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Subcutaneous immunotherapy (SCIT) for allergic rhinoconjunctivitis and asthma: Indications and efficacy

Subcutaneous immunotherapy (SCIT) for allergic rhinoconjunctivitis and asthma: Indications and efficacy
Author:
Peter S Creticos, MD
Section Editor:
Jonathan Corren, MD
Deputy Editor:
Anna M Feldweg, MD
Literature review current through: May 2024.
This topic last updated: Dec 02, 2022.

INTRODUCTION — Immunotherapy for allergic disease (AIT) involves the administration of allergen to which the patient is sensitive, for the purpose of modulating the untoward immune response to that allergen and alleviating allergic symptoms. AIT represents the only therapy capable of inducing a state of immune tolerance and, through its inherent disease-modifying properties, provides the potential to affect a sustained clinical benefit with long-lasting clinical remission of the allergic condition. In addition, it offers the possibility of preventing the development of new allergen sensitivities in the allergic patient, inhibiting the progression of allergic rhinitis to asthma, and improving a patient's quality of life and medication requirements.

Subcutaneous immunotherapy (SCIT) is the best-established form of this treatment. The indications and efficacy for SCIT with aeroallergens (ie, inhaled allergens, such as pollens, dust mites, animal danders, etc) will be reviewed here. SCIT with other allergens, such as venoms or food allergens, is reviewed separately. Oral and sublingual forms of immunotherapy, rush immunotherapy, mechanisms of action, and the preparation of allergen extracts are also discussed elsewhere.

(See "Hymenoptera venom immunotherapy: Efficacy, indications, and mechanism of action".)

(See "Food allergy management: Allergen-nonspecific therapies".)

(See "Sublingual immunotherapy for allergic rhinitis and conjunctivitis: SLIT-tablets".)

(See "Allergen immunotherapy for allergic disease: Therapeutic mechanisms".)

(See "SCIT: Preparation of allergen extracts for therapeutic use".)

(See "SCIT: Standard schedules, administration techniques, adverse reactions, and monitoring".)

(See "Subcutaneous aeroallergen immunotherapy: Accelerated schedules (cluster and rush)".)

(See "Anaphylaxis induced by subcutaneous allergen immunotherapy".)

BACKGROUND — AIT was first introduced as a treatment for "hay fever" in 1911 by British physicians who injected grass-allergic patients with a dilute solution of timothy grass pollen and demonstrated that immunized subjects experienced a meaningful (100-fold) decrement in ocular symptoms upon ocular challenge with timothy pollen extract [1,2].

The first controlled trials of AIT were performed in the 1950s [3,4]. In the 1960s, the benefit of AIT was shown to be specific to the allergen used in treatment, and major allergens in specific pollens were identified in the first double-blind, randomized, controlled trials using sham injections [5,6]. Studies of the mechanisms by which AIT altered the cellular and humoral pathways involved in the allergic diathesis followed. These studies of the interrelationships between a patient's serum IgE, basophil histamine releasability, skin test sensitivity, and clinical symptoms allowed a more precise understanding of the relationships between efficacy and allergen dose. For pollen allergy, it was also demonstrated that a perennial immunization regimen was superior to that of preseasonal "desensitization," as a result of inducing a persistent level of protective "blocking" antibody against pollen allergens. The results of these studies ushered in the modern era of allergen immunotherapy [7].

INDICATIONS — There are several questions that should be addressed to determine if aeroallergen SCIT is appropriate for a specific patient [8,9].

Does the patient have a disorder that responds to immunotherapy? — SCIT using preparations of aeroallergens may be indicated in the management of the following disorders:

Allergic rhinitis and/or allergic conjunctivitis, including:

Seasonal allergic rhinitis and/or conjunctivitis

Perennial allergic rhinitis and/or conjunctivitis

Both seasonal and perennial allergic rhinitis and/or conjunctivitis

Allergic asthma:

Seasonal allergic asthma

Perennial allergic asthma

Both allergic rhinitis and/or allergic conjunctivitis and allergic asthma

Clinical studies demonstrate that patients with both asthma and allergic rhinitis derive particular benefit [10-13].

"Local allergic rhinitis" has also been treated with SCIT, as discussed below. (See 'Local allergic rhinitis' below.)

Atopic dermatitis can respond to SCIT if the patient is sensitized to inhalant allergens. The use of immunotherapy for atopic dermatitis and the role of allergy in the pathogenesis of atopic dermatitis are discussed elsewhere. (See "Treatment of atopic dermatitis (eczema)" and "Role of allergy in atopic dermatitis (eczema)".)

