Authors: David Hiestand, MD, PhD, Fellow, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Kentucky, Lexington, Ky; and Barbara Phillips, MD, MSPH, Professor of Medicine, University of Kentucky; Director, Sleep Disorders Center, Samaritan Hospital, Lexington, Ky.
Editor’s Note—The field of allergy has its roots in the science of immunology, which was initially described as the body’s host defenses against foreign objects. The allergic reaction (type I immediate hypersensitivity) is simply a host response, through IgE mediated mechanisms, to common environmental stimuli. These reactions vary from unpleasant itching, sneezing, or wheezing, to life-threatening anaphylactic shock. While the term allergy actually has a very specific pathophysiologic meaning, common vernacular has led to a connotation representing a simple adverse reaction, and for others, allergy means any Gel and Coomb reaction, type 1 through type IV. It is often difficult for patients, and even health care professionals, to make this distinction. Adverse reactions, which are nonimmunologically mediated, may not be effectively treated with standard allergy therapies, especially as target-specific therapies evolve. Therefore, it is becoming increasingly important for health care providers to possess a thorough understanding of the features and mechanisms of the immune response in order to offer the most effective diagnosis and treatment.
The spectrum of allergic disease is extremely broad and includes a number of organ systems. Respiratory manifestations are most commonly encountered clinically, and include allergic rhinitis and asthma. Hypersensitivity pneumonitis, also known as extrinsic allergic alveolitis, is a much less common immunologically induced inflammatory lung disease. This disorder, however, is non-IgE mediated and will not be discussed in detail. Generally closely associated with rhinitis and asthma is allergic conjunctivitis. Several cutaneous manifestations, including atopic dermatitis and acute urticaria, are also quite common. Much less common, but potentially life threatening, is angioedema and anaphylaxis. Finally, the broad category of GI manifestations also causes considerable distress, particularly in the case of food allergies.
Agents that elicit an immune-mediated response include various inhaled allergens, such as pollens, molds, grasses, dusts, mites, low molecular weight chemicals, and drugs. Contact agents include plants, latex, low molecular weight chemicals, and drugs. Foods are capable of eliciting any manifestation of the allergic response. Likewise, insect stings, particularly hymenoptera, may elicit anything from local tissue response to anaphylaxis. Environmental agents inciting an IgE-mediated response have characteristic physical quantities. They are generally ubiquitous and relatively small molecular weight proteins. Very small agents require interaction with a hapten, which is simply a protein carrier, and the protein allergen complex actually comprises the actual antigen.
The mechanism of allergic response involves binding of allergen to IgE bound to mast cells and basophils. This interaction in turn elicits the release of preformed mediators. Preformed mediators elicit an immediate response, which is responsible for the acute symptoms of itching, sneezing, wheezing, and cough. Additionally, signaling cascades are initiated, which lead to propagation of the immune response including further inflammation and the sequelae of the late phase response.
Allergic disorders represent a global health problem. Allergic rhinitis is thought to affect around 15 million individuals in the United States, though it is likely under-reported because patients either frequently do not recognize their symptoms or they self-medicate with over-the-counter preparations. Asthma is less common but still affects around 5 million individuals in the United States. Atopic dermatitis is frequently associated with allergic rhinitis and asthma, as is allergic conjunctivitis. These disorders represent significant societal indirect and direct costs. Direct costs have, and will continue to escalate primarily due to the advancements in pharmacotherapy.
As a direct result of improved understanding of the pathophysiology of allergy and the recognition of the interaction between allergy and other illness, clinical practice guidelines have been developed which allow for efficient evaluation and therapy of these disorders. The overlap between allergic rhinitis and asthma has becoming increasingly apparent, and this has led to recognition that failure to treat one aspect of the global airway disorder may prevent sustained symptom relief. Complications of allergies manifested in the airways, such as sinusitis, otitis, allergic bronchopulmonary aspergillosis, and others, have been further defined, allowing for more effective management. The identification of the mechanisms of allergic disorders has identified several potential targets for therapy. These factors make the field of allergy exciting for both patients and practitioners.
The objective of this monograph is to provide an overview of the scope of allergic disorders, and review the current understanding of the mechanism of the allergic response. Due to the extensive nature of the topic, we will limit our discussion to systemic reactions eliciting an IgE-mediated response. Further, the intimate relationship between organs involved will be reviewed, particularly the relationship between allergic rhinitis and asthma. Part I included the current evaluation, including historical features, exposures, physical exam findings, and ancillary diagnostic options will be reviewed. Part II discusses current therapeutic options, including the most recent additions to the therapeutic armamentarium will be reviewed. A stepwise approach to diagnosis and management of allergic disorders will be outlined. Finally, the discussion will also seek to familiarize clinicians with targeted treatment modalities on the horizon.
