Agency for Healthcare Research and Quality (AHRQ)

Agency for Healthcare Research and Quality (AHRQ)
Subcutaneous and Sublingual Immunotherapy To Treat Allergic Rhinitis/Rhinoconjunctivitis and Asthma Prepared for: Agency for Healthcare Research and Quality (AHRQ) Subcutaneous and Sublingual Immunotherapy To Treat Allergic Rhinitis/Rhinoconjunctivitis and Asthma This slide set is based on a systematic review titled Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review, which was developed by the Johns Hopkins University Evidence-based Practice Center for the Agency for Healthcare Research and Quality (AHRQ Contract No I) and is available online at Comparative effectiveness reviews are comprehensive systematic reviews of the literature that usually compare two or more types of treatments, such as different drugs, for the same condition. This systematic review included 74 randomized controlled trials (RCTs) published between January 1967 and May 2012 and summarizes the evidence regarding the efficacy, comparative effectiveness, and safety of subcutaneous and sublingual immunotherapy for adult and pediatric patients. There are 74 RCTs on the efficacy and safety of subcutaneous immunotherapy, 60 RCTs on the efficacy and safety of sublingual immunotherapy, and 8 RCTs on head-to-head comparisons between both forms of immunotherapy. The primary goal of this continuing medical education activity is to examine the evidence guiding clinical treatment decisions and ultimately to aid clinicians in their care of patients with allergic rhinitis/rhinoconjunctivitis and/or asthma. Reference Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. Comparative Effectiveness Review No. 111 (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No I). AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality; March Available at

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 Outline of Material The material in this continuing medical education activity covers the results and conclusions from a systematic review titled Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. It will consist of an overview of the systematic review process used by the Agency for Healthcare Research and Quality; a background review on subcutaneous and sublingual immunotherapy; clinically relevant questions the review sought to answer and the results; a summary of the conclusions regarding the effectiveness and adverse effects of subcutaneous and sublingual immunotherapy; gaps in knowledge; and some resources for shared decisionmaking. Reference Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. Comparative Effectiveness Review No. 111 (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No I). AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality; March Available at

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 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, who are 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 reviews and the full report, with references for included and excluded studies, are available at Reference Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. Comparative Effectiveness Review No. 111 (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No I). AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality; March Available at Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No Available at

Rating the Strength of Evidence From the Comparative Effectiveness Review
The strength of evidence ratings are classified into four broad ratings: High High confidence that the evidence reflects the true effect. Further research is very unlikely to change our confidence in the estimate of effect. Moderate 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 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. Rating the Strength of Evidence From the Comparative Effectiveness Review Throughout this slide set, strength-of-evidence ratings are assigned to findings from analyses of included studies. Strength of evidence is typically assigned to reviews of medical treatments after assessing four domains: risk of bias, consistency, directness, and precision. Available evidence for each intervention/comparator pair for a specific outcome was assessed for each of these four domains; the domains were combined qualitatively to develop the strength of evidence for each outcome. References Agency for Healthcare Research and Quality. Methods Guide for Effectiveness and Comparative Effectiveness Reviews. AHRQ Publication No. 10(12)-EHC063-EF. Rockville, MD: Agency for Healthcare Research and Quality; April Chapters available at Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. Comparative Effectiveness Review No. 111 (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No I). AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality; March Available at Owens DK, Lohr KN, Atkins D, et al. AHRQ series paper 5: grading the strength of a body of evidence when comparing medical interventions—Agency for Healthcare Research and Quality and the Effective Health-Care Program. J Clin Epidemiol 2010 May;63(5): PMID: AHRQ Methods Guide for Effectiveness and Comparative Effectiveness Reviews. Available at Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No Available at Owens DK, Lohr KN, Atkins D, et al. J Clin Epidemiol May;63(5): PMID:

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 and 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 [IgE] in response to environmental allergens). 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 and 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 [IgE] in response to environmental allergens). References Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. Comparative Effectiveness Review No. 111 (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No I). AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality; March Available at Min YG. The pathophysiology, diagnosis and treatment of allergic rhinitis. Allergy Asthma Immunol Res Apr;2(2): PMID: Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No Available at Min YG. Allergy Asthma Immunol Res Apr;2(2): PMID:

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. Background: Management of Allergy Symptoms The medical management of patients with allergic rhinitis and asthma includes allergen avoidance, pharmacotherapy, and immunotherapy. Pharmacotherapies for allergic rhinitis symptoms include topical nasal corticosteroid or cromolyn preparations and/or antihistamines and decongestants. These must be used daily to provide effective control, raising critical issues related to long-term compliance, safety, and cost. Similarly, the long-term use of inhaled steroids for asthma control poses risks, especially if used together with nasal steroids to control seasonal or perennial respiratory conditions. Furthermore, long-acting bronchodilators have the potential to cause cardiovascular complications including arrhythmias and sudden death, and leukotriene antagonists have been associated with neuropsychiatric disturbances. Reference Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. Comparative Effectiveness Review No. 111 (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No I). AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality; March Available at Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No Available at