The utility of SCIT in the treatment of patients with allergic fungal rhinosinusitis, aspirin-exacerbated respiratory disease, or allergic bronchopulmonary aspergillosis, who also have a component of allergic rhinitis or asthma, has not been extensively studied. Clinicians vary in their use of SCIT for these disorders. (See "Aspirin-exacerbated respiratory disease" and "Treatment of allergic bronchopulmonary aspergillosis" and "Allergic fungal rhinosinusitis", section on 'Immunotherapy for fungal allergy' and "Treatment of allergic bronchopulmonary aspergillosis", section on 'Other interventions'.)

Is the allergen(s) clinically important? — A patient is a candidate for allergen immunotherapy only if it has been established that there is a clinically important allergic component to his/her disease. For patients with the disorders listed above, clinical relevance is established by the presence of both of the following:

Symptoms upon natural exposure to the allergen – It is sometimes easy to determine if patients have symptoms upon exposure (eg, symptoms upon intermittent exposure to cats), although in other situations, it is inferred when the patient has known exposure to an allergen and a temporal pattern of symptoms that is consistent with occurrence of that allergen, such as rhinitis and conjunctivitis during tree pollen season.

And

The presence of specific immunoglobulin E (IgE) to that allergen, demonstrated either through allergen skin testing or serum tests for allergen-specific IgE.

Have other measures been maximized? — The clinician should ensure that the patient has maximized environmental control measures and is on an optimal medication regimen. If the patient has not been compliant with medications, the reasons for this should be explored in-depth. (See "Allergen avoidance in the treatment of asthma and allergic rhinitis".)

SCIT is usually recommended for the treatment of allergic respiratory disease only after a period of pharmacologic management and observation. Medications are relatively easy for most patients to use, and when effective, they provide relief more rapidly than immunotherapy. A period of observation also allows the clinician to monitor the patient's disease over time, which is particularly important for adults with new-onset asthma in whom the differential should include other disorders that may present with respiratory symptoms (eg, other pulmonary conditions [chronic obstructive lung disease, chronic bronchitis, nonallergic asthma], gastroesophageal reflux disease, cough caused by chronic rhinosinusitis). These conditions should be considered first before initiating SCIT.

Is current management suboptimal? — Once the above questions have been addressed, it is appropriate to consider a trial of allergen immunotherapy in patients with significant allergic disease, for whom management is suboptimal for any of the following reasons:

Persistent symptoms on a seasonal and/or perennial basis

An inadequate or partial response to environmental control and pharmacotherapy

Noncompliance with maintenance medication regimen or suboptimal use of medication devices (eg, nasal sprays or inhalers)

Side effects related to medication use

Cost burden associated with chronic medication use

The indications for SCIT are summarized in the table (table 1).

The severity of the patient's condition, its duration (intermittent versus persistent; seasonal versus perennial), and the impact on work, schooling, and quality of life are important factors in deciding whether to initiate a course of SCIT. Tangential to these considerations is an understanding of the patient's anticipated goals, which highlights the importance of the establishing a strong patient-physician relationship and the role of shared decision-making in this process [13].

REFERRAL — Referral to a specialist in allergy and immunology should be sought for patients for whom immunotherapy may be appropriate. Allergists/immunologists are trained in the interpretation of diagnostic tests for specific allergies, decisions about the allergens to be employed in immunotherapy, and formulation of allergen extracts.

VARIABLES IN THE PRACTICE OF SCIT — Studies examining the efficacy of SCIT are confounded by several factors, and it is helpful to have historical perspective about some of these. Variables in the practice of SCIT include differing approaches to administration around the world, differences in production methods, the lack of standardized measures of clinically meaningful efficacy, and until recently, a need for definitions of effective doses and validated assessment tools. These issues are being systematically addressed over time, although consensus about the optimal means of assessing efficacy has not been reached.

One or multiple allergens — One important variable in the administration of SCIT is the use of a single or multiple allergens. Specifically, allergy/immunology specialists in the United States generally administer mixtures of all of the major relevant allergens (or a representative of each group of allergens) to which the patient has been shown to be sensitive. In contrast, it is common in Europe to administer only the one or two allergens that appear to cause the most symptoms for that individual patient, under the assumption that immunizing the patient against one allergen can reduce overall allergic reactivity. The question of whether immunotherapy using a single allergen can confer cross-desensitization to unrelated allergens has been addressed directly in a small number of trials [14-16].

A landmark study was a three-year randomized, double-blind, controlled trial of 87 patients allergic to both grass and ragweed pollen [15]. The group receiving preseasonal ragweed immunotherapy showed significant improvement in symptoms during ragweed season compared with the placebo group, as expected. In contrast, neither group received grass immunotherapy, and no improvements in symptom diaries were reported by either group during the grass pollen season. The clinical effect was paralleled by an increase in post-treatment IgG "blocking antibody" titers against ragweed. Immunoglobulin G (IgG) to grass pollen was not assessed.