Asthma is generally defined as a chronic inflammatory process with diffuse, reversible obstructive airways with hyper-reactivity in response to various stimuli. The classic description is of paroxysmal attacks of wheezing and breathlessness. Chronic cough, with minimal description of wheezing or breathlessness is also a common presentation. Equally important to recognize is that in extreme respiratory distress, wheezing may be absent, and patients may only display extreme dyspnea and prolonged expiration.
The mechanism of asthma is likely more complicated than simple allergen exposure. Classically, asthma has been subdivided into extrinsically and intrinsically mediated disease. Intrinsic asthma is typically felt to represent airway hyper-reactivity not mediated by allergen exposure, whereas extrinsic asthma is described as an allergen-mediated disorder. However, a large percentage of asthmatics are atopic.
The history in patients with asthma is often remarkable for episodes of breathlessness, wheezing, cough, and chest pain on exposure to irritants or with allergen exposure. Patients with seasonal symptoms often have allergies to pollens or molds. More commonly, however, patients have perennial symptoms with exacerbations due to indoor allergens. These are often worsened by nonspecific precipitants including exercise, upper respiratory tract infections, rhinitis, sinusitis, postnasal drip, aspiration, gastroesophageal reflux, changes in weather, stress, smoke, and dust. Occasionally, aspirin, NSAIDs, b-blockers, and aerosolized medicines may exacerbate asthma.
Patients may present at any age with asthma; however, childhood is often considered more prominent. Due to the inability of performing spirometry testing in children younger than 5 years, and the incidence of wheezing in infants and children, childhood asthma is often difficult to diagnose. Thirty percent of asthmatics are symptomatic by 1 year of age, and 80-90% have had symptoms by age 4-5.
While onset in adulthood is not uncommon, it is important to remember the adage that, "all that wheezes is not asthma." Wheezing or musical airflow is described in extrathoracic upper airway obstruction, intrathoracic airway obstruction, and lower airway obstruction.
Extrathoracic upper airway obstruction is a common cause of nonasthma musical airflow. Etiologies include postnasal drip syndrome, vocal cord dysfunction, tonsillar hypertrophy, and tumor or swelling in the region of the extrathoracic airway. Causes of intrathoracic upper airway obstruction include tracheomalacia, tracheal stenosis or tumors, and foreign bodies. Lower airway obstruction leads to wheezing in COPD, pulmonary edema, foreign body aspiration, and infectious causes of airway edema. Therefore, new onset wheezing requires a more detailed history with onset in late childhood or adulthood, and in cases where the possibility of foreign body aspiration is possible.
The family history in patients with asthma is often notable for parents or siblings with asthma. A child with a single parent with asthma has a 25% chance of having asthma. If both parents have asthma, chances are increased to 50%.
Typical physical examination findings in acute exacerbation include prolonged expiratory phase, use of accessory muscles of respiration, and wheezing. Chest hyperinflation may be apparent in patients with long-standing disease. Patients with severe exacerbations may have minimal wheezing due to sheer lack of air exchange. A finding of co-existent atopic conditions including eczema or rhinitis may lend support to a diagnosis of asthma. Digital clubbing is not associated with asthma, and presence should prompt an investigation into an alternative diagnosis (such as cyanotic heart disease, bronchiectasis, inflammatory bowel disease, and others). The most important characteristic, however, is reversibility of symptoms and physical findings by inhaled bronchodilators.
Evaluation for asthma typically does not include laboratory investigations. As in all allergic syndromes, elevations in serum IgE and total eosinophil count are commonly seen. These tests are nonspecific, however, and the best method of assessing the status of asthma is via spirometry. In-office spirometers are widely available for reasonable cost and should be considered standard of care in the management of asthma. In patients who describe classic symptoms of paroxysmal wheezing and coughing, spirometry may be a useful adjunct to quantify severity of disease. In patients with more atypical symptoms, such as primary cough or dyspnea, a demonstration of airway obstruction and hyper-reactivity may be helpful in making a diagnosis of asthma. Also, in patients who have been seemingly resistant to therapy, a bronchoprovocation challenge done off of inhaled agents may reveal absence of bronchial reactivity. The methacholine challenge has near 100% sensitivity. Specificity, however, is somewhat limited with approximately 1-7% of the normal population having a response to methacholine.
