Subcutaneous and Sublingual Immunotherapy To Treat Allergic RhinitisRhinoconjunctivitis

Subcutaneous and Sublingual Immunotherapy To Treat Allergic Rhinitis/Rhinoconjunctivitis and Asthma Prepared for: Agency for Healthcare Research and Quality (AHRQ) www. ahrq. gov

Outline of Material Agency for Healthcare Research and Quality Comparative Effectiveness Review (CER) Process Background Clinical Questions Addressed in the CER Summary of CER Results Conclusions Gaps in Knowledge Resources for Shared Decisionmaking

Agency for Healthcare Research and Quality (AHRQ) Comparative Effectiveness Review (CER) Development Topics are nominated through a public process, which includes submissions from health care professionals, professional organizations, the private sector, policymakers, the public, and others. A systematic review of all relevant clinical studies is conducted by independent researchers, funded by AHRQ, to synthesize the evidence in a report summarizing what is known and not known about the select clinical issue. The research questions and the results of the report are subject to expert input, peer review, and public comment. The results of these reviews are summarized into a Clinician Research Summary and a Consumer Research Summary for use in decisionmaking and in discussions with patients. The Research Summaries and the full report are available at www. effectivehealthcare. ahrq. gov/allergy-asthma-immunotherapy. cfm. Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No. 111. Available at http: //www. effectivehealthcare. ahrq. gov/allergy-asthma-immunotherapy. cfm.

Rating the Strength of Evidence From the Comparative Effectiveness Review The strength of evidence ratings are classified into four broad ratings: High confidence that the evidence reflects the true effect. Further research is very unlikely to change our confidence in the estimate of effect. Moderate confidence that the evidence reflects the true effect. Further research may change our confidence in the estimate of effect and may change the estimate. Low confidence that the evidence reflects the true effect. Further research is likely to change the confidence in the estimate of effect and is likely to change the estimate. Insufficient Evidence either is unavailable or does not permit a conclusion. AHRQ Methods Guide for Effectiveness and Comparative Effectiveness Reviews. Available at http: //www. effectivehealthcare. ahrq. gov/methodsguide. cfm. Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No. 111. Available at http: //www. effectivehealthcare. ahrq. gov/allergy-asthma-immunotherapy. cfm. Owens DK, Lohr KN, Atkins D, et al. J Clin Epidemiol. 2010 May; 63(5): 513 -23. PMID: 19595577.

Background: Allergic Rhinitis/Rhinoconjunctivitis and Asthma Allergic rhinitis is a common clinical problem affecting about 20 percent of the general population in North America. Allergens such as tree, grass, and weed pollens characteristically cause seasonal rhinoconjunctivitis and/or asthma. Allergens such as cat dander, cockroach, or dust mite may induce symptoms year-round are associated with perennial rhinitis and/or asthma. The prevalence of asthma in the general U. S. population is approximately 9 percent, and approximately 62 percent of individuals with asthma have evidence of atopy (i. e. , the genetic predisposition to produce elevated immunoglobulin E [Ig. E] in response to environmental allergens). Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No. 111. Available at http: //www. effectivehealthcare. ahrq. gov/allergy-asthma-immunotherapy. cfm. Min YG. Allergy Asthma Immunol Res. 2010 Apr; 2(2): 65 -76. PMID: 20358020.

Background: Management of Allergy Symptoms The medical management of patients with allergic rhinitis and allergic asthma includes: Allergen avoidance Pharmacotherapy Immunotherapy Daily use of pharmacotherapies for allergic asthma and rhinitis symptoms raises issues related to adherence, safety, and cost. Long-term use of inhaled steroids, long-acting bronchodilators, and leukotriene antagonists for asthma control can have adverse effects. Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No. 111. Available at http: //www. effectivehealthcare. ahrq. gov/allergy-asthma-immunotherapy. cfm

Background: Subcutaneous Immunotherapy for Allergies Allergen-specific immunotherapy is typically used for: Patients whose allergic rhinoconjunctivitis and asthma symptoms cannot be controlled by medication and environmental control Patients who cannot tolerate their medications Patients who do not comply with chronic medication regimens The U. S. Food and Drug Administration has approved the use of allergen extracts for subcutaneous immunotherapy in treating seasonal and perennial allergic rhinitis and allergic asthma. In the United States, a patient with allergies undergoing immunotherapy receives subcutaneous injections—in increasing doses until a maintenance dose is found—of an allergen-containing extract comprised of the relevant allergens to which he or she is sensitive in an attempt to suppress or eliminate allergy-related symptoms. Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No. 111. Available at http: //www. effectivehealthcare. ahrq. gov/allergy-asthma-immunotherapy. cfm.

