The use of subcutaneous injections of increasing concentrations of a distilled water extract of the pollen of Timothy grass for seasonal pollinosis was first reported by Leonard Noon of London in 1911. ] Since then, allergen immunotherapy (or hyposensitization) has been widely used as a preventive modality for respiratory allergies such as allergic rhinitis and asthma, and has become the treatment of choice for prophylaxis of insect sting allergy. Randomized, placebo-controlled studies using standardized vaccines have conclusively established its efficacy in prophylaxis to venom from stinging insects, and the evidence that it improves allergic rhinitis is also convincing.2'3
There is, however, continued controversy over the use of immunotherapy in allergic asthma despite numerous studies, using grass and ragweed pollen, dust mites, and animal dander, that show improvement in indices traditionally used in deterrnining the efficacy of immunotherapy. These include induction of protective or "blocking" IgG antibodies, inhibition of inflammatory responses to challenges with allergens, downregulation of T-cell responses, and amelioration of bronchial hyperreactivity. The controversy occurs because there is no clear correlation between these objective measures and symptom control, most side effects of immunotherapy occur in recipients with asthma, and asthma is a multifactorial disease. More recent studies on immunotherapy suggest that its early use in children with atopy may alter the natural course of allergy in preventing development of sensitization to new allergens.4
IMMUNOTHERAPY IN ALLERGIC RHINITIS
The mainstay of treatment of allergic rhinitis combines implementation of effective environmental control measures to niinimize exposure to allergens and irritants, pharmacotherapy, and immunotherapy.
The role of inhalant allergens in causing chronic inflammation in the nose is well established. Seasonal allergen exposure may lead to transient, nonspecific nasal hyperreactivity, which persists days or weeks after a specific pollen season. Allergies to perennial allergens may induce a more permanent inflammation, resulting in a more lasting nonspecific hyperreactivity and, possibly, changes in the architecture of the nasal subepithelial layers, much like airway remodeling in asthma. In many patients, effective symptom control with minimal side effects can be achieved with the regular use of controller medications. These medications, exemplified by intranasal corticosteroids, address the underlying inflammatory processes in the nose. Monotherapy with antihistamines for mild seasonal allergic rhinitis or its use as additive therapy in perennial and more severe seasonal allergic rhinitis can optimize symptom relief. However, allergen avoidance and immunotherapy offer the additional benefit of possibly modifying the natural course of the disease. This may be accomplished by preventing the development of new sensitivities to allergens or altering disease progression by reducing responses to allergic stimuli. These stimuli not only precipitate symptoms, but also cause chronic inflammation which can lead to persistent disease.
The efficacy of immunotherapy has been shown in most randomized, double-blind, placebo-controlled trials in allergic rhinitis due to pollen from ragweed, various grasses, and trees.5"7 Controlled pediatric studies have likewise shown that immunotherapy is efficacious for pollen-induced rhinitis.8 The end points in these studies were improved symptom scores and decreased use of medication. In certain studies, there were decreases in skin test sensitivity, nasal hyperreactivity, or the amounts of inflammatory mediators after nasal allergen challenge, conjunctival allergen challenge, or both; an increase in "blocking antibodies" (IgG); and a decrease in antigen-specific IgE antibodies. Immunotherapy with grass and ragweed pollen has also been shown to be effective in the treatment of allergic conjunctivitis, a common comorbidity of allergic rhinitis.
The use of standardized vaccines for mites, cat dander, and molds [Cladosporium and Alternaria) in double-blind, placebo-controlled trials9,10 has helped demonstrate the efficacy of immunotherapy in patients with allergic rhinitis who were sensitive to these perennial allergens.
Previous studies on the long-term efficacy of allergen immunotherapy in allergic rhinitis did not show prolonged efficacy after discontinuation.11 However, the results of more recent studies using standardized ragweed and grass extracts showed protective effects of immunotherapy several years after it was discontinued. Using standardized mite vaccines, Des Roches et al.12 showed that the persistent protective effects of immunotherapy are maximal when administered for at least 3 years. In this study, the degree of improvement in symptom control and reduction of the skin test response to allergen after discontinuation of immunotherapy correlated with the duration of immunotherapy. Using standardized cat vaccines, Hedlin et al. assessed the efficacy of a 3-year course of cat immunotherapy.13 Their findings showed that onethird of tiie patients still had increased tolerance to cat exposure 5 years after immunotherapy was discontinued.