In another randomized trial of 20 adults allergic to both dust mite and timothy grass pollen, subjects underwent three years of SCIT with one allergen or the other [14]. Both sensitivity during conjunctival challenge and immunologic changes demonstrated that immunotherapy was allergen-specific, although there was significant loss to follow-up and small numbers of patients completing the trial.

A related issue is whether multiple allergens can be given simultaneously without compromising efficacy by diluting any single allergen [17-19]. The effectiveness of using multiple allergens has not been extensively analyzed, since most of the studies of SCIT efficacy have used a single allergen. One literature review of 11 trials of SCIT found that the use of either one or two allergens was effective, but controlled trials involving higher numbers of allergens are lacking [20,21].

Composition of allergen extracts — Variation in the composition of extracts used for immunotherapy has also been a problem historically. Efforts are underway to "standardize" important aeroallergens, which is a process that ensures the composition and potency of specific extracts. The use of standardized allergens should further improve the consistency and quality of allergen immunotherapy. The first aeroallergen defined and standardized by major protein content (antigen E, later designated Amb a 1) was ragweed, a dominant seasonal allergen in North America. The subsequent development of immunoassays to the major allergen allowed for the design of studies that helped define the therapeutic mechanisms of immunotherapy. In addition, clinical studies provided solid evidence for efficacy and safety with properly administered dosing regimens [7,8,22,23]. An explanation of the standardization process and lists of standardized extracts are found elsewhere. (See "Allergen extracts: Composition, manufacture, and labeling", section on 'Standardization of allergen extracts' and "SCIT: Preparation of allergen extracts for therapeutic use", section on 'Types of allergen extracts'.)

Dosing — The dose of allergen administered in immunotherapy is another important variable. It has been established that there is an effective dose range for most allergens, and a coordinated international effort is ongoing to define that range for each of the important aeroallergens, although the process is far from complete. Prior to efforts to determine appropriate doses, the use of "maximally tolerated doses" (MTD) was an accepted approach to SCIT. A patient's MTD was defined by that dose which caused an untoward allergic reaction upon injection. Once the patient reacted, the subsequent maintenance injection regimen would be 1 or 2 doses lower (eg, 0.5 mL instead of 0.7 mL of the concentrate).

Subsequently, effective dose ranges were established for several allergens:

In the 1980s, using a model of nasal provocation, the optimal target dose for ragweed allergen immunotherapy was determined to be 6 to 12 mcg Amb a 1 per injection. Maintenance doses lower than this (eg, <2 to 3 mcg) did not provide consistent relief of rhinitis/conjunctivitis symptoms, while MTD (eg, 24 to 48 mcg/injection) carried a relatively high risk of systemic reactions [7,24-27].

Provocation studies with cat room exposure provided evidence for an optimal dose of cat major allergen (Fel d 1) of approximately 10 mcg per maintenance injection in patients with asthma and allergies to cat [28].

Bronchial challenge studies of patients with asthma and allergy to dust mite identified a target dose of approximately 7 mcg of the major protein (Der p 1) per maintenance injection [29].

These and subsequent studies provide the basis of the doses recommended for use in clinical practice. However, optimal doses have not been determined for many aeroallergens. Current dosing recommendations are reviewed in more detail elsewhere. (See "SCIT: Preparation of allergen extracts for therapeutic use", section on 'Dosing'.)

Preparation of extracts — There are differences in the preparation and processing of allergens worldwide, including the use of allergoid and depot preparations. The preparation of allergen extracts is reviewed separately. (See "Allergen extracts: Composition, manufacture, and labeling".)

EFFICACY — The overall efficacy of SCIT in treating allergic disease is supported by an extensive body of evidence [30].

Effective allergens — The effectiveness of SCIT for the treatment of inhalant allergy (allergic rhinitis/conjunctivitis and allergic asthma) has been demonstrated by placebo-controlled studies for the following allergens [22,31-35]:

Tree pollens (birch and mountain cedar)

Grass pollens (timothy and grass mixes)

Weed pollens (ragweed and Russian thistle)

Animal danders (cat and dog)

Dust mites (Dermatophagoides pteronyssinus and D. farinae)

Molds (Alternaria and Cladosporium)

Cockroach

Other allergens used in SCIT (other tree, grass, and weed pollens, molds and animal materials [rodent, horse, etc]), have not been studied as rigorously, although they are prepared and processed similarly to the well-studied extracts.

Clinical studies do not support the routine use of pollen immunotherapy solely for the purpose of treating oral allergy syndrome (also called pollen-food allergy syndrome [PFAS or PFS]), because patients do not consistently experience improvement in symptoms. The utility of immunotherapy in PFAS is reviewed elsewhere. (See "Management and prognosis of oral allergy syndrome (pollen-food allergy syndrome)", section on 'Immunotherapy'.)