As an alternative to methacholine, adenosine has been considered. Adenosine acts directly on mast cell receptors, leading to bronchial hyper-responsiveness via mast cell-mediated events, in contrast to methacholine, which acts directly on airway smooth muscle cells. Van Den Berge and colleagues demonstrated adenosine monophosphate was a better correlate of airway inflammation in asthma than methacholine.1 While not currently readily available, this test may become the standard evaluation for screening and/or monitoring patients with asthma within the next few years.
Currently, there are no readily available means to monitor asthma therapy. Several markers are used in research protocols and include exhaled nitric oxide, sputum eosinophilia, and methacholine or adenosine responsiveness. Currently, however, symptom scores and peak expiratory flow rate (PEFR) readings/improvements in lung function remain the mainstay of monitoring. PEFR monitoring by patients properly trained and committed to good effort provides a more reasonable indicator of exacerbation than self-reported symptoms or history/physical exam findings.
Asthma severity has been categorized by the National Asthma Education and Prevention Panel (NAEPP) based on frequency of symptoms and degree of airflow. Patients are classified in a stepwise fashion into intermittent or persistent symptoms. This stepwise approach has been developed as a means to guided appropriate pharmacotherapy. These recommendations are illustrated in Table 1.
Allergic rhinitis and asthma frequently coexist. Of patients with allergic rhinitis, asthma has been identified in 30-40%, whereas asthma is felt to occur in only about 3-5% of the general population. Conversely, 60-80% of patients with asthma report allergic rhinitis symptoms, compared to 20% of the general population.2 The concept of "one airway, one disease" has been the subject of a number of recent articles, and data are overwhelmingly in support of this concept.3
Another set of frequently coexisting conditions is chronic sinusitis and asthma. This is particularly important in adult-onset asthmatics with more severe asthma. A study of 89 non-smoking patients with severe asthma revealed sinus CT evidence of mucosal thickening in 84% of patients and extensive sinus disease in 24% of patients. The extent of CT evidence was correlated with serum and sputum eosinophilia, as well as exhaled nitric oxide, and PFT findings.4
A rather significant comorbid condition that can exist in an asthmatic (and cystic fibrosis) is allergic bronchopulmonary aspergillosis (ABPA). ABPA represents a hypersensitivity reaction to Aspergillus antigens leading to bronchial obstruction, inflammation, and mucoid impaction. This ultimately leads to bronchiectasis, and in advanced stages, fibrosis. ABPA may be expected in resistant asthma with recurrent episodes of obstruction, fever, malaise, brown mucous plugs, eosinophilia, and hemoptysis. Radiographic evidence includes parenchymal infiltrates, atelectasis, and bronchiectasis. Diagnostic criteria include skin test reactivity to Aspergillus antigens, as well as several other clinical criteria. This disorder can be difficult to treat, often requiring high-dose systemic steroids.
A unique clinical syndrome exists in the case of aspirin sensitive asthma, which is relatively uncommon, affecting 0.6% of the entire population, and 4.3% of those with asthma.5 The characteristic history includes persistent rhinitis appearing at an average age of 30 years, followed by asthma, aspirin sensitivity, and nasal polyposis. Rhinorrhea and nasal congestion are usually the first symptoms to develop, usually after a typical viral infection. Rhinitis then becomes perennial and difficult to treat, associated with recurrent, chronic sinusitis, anosmia, and nasal polyposis. Asthma and aspirin sensitivity develop an average of 1-5 years later.6 Following ingestion of aspirin or NSAIDs, acute asthma ensues within 3 hours, accompanied by profuse rhinorrhea, conjunctival injection, and occasionally scarlet flushing of the head and neck, peri-orbital edema, abdominal pain, and minor urticaria. Definitive diagnosis is established with certainty only by provocation testing with increasing doses of aspirin. Remember this is a non-IgE mediated mechanism.
Atopic dermatitis (see Table 2) manifests in a wide clinical spectrum from pityriasis alba to hand eczema to erythrodermic rash.7 The essential features include pruritis, age-dependent eczema, and chronic or relapsing dermatitis. Infants typically manifest with more acute dermatitis on the face, scalp, and extensor surfaces of the extremities.
Older children and adults who have had long-standing disease develop lichenification in the general distribution of the flexor surfaces of the extremities. Hand eczema can be seen more commonly in adults. Other features frequently associated include personal/family history of atopic disease, xerosis, cutaneous infections, elevated IgE, and positive skin tests often to dust mites and foods. The diagnosis is generally a clinical one based on the patterns noted above. There are no reliable tests for definitive diagnosis. The differential diagnosis is relatively broad but can be narrowed significantly by appropriate history and physical examination (see Table 3).