Background: Sublingual Immunotherapy for Allergies There is considerable interest in using similar allergen extracts as sublingual immunotherapy (SLIT) as an alternative to subcutaneous immunotherapy. SLIT involves placing drops or tablets with the allergen extract under the tongue for local absorption to desensitize the allergic individual over a period of months to years and to diminish allergic symptoms. In the United States, there currently are no sublingual forms of immunotherapy approved by the U. S. Food and Drug Administration. However, some U. S. physicians are using subcutaneous aqueous extracts off-label for sublingual desensitization in the treatment of allergic respiratory conditions. Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No. 111. Available at http: //www. effectivehealthcare. ahrq. gov/allergy-asthma-immunotherapy. cfm.

Systematic Review: Objective and Key Questions Objective To evaluate the efficacy, effectiveness, and safety of subcutaneous (SCIT) and sublingual (SLIT) immunotherapies that are presently available for use by clinicians and patients in the United States Key Questions For patients with allergic rhinoconjunctivitis and/or asthma: Efficacy and effectiveness of SCIT, SLIT, and SCIT versus SLIT Safety and effectiveness of SCIT, SLIT, and SCIT versus SLIT in the pediatric subpopulation Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No. 111. Available at http: //www. effectivehealthcare. ahrq. gov/allergy-asthma-immunotherapy. cfm

Outcomes of Interest Primary Outcomes Clinical endpoints: Symptom control Medication use Quality of life Disease evolution/remission New allergen sensitivities Overall health care utilization Missed days of school/work Secondary Outcomes Functional tests (pulmonary function test‒forced expiratory volume) Provocational test Adherence Convenience and compliance Biomarkers Adverse Effects Local reactions Skin, mouth, and throat (including irritation, itching, swelling, or pain in the oral cavity) General symptoms (such as headache, fatigue, arthritis) Systemic reactions Ocular Rhinitis/nasal Cutaneous Rash Gastrointestinal Respiratory/asthma Cardiovascular Anaphylaxis Death Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No. 111. Available at http: //www. effectivehealthcare. ahrq. gov/allergy-asthma-immunotherapy. cfm.

Overview of Studies Included in the Systematic Review 142 studies were included in the review with these populations: adults only (52%), children only (24%), and adults and children (22%). Studies on SLIT mainly included patients with allergic rhinitis and/or mild asthma. All included studies were randomized controlled trials. Efficacy and safety of SCIT: n = 74 Efficacy and safety of SLIT*: n = 60 Comparisons of SCIT versus SLIT: n = 8 The types of scales/scoring systems used in the studies were not uniform. Followup varied and ranged from one pollen season to 6 years. Standard therapy varied across trials. Due to heterogeneity in reported outcomes, results often only reflect the percentage of trials in which a significant effect was seen for the immunotherapy arm versus controls and not the magnitude of effect. *SLIT refers to allergen extracts that are administered sublingually in the form of drops. Studies on sublingual tablets are not included here. Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No. 111. Available at http: //www. effectivehealthcare. ahrq. gov/allergy-asthma-immunotherapy. cfm.

Included Studies by Type of Allergen for SCIT, SLIT, and SCIT Versus SLIT Allergen SCIT SLIT SCIT vs. SLIT Dust mite 21 14 6 Grass 11 15 ‒ Weeds 9 7 ‒ Cat 5 2 ‒ Dog 1 ‒ ‒ Mold 6 2 ‒ Tree 6 13 2 15 7 ‒ Multiple allergens SCIT = subcutaneous immunotherapy; SLIT = sublingual immunotherapy Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No. 111. Available at http: //www. effectivehealthcare. ahrq. gov/allergy-asthma-immunotherapy. cfm.