Allergic rhinoconjunctivitis — A number of randomized trials have demonstrated that allergen immunotherapy with the following specified allergens is efficacious in treating allergic rhinoconjunctivitis: birch, mountain cedar, grass, ragweed, and Parietaria pollens; cat, dog, Alternaria and Cladosporium molds; cockroach; and dust mites [5,31-33,36-46].

A 2007 meta-analysis evaluated 51 randomized trials published between 1950 and 2006 that assessed the efficacy of immunotherapy with pollen vaccines in the treatment of 2871 adults and children with seasonal allergic rhinitis [22]. The duration of immunotherapy ranged from three days to three years, with an average number of 18 injections per subject. Patients receiving immunotherapy experienced a significant reduction (expressed as standard mean difference, or SMD) in both symptom scores SMD -0.73 (95% CI -0.97 to -0.50) and medication use -0.57 (95% CI -0.82 to -0.33).

Most studies of the effect of immunotherapy on allergic conjunctivitis were performed in patients with concomitant rhinitis. However, one review examined the effects of SCIT on ocular allergy by analyzing 15 studies of varying rigor that documented ocular symptoms [47]. Twelve showed benefit in terms of reduced ocular symptoms scores, medication use, or decreased reactivity upon conjunctival provocation challenges.

The magnitude of effect of SCIT on allergic rhinitis was assessed in a study of patients with allergic rhinoconjunctivitis, some of whom also had allergic asthma [48]. In this study, SCIT was approximately equivalent in efficacy to glucocorticoid nasal sprays. It is probable that the two therapies together are additive and that the combination of a glucocorticoid nasal spray and SCIT represents the most effective medical management of allergic rhinitis available, although SCIT has not been compared with other therapies in head-to-head trials.

Local allergic rhinitis — Local allergic rhinitis is a term applied to a subset of patients with classic rhinitis symptoms who test negative for allergen-specific IgE on skin testing and in vitro immunoassays but who react to nasal challenge with allergen, especially dust mite, with symptoms and signs similar to those in patients with typical allergic rhinitis and significantly different from controls without rhinitis [49,50]. There is evidence that such patients produce allergen-specific IgE locally in the nasal tissues. A systematic review and meta-analysis that included four randomized trials (156 patients) evaluated the effects of AIT (administered with an aluminum-containing adjuvant) on various clinical parameters (symptom scores, medication scores, combined scores, and quality of life) and immunologic changes associated with successful AIT [51]. Although limited by the small number of patients, heterogeneity of study design and scoring methods, and high dropout rate, the analysis provides both clinical and immunologic data supporting benefit, although further studies are needed. A standardized method of intranasal challenge would also be necessary to identify patients with local allergic rhinitis before AIT could be routinely recommended.

Allergic asthma

Careful selection of patients — Proper selection of patients is crucial for clinical success [52,53]. Asthma triggers vary significantly among individuals, and allergen exposure may be just one of several triggers that are important for a given patient. Thus, patients for whom allergen exposure is clearly an important trigger are more likely to experience meaningful benefit. In contrast, SCIT might not produce clinically meaningful improvement in a patient whose asthma is largely triggered by viral illnesses or irritant exposure (eg, tobacco smoke), even if they are sensitized to several allergens.

Another important factor may be the duration of allergic disease. New-onset allergic asthma may be more responsive to SCIT than longstanding disease [52]. For example, a school-aged child with new asthma symptoms in response to a pet may benefit more from immunotherapy than a middle-aged patient with lifelong asthma who had increased wheezing after bringing a new animal into the home.

Efficacy studies — Double-blind, placebo-controlled studies of specific allergens (short ragweed, mixed grass, D. pteronyssinus, Cladosporium, cat, or dog) have shown significant benefit in carefully selected patients with allergic asthma [31,37,54,55].

Several meta-analyses support the efficacy of SCIT in allergic asthma [45,56]. One reviewed 88 trials, including 42 trials of immunotherapy for dust mite allergy, 27 for pollen allergy, 10 for animal dander allergy, 2 for Cladosporium mold allergy, and 6 using multiple allergens [56]. Overall, there was a significant improvement in asthma symptom scores (SMD -0.59, 95% CI -0.83 to -0.35), and it would have been necessary to treat three patients (95% CI 3- 5) with immunotherapy to avoid one deterioration in asthma symptoms. The combined SMD for medication requirements was ‐0.53 (95% CI ‐0.80 to ‐0.27), showing a significant reduction in medication use following AIT. AIT also significantly reduced allergen-specific bronchial hyper-reactivity, with some reduction in nonspecific bronchial hyperreactivity.