Urticaria and angioedema are common conditions, affecting up to 20% of the population. Urticarial lesions are usually intensely pruritic, well-circumscribed, raised, and erythematous with central pallor. Lesions may enlarge and coalesce, but generally resolve over a few hours. Angioedema is similar in distribution but typically involves deeper cutaneous layers, is slightly painful, and may last longer. Urticaria and angioedema can be divided into acute and chronic forms. The acute form typically lasts less than 6 weeks and is most commonly allergic in etiology. The chronic form is characterized by symptoms greater than 6 weeks and is rarely secondary to allergic etiology. The clinical picture of acute urticaria is generally not difficult to identify. The etiologic agent, however, can be quite difficult to identify. As with rhinitis and asthma, not all urticarial lesions are IgE mediated, thus affecting therapy (see Table 4).
Anaphylaxis represents the most extreme of allergic reactions. While true anaphylaxis is IgE mediated, nonspecific anaphylactoid reactions can occur in the absence of IgE. Anaphylaxis represents a systemic process potentially affecting all organ systems. The most common initial symptoms are urticaria and angioedema. Any symptom, however, in the context of possible exposure to physical agent, followed by swelling of the oropharyngeal tissues, wheezing, and hypotension, is consistent. Generally, symptoms occur within minutes, up to 1 hour. Symptoms may be delayed, however, depending on route of exposure. It is also important to consider the possibility of a late-phase response, requiring prolonged monitoring even after the initial evaluation and management.
The treatment of allergic disorders is multifaceted. Avoidance of allergen exposure has been the classic first-line approach to therapy. As previously discussed, exposure to allergens including dust mites, pollens, and endotoxins clearly lead to exacerbations; therefore, avoidance would be the natural first-line in the reduction of symptoms. Frequently, however, reduction of inflammation, inhibition of mediator action, and modulation of the immune system is necessary when avoidance is impractical or impossible.
Avoidance of exposure to causative agents can be a daunting task with either indoor or outdoor allergens. General recommendations include avoidance of exposure to household dust mites, pet danders, molds, and known causative outdoor allergens. Minimization of exposure to dust mites is frequently recommended through use of airtight allergen proof covers on mattresses, box springs, and pillowcases. Interestingly, however, a pair of recent studies showed that allergen-impermeable bed covers had no significant efficacy in the therapy of asthma or allergic rhinitis.8,9 A similar study showed lack of efficacy in atopic dermatitis symptoms.10 These measures are not without cost, and while rationale exists for their use, scientific data are clearly lacking. Routine cleaning of bed linens in hot (> 70°F) water is thought to reduce exposure to dust mites and has no significant cost or burden. In general it is very difficult for children to avoid exposure to pet danders, particularly if they are from a family pet. When the elimination of exposure is not practical, limitation of exposure, particularly in sleeping quarters, is a reasonable compromise. Elimination of carpets, upholstered furniture, and stuffed animals from sleeping quarters (as these are rich sources of dust mites) is also encouraged. Although once thought to be an effective means of limiting symptoms of asthma, humidifiers serve as reservoirs for molds and other allergens and should be avoided. Decreasing indoor humidity to 45% is helpful in eliminating mold and mite growth. Lastly, smoke from wood-burning stoves and cigarette use should be minimized, as these nonspecific irritants exacerbate the inflammatory process, leading to increased symptoms. Individuals should avoid smoking, and individuals with affected children should avoid smoking in the house, car, and other enclosed spaces.
The primary pharmacologic agents for allergy symptoms are inhibitors of histamine and leukotriene action, mast cell stabilizers, sympathomimetics, and glucocorticoids. For allergic rhinitis and asthma, locally acting glucocorticoids show the highest efficacy. Allergic conjunctivitis is often treated with systemic antihistamines, though locally acting antihistamines, mast cell stabilizers, or anti-inflammatory agents are available. Cutaneous manifestations of allergies are also improved by systemic antihistamines but may require topical or even systemic glucocorticoids with significant flares.