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. Background: Subcutaneous Immunotherapy for Allergies Allergen-specific immunotherapy is typically recommended for patients whose allergic rhinoconjunctivitis and asthma symptoms cannot be controlled by environmental control and pharmacotherapy, those who cannot tolerate their medications, or those who do not comply with chronic medication regimens. Over the years, allergen-specific immunotherapy has proven to be safe. The U.S. Food and Drug Administration approved the use of subcutaneous allergen extracts (subcutaneous immunotherapy) for the treatment of seasonal and perennial allergic rhinitis, allergic asthma, and venom sensitivity. In the United States, a patient with allergies receives increasing doses of an allergen-containing extract (comprised of the relevant allergens to which the patient is sensitive) until a maintenance dose is found to suppress or eliminate allergic symptoms. With continued administration, it is expected that the treatment regimen will make the patient tolerant of the offending allergen and will suppress future untoward responses to the allergen(s) through modulation of the patient’s immune system. Reference Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. Comparative Effectiveness Review No. 111 (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No I). AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality; March Available at Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No Available at

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. Background: Sublingual Immunotherapy for Allergies There is considerable interest in using similar allergen extracts as sublingual immunotherapy (SLIT) as an alternative to subcutaneous immunotherapy. However, this is not an approved use of these materials in the United States, and such use would be considered off-label. An increasing number of U.S. physicians are attempting to employ this alternate desensitization approach in treating allergic respiratory conditions based on European and U.S. studies and approval of certain oral products by the European Medicines Agency; however, because of differing standardization of potency in Europe and the United States, doses have been extremely hard to translate between countries. In 1996, a task force assembled by the World Allergy Organization on Immunotherapy cited the emerging clinical data on oral immunotherapy and its potential as a viable alternative to subcutaneous therapy; this meeting encouraged continued clinical investigation to characterize optimal techniques. Interest has also increased considerably about using sublingual immunotherapy as an alternative to subcutaneous therapy based on its perceived improved safety margin (reduced risk of anaphylaxis), its simple and convenient oral dosing regimen (avoiding the discomfort of injections and the inconvenience of office visits for allergy shots), and its possibly shorter time to achieve effect. Reference Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. Comparative Effectiveness Review No. 111 (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No I). AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality; March Available at Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No Available at

Systematic Review: Objective and Key Questions
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 of SCIT, SLIT, and SCIT versus SLIT Safety and effectiveness of SCIT, SLIT, and SCIT versus SLIT in the pediatric subpopulation Systematic Review: Objective and Key Questions The primary objective of the systematic review was 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. The Key Questions that were used to address this objective included the efficacy and safety of SCIT, SLIT, and SCIT versus SLIT for patients with allergic rhinoconjunctivitis and/or asthma. The safety and effectiveness of SCIT, SLIT, and SCIT versus SLIT was also evaluated in the pediatric subpopulation. Reference Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. Comparative Effectiveness Review No. 111 (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No I). AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality; March Available at Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No Available at

Outcomes of Interest Primary Outcomes Adverse Effects
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 Outcomes of Interest When subcutaneous (SCIT) or sublingual (SLIT) immunotherapy is administered to patients with respiratory allergies, it results in intermediate outcomes including changes in immunologic parameters and long-term outcomes such as improvement of symptoms and quality of life and reduction of health care costs. However, adverse events may occur at any point after treatment is administered. The approach taken for the synthesis of this body of literature addressed each of the Key Questions separately for the studies evaluating SCIT, for the studies evaluating SLIT, and for the studies that compared SLIT with SCIT. Reference Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. Comparative Effectiveness Review No. 111 (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No I). AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality; March Available at Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No Available at

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. Overview of Studies Included in the Systematic Review All 142 included studies were randomized controlled trials. There were 74 studies that investigated the efficacy and safety of subcutaneous immunotherapy (SCIT), 60 studies that investigated the efficacy and safety of sublingual immunotherapy (SLIT), and 8 studies that compared SCIT and SLIT, with only 3 of these studies reporting findings from head-to-head comparisons between both forms of allergen immunotherapy. Studies on SLIT mainly included patients with allergic rhinitis and/or mild asthma. For age ranges of the patient populations, 52 percent of studies included adults only, 24 percent included children only, and 22 percent included adults and children. The types of scales and/or 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 and could include environmental control and/or medications such as topical nasal corticosteroid or cromolyn preparations, oral antihistamines, decongestants, beta-agonists, oral steroids, bronchodilators, ocular corticosteroids, and montelukast. 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. Reference Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. Comparative Effectiveness Review No. 111 (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No I). AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality; March Available at *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 Available at

Included Studies by Type of Allergen for SCIT, SLIT, and SCIT Versus SLIT
SCIT vs. SLIT Dust mite 21 14 6 Grass 11 15 ‒ Weeds 9 7 Cat 5 2 Dog 1 Mold Tree 13 Multiple allergens Included Studies by Type of Allergen for SCIT, SLIT, and SCIT Versus SLIT This table represents the number of studies included for each type of allergen that was included in analyses of subcutaneous immunotherapy (SCIT), sublingual immunotherapy (SLIT), and SCIT versus SLIT. Dust mites could include Dermatophagoides pteronyssinus or D. farinae or unspecified dust mites. Grass could include Bermuda grass, cocksfoot, meadow fescue, orchard grass, rye (Secale cereale or unspecified), Timothy grass, unspecified grass, or grass mix. Weeds could include English plantain, Kochia, mugwort, Parietaria, tagweed (short, Western, or unspecified), Russian thistle, or sagebrush. Mold could include Alternaria, Aspergillus, or Cladosporium. Tree could include American elm, bald cypress, birch, cottonwood, date sugar palm/wild date palm, Japanese cedar, London plane, maple, mountain cedar, olive, red/green ash, white birch, white oak, or tree mix. Reference Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. Comparative Effectiveness Review No. 111 (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No I). AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality; March Available at SCIT = subcutaneous immunotherapy; SLIT = sublingual immunotherapy Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No Available at