Based upon the collective body of evidence, SCIT was added to the National Asthma Education and Prevention Program (NAEPP) guidelines for asthma management in 2007 and is recommended as an adjunct to standard pharmacotherapy [57]. Practice parameters subsequently delineated optimal target dosing for clinical practice [8]. However, given the heterogeneity of asthma, it remains difficult to predict the degree of improvement in clinical asthma symptoms that will be achieved with SCIT in a given individual patient. (See "Ongoing monitoring and titration of asthma therapies in adolescents and adults".)

OUTCOME MEASURES IN CLINICAL TRIALS — There have been efforts to standardize the outcome measures in trials of immunotherapy for respiratory allergy, to use validated tools that can be compared across studies, and to reach consensus about what degree of therapeutic benefit should be considered clinically meaningful [58-60].

In 2012, the World Allergy Organization (WAO) proposed that a 20 percent mean reduction in total combined score (TCS, a measure of symptoms and medication use) compared with placebo be considered the minimum change that corresponds to a clinically meaningful benefit [61].

For an allergen immunotherapy therapeutic agent to get approved by the US Food and Drug Administration (FDA), two statistical efficacy criteria must be met:

(1) The TCS must demonstrate an average relative difference of 15 percent compared with placebo (ie, the point estimate).

(2) The upper limit of the 95% confidence interval (CI) around the point estimate (ie, the smallest estimated treatment effect) must be at least 10 percent different from the placebo group, to demonstrate a clear separation between active treatment and placebo.

These statistical tests were selected after rigorous internal evaluation by the agency and have been mandated to more clearly identify and define a statistically significant, clinically meaningful, and predictable therapeutic effect when comparing allergen immunotherapy with placebo.

TEMPORAL COURSE OF IMPROVEMENT

Time to onset of benefit — The beneficial effects of SCIT for allergic respiratory disease begin during the first year of therapy and continue throughout the period in which the patient receives injections [31,32,36,62].

Duration of therapy — There is consensus that an initial course of immunotherapy should consist of three to five years of maintenance treatment. After this, the clinician and patient should meet to review overall impact on quality of life and, based upon these factors, decide if treatment will be continued.

A minimum of three years has been identified in several studies as an effective initial treatment period and one that provides some lasting benefit after the injections are discontinued:

A prospective controlled trial of 40 asthmatic patients who were treated with standardized dust mite SCIT for one to eight years found that in the three years after stopping therapy, the relapse rate was 48 percent in patients who had completed three or more years of treatment, compared with 62 percent in those who had completed less than three years [63].

Another study of patients with allergic rhinitis and asthma attributable to dust mite allergy found that three years on an effective dose and with good adherence of SCIT achieved significant clinical benefit, and only a small additional improvement in rhinitis symptoms was gained from extending therapy to five years [64].

In a multiyear double-blind trial, 32 grass-allergic patients who had experienced relief from three to four years of grass pollen SCIT were randomized to continued immunotherapy or placebo injections and compared with patients who never received SCIT. There was no difference between the two immunotherapy groups for at least the next two years, and symptoms scores were markedly lower than in the control group (figure 1) [36]. In addition, immunologic markers provided strong supportive evidence of the treatment's effect, with an inhibition of late-phase skin test reactivity, and reduction in CD3+ T cell infiltration into the tissue and IL-4 messenger RNA expression. This work led to the currently accepted recommendation that SCIT be administered for a minimum of 3 years.

Persistence of benefit after discontinuation — We counsel patients that several more years of continued relief is typical after SCIT is discontinued, although there is a risk of earlier relapse that is not predictable. In the case of relapse, it is possible to start immunotherapy again. Reliable biomarkers for determining which patients will experience lasting benefit from SCIT have not been identified. Neither skin tests nor serum immunoglobulin G (IgG) antibodies, local antibody production, or in vitro T cell responses have been demonstrated to predict outcomes after the cessation of treatment [65,66].

A small number of studies have evaluated the persistence of benefit after discontinuation of SCIT with variable results [24,36,63,67]. Long-term, blinded, placebo-controlled trials of SCIT are difficult to perform because of the prolonged time periods and significant patient effort involved. Until more data are available, it is not possible to give patients a precise estimate of how long the beneficial effects of SCIT will last after discontinuation of therapy. Patient age, extent and type of allergic disease, and other factors may be important, but these have not been specifically studied [24,36,63].

In the grass-pollen SCIT study mentioned previously, there was no relapse of symptoms during the designated two-year period of follow-up [36].