Currently, the mainstay of pharmacotherapy in allergy and asthma is glucocorticoid therapy in the form of locally acting agents when possible. In the treatment of asthma, the NAEPP has identified inhaled corticosteroids as the primary treatment modality for persistent asthma (mild, moderate, and severe). Newer inhaled steroids such as fluticasone, budesonide, and mometasone are more potent per milligram and have lower oral absorption and greater first-pass hepatic inactivation than older inhaled corticosteroids such as beclomethasone, triamcinolone, and flunisolide.11 Table 5 identifies the relative potencies of the available inhaled steroids. In terms of delivery systems, nebulization, meter dose inhalation (MDI) with spacers, and various dry powder inhalation (DPI) devices are all effective means of administering medicine. Patient compliance and cooperation may, however, favor one system over another. For instance, infants will require administration via nebulization or MDI with spacer and mask. Children older than 5 years are often capable of administering medicine via a DPI or MDI device.
The extent of systemic absorption of inhaled steroids continues to be an area of active investigation. A number of studies have shown limited adverse effects of inhaled corticosteroids on growth, bone mineral density, cataracts, and the hypothalamic-pituitary-adrenal access when used at recommended dosages. Studies on vertical growth have involved budesonide and beclomethasone but have been generalized to all inhaled corticosteroids. Of the end points evaluated in the inhaled steroid studies, growth velocity has been shown to be slowed (~1 cm) in the first year of therapy, but this effect has not been demonstrated convincingly in final adult height. Furthermore, the consequences of prolonged systemic corticosteroids are well known, and the efficacy of inhaled steroids is superior to that of other therapies. The long-term effects of excessive doses when initiated in childhood and continued into adulthood remain to be determined, but certainly will be less severe than those of persistent, repeated doses of systemic steroids. Furthermore, untreated asthma can cause growth delay in children. Physicians caring for children and adolescents who are taking any form of corticosteroid should carefully monitor growth and weigh the benefits of asthma control against the possibility of growth suppression or delay.12
In addition to inhaled steroids, the NAEPP recommends the use of a long-acting b-agonist in moderate-to-severe asthma. The two currently available products are salmeterol and formoterol. Salmeterol is available as a DPI, both as a single agent and in a combined formulation with fluticasone. Its onset of action is 5-20 minutes, reaching peak effect in 2-4 hours, and lasting 12 hours. It is not to be used for symptom relief or exacerbations. There have been a number of studies observing an increased rate of fatal attacks of asthma associated with use of long-acting b-agonists (LABA), questionably due to the use of LABA without ICS. Their use should be restricted to add-on therapy with inhaled corticosteroids or as the single-use agent in patients with mild exercise induced asthma. Furthermore, their use should be carefully monitored for signs of overuse. The usual dose for MDI in children > 12 and adults is 2 puffs (21 mg/puff) twice a day. The DPI formulation contains 50 mg/blister and is approved for children > 4 and adults at a dose of 1 puff twice a day. The combination of fluticasone/salmeterol is available with 100, 250, or 500 mg of fluticasone with 50 mg of salmeterol in a DPI diskus. This drug is approved for use in children > 12 at a dose of 1 puff twice a day. The fluticasone dose is chosen based on severity of disease but is often initiated at the higher dose for more moderate-to-severe disease, and titrated down if possible.
Formoterol is a relatively new addition to the market. It is available as a DPI with 12 mg/single-use capsules. It is generally felt to have a shorter onset of action, with time to peak improvement in FEV1 at 1-3 hours and elimination half time of 10-14 hours. It is approved for children > 5 and adults at a dose of 1 capsule every 12 hours. It is also not recommended for acute exacerbations and should not be taken more frequently than every 12 hours. There have been no large, randomized, controls comparing the 2 long-acting b-agonists, but smaller series suggest equal-to-greater efficacy of formoterol with more rapid onset of action.
Short-acting b-agonists remain the mainstay of acute exacerbations of bronchospasm. Routine formulations include MDIs, DPIs, and solutions for nebulization. The introduction of levalbuterol, the (R)-enantiomer of racemic albuterol, has recently entered the market. The (R)-enantiomer was developed based on data indicating that it possessed all of the bronchodilatory properties in racemic albuterol, and that the (S)-enantiomer may have bronchoconstrictive and pro-inflammatory actions. Initial studies demonstrated greater efficacy with reduced toxicity (primarily cardiac) using this formulation. Data on larger populations, however, are needed to identify whether this is a superior drug for use in acute and chronic treatment of asthma. Onset of action is 10-17 minutes with peak effect at 1.5 hours and total duration of 5-6 hours. It is approved for children 6-11 at a dose of 0.31-0.63 mg 3 times per day and for children ³ 12 and adults at a dose of 0.63-1.25 mg 3 times per day. The cost of levalbuterol may be up to 5 times the cost of racemic albuterol.