In addition to the standardization of vaccines, the determination of optimal effective doses of allergen was an important development that led to stronger studies demonstrating the efficacy of allergen-specific immunotherapy. Using clinical indices and responses to nasal allergen challenges to a range of vaccine doses, Créticos et al.14-15 helped establish optimal effective doses for ragweed immunotherapy. These dose-response studies provided a model for the determination of dosage parameters and optimal maintenance doses for immunotherapy to other inhalant allergens.
In 1997, Des Roches et al. studied 44 children younger than 6 years who were allergic to dust mites alone. Half received immunotherapy with standardized mite vaccines for 3 years and half did not. Only 10 of the 22 who received immunotherapy had new sensitivities, whereas all children in the non-intervention group did.4 The study highlights a new concept in the use of immunotherapy - that this may serve as prophylaxis against further sensitization. However, this observation needs further confirmation.
Clearly, the efficacy of specific allergen immunotherapy in the treatment of allergic rhinitis has been well demonstrated and established.
IMMUNOTHERAPY IN ASTHMA
Similar to the treatment of allergic rhinitis, avoidance of known allergens and irritants and pharmacotherapy using controller and quick-relief medications are the mainstays of treatment for chronic bronchial asthma. We assume that immunotherapy increases tolerance to specific allergens. Therefore, it is plausible that immunotherapy could decrease asthma exacerbations caused by exposure to seasonal and perennial allergens. Evidence is also emerging that immunotherapy can downregulate immune responses to antigen and thereby halt the progression of chronic inflammation. This immune system modulation may potentially attenuate bronchial hyperreactivity, a major pathophysiologic component of asthma. An intriguing possible use for immunotherapy could be the prevention of asthma in children who have allergic rhinitis. The European study Preventive Allergy Treatment (PAT) was designed to answer the question, "Does specific allergen immunotherapy prevent the development of asthma?" Preliminary reports suggest that immunotherapy impedes progression from allergic rhinoconjunctivitis to asthma.16
A meta-analysis of clinical trials of allergen immunotherapy in asthma from 1966 to 1990 was done to assess its efficacy. The analysis used a computerized bibliographic search of 20 randomized, placebo-controlled, double-blind trials of allergen immunotherapy in asthma. The parameters extracted included asthma symptoms, medication requirements, pulmonary function, and bronchial hyperreactivity.
Categoric outcomes were expressed as odds ratios and continuous outcomes as effect sizes. The combined odds of symptomatic improvement from immunotherapy with any allergen were 3.2 (95% confidence interval [CI95], 2.2 to 4.9). The odds for reduction in medication use after mite immunotherapy were 4.2 (CI95, 2.2 to 7.9). The combined odds for reduction in bronchial hyperreactivity were 6.8 (O95, 3.8 to 12.0). The mean effect size for any allergen immunotherapy on all continuous outcomes was 0.71 (CI95, 0.43 to 1.00), which could respond to a mean 7.1% predicted improvement in forced expiratory volume 1 second (FEV1) from immunotherapy. Although the benefits of allergen immunotherapy could be overestimated because of unpublished studies with negative results, an additional 33 such studies would be necessary to overturn these results.17
Since 1990, at least 10 other studies have assessed the efficacy of allergen immunotherapy in asthma by measuring bronchial hyperreactivity, pulmonary function, symptom scores, and other parameters. In 1995, Hedlin et al. showed a decrease in nonspecific bronchial hyperreactivity in patients with asthma who were sensitive to cats after 3 years of immunotherapy with cat dander antigen. In 1999, the same group reported that using cat or dust mite antigens in combination with pollen immunotherapy for 3 years in patients sensitive to cats or dust mites led to a reduction in bronchial hyperreactivity.18 Similar results have been shown in studies using pollen and mite vaccines.