A study of 20 patients with ragweed-allergic rhinitis treated with SCIT for three years or more were randomized to continue treatment for one more year or switch to placebo [24]. During the first ragweed season after randomization, neither group showed a significant relapse in symptom scores from previous seasons. The treated patients continued to show suppression of responses to nasal challenge with ragweed extract, while the placebo patients showed a partial return of nasal responses to challenge, although not to pretreatment levels.

In contrast, the previously described study of 40 patients with allergic asthma concluded that rates of relapse were significant [63]. During the initial three years after stopping immunotherapy, 55 percent of the group relapsed. Relapse was defined as recurrence of asthma symptoms persisting a week or longer, a forced expiratory volume in one second (FEV1) of 80 percent or less of the patient's value at the end of SCIT, and/or the need for regular inhaled bronchodilators or anti-inflammatory medications. This study did not attempt to measure the severity of symptoms, so there may have been benefits that were not assessed. The findings may also reflect the more complex pathophysiology of asthma compared with allergic rhinitis. (See 'Duration of therapy' above.)

PREVENTIVE EFFECTS — There is evidence that AIT can delay or prevent sensitization to additional allergens and help prevent the development of asthma, based primarily on studies in children [56]. Based on these data, the National Asthma Education and Prevention Program (NAEPP) guidelines for asthma management recommended SCIT as an adjunct to standard pharmacotherapy beginning in 2007 [57].

Delay or prevention of sensitization to other allergens — Several studies have shown that specific AIT can prevent or delay the development of new allergen sensitivities in children sensitized to dust mites [68,69].

Prevention of asthma — Approximately 20 percent of children with allergic rhinoconjunctivitis develop asthma at some point later in life [70]. Studies in the 1950s and 1960s found that children treated with three years of allergen immunotherapy were less likely to develop asthma than those treated with placebo injections [17,18]. In 14 years of longitudinal follow-up of the same cohort, 72 percent of immunized children were asthma-free, compared with 22 percent of placebo-treated patients [19].

In the 2002 PAT study, 205 children (ages 6 to 14) with moderate-to-severe birch and/or grass rhinoconjunctivitis were randomized to three years of SCIT or to an open control group [71]. Before the start of SCIT, 20 percent of children were identified as having mild asthma symptoms that did not require asthma medications during the pollen seasons. Rhinitis symptom scores improved in the SCIT-treated versus the control group, indicating an effective immunizing dose. After three years, SCIT-treated children showed a 2- to 3-fold reduction in the development of asthma as compared with controls and had improved methacholine challenge tests compared with controls. At 5- and 10-years of follow-up, there was a sustained preventative effect of similar magnitude on development of asthma [72,73]. At 10 years (7 years after SCIT), the odds ratio for no asthma was 4.6 (95% CI 1.5-13.7) in favor of the SCIT-treated children. There were also continued positive effects on methacholine challenge and improvement in rhinitis/conjunctivitis scores.

A 2017 meta-analysis evaluating the preventative effects of allergen immunotherapy (both subcutaneous and sublingual) included 32 studies of sufficient quality and found evidence of a reduction in the short-term (<2 years) risk of developing asthma among patients with allergic rhinitis (relative risk 0.40, 95% CI 0.30-0.54) [74]. The analysis also examined the longer-term risk of asthma development, as well as the ability of immunotherapy to prevent the occurrence of a first allergic disease in sensitized but asymptomatic individuals or to prevent sensitization to new allergens. For these outcome measures, there were consistent trends toward benefit, although the findings were not conclusive (confidence intervals included no effect).

SPECIAL PATIENT GROUPS — The safety of SCIT in certain patient groups warrants special consideration, including individuals with more severe asthma, those requiring beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, patients with autoimmune disease or immunodeficiency, and pregnant women.

Severe or unstable asthma — The administration of SCIT may impart unacceptable risk for patients with severe or unstable asthma, because these individuals are at greater risk for systemic allergic reactions involving severe bronchospasm [75-77]. This includes patients who require chronic oral glucocorticoid therapy or have had severe exacerbations requiring hospitalization or intubation in the previous six months. The World Health Organization (WHO) task force on immunotherapy recommended that SCIT not be administered to patients with asthma who have a forced expiratory volume in one second (FEV1) <75 percent and that all patients with asthma on SCIT be carefully monitored. These high-risk patients can sometimes be managed with anti-IgE therapy first, and once stabilized, they may then be able to undergo SCIT while continuing to receive anti-IgE [78,79]. (See "Anti-IgE therapy".)

Pregnancy — SCIT is not usually initiated during pregnancy, although it may be continued in women who were receiving the therapy prior to becoming pregnant. Dose adjustments during pregnancy are discussed separately. (See "Recognition and management of allergic disease during pregnancy", section on 'Allergen immunotherapy'.)

