse are the leading causes of death from anaphylaxis. These may be early events, occurring within seconds of exposure to inciting allergen, or they may develop more gradually. Patients with a history of asthma, or those with cardiac disease and using beta-blockers, are at greatest risk for severe reaction.60 The vast majority of patients will have pruritus (especially of hands, feet, groin, and palatal and nasal areas61), urticaria, or angioedema. Laryngeal edema may manifest as hoarseness, stridor, or a "lump in the throat," while wheezing and chest tightness signify lower airway obstruction. Hypotension, chest pain, arrhythmias, and shock represent cardiovascular involvement.60 Myocardial infarction secondary to anaphylaxis has been reported.70 Nausea, vomiting, diarrhea, anxiety, and a sense of impending doom also are common, as are confusion, dizziness, and seizures, which probably reflect cerebral hypoperfusion.61
Principles of Management. It is critical to think of anaphylaxis as one end of a spectrum of clinical disorders that includes asthma, urticaria, and angioedema. Although anaphylaxis implies systemic collapse, clinically it may include aspects of bronchospasm, skin disorders, and laryngeal edema. Distinguishing whether a patient technically is suffering from angioedema rather than anaphylaxis is clinically unimportant in the acute setting; ultimately, initial management is identical.
Patients with suspected anaphylactic reactions must be triaged to a treatment area immediately. Since there is no way to predict how rapidly a reaction will progress, all patients should receive an immediate assessment of the stability of their ABCs. Voice changes, shortness of breath, lingual or oropharyngeal angioedema suggest impending airway obstruction and warrant immediate pharmacotherapy and preparation for intubation. All patients with symptoms of a systemic reaction should undergo close blood pressure monitoring, have two large-bore IVs started, and have intubation and cricothyroidotomy equipment at the bedside. If there are no immediate signs of airway obstruction or cardiovascular collapse, patients should be questioned about inciting allergens and previous history of similar reactions. If the etiology is known, exact time from exposure to symptom onset should be obtained.
First-Line TherapyEpinephrine. Epinephrine is the drug of choice for treatment of systemic anaphylaxis.50,58,60,61,71 Both the alpha and beta-agonist effects of epinephrine counteract the multiple actions of vasoactive mediators. Alpha-agonist activity reverses peripheral vasodilation and increases both systolic and diastolic blood pressure. Angioedema and urticaria, which often accompany anaphylaxis, also are reduced through alpha-mediated peripheral vasoconstriction. Epinephrine’s beta-agonist activity promotes bronchodilation and enhances cardiac inotropy and chronotropy. Beta-agonist actions also facilitate production of cAMP, which is thought to further decrease mediator release.58
Unfortunately, the same mechanisms of action that make epinephrine so useful in the treatment of anaphylaxis can be potentially associated with serious side-effects. Excessive stimulation of alpha-receptors with subsequent peripheral vasoconstriction may precipitate a hypertensive crisis, causing cerebral hemorrhage, pulmonary edema, or other sequelae. Similarly, overstimulation of beta-receptors may induce arrhythmias or myocardial ischemia secondary to increased myocardial oxygen demand.58,70 However, the adverse side effects of epinephrine can be largely mitigated by employing proper dose and route of administration, even in those with relative contraindications (e.g., cardiovascular disease, pregnancy, elderly). Ultimately, epinephrine is warranted in any life-threatening reaction that is refractory to other treatments. In a case study of 13 children who had fatal or near-fatal food-induced anaphylaxis, none of the fatalities received epinephrine prior to onset of severe respiratory symptoms; however, all patients who survived received epinephrine before or within five minutes of onset of respiratory symptoms. Interestingly, even the survivors (who received early epinephrine) eventually required intubation.68
Dose and Route. Indications for epinephrine, and its preferred route of administration, are based on the severity of the anaphylactic reaction. (See Table 7.) Although a very small percentage of adults may be managed with agents other than epinephrine, SQ epinephrine is recommended, even in patients with mild presentations. However, all patients with more severe reactions (e.g., laryngeal edema, hypotension) should receive 0.3 mg to 0.5 mg subcutaneously q 15-20 minutes until symptoms abate. The pediatric dose is 0.01 mg/kg at the same dosing frequency.58 Intramuscular injection of epinephrine is warranted in both pediatric and adult patients who exhibit signs of impending airway obstruction, hypotension, or poor response to the subcutaneous route.60 A systolic blood pressure of 60 mmHg is sufficient to absorb IM or SQ epinephrine.50 Racemic epinephrine 2.25% diluted in 2.5 cc of normal saline also should be used in patients with signs or symptoms of airway compromise.49,60 Nebulized albuterol may improve symptoms of bronchospasm.
Intravenous Epinephrine. Patients with airway obstruction, severe bronchospasm, or hypotension refractory to IM and racemic epinephrine may require IV epinephrine. The dose of IV epinephrine is somewhat controversial, and no studies have established a definitive dose that is both safe and therapeutic in systemic anaphylaxis. However, pharmacological studies suggest that slow, low-dose infusion rates stimulate beta-receptors more than alpha-receptors, thus producing bronchodilation and modest increase in systolic blood pressure. Fast, high-dose infusions appear to preferentially stimulate alpha-receptors, causing severe hypertension, arryhthmias, and myocardial ischemia. The American Heart Association’s Advanced Cardiac Life Support (ACLS) protocol for IV epinephrine in adults is an initial dose of 1 mcg/min, titrated to 4 mcg/min if symptoms persist.72 Other authors recommend a 100 mcg bolus at 10 mcg/min.58 These concentrations are obtained by mixing 1 mg of epinephrine in 100 cc normal saline, to give a concentration of 10 mcg/cc. In pediatric patients, the infusion rate begins at 0.1 mcg/kg/min, increasing to a maximum of 1.5 mcg/kg/min. This solution is prepared as above.58
Fluids. Hypotension should be treated with IV fluids since profound plasma volume loss (up to 50% in 10 minutes) has been reported.73 Anaphylactic shock that remains refractory to volume replacement should be treated with dopamine or other pressors. These patients may also require central venous pressure monitoring or pulmonary artery catheterization for more precise fluid management.
