Allergy Immunotherapy
Allergic diseases have increased in prevalence over the last 20 years, affecting as many as 40 to 50 million people in the United States. Allergen immunotherapy has been a therapeutic option for more than 100 years, and its use is supported by multiple placebo-controlled trials. Allergen immunotherapy alters the course of allergic diseases through a series of injections of a mixture of extracts composed of clinically relevant allergens. The World Health Organization has replaced the term allergen extract with allergen vaccine to reflect that allergen vaccines are used in medicine as immune modifiers.
Indications
Allergen immunotherapy is used in the treatment of allergic rhinitis, allergic asthma, and stinging insect venom hypersensitivity. The diagnosis of these diseases is made by history and physical examination supported by testing to confirm IgE sensitization. Skin testing by prick or intradermal method is the preferred objective assessment, but in vitro tests such as the radioallergosorbent test are an alternative, especially when skin testing is unable to be performed.
Candidates for venom or Hymenoptera immunotherapy include all patients who have experienced life-threatening allergic reactions or non-life-threatening systemic reactions to Hymenoptera stings. The risk of ana-phylaxis for a venom-allergy patient from an insect sting is greater than the risk of anaphylaxis from immunotherapy. In patients younger than 16 years with only urticaria to Hymenoptera stings, immunotherapy is not generally recommended. However, in patients older than 16 years with only cutaneous reactions, immunotherapy is a recommended option. Venom immunotherapy is not indicated for patients who have only had local reactions at the stinging site, even large local reactions.
Immunotherapy is also effective for pollen, mold, animal dander, dust mite, and cockroach allergies. Symptomatic patients with allergic rhinitis and asthma despite allergen avoidance and pharmacotherapy are candidates for immunotherapy. Other candidates include allergic rhinitis or asthma patients having undesirable adverse reactions to medications, or those wishing to reduce or eliminate long-term pharmacotherapy. In addition to reducing symptoms to current allergens, immunotherapy may prevent the development of sensitization to new allergens or progression of allergic rhinitis to asthma, especially in children.
Mechanism
The exact mechanism of how immunotherapy works is not fully understood, but it involves shifting a patient’s immune response to allergen from a predominantly allergic T-lymphocyte (TH2) response to a “nonallergic” T-lymphocyte (TH1) response. Lymphocytes of a TH2 phenotype typically produce IL-4 and IL-5, cytokines needed for IgE production and eosinophil survival. Findings of increased production of IFN-y and a decreased production of IL-4 and IL-5 have not, however, been consistently demonstrated after immunotherapy. What has been consistent is the increased production of allergen-specific IL-10. IL-10 causes a shift in allergen-specific IgE to allergen-specific IgG4. This change may be orchestrated by regulatory T cells that downregulate allergic immune responses in part through the release of IL-10 and T-cell growth factor alpha (TGF-a). With allergen immunotherapy, the seasonal increase in allergen-specific IgE is blunted while protective allergen-specific IgG4 production is increased. However, these changes in IgE and IgG may not correlate with clinical efficacy, so periodic skin testing or in vitro IgE antibody measurements are not always useful in evaluating responses to immunotherapy.
Contraindications
Relative contraindications for immunotherapy include medical conditions that reduce patients’ ability to survive a serious systemic allergic reaction, such as coronary artery disease or the concurrent use of P-blockers (including eye drops) or angiotensin-converting enzyme inhibitors.
Table. Immunotherapy
| Currently Indicated | Allergic rhinitis Allergic asthma Venom allergy |
| Not Indicated | Atopic dermatitis
Food allergy Chronic urticaria/angioedema |
| Relative Contraindications | Unstable asthma
Concurrent use of p-blockers or angiotensin-converting enzyme inhibitors Severe coronary artery disease Malignancy Unable to communicate clearly (children <5y) |
b-Adrenergic blocking agents may make the treatment of immunotherapy-related systemic reactions more difficult. Despite this, immunotherapy is indicated for patients with life-threatening stinging insect hypersensitivity receiving b-blockers. Allergen immunotherapy should not be initiated in asthmatic patients unless the patient’s asthma is relatively stable with pharmacotherapy. Patients who are mentally or physically unable to communicate clearly, such as very young children, are not good candidates for immunotherapy because it may be difficult for them to report early symptoms of a systemic reaction. Pregnancy is not a contraindication for immunotherapy, but by custom immunotherapy is not initiated during pregnancy. If a patient becomes pregnant while already on immunotherapy, the dose is not increased during the pregnancy but maintained at the current level in an attempt to avoid anaphylactic reactions.
Dosing
Safety
The greatest concern with immunotherapy is safety. Local reactions at the injection site, such as redness, swelling, and warmth, are common. These reactions can be lessened with HI antagonists prior to injections. Local reactions can be managed with treatments such as cold compresses or topical corticosteroids. Large local, delayed reactions (25 mm or larger) do not appear to be predictors of developing severe systemic reactions, and generally they do not require adjustment of dosing schedules. However, some patients with a greater frequency of large local reactions (more than 10% of injections) may be at increased risk for future systemic reactions, and dosing adjustments may be necessary.
The incidence of systemic reactions, such as urticaria, angioedema, increased respiratory symptoms (nasal, pulmonary, ocular), or hypotension, ranges from 0.05% to 3.2% per injection, or 0.84% to 46.7% of patients. Risk factors for systemic reactions include errors in dosing, symptomatic asthma, a high degree of allergen hypersensitivity, concomitant use of P-blocker medications, injections from a new vial, and injections given during periods when allergic symptoms are active, especially during the allergy season. A recent survey of 1700 allergists reported that 58% of responders had an event in which a patient received an injection meant for another patient, and 74% reported that patients had received an incorrect amount of vaccine. These errors resulted in a multitude of adverse events, including local reactions, systemic reactions, and even one fatality. Thus it is extremely important to make sure patients are questioned about potential risk factors and the correct vials are used to administer immunotherapy injections.