Included Studies for Subcutaneous Immunotherapy Versus Placebo or Standard Therapy 74 articles were included with a total of 4, 350 patients. The primary diagnoses were: Asthma in 19 studies Asthma with rhinitis in 18 studies Rhinoconjunctivitis in 14 studies Asthma with rhinoconjunctivitis in 14 studies Types of allergens evaluated: Seasonal allergens such as trees, grasses, weeds, and seasonal molds in 59 percent of studies Perennial allergens in 38 percent of studies Seasonal and perennial allergens in 3 percent of studies The heterogeneity of the data on clinical outcomes precluded pooling of the data for further analysis. Consequently, the results often only reflect the percentage of trials in which a significant effect was seen for the immunotherapy arm versus controls and not the magnitude of effect. Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No. 111. Available at http: //www. effectivehealthcare. ahrq. gov/allergy-asthma-immunotherapy. cfm.

Subcutaneous Immunotherapy Versus Placebo or Standard Therapy: Asthma Outcomes Primary Outcome Results* Asthma symptom 17‒ 84% greater score improvement vs. controls No. of RCTs, No. of Patients (n) Strength of Evidence 16 RCTs, n = 1, 178 High Use of asthma medications Decreased in 42% of studies vs. controls 12 RCTs, n = 1, 062 High Combined asthma symptom and medication score Significant improvement in 83% of studies vs. placebo 6 RCTs, n = 196 Low RCT = randomized controlled trial Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No. 111. Available at http: //www. effectivehealthcare. ahrq. gov/allergy-asthma-immunotherapy. cfm.

SCIT Versus Placebo or Standard Therapy: Rhinitis/Rhinoconjunctivitis Outcomes (1 of 2) Primary Outcome Results Rhinitis/ rhinoconjunctivitis symptoms Significant improvement in 73% of studies vs. controls Use of rhinitis/ rhinoconjunctivitis medications Significantly decreased in 70% of studies vs. controls Combined rhinitis/ rhinoconjunctivitis symptom and medication score Significant improvement in 83% of studies vs. controls No. of RCTs, No. of Patients (n) Strength of Evidence 25 RCTs, n = 1, 734 High 10 RCTs, n = 564 Moderate 6 RCTs, n = 400 Low RCT = randomized controlled trial; SCIT = subcutaneous immunotherapy Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No. 111. Available at http: //www. effectivehealthcare. ahrq. gov/allergy-asthma-immunotherapy. cfm.

SCIT Versus Placebo or Standard Therapy: Rhinitis/Rhinoconjunctivitis Outcomes (2 of 2) Primary Outcome Results No. of RCTs, Strength No. of Patients (n) of Evidence Conjunctivitis symptoms Significant improvement in 43% of studies vs. placebo 14 RCTs, n = 1, 104 High Combined symptoms (nasal, ocular, and bronchial) Significant improvement in 67% of studies vs. placebo 6 RCTs, n = 591 High Disease-specific quality of life in patients with rhinitis/ rhinoconjunctivitis Significant improvement by RQLQ in 67% of studies vs. placebo 6 RCTs, n = 889 High RCT = randomized controlled trial; RQLQ = Rhinoconjunctivitis Quality of Life Questionnaire; SCIT = subcutaneous immunotherapy Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No. 111. Available at http: //www. effectivehealthcare. ahrq. gov/allergy-asthma-immunotherapy. cfm.

SCIT Versus Placebo or Standard Therapy: Asthma Plus Rhinitis/Rhinoconjunctivitis Outcomes Primary Outcome Results Asthma plus rhinitis/ rhinoconjunctivitis symptoms 21‒ 68% greater improvement vs. controls Use of asthma plus rhinoconjunctivitis medications • 14– 83% greater reduction in asthmabased studies vs. controls • Significantly decreased in 91% of rhinitis-based studies vs. controls No. of RCTs, No. of Patients (n) Strength of Evidence 5 RCTs, n = 175 Moderate 5 RCTs, n = 203 High 11 RCTs, n = 768 RCT = randomized controlled trial; SCIT = subcutaneous immunotherapy Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No. 111. Available at http: //www. effectivehealthcare. ahrq. gov/allergy-asthma-immunotherapy. cfm.