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. Included Studies for Subcutaneous Immunotherapy Versus Placebo or Standard Therapy The 74 included articles, with 4,350 subjects, were published between 1967 and The primary diagnoses were asthma in 19 studies, asthma with rhinitis in 18 studies, rhinoconjunctivitis in 14 studies, and asthma with rhinoconjunctivitis in 14 studies. The majority of studies (44 studies or 59%) evaluated seasonal allergens including trees, grasses, weeds, and seasonal molds, followed by perennial allergens in 28 studies (38%); only 2 studies (3%) included both seasonal and perennial allergens. Forty-eight studies used a single allergen, whereas the remaining 26 studies used multiple allergens. The most common allergen studied was dust mite (21 studies or 31%). 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. Reference Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. Comparative Effectiveness Review No. 111 (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No I). AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality; March Available at Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No Available at

No. of RCTs, No. of Patients (n)
Subcutaneous Immunotherapy Versus Placebo or Standard Therapy: Asthma Outcomes Primary Outcome Results* No. of RCTs, No. of Patients (n) Strength of Evidence Asthma symptom score 17‒84% greater improvement vs. controls 16 RCTs, n = 1,178 High Use of asthma medications Decreased in 42% of studies vs. controls 12 RCTs, n = 1,062 Combined asthma symptom and medication score Significant improvement in 83% of studies vs. placebo 6 RCTs, n = 196 Low Subcutaneous Immunotherapy Versus Placebo or Standard Therapy: Asthma Outcomes Various measures of asthma symptoms were used. Sixteen studies reporting asthma symptom scores included 1,178 participants. Across studies, the immunotherapy group showed an improvement in asthma symptom scores ranging from 17 to 84 percent greater than the comparison group. The overall strength of evidence is high grade to support the use of subcutaneous immunotherapy to improve asthma symptom scores. Twelve studies reported asthma medication consumption and included 1,062 participants. The most prevalent single allergen studied was dust mite in six studies. The overall strength of evidence is high grade that subcutaneous immunotherapy reduces asthma medication use. Six asthma studies that included 196 participants reported combined asthma symptom-medication scores. Five were placebo-controlled studies, and all five studies demonstrated significant improvement in the immunotherapy group when compared with placebo. One study that compared immunotherapy to pharmacotherapy showed a nonsignificant reduction in the symptom-medication scores in the immunotherapy group. The strength of evidence is low to support that subcutaneous immunotherapy improves asthma symptom and medication scores. Reference Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. Comparative Effectiveness Review No. 111 (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No I). AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality; March Available at RCT = randomized controlled trial Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No Available at

SCIT Versus Placebo or Standard Therapy: Rhinitis/Rhinoconjunctivitis Outcomes (1 of 2)
Primary Outcome Results No. of RCTs, No. of Patients (n) Strength of Evidence Rhinitis/ rhinoconjunctivitis symptoms Significant improvement in 73% of studies vs. controls 25 RCTs, n = 1,734 High Use of rhinitis/ rhinoconjunctivitis medications Significantly decreased in 70% of studies vs. controls 10 RCTs, n = 564 Moderate Combined rhinitis/ rhinoconjunctivitis symptom and medication score Significant improvement in 83% of studies vs. controls 6 RCTs, n = 400 Low SCIT Versus Placebo or Standard Therapy: Rhinitis/Rhinoconjunctivitis Outcomes (1 of 2) Rhinitis/rhinoconjunctivitis symptom scores were included from studies that enrolled patients with rhinitis/rhinoconjunctivitis with or without asthma. Nineteen studies (73%) reporting rhinitis/rhinoconjunctivitis symptom scores demonstrated statistically significant improvement in rhinitis/rhinoconjunctivitis symptoms with subcutaneous immunotherapy (SCIT). Overall, 25 randomized controlled trials reported rhinitis/rhinoconjunctivitis symptom scores in 1,734 participants. The overall strength of evidence is high to support that SCIT improves rhinitis/rhinoconjunctivitis symptoms. Ten studies that included 564 patients reported on rhinitis/rhinoconjunctivitis medication scores. They all used some type of numeric scoring scale for medication use but were inconsistent across studies. Rhinitis/rhinoconjunctivitis medications included oral antihistamines and intranasal corticosteroids. Seven trials demonstrated significant improvement with SCIT. In six of these studies the comparator was placebo, and in one study the comparator was pharmacotherapy. The overall strength of evidence is moderate to support that SCIT decreases medication use for rhinitis/rhinoconjunctivitis. Six studies that included 400 patients reported combined rhinitis/rhinoconjunctivitis symptom and medication scores. In five studies, nasal, ocular, and bronchial symptoms were scored in addition to medication use, specifically beta-agonist, oral and nasal steroid, and antihistamine use. Only nasal and ocular symptoms were reported along with nasal corticosteroids and antihistamines in one study. Five of the six studies reported a significant improvement in combination symptom plus medication score with SCIT. The overall strength of evidence is low to support that SCIT improves combination symptom plus medication scores. Reference Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. Comparative Effectiveness Review No. 111 (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No I). AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality; March Available at RCT = randomized controlled trial; SCIT = subcutaneous immunotherapy Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No Available at