It is unclear if premedication with antihistamines can reduce the frequency of systemic reactions in conventional immunotherapy, but in cluster or rush immunotherapy, premedication can reduce the rate of systemic reactions.
The incidence of fatalities due to immunotherapy has not changed much over the last 30 years in the United States. From 1990 to 2001, fatal reactions occurred at a rate of 1 per 2.5 million injections, with an average of 3.4 deaths per year. Most fatal reactions occurred with maintenance doses of immunotherapy. The patient population at greatest risk was poorly controlled asthmatics. In many of the fatalities, there was either a substantial delay in giving epinephrine or epinephrine was not administered at all. The incidence of near-fatal reactions (respiratory compromise, hypotension, or both, requiring epinephrine) is 2.5 times more frequent than fatal reactions.
Treatment of anaphylaxis
Systemic allergic reactions can be life threatening and need to be treated rapidly. Most systemic reactions are limited to the skin, such as urticaria. Respiratory symptoms are seen alone or with skin manifestations in 42% of systemic reactions. Epinephrine is the standard of care for severe systemic or anaphylactic reactions. Treatment of anaphylactic reactions includes placing a tourniquet above the injection sites and immediately injecting epinephrine 1:1000 intramuscularly. For adults, the dose is typically 0.2 to 0.5 mL, and for children, 0.01 mL/kg (maximum, 0.3 mg dose) every 5 to 10 minutes as needed. For convenience, subcutaneous injection at the arm (deltoid) is frequently used, but intramuscular injection into the anterolateral thigh produces higher and more rapid peak levels of epinephrine.
Immunotherapy in general practice
Efficacy and outcomes
Once maintenance dosing is achieved for venom immunotherapy, 80% to 98% of individuals will be protected from systemic symptoms upon sting challenges. Maintenance therapy is generally recommended for 3 to 5 years, with growing evidence that 5 years of treatment provides more lasting benefit. A low risk of systemic reactions to stings (approximately 10%) appears to remain for many years after discontinuing venom immunotherapy. In children who have received venom immunotherapy, the chance of systemic reaction to a sting after discontinuation of immunotherapy is even lower.
The efficacy of immunotherapy for allergic rhinitis has been clearly demonstrated in a number of clinical trials. These studies have shown significant improvements in symptoms, quality of life, medication use, and immunologic parameters. Allergen immunotherapy for allergic rhinitis is also beneficial for at least 3 to 6 years after completion of a 3-year course of treatment.
The efficacy of immunotherapy for asthma has been assessed in many trials, but some studies have been difficult to interpret either because of the use of poor quality allergen extracts or suboptimal study design. The risk/benefit ratio of immunotherapy for asthma must always be considered. Currently, professional societies recommend that patients with asthma and forced expiratory volume in 1 second (FEVj) values less than 70% should not receive immunotherapy. A Cochrane review in 2004 examined the role of allergen immunotherapy for asthma. This review of 75 trials with 3100 patients found a significant reduction in asthma symptoms and medication use, and an improvement in bronchial hyperreactivity associated with the administration of allergen-specific immunotherapy. The reviewers concluded that immunotherapy is effective in asthma, and commented that one trial found that the size of the benefit was possibly comparable to inhaled corticosteroids.
Evidence-based medicine
This study evaluates the use of immunotherapy versus placebo in 206 children, 6 to 14 years of age, with only allergic rhinitis. The children were treated for 3 years with grass and/or birch extract depending on their sensitivities. After 3 years of immunotherapy, 19 patients developed asthma; 60 did not. In the placebo arm, 32 children developed asthma over 3 years, whereas 40 did not. The odds ratio for developing asthma in those receiving placebo was 2.5 times greater than that for children treated with allergen immunotherapy. This study was the first to demonstrate clearly that allergy immunotherapy may prevent or delay the onset of asthma in children with allergic rhinitis.
This study by Golden and colleagues evaluated the long-term outcomes of venom immunotherapy in 512 sensitized children. The mean follow-up was 18 years with a mean duration of immunotherapy of 3.5 years. The rate of systemic reactions after being restung was significantly greater among patients not treated with immunotherapy (17%) compared to those treated with venom immunotherapy (3%). In those treated with immunotherapy who only had skin manifestations prior to therapy, none had systemic reactions when restung.
Conclusion
Allergen immunotherapy has been a valuable tool in treating allergic rhinitis, asthma, and stinging insect hypersensitivity for decades. Although newer pharmaco-logic agents continue to become available, immunotherapy is still the only available treatment that alters the natural course of allergic diseases. Even though there are some risks, these can be minimized when immunotherapy is given in an appropriate environment to carefully selected patients. Recent guidelines have been established to further reduce the risks by establishing a universal system of reporting dilutions and establishing appropriate dosing. Despite a large body of evidence demonstrating the positive therapeutic benefits of immunotherapy, only 3 million patients in the United States are receiving immunotherapy out of a potential 40 to 50 million allergic patients, many of whom could benefit from this therapy. Newer therapies, such as anti-IgE (omalizumab), when used with immunotherapy, may improve the efficacy and safety profile of immunotherapy in the future. In addition, newer forms of immunotherapy such as T-cell peptides or immunostimulating sequences of DNA containing CpG motifs combined with allergens are currently under investigation.
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