Conversely, Adkinson et al. reported in 1997 that immunotherapy with multiple aeroallergens for 2 years was of no discernible benefit in allergic children with perennial asthma who were receiving appropriate medical treatment. The authors ascribed the results to significant improvements in the patients even prior to randomization because of diligent follow-up every 2 to 3 weeks and optimal environmental control measures.19
A review of 12 pediatric studies on immunotherapy from 1966 to 1994 by Sigman and Mazer concluded that the literature is unclear as to when immunotherapy should be started for asthma. In their analysis, most of the studies demonstrated either an improvement in asthma symptoms, a decrease in bronchial hyperreactivity to the specific allergen, or both. Few studies demonstrated no clinical efficacy. Sigman and Mazer concluded that, although there are suggestions that immunotherapy should be considered for the child with mild or moderate asthma and mite sensitivity when pharmacotherapy is not efficacious, the immunomodulatory properties may make immunotherapy better tailored for early intervention in asthma compared with treatment once symptoms have occurred.20
A lack of pediatric studies that demonstrate consistent efficacy in asthma, correlation of clinical improvement with immunologic indices, longterm effects of immunotherapy, and concerns about the increased risk of systemic reactions in children younger than 5 years have made it difficult to determine the role of immunotherapy in the treatment of pediatric asthma. This absence of consensus has led to differing opinions, as reflected by decreased use of immunotherapy for asthma in the United Kingdom and the Nordic countries as compared with the United States. In a position paper on allergen immunotherapy sponsored by the World Health Organization (WHO) and released in 1998,21 experts from 9 national and international asthma agencies reached the conclusion that immunotherapy in pediatric asthma is indicated for children older than 5 years who have mild to moderate and well-controlled asthma and laboratory evidence that their disease is due to IgE-mediated allergy.
MECHANISMS OF ACTION
Exposure of sensitized allergic individuals to allergen leads to cross-linking of antigen-specific IgE bound to mast cells. The latter are found in the connective tissue and mucosa of target organs such as the nose and the airways. This results in mast cell degranulation and release of preformed and newly formed inflammatory mediators (eg, prostaglandins, leukotrienes, histamines, and other eicosanoids). This early response, also called the acute phase of inflammation, is characterized by acute symptoms of rhinorrhea, congestion, and sneezing in allergic rhinitis and wheezing and coughing in asthma.
A late-phase inflammatory response frequently occurs in which other inflammatory cells, eosinophils and T-lymphocytes in particular, are recruited to the target site. It has been substantially shown through biopsy and bronchial lavage studies that the T-cells from individuals with atopy are biased toward secretion of cytokines IL4 and IL-5 (Th2-type profile). In contrast, the Tcells of individuals without atopy produce more cytokines of the ThI -type (interferon-gamma [IFN-7]). IL-4 promotes the production of more IgE antibody in B-cells and IL-5 promotes eosinophil growth, differentiation, and survival. These T-cell-derived cytokines play major roles in both the humoral and the cell-mediated aspects of allergic inflammation.
EFFECT OF IMMUNOTHERAPY ON EFFECTOR CELLS AND MEDIATORS
The transepithelial migration of mast cells in allergic rhinitis facilitates an interface with allergen that results in symptom formation. Immunohistochemical techniques and metachromatic staining have identified these mast cells in the mucosa. A study of dust mite immunotherapy in adults with allergic rhinitis demonstrated that patients who underwent and responded to immunotherapy clinically had a significant reduction in the number of metachromatic cells in the nasal mucosa.22 A similar study in adults sensitive to grass pollen showed decreased numbers of both mucosal and connective tissue mast cells. These findings correlated with symptom control improvement and lower medication requirements.
Eosinophils are the main effector cells responsible for the late-phase response of inflammation. Thus, quantification of activated eosinophils (EG2+) and their products in the nose, skin, and bronchial airways has become useful in determining the effects of treatment on the late-phase response.