Included Studies for Sublingual Immunotherapy Versus Placebo or Standard Therapy 60 articles on sublingual immunotherapy (SLIT) that included 4, 870 patients were eligible for inclusion. Allergens evaluated included: Seasonal allergens (66%) Perennial allergens (31%) Both seasonal and perennial allergens (3%) Comparators included: Placebo (71%) Another sublingual intervention without a placebo group (15%) Conventional treatment without placebo (pharmacotherapy or rescue medications; 14%) Duration of treatment ranged from 3 months to 5 years. There was great heterogeneity in: Dosages of maintenance or cumulative treatments The units to report dosing Standard therapy used across trials Reported results often only reflect the percentage of trials in which a significant effect was seen for the immunotherapy arm versus controls and not the magnitude of effect. Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No. 111. Available at http: //www. effectivehealthcare. ahrq. gov/allergy-asthma-immunotherapy. cfm.

Sublingual Immunotherapy Versus Placebo or Standard Therapy: Asthma Outcomes Primary Outcome Results Asthma symptom Significant score improvement across all studies vs. controls No. of RCTs, No. of Patients (n) Strength of Evidence 13 RCTs, n = 625 High RCT = randomized controlled trial Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No. 111. Available at http: //www. effectivehealthcare. ahrq. gov/allergy-asthma-immunotherapy. cfm.

SLIT Versus Placebo or Standard Therapy: Rhinitis/Rhinoconjunctivitis Outcomes Primary Outcome Results No. of RCTs, No. of Patients (n) Strength of Evidence Rhinitis/ rhinoconjunctivitis symptoms Significant improvement in 56% of studies vs. controls 36 RCTs, n = 2, 658 Moderate Conjunctivitis symptoms Significant improvement in 46% of studies vs. placebo 13 RCTs, n = 1, 074 Moderate Disease-specific Significant improvement quality of life in patients by RQLQ in 75% of with rhinitis/ studies vs. controls rhinoconjunctivitis 8 RCTs, n = 819 Moderate RCT = randomized controlled trial; RQLQ = Rhinoconjunctivitis Quality of Life Questionnaire Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No. 111. Available at http: //www. effectivehealthcare. ahrq. gov/allergy-asthma-immunotherapy. cfm.

SLIT Versus Placebo or Standard Therapy: Asthma Plus Rhinitis/Rhinoconjunctivitis Outcomes Primary Outcome Results No. of RCTs, No. of Patients (n) Strength of Evidence Asthma plus rhinitis/ rhinoconjunctivitis symptoms Significantly improved in 80% of studies vs. controls 5 RCTs, n = 308 Moderate Use of asthma plus rhinoconjunctivitis medications Significant improvement in 47% of studies vs. controls 38 RCTs, n = 2, 724 Moderate Asthma plus rhinitis/ rhinoconjunctivitis symptom and medication score Significant improvement in 68% of studies vs. controls 19 RCTs, n = 1, 462 Moderate RCT = randomized controlled trial Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No. 111. Available at http: //www. effectivehealthcare. ahrq. gov/allergy-asthma-immunotherapy. cfm.

Subcutaneous Versus Sublingual Immunotherapy: All Outcomes No. of RCTs, No. of Patients (n) Strength of Evidence Improves asthma symptom SCIT may improve asthma score symptoms more effectively than SLIT 4 RCTs, n = 171 Low Improves rhinitis/ rhinoconjunctivitis symptoms SCIT is superior to SLIT for improving allergic nasal and/or eye symptoms 6 RCTs, n = 412 Moderate Decreases use of asthma plus rhinoconjunctivitis medications There are no consistent differences between SCIT and SLIT 5 RCTs, n = 219 Low 2 RCTs, n = 65 Low Primary Outcome Results Improves asthma plus SCIT is favored in 1 of 2 rhinitis/rhinoconjunctivitis studies symptom and medication score RCT = randomized controlled trial; SCIT = subcutaneous immunotherapy; SLIT = sublingual immunotherapy Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No. 111. Available at http: //www. effectivehealthcare. ahrq. gov/allergy-asthma-immunotherapy. cfm.

Included Studies for SCIT Versus Placebo or Standard Therapy in the Pediatric Population Thirteen studies on subcutaneous immunotherapy included 920 pediatric patients. The pediatric population ranged in age from 3 to 18 years. Primary diagnoses included: Asthma in 7 studies Asthma with rhinitis in 3 studies Asthma with rhinoconjunctivitis in 2 studies Rhinoconjunctivitis in 1 study All studies allowed either conventional pharmacotherapy or rescue allergy medications during the study. Standard therapy varied across studies. Due to heterogeneity in reported clinical outcomes, results often only reflect the percentage of trials in which a significant effect was seen for the immunotherapy arm versus controls and not the magnitude of effect. Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No. 111. Available at http: //www. effectivehealthcare. ahrq. gov/allergy-asthma-immunotherapy. cfm.