Beta-blocker and ACE-inhibitor therapy — Patients on chronic beta-blocker treatment for cardiovascular disease are at some risk for a poor outcome if they have an anaphylactic reaction to an immunotherapy injection, since they may not respond properly to epinephrine or other vasopressor agents used to treat the reaction. Patients receiving angiotensin-converting enzyme (ACE) inhibitors are theoretically at increased risk during anaphylaxis, possibly due to the inhibition of conversion of angiotensin I to angiotensin II, resulting in poorer response to hemodynamic stress during hypotension or to accumulated bradykinin, a potent vasodilator. The data behind these conclusions are presented elsewhere. (See "Anaphylaxis induced by subcutaneous allergen immunotherapy", section on 'Beta-adrenergic blockers' and "Anaphylaxis induced by subcutaneous allergen immunotherapy", section on 'ACE inhibitors'.)

As with any therapeutic decision, the risk must be weighed against the benefit [8]. Most clinicians avoid administering SCIT to patients on significant doses of beta-blockers. In some cases, hypertension or other cardiovascular disorders can be treated with medications that do not carry these risks. A European guideline considers beta-blocker use to be relatively contraindicated in aeroallergen SCIT, although not with venom immunotherapy in patients with clear indications for both interventions, since venom immunotherapy is considered potentially lifesaving [77]. Unlike immunotherapy for venom allergy, immunotherapy for allergic rhinitis or asthma is generally considered elective. The use of beta-blockers and ACE inhibitors in patients receiving venom immunotherapy is discussed in more detail elsewhere. (See "Hymenoptera venom immunotherapy: Efficacy, indications, and mechanism of action", section on 'Patients requiring ACE inhibitors or beta blockers'.)

Autoimmune disease — Questions about the safety of administering SCIT to patients with autoimmune disease have been raised, based upon theoretical concern about modulating the immune response in patients who may have aberrant immune regulation. Unfortunately, there are no substantive data examining the issue [62]. One European guideline considers autoimmune disease that is active (ie, not responding to therapy) to be an absolute contraindication, while stable, controlled autoimmune disease is a relative contraindication [77]. We suggest the decision to administer SCIT to a patient with concomitant allergic and autoimmune disease be made cooperatively with the patient after careful consideration of the potential risks and benefits for that individual.

HIV infection — It is our clinical experience that patients with established human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) and significant allergic disease can benefit from SCIT, particularly as improvements in the control of HIV transform this disease into a chronic condition. However, the safety of SCIT in patients newly infected with HIV has not been studied to determine if immunotherapy could adversely impact progression of the infection.

OTHER CONSIDERATIONS

Age of patient — SCIT is appropriate for both adults and children, and there are no defined age limits for its administration.

In practice, young children do not understand and may be traumatized by repeated injections, and there are concerns about the ability of children to report early symptoms of a systemic allergic reaction. In addition, sublingual immunotherapy offers an easier route of administration. For these reasons, most guidelines consider age under five years to be a relative contraindication SCIT [77,80-82]. However, by school age, most children are mature enough to cooperate with immunotherapy and can understand the benefits. Data about safety and efficacy in young children are limited [83], although in the small number of studies of immunotherapy in young children (usually given for Hymenoptera venom allergy), therapy was usually well-tolerated and beneficial [84]. There is also evidence that immunotherapy administered to children with allergic rhinitis can prevent the progression to allergic asthma. Thus, for older children with allergic rhinitis that requires chronic pharmacotherapy, SCIT becomes a more attractive treatment option, especially for those with a strong family history of asthma. (See 'Preventive effects' above.)

There is no strict upper limit to the age at which immunotherapy can be beneficial. Several placebo-controlled studies that demonstrated efficacy have included subjects up to 60 years of age. A specific study in patients aged 54 and older found efficacy in rhinitis and asthma due to ragweed and birch pollens [85]. However, the presence of comorbid cardiac or pulmonary conditions might increase the risk of a poor outcome following a systemic reaction. In addition, duration of disease is also important, especially in the treatment of allergic asthma. (See 'Careful selection of patients' above.)

Cost-effectiveness — In both European and American studies, SCIT was found to be cost-effective, particularly in patients who otherwise required both nasal and pulmonary inhaled medications [10,12,86-93]. The cost of SCIT is obviously dependent upon the care delivery structure in which it is administered. However, statistically significant health care cost benefits were demonstrated in both adults and children with allergic rhinitis within three months of initiating SCIT in one American study [92].

Adherence — Traditional SCIT requires multiple, regularly scheduled visits to a health care provider. In the United States, it is common practice to administer one or two sets of injections each week, beginning with low doses and gradually increasing to the effective therapeutic range for each allergen. Effective doses are typically reached within three to six months, after which visits are needed every two to four weeks for the remainder of treatment period.