Several researchers have shown a decrease in tissue eosinophilia after immunotherapy. Rak et al. studied 20 patients with asthma and allergic rhinitis who received immunotherapy to birch tree pollen comparing them with untreated control subjects. Fiberoptic bronchoscopy, bronchioalveolar lavage, and histamine challenge to measure nonspecific airway hyperresponsiveness were done before and during birch tree pollen season. They found a decrease in bronchial airway eosinophils and eosinophil cationic protein in the patients who underwent immunotherapy as compared with the untreated control subjects. They also showed that the decrease in the cell counts correlated with improvement of symptoms and a reduction in nonspecific airway hyperresponsiveness.23
Furin et al. reported decreased amounts of eosinophils in nasal lavage fluid before and 24 hours after nasal allergen challenge in patients who received ragweed pollen immunotherapy as compared with untreated control subjects.24 Durham et al. demonstrated a similar decrease in nasal mucosal eosinophil counts before and 24 hours after allergen provocation in patients treated with immunotherapy. The inhibition of the late response correlated with the decrease in both total and activated eosinophils.25
Numerous studies show that immunotherapy leads to reduced amounts of inflammatory mediators involved in the early and the late phases of inflammation in the skin, peripheral blood, nasal mucosa, and airways. Iliopoulos et al. demonstrated decreased levels of histamine, tosylarginine methyl ester (TAME) esterase activity, and kinins in the nose after nasal allergen challenge in both early and late phases of inflammation in patients treated with immunotherapy.26 An earlier study by Créticos et al. showed decreased levels of the same mediators and prostaglandin D2 in both early and late phases of inflammation after ragweed pollen provocation in patients treated with immunotherapy. Studies of the effects of immunotherapy on bronchial early- and late-phase inflammation after provocation with dust mite antigen revealed that clinical improvement correlated with a preferential reduction of late-phase inflammatory components.
EFFECTS OF IMMUNOTHERAPY ON HUMORAL IMMUNITY
A number of immunologic changes in antibody production following immunotherapy have historically been accepted as mainly responsible for the efficacy of immunotherapy. Among these changes are: (1) a rise in serum IgG "blocking" antibodies, including IgGl and IgG4 idiotypes; (2) a suppression of the usual rise in IgE antibodies following allergen exposure and a slow decline over time of specific IgE antibodies; (3) an increase in antigen-specific IgA and IgG antibodies in nasal secretions; (4) the production of antigen-specific anti-idiotypic antibodies; and (5) an increase in antigen-specific IgM and secretory IgA in secretions and mucosa.
Correlations between the quantity of these antibodies and clinical improvement have been difficult to establish. In general, those who have higher titers of antigen-specific IgG have more favorable clinical responses than do those who have lower levels, but there clearly are inconsistencies. Studies of IgG idiotypes show that the initial response to immunotherapy is increased production of both IgGl and IgG4 antibodies. However, with continued immunotherapy, circulating antibodies become almost entirely of the IgG4 subtype. Likewise, no clear relationship between levels of IgG4 and clinical improvement has been demonstrated. Antibodies in secretions and in the mucosa may be ideally located to interfere in the allergen-mucosa interface. However, little, if any, correlation has been seen with the rise in these antibody titers and clinical improvement.
Whether immunotherapy-induced production of these allergen-specific antibodies is responsible for the clinical efficacy of immunotherapy is a matter of debate. Moreover, if these antibodies are responsible for its efficacy, what is the mechanism for this? A prevailing theory is that these allergenspecific antibodies, especially IgG and its idiotypes, act as "blocking antibodies" by competing with IgE for allergen binding. This then inhibits IgE-dependent activation of mast cells and basophils. Supporting evidence comes from studies showing that IgG antibodies may block IgE binding to birch pollen antigen.
On the other hand, IgE binding to allergen in serum immunoblots remains unaltered after immunotherapy-induced production of blocking antibodies. Furthermore, clinical improvement in "rush" immunotherapy protocols, where increasing concentrations of extract are given over a shorter period of time, has been demonstrated prior to detection of increasing titers of blocking antibodies.
Based on the above, it has become clear that the theory of immunotherapy-induced production of blocking antibodies falls short as the sole basis for the clinical efficacy of immunotherapy. Quantification of serum allergen-specific antibodies can, however, be a marker for an immunologic response to allergen-specific immunotherapy.