First-line therapy in allergic rhinitis is intranasal steroids. Currently available intranasal steroids are shown in Table 6. There are few double-blinded, randomized trials comparing efficacy of inhaled steroids. Patient tolerance and compliance are limiting factors in efficacy. Products are available with Freon or aqueous propellants. Aqueous formulations may be preferred in patients who develop mucosal drying, crusting, or epistaxis.
Antihistamines serve as an adjunct to nasal steroids in allergic rhinitis. They are not as efficacious as nasal steroids, but they do reduce sneezing, rhinorrhea, and itching.13 They are typically more efficacious if initiated prophylactically prior to exposure. They are also a useful adjunct in patients with allergic conjunctivitis and eczema. Traditionally, adequate treatment requires continuous use throughout a seasonal exacerbation; however, some of the newer agents may possess more long-lasting immunomodulatory effects. These studies are ongoing and currently offer no strong indication for choosing one agent over another.
Older, first-generation antihistamines include diphenhydramine, chlorpheniramine, brompheniramine, promethazine, and triprolidine. They are lipophilic, thus crossing the blood-brain barrier and causing sedation. Sedation occurs in at least 20% of individuals and may cause cognitive dysfunction even in patients who perceive no sedation or impairment from the drug. First-generation antihistamines contain not only H1 antagonistic properties, but also anticholinergic and antiadrenergic properties. Thus, other side effects include drying of the mouth and urinary hesitancy, particularly in the elderly. All are available over the counter either as single agents or as combination drugs, often with decongestants and cough suppressants. All are approved for children older than 2 years. A formulation of carbinoxamine maleate-pseudoephedrine (Rondec®) is approved for children older than 1 month.
Newer, nonsedating antihistamines are often termed second-generation antihistamines. Those currently available in the United States include acrivastine, cetirizine, desloratadine, fexofenadine, and loratadine. These agents have advantages in that they have no sedating effects, have a rapid onset of action, and have fewer anticholinergic side effects. They may have effects beyond H1 antagonism, though the significance of these effects remains to be determined. There have been a large number of comparative trials in the treatment of allergic rhinitis, but none has clearly demonstrated superiority of one agent over another. Therefore, the choice of agent should be based on cost, compliance, tolerance, and adverse events. In the treatment of urticaria, cetirizine has been shown to be slightly more efficacious than the other agents currently available in the United States, though all agents have some activity. And in the treatment of atopic dermatitis, adjunctive therapy with cetirizine and loratadine demonstrate efficacy in the reduction of pruritus.14
Topical antihistamines have also been developed for use in ocular, nasal, and cutaneous manifestations of allergy. Ocular agents currently available include emedastine and levocabastine with pure H1 receptor antagonism, and olopatadine, which has also been shown to inhibit mast cell release of histamine, tryptase, and prostaglandin D2. These agents are as effective as oral H1 antagonists in decreasing symptoms and offer more rapid onset of action. Their local action, however, limits use to individuals with minimal nasal, respiratory, or cutaneous manifestations of allergies, and to individuals who are inadequately treated with oral agents.
Currently available intranasal antihistamines include azelastine and levocastine. Their advantage is more rapid effectiveness. Long term, however, they are less effective than intranasal corticosteroids13 and have limited practical use.
Mast cell stabilizers have been developed for the treatment of ocular, nasal, and respiratory allergic manifestations. These agents have been shown to have modest effects in mild asthma, allergic conjunctivitis, and allergic rhinitis but do not significantly reduce inflammation. Their only significant benefit is absence of significant side effects. With the mounting evidence regarding the safety of low-dose inhaled steroids in asthma and paucity of side effects from second-generation antihistamines, these agents have decreasing practical use.
Leukotriene inhibitors and antagonists act by blocking the function of cysteinyl leukotrienes. The currently available leukotriene modifiers include montelukast, zafirlukast, and zileuton. All are approved for use in asthma. Montelukast has recently been granted an additional indication for allergic rhinitis. It is useful as adjunctive therapy with efficacy less than that of inhaled or nasal steroids. In the treatment of allergic rhinitis, it is no more effective than H1 antagonists or intranasal steroids and is more expensive than either.
For those individuals with severe allergic reactions, systemic corticosteroids are frequently used. Systemic corticosteroids are useful in exacerbations of severe urticaria, angioedema, and late-phase anaphylaxis. They remain a mainstay of therapy for severe asthma exacerbations. They are rarely needed in allergic rhinitis. Dosing is related to severity of illness, but most exacerbations can be treated with an equivalent dose of prednisone 40 mg for 7-10 days. Acute, severe exacerbations of asthma are frequently treated with parenteral steroids, usually with methylprednisone 125 mg intravenously, tapered over several days.