SCIT Versus Placebo or Standard Therapy: Rhinitis/Rhinoconjunctivitis Outcomes (2 of 2)
Primary Outcome Results No. of RCTs, No. of Patients (n) Strength 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 Disease-specific quality of life in patients with rhinitis/ rhinoconjunctivitis Significant improvement by RQLQ in 67% of studies vs. placebo n = 889 SCIT Versus Placebo or Standard Therapy: Rhinitis/Rhinoconjunctivitis Outcomes (2 of 2) Fourteen subcutaneous immunotherapy (SCIT) studies that included 1,104 patients reported conjunctivitis symptom scores and were included in the strength-of-evidence analysis for this outcome. Six studies demonstrated significant improvement in conjunctivitis symptom scores in the immunotherapy group when compared with placebo. The most commonly evaluated allergen was Timothy grass in five studies. The overall strength of evidence is high to support that SCIT improves allergic conjunctivitis symptoms. Six rhinitis/rhinoconjunctivitis studies that included 591 individuals reported combined scores including nasal, ocular, and bronchial symptom scores and were included in the strength-of-evidence rating analysis for this outcome. The total symptom scores used numeric scales that were not validated and varied between studies. Three studies showed significant improvement in combined symptom scores when compared with placebo and one study in the comparison of post-treatment symptoms to pretreatment symptoms. The strength of evidence is high to support that subcutaneous immunotherapy improves combined (nasal, ocular, and bronchial) symptoms scores. Six studies with 889 subjects included quality-of-life outcomes. Four of the six studies reported significant improvement in disease-specific quality of life when compared with placebo. The instruments used to assess quality of life were validated, disease-specific instruments: the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ; adult, pediatric, adolescent, and Japanese-language versions) and/or the Short Form (36) Health Survey (SF-36®). The evidence is high to support that SCIT improves disease-specific quality of life among individuals with rhinitis/rhinoconjunctivitis. Reference Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. Comparative Effectiveness Review No. 111 (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No I). AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality; March Available at 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 Available at

SCIT 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 21‒68% greater improvement vs. controls 5 RCTs, n = 175 Moderate Use of asthma plus rhinoconjunctivitis medications 14–83% greater reduction in asthma-based studies vs. controls Significantly decreased in 91% of rhinitis-based studies vs. controls 5 RCTs, n = 203 11 RCTs, n = 768 High SCIT Versus Placebo or Standard Therapy: Asthma Plus Rhinitis/Rhinoconjunctivitis Outcomes Five asthma studies that included 175 participants reported asthma plus rhinoconjunctivitis symptom scores, each using a different allergen. The immunotherapy group showed improvement ranging from 21 to 68 percent greater than the comparison group. The overall strength of evidence is moderate to support the use of subcutaneous immunotherapy (SCIT) to improve combined asthma and rhinoconjunctivitis symptom scores. Five asthma-based studies that included 203 participants reported asthma plus rhinoconjunctivitis medication scores, each investigating a different allergen. All five studies demonstrated a significant reduction in asthma and rhinoconjunctivitis medication consumption in the immunotherapy group when compared with the comparison groups. The immunotherapy group experienced a 14-percent to 83-percent greater reduction in combined asthma and rhinoconjunctivitis medication consumption than the comparison group. The overall strength of evidence is high that SCIT reduces asthma and rhinoconjunctivitis medication consumption. Eleven rhinitis-based studies that included 768 patients reported on asthma plus rhinitis/rhinoconjunctivitis medication scores. Comparator medications included those used by patients with asthma and rhinitis/rhinoconjunctivitis, including inhaled beta-agonists and oral corticosteroids. Ten studies demonstrated significant improvement with SCIT when compared with placebo or when comparing medication use after treatment to a pretreatment period. The overall strength of evidence is high to support that subcutaneous immunotherapy decreases combined medication use. Reference Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. Comparative Effectiveness Review No. 111 (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No I). AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality; March Available at RCT = randomized controlled trial; SCIT = subcutaneous immunotherapy Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No Available at

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. Included Studies for Sublingual Immunotherapy Versus Placebo or Standard Therapy Sixty articles on sublingual immunotherapy (SLIT) that included 4,870 patients were eligible for inclusion. These articles were published between 1993 and Most studies enrolled adults only, although 16 randomized controlled trials included both adults and children and 18 exclusively studied children. The majority of studies evaluated seasonal allergens (66%), followed by perennial allergens (31%); a small number of studies included both seasonal and perennial allergens (3%). Half of the studies used only one allergen in their study protocols, while the other half used multiple allergens. The trials compared SLIT to placebo (71%), to another sublingual intervention without a placebo group (15%), or to a conventional treatment without placebo (pharmacotherapy or rescue medications; 14%). All studies allowed either conventional pharmacotherapy or rescue allergy medications in both the sublingual therapy arm and in the comparison arm. The maintenance dosing interval varied from daily to weekly, and the duration of treatment ranged from 3 months to 5 years. There was great heterogeneity in the reporting of the maintenance or cumulative dose delivered to the study participants, and the studies used a variety of units to report dosing. Standard therapy varied across trials and could include environmental control and/or medications such as topical nasal corticosteroid or cromolyn preparations, oral antihistamines, decongestants, beta-agonists, oral steroids, bronchodilators, ocular corticosteroids, and montelukast. 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. Reference Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. Comparative Effectiveness Review No. 111 (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No I). AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality; March Available at Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No Available at