EFFECTS OF IMMUNOTHERAPY ON T-CELL FUNCTION
An increased understanding of the pathophysiologic processes in atopy and asthma has uncovered the pivotal role that T-cells play in mediating the allergic response. Cytokines derived from Th2 T-lymphocytes orchestrate IgE switching in Bcells, promote the growth, differentiation, and survival of eosinophils, and enhance the responses of these cells to chemotactic agents. We also know that the effects of these Th2-type cytokines are counteracted by the Thl-type cytokines, which induce a non-atopic "protective pro-inflammatory" response. It is then reasonable to speculate that immunotherapy may act by changing the T-lymphocyte response from an "allergic" Th2 type to a "protective" ThI response. There is evidence from studies using peripheral blood and tissues that immunotherapy may decrease the production of Th2-type cytokines, increase the production of Thl-type cytokines, or induce a state of unresponsiveness to allergen.
How this switch occurs is the subject of ongoing studies. Reports have speculated on the role of other modulatory cytokines such as IL-12. IL-12 is a potent inducer of the Thl-type T-cell response. It is produced by various cells, including macrophages, dendritic cells, and B-cells, and inhibition of the late cutaneous response in patients who underwent grass pollen immunotherapy was associated with an increase in IL-12 mRNA-positive cells. This suggests that the increases in Thltype cytokines such as IFN-7, which are induced by immunotherapy, may be mediated by cytokines such as IL-12.27
The induction of anergy in helper CD4+ T-cells has been shown in vivo after stimulation with bacterial superantigens28 and in proliferation assays in vitro following immunotherapy.29 These anergic cells fail to respond to restimulation with allergen, but they proliferate in response to IL-2, a cytokine that induces lymphocyte growth. Durham theorizes that rescue of allergen-induced T-cell proliferation by addition of IL-2 is evidence that allergen-specific T-cells were anergized in vivo.30 When T-cells from these patients were restimulated with allergen, expanded in vitro, and stimulated with mitogens to induce cytokine production, they showed enhanced expression of the Thl-type protective cytokines.29 He says that although they appear superimposed, T-cell anergy and immune deviation may occur by separate mechanisms and in different populations of T-cells.
The proposed mechanisms of immunotherapy on T-cell function need further study. The association between immune deviation and anergy also needs clarification. The role of modulatory cytokines such as IL-12 and IL-IO, signaling pathway mechanisms, and the role of CD8 suppressor cells need to be better understood.
NEW APPROACHES TO 1MMUN0M0DULATI0N
The gaps in our knowledge and the overlap and interplay among the humoral, cell-mediated, and nonspecific compartments of the immune system in allergic disease and chronic inflammatory states have made the development of new forms of immunomodulation challenging. A current novel approach for allergic rhinitis and asthma uses Tcell reactive peptides to directly induce anergy. This circumvents the risk of anaphylaxis during the build-up or induction phase of immunotherapy. Other alternatives to classic immunotherapy include passive therapy with antigen DNA vaccination using plasmids, humanized anti-IgE monoclonal antibodies, antibodies targeting Th2-type cytokines such as IL-4, IL-5, and IL-13, and broadbased therapy with intravenous immunoglobulins. Adjuvant therapy with vaccines and cytokines might potentiate the induction of immune deviation or anergy by specific allergen.
PEDIATRIC INDICATIONS FOR IMMUNOTHERAPY
Indications for immunotherapy in children, as stated in the 1998 World Health Organization position paper on allergen immunotherapy, include (1) IgE-mediated rhinoconjunctivitis, (2) allergic asthma, and (3) severe anaphylactic reactions to Hymenoptera stings.
Certain factors must first be considered and evaluated before beginning immunotherapy. These include (1) demonstration that the disease is due to IgE-mediated allergy through history and positive results on skin tests, serum-specific IgE, or both; (2) determination of all symptoms caused by allergens; (3) assessment of allergen exposure in the patient's environment through a detailed environmental survey; (4) implementation of environmental control measures; (5) assessment of the severity of the disease to be treated, including its impact on clinical, humanistic, and economic indices; (6) assessment of the efficacy of available treatment modalities; (7) assessment of the patient's attitude toward immunotherapy and other treatment modalities; (8) assessment of the adherence to treatment regimens; (9) assessment of the cost and duration of each form of treatment; and (10) assessment of the risk incurred from poor control of the disease and from each treatment modality.