Pediatric Patients—SCIT Versus Placebo or Standard Therapy: Asthma Outcomes Primary Outcome Results Asthma symptom Significant score improvement in 50% of studies vs. controls Use of asthma medications Significant reduction in 50% of studies No. of RCTs, No. of Patients (n) Strength of Evidence 6 RCTs, n = 550 Moderate 4 RCTs, n = 470 Low RCT = randomized controlled trial; SCIT = subcutaneous immunotherapy Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No. 111. Available at http: //www. effectivehealthcare. ahrq. gov/allergy-asthma-immunotherapy. cfm.

Pediatric Patients—SCIT Versus Placebo or Standard Therapy: Rhinitis/Rhinoconjunctivitis Outcomes Results No. of RCTs, No. of Patients (n) Strength of Evidence Rhinitis/ rhinoconjunctivitis symptoms Significant improvement in 67% of studies vs. placebo 3 RCTs, n = 285 Moderate Conjunctivitis symptoms Significant improvement in 67% of studies vs. placebo 3 RCTs, n = 285 Low Disease-specific quality of life in patients with rhinitis/ rhinoconjunctivitis Significant improvement in both studies vs. controls 2 RCTs, n = 350 Low Primary Outcome RCT = randomized controlled trial ; SCIT = subcutaneous immunotherapy Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No. 111. Available at http: //www. effectivehealthcare. ahrq. gov/allergy-asthma-immunotherapy. cfm.

Pediatric Patients—SCIT Versus Placebo or Standard Therapy: Asthma Plus Rhinitis/Rhinoconjunctivitis Outcomes No. of RCTs, Strength No. of Patients (n) of Evidence Primary Outcome Results Use of asthma plus rhinoconjunctivitis medications Decreased in both studies vs. controls 2 RCTs, n = 80 Low Improves combined asthma or asthma plus rhinitis/ rhinoconjunctivitis symptom and medication score Significant improvement in both studies vs. placebo 2 RCTs, n = 85 Low RCT = randomized controlled trial; SCIT = subcutaneous immunotherapy Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No. 111. Available at http: //www. effectivehealthcare. ahrq. gov/allergy-asthma-immunotherapy. cfm.

Included Studies for SLIT Versus Placebo or Standard Therapy in the Pediatric Population 18 studies including 1, 583 pediatric patients (≤ 18 years of age) Primary diagnoses: Asthma (n = 3 studies) Rhinitis (n = 2 studies) Rhinoconjunctivitis (n = 4 studies) Asthma and rhinitis (n = 4 studies) Asthma with rhinoconjunctivitis (n = 5 studies) Perennial and/or seasonal allergies were included Comparator groups included: Placebo (n = 15 studies) Sublingual immunotherapy (SLIT) comparator group (n = 3 studies) Pharmacotherapy/symptomatic therapy (n = 2 studies) Due to heterogeneity in reported clinical outcomes, results often only reflect the percentage of trials in which a significant effect was seen for the immunotherapy arm versus controls and not the magnitude of effect. Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No. 111. Available at http: //www. effectivehealthcare. ahrq. gov/allergy-asthma-immunotherapy. cfm.

Pediatric Patients—SLIT Versus Placebo or Standard Therapy: Asthma Outcomes Primary Outcome Asthma symptom score Results Significant improvement in all studies vs. controls No. of RCTs, No. of Patients (n) Strength of Evidence 9 RCTs, n = 471 High RCT = randomized controlled trial; SLIT = sublingual immunotherapy Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No. 111. Available at http: //www. effectivehealthcare. ahrq. gov/allergy-asthma-immunotherapy. cfm.