Angioedema is generally treated with subcutaneous epinephrine, along with H1 and H2 blockade. Additionally, a parental dose of corticosteroid is often administered in attempt to reduce any late-phase response, though data supporting this practice are limited.
Specific immunotherapy was first described approximately 100 years ago. It involves administration of allergen extracts as vaccines to affect immunomodulation. The Joint Task Force of American Academy of Allergy, Asthma, and Immunology and the American College of Allergy, Asthma, and Immunology has recently published a practice parameter on allergen immunotherapy.
Allergen immunotherapy has been shown to be effective and long lasting in the treatment of seasonal allergic rhinitis and, to a lesser extent, in perennial allergic rhinitis, when continued for several years.16 Meta-analysis of immunotherapy in asthma has shown overall clinical benefit.17,18 It should be noted, however, that a number of studies in asthma have failed to show efficacy.19 Immunotherapy is considered highly effective in patients with bee and wasp venom hypersensitivity and should be offered to all patients with anaphylaxis to stinging insects. Allergen immunotherapy is not effective and not recommended in the treatment of food allergies.
The effects of immunotherapy are persistent after discontinuation of therapy, in contrast to all other pharmacologic agents, which require continued and prophylactic use. The mechanism of action involves the modulation of the immune response with reduction in Th2-dependent cytokines and IgE as well as eliciting blocking IgG antibodies. A meta-analysis of 16 studies in the treatment of allergic rhinitis showed that immunotherapy was superior to control treatment groups,18 but there have been no recent studies comparing the efficacy of nasal steroids vs allergen specific immunotherapy.
The major risk of allergen-specific immunotherapy is that of potentially fatal anaphylaxis. Relative contraindications include deficiencies of the immune system, malignancy, b-blocker therapy, severe or irreversible airways obstruction (FEV1 < 70%), contraindications to epinephrine, and children < 5. Currently, immunotherapy is recommended by the Joint Task Force in specific patients with allergic rhinitis, allergic asthma, and Hymenoptera reactions. These recommendations are listed in Table 7. The pharmacoeconomics of immunotherapy is a source of some debate. The direct costs of immunotherapy exceeds that of drug therapy, and the extent to which drug therapy can be eliminated is crucial to the argument that immunotherapy offers an overall economic advantage. These issues will remain to be resolved, especially in light of newer, potentially expensive drug therapies.
With the identification of the mechanisms of the components of the allergic response, new potential targets for treatments are being identified. Thomas Casale has recently discussed preclinical targets, which have shown promise in animal models of allergic inflammation. These therapies include transcription factor antagonists, peroxisome proliferators-activated receptor antagonists, cytokine antagonists, peptide immunotherapy, and DNA vaccines.19 Agents have been developed targeting each of these immune response mechanisms and are currently in various stages of clinical trials.
One new therapy that has shown promise in clinical trials involves the antagonism of IgE through a humanized monoclonal antibody (rhuMAb-E25, "omalizumab"). Studies in human subjects show that treatment lowers serum levels of free IgE, down-regulates IgE receptors expressed on basophils, and reduces antigen-stimulated histamine release.20 Phase 3 studies have shown that in patients with moderate-to-severe asthma, treatment improves asthma control, lowers exacerbation rates when added to corticosteroid therapy, and enables reduction in corticosteroid dose.21 In a study of moderate-to-severe ragweed induced allergic rhinitis patients, omalizumab conferred improvement in nasal symptom severity score, serum IgE, and rhinitis-specific quality of life.22 This therapy is quite expensive, and no comparative trials have been conducted against standard therapy. Therefore, much remains to be determined regarding anti-IgE therapy, and it should not be considered the standard therapy at this time, although the FDA has approved it for the treatment of moderate-to-severe persistent allergic asthma uncontrolled on ICS therapy. In summary, the approach to patients with allergic disorders requires focused attention to each of the organ systems affected. Ocular, cutaneous, and respiratory manifestations are most common and may respond to limited therapy including antihistamines and locally acting corticosteroids. As noted above, assessment of response to therapy can be difficult in allergic rhinitis, as there are few objective measures of therapeutic efficacy. Questions regarding postnasal drainage, cough, sneezing, and itching are likely most effective. In the case of asthma, subjective measures generally include wheezing, nocturnal symptoms, exercise symptoms, albuterol use, symptom-free days, oral steroid requirements, ED visits, and hospitalizations. Subjective data for practical purposes include peak expiratory flow or spirometry. Future measures may include exhaled nitric oxide and serum inflammatory markers. In the management of asthma, the NAEPP recommends a stepwise approach based on symptoms. This approach is illustrated in the Figure.