Sublingual Immunotherapy Versus Placebo or Standard Therapy: Asthma Outcomes Primary Outcome Results No. of RCTs, No. of Patients (n) Strength of Evidence Asthma symptom score Significant improvement across all studies vs. controls 13 RCTs, n = 625 High RCT = randomized controlled trial Sublingual Immunotherapy Versus Placebo or Standard Therapy: Asthma Outcomes Asthma symptoms scores were reported in 13 studies that included 625 patients. In all 13 studies, asthma symptom scores showed significant improvement in asthma symptoms with sublingual immunotherapy (SLIT). Comparators included placebo, pretreatment/post-treatment analyses, inhaled corticosteroids, and montelukast. There is high-grade evidence that SLIT reduces asthma symptoms. Reference Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. Comparative Effectiveness Review No. 111 (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No I). AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality; March Available at Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No Available at

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 Disease-specific quality of life in patients with rhinitis/ rhinoconjunctivitis Significant improvement by RQLQ in 75% of studies vs. controls 8 RCTs, n = 819 SLIT Versus Placebo or Standard Therapy: Rhinitis/Rhinoconjunctivitis Outcomes Rhinitis or rhinitis plus conjunctivitis symptom scores were reported in 36 studies that included 2,658 patients. The most common allergen was grass or grass mix, followed by dust mite and tree/tree mix. Comparator groups included placebo and pharmacotherapy. Fifty-six percent of sublingual immunotherapy (SLIT) studies reporting rhinoconjunctivitis symptoms demonstrated significant improvement in allergic rhinoconjunctivitis scores with SLIT. There is moderate-grade evidence that SLIT improves control of rhinitis or rhinoconjunctivitis symptoms, particularly with grass mix allergens. Conjunctivitis symptoms were reported in 13 studies that included 1,074 patients. Forty-six percent of the studies demonstrated significant improvement in conjunctivitis symptom scores when compared with placebo or to pretreatment symptom levels in the SLIT arm. There is moderate-grade evidence that SLIT reduces conjunctivitis symptoms. Quality of life was reported in 8 studies involving 819 subjects. The instrument used to assess quality of life was a validated, disease-specific instrument: the Rhinoconjunctivitis Quality of Life Questionnaire (adult, pediatric, adolescent, and Japanese-language versions). Six studies demonstrated improved quality of life in the SLIT groups when compared with placebo or when comparing initial to final quality-of-life scores. Reference Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. Comparative Effectiveness Review No. 111 (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No I). AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality; March Available at RCT = randomized controlled trial; RQLQ = Rhinoconjunctivitis Quality of Life Questionnaire Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No Available at

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 Asthma plus rhinitis/ rhinoconjunctivitis symptom and medication score Significant improvement in 68% of studies vs. controls 19 RCTs, n = 1,462 SLIT Versus Placebo or Standard Therapy: Asthma Plus Rhinitis/Rhinoconjunctivitis Outcomes Asthma plus rhinitis or rhinoconjunctivitis symptom scores were reported in 5 trials of sublingual immunotherapy (SLIT) involving 308 participants. Comparators included placebo or pharmacotherapy. Four trials reported combined asthma plus rhinitis or rhinoconjunctivitis symptom scores and demonstrated statistically significant positive effects on combined asthma plus rhinitis/rhinoconjunctivitis symptoms with SLIT. There is moderate-grade evidence that SLIT reduces asthma and/or rhinitis or rhinoconjunctivitis symptoms. Combined asthma plus rhinoconjunctivitis medication use was reported in 38 studies that included 2,724 patients. In 47 percent of the studies, patients taking SLIT had significantly improved medication scores. There is moderate-grade evidence that SLIT reduces medication use. Combined symptom and medication scores were reported in 19 studies that included 1,462 patients. Comparators were placebo, pharmacotherapy/conventional therapy, or pretreatment versus post-treatment analyses. Thirteen studies reported a combined symptom plus medication score and demonstrated significant improvement in scores with SLIT. There is moderate-grade evidence that SLIT reduces medication use and improves symptom control. Reference Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. Comparative Effectiveness Review No. 111 (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No I). AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality; March Available at RCT = randomized controlled trial Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No Available at

Subcutaneous Versus Sublingual Immunotherapy: All Outcomes
Primary Outcome Results No. of RCTs, No. of Patients (n) Strength of Evidence Improves asthma symptom score SCIT may improve asthma 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 Improves asthma plus rhinitis/rhinoconjunctivitis symptom and medication score SCIT is favored in 1 of 2 studies 2 RCTs, n = 65 Subcutaneous Versus Sublingual Immunotherapy: All Outcomes Four trials of dust mite allergen immunotherapy reported improvement in asthma symptom scores. Two studies reported changes in subcutaneous (SCIT) and sublingual (SLIT) immunotherapy groups when compared with placebo and two when compared with pharmacotherapy. All four studies reported significant changes in asthma symptom scores in the SCIT treatment group. The strength of evidence is low (4 studies, N = 171) to support SCIT over SLIT for allergic asthma symptom control. Six studies reported rhinitis or rhinoconjunctivitis symptom scores in 412 patients. Three trials demonstrated that both SLIT and SCIT reduced symptoms significantly when compared with placebo or with pharmacotherapy. One of these showed that SCIT resulted in a significantly greater reduction in symptom scores when compared with SLIT. The other two studies showed no significant difference between SLIT and SCIT for reducing rhinitis/rhinoconjunctivitis symptoms. One study reported a significant difference in rhinitis symptoms in participants receiving combined SCIT and SLIT when compared with pharmacotherapy. The strength of evidence is moderate that SCIT is more effective than SLIT in reducing allergic nasal and/or eye symptoms. Medication scores were reported in 5 studies that included 219 patients. The evidence was inconsistent; consequently, there is low-strength evidence that there may not be a difference between SCIT and SLIT in reducing medication use. Two studies including 65 patients reported improvement in symptom and medication scores. A dust mite trial reported significant improvement post-treatment when compared with pretreatment in the SCIT group. The SLIT group showed significant improvement during early treatment, but the effect was not sustained at 2 years. Another study in patients allergic to tree pollen reported no significant differences in symptoms and medication scores between the SLIT and SCIT groups. None of the studies reported between-group differences. The evidence is low to support SCIT over SLIT for improving combined medication and symptom scores for patients allergic to dust mite. Reference Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. Comparative Effectiveness Review No. 111 (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No I). AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality; March Available at RCT = randomized controlled trial; SCIT = subcutaneous immunotherapy; SLIT = sublingual immunotherapy Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No Available at