Clinicians or staff should discuss the time commitment required with patients/caregivers in detail when planning to begin SCIT, since adherence to the treatment schedule is necessary to obtain maximal benefit. It is also helpful to schedule regular follow-up visits, especially during the first year of immunotherapy, to review the patients' progress and address adherence issues that may arise. Patients who frequently miss injections will have trouble advancing to the higher doses that confer most of the clinical effect. On the other hand, perfect compliance may not be essential for a good clinical outcome, as demonstrated in a study of over 3000 low-income children with asthma who were treated with immunotherapy [89]. Despite the fact that only 16 percent completed the recommended three years of treatment, resource use and cost of care for this group were significantly decreased compared with pretreatment levels.

Accelerated (ie, cluster and rush) schedules of SCIT have been developed, which allow patients to reach effective therapeutic doses within a few weeks or days. Rates of adverse allergic reactions are generally higher with the most accelerated protocols, although many patients tolerate cluster schedules well and prefer the greater convenience. (See "Subcutaneous aeroallergen immunotherapy: Accelerated schedules (cluster and rush)".)

Monitoring — Practice parameters suggest that patients receiving SCIT should be evaluated clinically each year to determine if any adjustments in dose or allergen mix are indicated. SCIT should be continued for at least three years in those who experience subjective benefit. There is no objective testing that is routinely performed to assess a patient's progress. Neither repeat skin testing nor laboratory tests provide useful information about how well SCIT is working for a specific patient. (See "Allergen immunotherapy for allergic disease: Therapeutic mechanisms", section on 'Changes in skin test reactivity'.)

FUTURE DIRECTIONS — Novel forms of SCIT are directed at developing therapeutic constructs that improve safety, foster compliance, and induce a state of immune tolerance to the allergen(s) to which a patient is allergic [94-97].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Allergen immunotherapy for the treatment of respiratory allergy".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Allergy shots (The Basics)")

SUMMARY AND RECOMMENDATIONS

Definition and overview – Subcutaneous immunotherapy (SCIT) for allergic disease involves the gradual administration of increasing amounts of allergen to induce protective immunologic responses. Immunotherapy is the only means of altering the abnormal immune response that underlies allergic disease in a semipermanent manner. SCIT is the most established form of this treatment. As most commonly practiced, SCIT involves one or more injections per visit, administered at regularly scheduled intervals over a period of three to five years. (See 'Introduction' above.)

Indications – SCIT is effective in the treatment of allergic rhinitis, allergic conjunctivitis, and allergic asthma, in both children and adults. Patients should fulfill the criteria shown in the table (table 1). (See 'Indications' above.)

Allergic rhinitis and/or allergic conjunctivitis – In adults and children with moderate-to-severe allergic rhinitis and/or allergic conjunctivitis, we suggest SCIT for those who fulfill the criteria shown in the table (table 1) (Grade 2A). The magnitude of the effect of SCIT for allergic rhinitis is believed to be approximately equivalent to that of glucocorticoid nasal sprays, and the two together may be additive. (See 'Allergic rhinoconjunctivitis' above.)

Allergic asthma – In adults and children with mild-to-moderate allergic asthma, with or without rhinitis, we suggest SCIT for those who fulfill the criteria shown in the table (table 1) (Grade 2B). Patients with clear allergen-induced exacerbations or new-onset disease are most likely to experience clinically meaningful improvement. (See 'Allergic asthma' above.)

Contraindications

Severe or very labile asthma is a relative contraindication to SCIT, as patients with unstable asthma are at risk for severe bronchospasm during systemic reactions, and the risk is felt to outweigh the benefit in many cases. (See 'Severe or unstable asthma' above.)

SCIT is not usually initiated during pregnancy, although it may be continued, without increasing the doses given, in women who were tolerating and benefiting from the therapy prior to becoming pregnant. (See 'Special patient groups' above.)

Referral – Referral to a specialist in allergy and immunology should be sought for patients for whom immunotherapy may be appropriate. (See 'Referral' above.)

Efficacy – The allergens that are known to be effective in SCIT include several tree, grass, and weed pollens; cat and dog danders; dust mites; certain molds; and cockroach. Beneficial effects are usually seen within the first year of treatment. (See 'Efficacy' above.)

Duration of treatment – A course of immunotherapy usually consists of three to five years of treatment. After this, the clinician and patient should review the overall impact of treatment on quality of life and based upon these factors, decide if treatment will be continued. (See 'Duration of therapy' above.)

Preventative effects – SCIT can help prevent the progression of allergic disease and may be particularly valuable in helping patients with allergic rhinitis/conjunctivitis avoid the development of allergic asthma. (See 'Preventive effects' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Philip S Norman, MD, who contributed to an earlier version of this topic review.

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References

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