Relative contraindications for immunotherapy include (1) serious immunopathologic and immunodeficiency diseases and states; (2) malignancy; (3) severe psychological disorders; (4) treatment with ß-blockers, even when administered topically; (5) severe asthma uncontrolled by pharmacotherapy, irreversible airways obstruction as evidenced by FEV1 consistently under 70% of that predicted after adequate pharmacologic treatment (except for Hymenoptera venom hypersensitivity), or both; (6) poor compliance; (7) significant cardiovascular diseases that increase the risk of side effects from epinephrine, except for Hymenoptera venom hypersensitivity; and (8) age younger than 5 years, except for Hymenoptera venom hypersensitivity. Pregnancy is not considered a contraindication for continuation of maintenance doses of immunotherapy, but, in general, treatment should not be started or increased during pregnancy.
Successful immunotherapy is predicated on accurate diagnosis, precise determination of sensitivities to allergen, comprehensive assessment of risk factors, accurate identification of candidates most likely to benefit from the treatment, and effective patient-family education and communication.
SAFETY ISSUES IN IMMUNOTHERAPY
Specific allergen immunotherapy is generally regarded as a safe form of treatment for respiratory allergies and Hymenoptera sensitivity. It is estimated that between 7 and 10 million immunotherapy injections are given each year. The risk of a fatal systemic reaction from the procedure is extremely small. However, reactions can and do occur with this form of treatment. A review of several studies on the safety of allergen immunotherapy reveal a range of rates from 0.3% to 14% for local and systemic reactions.31
Local reactions occur at the injection site and may include swelling, redness, itching, discomfort, and subcutaneous nodules. Most occur within the mandatory waiting time of 20 to 30 minutes after a shot is given, but late local reactions also happen. Adjustments in vaccine doses may be necessary when such reactions occur. Systemic reactions are characterized by symptoms distant from or including the shot site. A grading of systemic reactions was proposed in the European Academy of Allergology and Clinical Immunology (EAACI) position paper on immunotherapy32: (1) nonspecific systemic reactions, which include discomfort, headache, and arthralgia and are probably not IgE mediated; (2) mild systemic reactions, which include mild rhinitis, asthma, or both (peak expiratory flow rate [PEFR] more than 60% of personal best) responding adequately to antihistamines, inhaled ß2-agonists, or both; (3) non-life-threatening systemic reactions such as urticaria, angioedema, or severe asthma (PEFR less than 60% of personal best) responding well to treatment; and (4) anaphylactic shock with a rapid onset of systemic symptoms, including lightheadedness, hypotension, bronchial obstruction, and flushing, that requires intensive treatment. Most systemic reactions are mild and begin within 15 to 20 minutes after injection, but some start after 30 minutes. Maintenance immunotherapy is associated with fewer systemic reactions than the build-up phase, especially with accelerated or rush protocols. Large local reactions do not seem to predict the onset of a subsequent systemic reaction. When systemic reactions occur, révaluation of the patient's immunotherapy regimen is indicated.
In 1987, Lockey et al. reported 46 deaths from immunotherapy during a 39-year period (1945 to 1984).33 A follow-up article in 1993 by the same authors added 17 immunotherapy-related fatalities from 1985 to 1989.34 Onset of anaphylaxis occurred within 20 minutes after an injection in almost 80% of those who had adequate documentation, emphasizing the importance of the mandatory 20- to 30- minute waiting period after shot administration. Other risk factors from these and other studies included (1) errors in dosage and dosage adjustments; (2) presence of poorly controlled, symptomatic asthma; (3) high degree of sensitivity as measured by tests and specific IgE measurements; (4) concomitant use of ß-blockers; (5) injections from new vials; and (6) injections made during periods of exacerbation of symptoms.
To minimize the chances of reactions, these risk factors should be adequately addressed. Moreover, immunotherapy should be administered under the supervision of a physician well trained in its use and indications. Injections should be administered by personnel trained in the recognition and treatment of medical emergencies (especially anaphylaxis and cardiopulmonary resuscitation) and in offices equipped to address life-threatening emergencies.
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30. Durham SR, Till SJ. Immunologic changes associated with allergen immunotherapy. J Allergy Clin Immunol. 1998;102: 157-164.
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34. Reid MJ, Lockey RF, Turkeltaub PC, Platts-Mills TA. Survey of fatalities from skin testing and immunotherapy: 1985-1989. J Allergy Clin Immunol. 1993;92(Pt 1):6-15.