For those patients who fail to respond, consideration of coexisting illnesses such as sinusitis and gastroesophageal reflux disease should be made. Escalation of therapy to maximum tolerated doses should be considered. Should individuals fail to respond to maximum therapy in the absence of coexisting illnesses, consideration of referral to an allergist for skin testing and possible immunotherapy should be made. These recommendations are summarized in Table 8.
1. Van Den Berge M, et al. PC(20) adenosine 5’-monophosphate is more closely associated with airway inflammation in asthma than PC (20 ) methacholine. Am J Respir Crit Care Med. 2001;163:1546-1550.
2. Crystal-Peters J, et al. Treating allergic rhinitis in patients with comorbid asthma: The risk of asthma-related hospitalization and emergency department visits. J Allergy Clin Immunol. 2002; 109:57-62.
3. Togias T. Rhinitis and asthma: Evidence for respiratory system integration. J Allergy Clin Immunol. 2003;111:1171-1183.
4. Ten Brinke A, et al. Chronic sinusitis in severe asthma is related to sputum eosinophilia. J Allergy Clin Immunol. 2002;109: 621-626.
5. Kasper E, et al. Prevalence of asthma with aspirin hypersensitivity in the adult population of Poland. Allergy. In press.
6. Szczeklik A, et al, on behalf of the AIANE investigators: Natural history of aspirin induced asthma. Eur Resp J. 2000;16:432-436.
7. Williams HC. Diagnostic criteria for atopic dermatitis: Where do we go from here? Arch Dermatol. 1999;135:583-586.
8. Woodcock A, et al. Control of exposure to mite allergen and allergen-impermeable bed covers for adults with asthma. N Engl J Med. 2003;349:225-236.
9. Terreehorst I, et al. Evaluation of impermeable covers for bedding in patients with allergic rhinitis. N Engl J Med. 2003;349:237-246.
10. Oosting A, et al. Effect of mattress encasing on atopic dermatitis outcome measures in a double-blind, placebo-controlled study: The Dutch Mite Avoidance Study. J Allergy Clin Immunol. 2002; 110:500-506.
11. Pederson S. Do inhaled corticosteroids inhibit growth in children? Am J Respir Crit Care Med. 2001;164:521-535.
12. NAEPP Guidelines for the Diagnosis and Management of Asthma: Update on Selected Topics 2002. J Allergy Clin Immunol. 2002;110(5 Suppl):S160-S168.
13. Yanez A, Rodrigo GJ. Intranasal corticosteroids versus topical H1 receptor antagonist for the treatment of allergic rhinitis: A systematic review with meta-analysis. Ann Allergy Asthma Immunol. 2002;89:479-484.
14. Slater JW, et al. Second Generation Antihistamines: A comparative review. Drugs. 1999;57(1):31-47.
15. Durham SB, et al. Long-term clinical efficacy of grass pollen immunotherapy. N Engl J Med. 1999;341:468-475.
16. Abramson MJ, et al. Is allergen immunotherapy effective in asthma? A meta-analysis of randomized controlled trials. Am J Resp Crit Care Med. 1995;151:969-974.
17. Ross RN, et al. Effectiveness of specific immunotherapy in the treatment of asthma: A meta-analysis of prospective, randomized, double-blind, placebo-controlled studies. Clin Ther. 2000;22: 329-341.
18. Portnoy JM. Immunotherapy for asthma: Unfavorable studies. Ann Allergy Asthma Immunol. 2001;87(Suppl):28-32.
19. Casale TB. Future therapies of allergy: New approaches to treatment of asthma. Program and abstracts of the World Allergy Organization Congress—XVII ICACI; September 9-12, 2003; Vancouver, British Colombia, Canada.
20. Chang TW. The pharmacolical basis of anti-IgE therapy. Nat Biotechnol. 2000;18:157-162.
21. Soler M, et al. The anti-IgE antibody omalizumab reduces exacerbations and steroid requirement in allergic asthmatics. Eur Respir J. 2001;18:254-261.
22. Casale TB, et al. Effect of omalizumab on symptoms of seasonal allergic rhinitis: a randomized controlled trial. JAMA. 2001; 286(23):2956-2967.