Pediatric Patients—SLIT Versus Placebo or Standard Therapy: Rhinitis/Rhinoconjunctivitis Outcomes Primary Outcome Results No. of RCTs, No. of Patients (n) Strength of Evidence Rhinitis/ rhinoconjunctivitis symptoms Significant improvement in 42% of studies vs. controls 12 RCTs, n = 1, 065 Moderate Conjunctivitis symptoms Significant improvement in 40% of studies vs. placebo 5 RCTs, n = 513 Moderate RCT = randomized controlled trial; SLIT = sublingual immunotherapy Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No. 111. Available at http: //www. effectivehealthcare. ahrq. gov/allergy-asthma-immunotherapy. cfm.

Pediatric Patients—SLIT Versus Placebo or Standard Therapy: Asthma Plus Rhinitis/Rhinoconjunctivitis Outcomes Primary Outcome Results No. of RCTs, No. of Patients (n) Strength of Evidence Asthma plus rhinitis/ rhinoconjunctivitis symptoms Significant improvement with high- and low-dose SLIT vs. placebo 1 RCT, n = 98 Moderate Use of asthma plus rhinoconjunctivitis medications Significantly reduced in 42% of studies vs. controls 13 RCTs, n = 1, 078 Moderate Asthma plus rhinitis/ rhinoconjunctivitis symptom and medication score Significant improvement in 50% of studies vs. controls 2 RCTs, n = 329 Low RCT = randomized controlled trial; SLIT = sublingual immunotherapy Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No. 111. Available at http: //www. effectivehealthcare. ahrq. gov/allergy-asthma-immunotherapy. cfm.

Pediatric Patients—SCIT Versus SLIT: All Outcomes Primary Outcome Results No. of RCTs, No. of Patients (n) Strength of Evidence Improves asthma symptom score SCIT is favored in 67% of studies vs. SLIT 3 RCTs, n = 135 Low Improves asthma plus rhinitis/ rhinoconjunctivitis symptoms SCIT may be favored over SLIT for reducing nasal and/or eye symptoms 3 RCTs, n = 135 Low Decreases use of asthma SLIT may decrease plus rhinoconjunctivitis medication use more medications than SCIT, but results are inconsistent RCT = randomized controlled trial; SCIT = subcutaneous immunotherapy; SLIT = sublingual immunotherapy Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No. 111. Available at http: //www. effectivehealthcare. ahrq. gov/allergy-asthma-immunotherapy. cfm.

Adverse Effects: Subcutaneous Immunotherapy in Adults Local reactions (such as redness, swelling, pruritus, or induration at the injection site) were usually mild and occurred in 5 to 58 percent of patients and 0. 6 to 54 percent of injections and were more common than systemic reactions. The most common systemic reactions were respiratory reactions, occurring in up to 46 percent of patients and in up to 3 percent of injections. General symptoms (such as headache, fatigue, and arthritis) occurred in up to 44 percent of patients and were usually mild or unspecified. Gastrointestinal reactions were reported in only one study. Thirteen anaphylactic reactions were reported in four trials. No deaths were reported in the included studies. Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No. 111. Available at http: //www. effectivehealthcare. ahrq. gov/allergy-asthma-immunotherapy. cfm.

Adverse Effects: Sublingual Immunotherapy in Adults Local reactions (such as irritation, itching, swelling, or pain in the oral cavity) were common and usually mild and occurred in 0. 2 to 97 percent of patients receiving sublingual immunotherapy (SLIT). Systemic reactions occurred more frequently in the SLIT arm versus controls and included ocular, rhinitis/nasal, respiratory/asthma, cutaneous, gastrointestinal, and cardiovascular adverse effects. No life-threatening reactions, anaphylaxis, or deaths were reported in the included trials. SLIT studies mainly include patients with allergic rhinitis and/or mild asthma. Safety outcomes should not be extrapolated to more severely affected patients. Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No. 111. Available at http: //www. effectivehealthcare. ahrq. gov/allergy-asthma-immunotherapy. cfm.

Adverse Effects: Subcutaneous Versus Sublingual Immunotherapy in Adults The recording and reporting of the adverse events was neither uniform nor comparable across studies. Local reactions were common and were all of mild or moderate severity. There was one report of anaphylaxis with subcutaneous immunotherapy. There were no reported deaths in the included studies. Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No. 111. Available at http: //www. effectivehealthcare. ahrq. gov/allergy-asthma-immunotherapy. cfm.