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. Included Studies for SCIT Versus Placebo or Standard Therapy in the Pediatric Population Thirteen articles on subcutaneous immunotherapy (SCIT) were eligible for inclusion in this review. The 13 articles, with 920 subjects, were published between 1982 and The pediatric population ranged in age from 3 to 18 years. The primary diagnoses of the subjects studied in the articles included asthma in seven studies, rhinitis in zero studies, rhinoconjunctivitis in one study, asthma with rhinitis in three studies, and asthma with rhinoconjunctivitis in two studies. All studies allowed either conventional pharmacotherapy or rescue allergy medications during the study. The types of scales and/or 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 and could include environmental control and/or medications such as topical nasal corticosteroid or cromolyn preparations, oral antihistamines, decongestants, beta-agonists, oral steroids, bronchodilators, ocular corticosteroids, and montelukast. 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. Reference Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. Comparative Effectiveness Review No. 111 (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No I). AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality; March Available at Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No Available at

Pediatric Patients—SCIT Versus Placebo or Standard Therapy: Asthma Outcomes Primary Outcome Results No. of RCTs, No. of Patients (n) Strength of Evidence Asthma symptom score Significant improvement in 50% of studies vs. controls 6 RCTs, n = 550 Moderate Use of asthma medications Significant reduction in 50% of studies 4 RCTs, n = 470 Low RCT = randomized controlled trial; SCIT = subcutaneous immunotherapy Pediatric Patients—SCIT Versus Placebo or Standard Therapy: Asthma Outcomes Asthma symptom scores were reported in 6 asthma studies that included 550 patients. Only three studies demonstrated a statistically significant improvement in asthma symptoms from subcutaneous immunotherapy (SCIT) when compared with pharmacotherapy or with placebo. The overall strength of evidence is moderate that SCIT using a single allergen improves asthma symptoms in the pediatric population. Asthma medication scores were reported in 4 studies that included 470 patients. Two studies reported a significant difference in medication consumption in favor of the immunotherapy group when compared with pharmacotherapy. The overall strength of evidence is low grade to support the use of SCIT to improve asthma medication use in the pediatric population. Reference Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. Comparative Effectiveness Review No. 111 (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No I). AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality; March Available at Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No Available at

Pediatric Patients—SCIT 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 67% of studies vs. placebo 3 RCTs, n = 285 Moderate Conjunctivitis symptoms Low Disease-specific quality of life in patients with rhinitis/ rhinoconjunctivitis Significant improvement in both studies vs. controls 2 RCTs, n = 350 Pediatric Patients—SCIT Versus Placebo or Standard Therapy: Rhinitis/Rhinoconjunctivitis Outcomes Rhinitis/Rhinoconjunctivitis symptom scores were reported in 3 studies that included 285 patients. Two studies reporting rhinitis/rhinoconjunctivitis symptom scores demonstrated statistically significant improvement in rhinitis/rhinoconjunctivitis symptoms with subcutaneous immunotherapy (SCIT) when compared with placebo. The overall strength of evidence is moderate to support that SCIT improves rhinitis/rhinoconjunctivitis symptoms in the pediatric population. Conjunctivitis symptom scores were reported in 3 SCIT studies that included 285 patients; the comparator in these three studies was placebo. Two of these studies showed significant improvement in conjunctivitis symptoms after SCIT when compared with placebo. The overall strength of evidence is low to support that SCIT improves allergic ocular symptoms in the pediatric population. Quality of life was reported in 2 trials comparing SCIT to placebo with medication treatment in a total of 350 patients. A similar increase in quality of life was also seen in the parents of children with symptoms. There is low-grade evidence to support that SCIT improves disease-specific quality of life among children and adolescents with rhinitis/rhinoconjunctivitis. Reference Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. Comparative Effectiveness Review No. 111 (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No I). AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality; March Available at RCT = randomized controlled trial ; SCIT = subcutaneous immunotherapy Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No Available at

Pediatric Patients—SCIT Versus Placebo or Standard Therapy: Asthma Plus Rhinitis/Rhinoconjunctivitis Outcomes Primary Outcome Results No. of RCTs, No. of Patients (n) Strength of Evidence 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 Pediatric Patients—SCIT Versus Placebo or Standard Therapy: Asthma Plus Rhinitis/Rhinoconjunctivitis Outcomes Two studies reported combined asthma and rhinoconjunctivitis medication scores and investigated molds, Cladosporium, and Alternaria. Both studies demonstrated a reduction in asthma and rhinoconjunctivitis medication consumption in the subcutaneous immunotherapy (SCIT) group when compared with the comparison groups. The strength of evidence is low grade to support that SCIT decreases the use of combined asthma and rhinoconjunctivitis medications scores in the pediatric population. Two asthma studies reported combined symptom-medication scores for asthma or asthma plus rhinoconjunctivitis in 85 patients. Both studies demonstrated significant improvement in the SCIT group when compared with placebo. The strength of evidence is low grade to support that therapy improves asthma symptom-medication scores in the pediatric population. Reference Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. Comparative Effectiveness Review No. 111 (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No I). AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality; March Available at RCT = randomized controlled trial; SCIT = subcutaneous immunotherapy Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No Available at