Antihistamines. Antihistamines will not reverse end-organ effects, hypotension, or fluid loss in patients with anaphylaxis. Nevertheless, antihistamines remain an important adjunctive therapy by blocking further release of histamine and providing symptomatic relief in anaphylactic reactions accompanied by urticaria. As previously mentioned, H-2 agents probably have no direct effect when given alone but may act synergistically with H-1 blockers.74 Diphenhydramine 1 mg/kg up to a maximum 50 mg q 6 h, and cimetidine 4 mg/kg have been proposed.64 There is no evidence of superiority of a 25 mg vs. 50 mg dosage of diphenhydramine.
Second-Line TherapyGlucagon. The use of glucagon in anaphylaxis is largely anecdotal. However, patients on beta-blockers or those who have contraindications to epinephrine may benefit from a trial of this naturally occurring hormone. Glucagon is produced by the pancreas and serves a variety of functions including the stimulation of cyclic AMP. Increased levels of cardiac cyclic AMP may enhance contractility and cardiac output in patients with hypotension due to anaphylaxis. Patients on beta-blockers who experience anaphylaxis present a special challenge. When epinephrine is given for symptoms of anaphylaxis, peripheral beta-blockage results in unopposed alpha stimulation, possibly leading to malignant hypertension with serious consequences. Glucagon represents a safer alternative since the adrenergic receptors are bypassed.58,75-77 Patients who may benefit from glucagon should receive an initial 1 mg IV bolus.64,76,77 Because of its short half-life, repeat doses often are required and can be given q 5 min.78 Glucagon is generally well-tolerated.
Steroids. Steroids play no role in the immediate reversal of anaphylaxis since the onset of action may be delayed as much as 4-6 hours. However, steroids can inhibit or lessen biphasic and protracted anaphylactic reactions (especially bronchospasm) and should be administered. Methylprednisolone (SoluMedrol) 125 mg IV, or prednisone 60 mg po are common formulations.60
Experimental Treatment. Recently, methylene blue was shown anecdotally to reverse anaphylactic shock in several patients refractory to epinephrine.48
Disposition. All patients with systemic anaphylaxis should be observed for at least 6-8 hours, even if they have had prompt reversal of all symptoms and signs with standard therapy. The majority of biphasic reactions occur within this time period.50 Patients with more severe reactions (e.g., hypotension or airway obstruction) must be observed for 24-48 hours, even in the absence of persistent symptoms. Approximately 10% of patients with severe anaphylaxis will need repeated administration of epinephrine, even if they had complete resolution of symptoms between injections.79 In one study, 28% of patients who responded to initial therapy had life-threatening recurrences up to eight hours after apparent remission.69 Elderly patients, those with asthma or underlying cardiac disease, and those on beta blockers also should be considered for admission even with mild reactions. Keep in mind that patients may have deceptively mild symptoms for two hours or more before severe compromise occurs.68 All patients should receive a self-injectable kit (Epi-pen, Ana-kit) and be instructed in its use. Physicians are often remiss in prescribing these epinephrine kits. In one study, 40% of children with hymenoptera allergy did not receive an epinephrine prescription.80
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Physician CME Questions
11. Allergic rhinitis is most common during:
a. infancy.
b. childhood and adolescence.
c. middle age.
d. elderly.
12. Which one of the following statements is correct?
a. First-generation antihistamines are more effective than second-generation in treatment of allergic rhinitis.
b. Side-effect profiles of first- and second-generation antihistamines are essentially the same.
c. First-generation antihistamines are associated with torsades des pointes when combined with antimicrobial medicines.
d. First-generation antihistamines should be prescribed with caution in the elderly and in children.
13. Which of the following antihistamines is associated with torsades des pointes?
a. Fexofenadine (Allegra)
b. Cetirizine (Zyrtec)
c. Loratadine (Claritan)
d. Terfenadine (Seldane)
14. Which of the following statements is correct?
a. There are significant differences in onset of action among second-generation antihistamines.
b. Second-generation antihistamines are not differentiated based on half-lives.
c. All second-generation antihistamines are associated with significant sedation.
d. Second-generation antihistamines generally are less expensive than first-generation ones.
15. Nasal steroids:
a. are not useful in allergic rhinitis.
b. are associated with significant side effects that limit their use.
c. are fundamental in the treatment of perennial allergic rhinitis.
d. are effective within hours.
16. Which statement is true regarding urticaria and angioedema?
a. Autoimmune disorders are the most common cause.
b. Laboratory workup is fundamental in establishing an etiology.
c. Treatment includes epinephrine in patients with airway compromise.
d. Oral steroids should not be given.
17. Regarding epinephrine in the treatment of anaphylaxis:
a. IV epinephrine should be initial therapy in all patients.
b. racemic epinephrine is contraindicated in adults.
c. slow, low-dose IV infusions are preferred over fast, high-dose ones.
d. all forms of epinephrine are contraindicated in pregnant patients and those with underlying cardiovascular disease.
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