Adverse Effects: Subcutaneous Immunotherapy in Pediatric Patients Local reactions were the most common adverse reactions in the pediatric population receiving subcutaneous immunotherapy. There were no reports of anaphylaxis or deaths. Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No. 111. Available at http: //www. effectivehealthcare. ahrq. gov/allergy-asthma-immunotherapy. cfm.

Adverse Effects: Sublingual Immunotherapy in Pediatric Patients Local reactions (such as irritation, itching, swelling, or pain in the oral cavity) were common but mild. No life-threatening reactions, anaphylaxis, or deaths were reported in these trials. The strength of evidence for all other adverse effects is insufficient. Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No. 111. Available at http: //www. effectivehealthcare. ahrq. gov/allergy-asthma-immunotherapy. cfm.

Adverse Effects: Subcutaneous Versus Sublingual Immunotherapy in Pediatric Patients Local reactions were reported in both patient groups. No systemic reactions were reported in patients receiving sublingual immunotherapy. In the pediatric population taking subcutaneous immunotherapy, one anaphylaxis event and three respiratory systemic reactions were reported. Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No. 111. Available at http: //www. effectivehealthcare. ahrq. gov/allergy-asthma-immunotherapy. cfm.

Overview of Conclusions (1 of 2) There is sufficient evidence to support the overall effectiveness and safety of both subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) for treating allergic rhinoconjunctivitis and asthma. However, there is not enough evidence to determine if either SCIT or SLIT is superior. SCIT and SLIT are usually safe, although local reactions are commonly reported regardless of the mode of delivery. Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No. 111. Available at http: //www. effectivehealthcare. ahrq. gov/allergy-asthma-immunotherapy. cfm.

Overview of Conclusions (2 of 2) Serious, life-threatening reactions are rare, although they can occur. Studies of sublingual immunotherapy (SLIT) mainly include patients with allergic rhinitis and/or mild asthma. Safety outcomes should not be extrapolated to more severely affected patients. Most of the studies in the review used a single allergen for immunotherapy, and it may be difficult to extrapolate these results to the use of multiple-allergen regimens, which are commonly used in clinical practice in the United States. Due to the wide variety of reported regimens, the target SLIT maintenance dose and duration of therapy are unclear. Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No. 111. Available at http: //www. effectivehealthcare. ahrq. gov/allergy-asthma-immunotherapy. cfm.

Gaps in Knowledge Additional studies are needed on: The efficacy and safety of multiple-allergen subcutaneous (SCIT) and sublingual (SLIT) immunotherapy The effectiveness of single-allergen versus multiple-allergen SCIT and SLIT for desensitization The efficacy and safety of SCIT and SLIT in specific subpopulations (pregnant women, monosensitized vs. polysensitized patients, patients with severe asthma, and urban vs. rural patients) Whether or not SCIT and SLIT can prevent or modify the atopic march in pediatric patients at high risk for allergic rhinitis and asthma, as well as the optimal age to initiate therapy Determining the target maintenance dose, dosing strategies, and the necessary durations of treatment for SCIT and SLIT Direct comparisons of SCIT to SLIT in pediatric and adult patients Optimizing allergen standardization for subcutaneous and sublingual regimens Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No. 111. Available at http: //www. effectivehealthcare. ahrq. gov/allergy-asthma-immunotherapy. cfm.

Shared Decisionmaking: What To Discuss With Your Patients The benefits and adverse effects of subcutaneous (SCIT) or sublingual (SLIT) immunotherapy for them or their child Any comorbid conditions that they or their child may have that would affect their ability to take SCIT or SLIT Other prescription or over-the-counter medications they are taking during SCIT or SLIT treatment What adverse effects to look for and when to call their doctor How often they should be taking SCIT or SLIT How long they can expect to take SCIT or SLIT The costs of SCIT and SLIT Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No. 111. Available at http: //www. effectivehealthcare. ahrq. gov/allergy-asthma-immunotherapy. cfm.

Resource for Patients Allergy Shots and Allergy Drops for Adults and Children, A Review of the Research is a free resource that can help patients talk with their health care professionals about treatment options. It provides information about: Allergies in general How allergies are treated Allergy shots and allergy drops The benefits of allergy shots and allergy drops for adults and children Possible side effects of allergy shots and allergy drops for adults and children Questions to discuss with their doctor Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No. 111. Available at http: //www. effectivehealthcare. ahrq. gov/allergy-asthma-immunotherapy. cfm.