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. Included Studies for SLIT Versus Placebo or Standard Therapy in the Pediatric Population Eighteen studies that included 1,583 patients focused exclusively on the pediatric population (18 years of age or younger). The publication dates of the included studies ranged from 1990 through The primary diagnoses of the study subjects included: asthma in three studies; rhinitis in two studies; rhinoconjunctivitis in four studies; asthma and rhinitis in four studies; and asthma with rhinoconjunctivitis in five studies. Studies included perennial and/or seasonal allergens. The comparator groups included placebo (15 studies), another sublingual comparator group (3 studies), conventional treatment (pharmacotherapy) or a symptomatic therapy comparator group (2 studies; 20%). All studies allowed either conventional pharmacotherapy (12 studies) or only rescue allergy medications (6 studies) during the study. The maintenance dosing interval varied from daily to twice a week. Duration of treatment of the included studies ranged from 6 months to 3 years. Studies used various units to report dosing, and many studies did not include a cumulative dose. Due to heterogeneity in reported clinical outcomes, results often only reflect the percentage of trials where a significant effect was seen for the immunotherapy arm versus controls and not the magnitude of effect. Reference Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. Comparative Effectiveness Review No. 111 (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No I). AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality; March Available at Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No Available at

Pediatric Patients—SLIT Versus Placebo or Standard Therapy: Asthma Outcomes Primary Outcome Results No. of RCTs, No. of Patients (n) Strength of Evidence Asthma symptom score Significant improvement in all studies vs. controls 9 RCTs, n = 471 High RCT = randomized controlled trial; SLIT = sublingual immunotherapy Pediatric Patients—SLIT Versus Placebo or Standard Therapy: Asthma Outcomes Asthma scores and asthma combined symptom scores were included from studies only if objective measures of lung function were used to diagnose subjects with asthma; studies using clinical symptoms only to diagnose asthma were not included in the asthma symptom scores analyzed. Two studies used visual analog scale scores, and the remainder used purely numeric systems to score the presence/absence of asthma symptoms and severity. All the studies reporting asthma symptom scores demonstrated significant improvement in asthma symptoms with sublingual immunotherapy (SLIT). The overall strength of evidence is high to support use of SLIT to improve asthma symptoms scores. Reference Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. Comparative Effectiveness Review No. 111 (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No I). AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality; March Available at Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No Available at

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 Pediatric Patients—SLIT Versus Placebo or Standard Therapy: Rhinitis/Rhinoconjunctivitis Outcomes Rhinitis or combined rhinitis plus conjunctivitis symptom scores were reported in 12 articles involving 1,065 patients. Overall, 5 (42%) of the 12 sublingual immunotherapy (SLIT) studies reporting rhinoconjunctivitis symptoms demonstrated significant improvement in allergic rhinoconjunctivitis scores with SLIT. There is moderate-grade evidence that SLIT improves control of rhinitis or rhinoconjunctivitis symptoms. Conjunctivitis symptom scores were reported in 5 trials involving 513 patients. The comparator in all studies reporting conjunctivitis scores was placebo. Two studies demonstrated significant improvement in conjunctivitis symptom scores when compared with placebo or to pretreatment symptom levels in the SLIT arm. There is moderate-grade evidence that SLIT reduces conjunctivitis symptoms. Quality of life was reported in 2 studies involving 461 subjects. The instruments used to assess quality of life in both studies were validated, disease-specific instruments: the pediatric and adolescent versions of the Rhinoconjunctivitis Quality of Life Questionnaires. One study found no improvement in quality of life. The other study found no difference between the SLIT and placebo groups in both children and adolescents after 2 years. There is insufficient evidence that SLIT affects disease-specific quality of life in children and adolescents. Reference Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. Comparative Effectiveness Review No. 111 (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No I). AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality; March Available at RCT = randomized controlled trial; SLIT = sublingual immunotherapy Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No Available at

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 rhinoconjunctivitis symptom and medication score Significant improvement in 50% of studies vs. controls 2 RCTs, n = 329 Low Pediatric Patients—SLIT Versus Placebo or Standard Therapy: Asthma Plus Rhinitis/Rhinoconjunctivitis Outcomes One study involving 98 participants reported combined symptom scores. Valovirta et al. (2006) reported on the “asthma combined symptom score,” which included asthma plus rhinoconjunctivitis symptoms and used numeric scoring systems. This study, with medium risk of bias and comparing sublingual immunotherapy (SLIT) to placebo over the whole pollen season, demonstrated statistically significant positive effects on combined asthma plus rhinoconjunctivitis symptoms with SLIT. There is moderate-grade evidence that SLIT reduces asthma and/or rhinitis or rhinoconjunctivitis symptoms. Medication scores were reported in 14 (77%) of the pediatric SLIT trials. Four of the 13 studies (42%) reporting medication scores demonstrated significant improvement in this domain with SLIT. There is moderate-grade evidence that SLIT reduces medication use. Combined symptom plus medication scores were reported in 2 of the SLIT studies included in this review and involved 329 patients. One study reporting a combination symptom plus medication score demonstrated significant improvement with SLIT when compared with controls. One study of grass-mix allergen showed no significant difference between SLIT and conventional therapy. There is low-grade evidence that SLIT reduces combined medication use and symptom scores. Reference Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. Comparative Effectiveness Review No. 111 (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No I). AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality; March Available at Valovirta E, Jacobsen L, Ljorring C, et al. Clinical efficacy and safety of sublingual immunotherapy with tree pollen extract in children. Allergy Oct;61(10): PMID: RCT = randomized controlled trial; SLIT = sublingual immunotherapy Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No Available at

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 Decreases use of asthma plus rhinoconjunctivitis medications SLIT may decrease medication use more than SCIT, but results are inconsistent 3 RCTs, n = 135 Pediatric Patients—SCIT Versus SLIT: All Outcomes Inadequate evidence exists to support sublingual (SLIT) over subcutaneous (SCIT) immunotherapy or vice versa for improving asthma or rhinitis symptoms or medication use. Low-grade evidence favors SCIT over SLIT for allergic asthma symptom control, based on 3 randomized controlled trials (RCTs) with 135 subjects. Low-grade evidence favors SCIT over SLIT for allergic nasal and/or eye symptom control, based on 3 RCTs with 135 subjects. Low-grade evidence exists to suggest little difference between routes of therapy for reducing medication use, based on 3 RCTs with 135 subjects. Reference Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. Comparative Effectiveness Review No. 111 (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No I). AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality; March Available at RCT = randomized controlled trial; SCIT = subcutaneous immunotherapy; SLIT = sublingual immunotherapy Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No Available at

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. Adverse Effects: Subcutaneous Immunotherapy in Adults Not all studies reported adverse effects. Due to the lack of a consistent reporting system across studies, a meta-analysis of adverse effects was not possible. Local reactions occurred in 5 to 58 percent of patients and in 0.6 to 54 percent of injections and were more common than systemic reactions. Most local reactions were mild. 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. Most of the systemic reactions were either 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. Reference Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. Comparative Effectiveness Review No. 111 (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No I). AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality; March Available at Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No Available at

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. Adverse Effects: Sublingual Immunotherapy in Adults Not all studies reported adverse effects. Due to the lack of a consistent reporting system across studies, a meta-analysis of adverse effects was not possible. 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 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. The strength of evidence is insufficient for definitive statements about the safety of SLIT, although few serious events were reported in the included studies. However, SLIT studies mainly include patients with allergic rhinitis and/or mild asthma. Safety outcomes should not be extrapolated to more severely affected patients. Reference Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. Comparative Effectiveness Review No. 111 (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No I). AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality; March Available at Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No Available at

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. Adverse Effects: Subcutaneous Versus Sublingual Immunotherapy in Adults Not all studies reported adverse effects. Due to the lack of a consistent reporting system across studies, a meta-analysis of adverse effects was not possible. 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. Reference Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. Comparative Effectiveness Review No. 111 (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No I). AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality; March Available at Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No Available at

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. Adverse Effects: Subcutaneous Immunotherapy in Pediatric Patients Not all studies reported adverse effects. Due to the lack of a consistent reporting system across studies, a meta-analysis of adverse effects was not possible. Local reactions were the most common adverse reactions in the pediatric population receiving subcutaneous immunotherapy. There were no reports of anaphylaxis or deaths. Reference Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. Comparative Effectiveness Review No. 111 (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No I). AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality; March Available at Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No Available at

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. Adverse Effects: Sublingual Immunotherapy in Pediatric Patients Not all studies reported adverse effects. Due to the lack of a consistent reporting system across studies, a meta-analysis of adverse effects was not possible. 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. Reference Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. Comparative Effectiveness Review No. 111 (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No I). AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality; March Available at Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No Available at

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. Adverse Effects: Subcutaneous Versus Sublingual Immunotherapy in Pediatric Patients Not all studies reported adverse effects. Due to the lack of a consistent reporting system across studies, a meta-analysis of adverse effects was not possible. 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. Reference Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. Comparative Effectiveness Review No. 111 (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No I). AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality; March Available at Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No Available at

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. Overview of Conclusions (1 of 2) Evidence is sufficient to support the overall effectiveness and safety of both subcutaneous (SCIT) and sublingual (SLIT) immunotherapy for treating allergic rhinoconjunctivitis and asthma. However, there is not enough evidence to determine which mechanism of delivery is superior. SCIT and SLIT are usually safe, although local reactions are commonly reported regardless of the mode of delivery. Reference Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. Comparative Effectiveness Review No. 111 (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No I). AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality; March Available at Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No Available at

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. 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. Reference Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. Comparative Effectiveness Review No. 111 (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No I). AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality; March Available at Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No Available at

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 Gaps in Knowledge The systematic review identified several areas where future research will help to address the gaps in clinical knowledge. Additional studies are needed in these areas: The efficacy and safety of multiple-allergen subcutaneous (SCIT) and sublingual (SLIT) immunotherapies 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 Reference Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. Comparative Effectiveness Review No. 111 (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No I). AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality; March Available at Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No Available at

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 Shared Decisionmaking: What To Discuss With Your Patients To facilitate shared decisionmaking, consider discussing these topics 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 Reference Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. Comparative Effectiveness Review No. 111 (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No I). AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality; March Available at Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No Available at

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 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 also provides information about allergies in general, how allergies are treated, the benefits and possible side effects of allergy shots and allergy drops for adults and children, and questions to discuss with their doctor. Reference Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. Comparative Effectiveness Review No. 111 (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No I). AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality; March Available at Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No Available at

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