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Comparative Effectiveness Review Summary Guides for Clinicians [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2007-.

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

Subcutaneous and Sublingual Immunotherapy To Treat Allergic Rhinitis/Rhinoconjunctivitis and Asthma

Authors

1.

Affiliations

1 Baylor College of Medicine, Houston, Texas

Issued: .

Research Focus for Clinicians

A systematic review was undertaken to summarize the evidence regarding the efficacy, comparative effectiveness, and safety of subcutaneous and sublingual immunotherapy for adult and pediatric patients. All included studies are randomized controlled trials (RCTs) and were published from January 1967 to May 2012. There are 74 RCTs on the efficacy and safety of subcutaneous immunotherapy (SCIT), 60 RCTs on the efficacy and safety of sublingual immunotherapy (SLIT), and 8 RCTs on head-to-head comparisons between both forms of immunotherapy. This summary is provided to assist clinicians in decisionmaking along with a patient’s values and preferences. Reviews of evidence should not be construed to represent clinical recommendations or guidelines. The HTML version of this clinician research summary provides links from findings in the Clinical Bottom Line and other tables to the full report for a more detailed discussion of the studies included in each analysis. The full report and the HTML version of this clinician research summary are available at www.effectivehealthcare.ahrq.gov/allergy-asthma-immunotherapy.cfm

Background

The medical management of patients with allergic rhinitis and allergic asthma includes allergen avoidance, pharmacotherapy, and immunotherapy. Daily use of pharmacotherapies for allergic 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 have risks for moderate to severe adverse effects.

Allergen immunotherapy is typically used for patients whose allergic rhinoconjunctivitis and allergic asthma symptoms cannot be controlled by medication and environmental control, patients who cannot tolerate their medications, or patients who do not comply with chronic medication regimens. The U.S. Food and Drug Administration (FDA) has approved the use of allergen extracts for SCIT for treating allergic rhinitis and allergic asthma.

In the United States, a patient with allergies undergoing immunotherapy receives subcutaneous injections—in increasing doses—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. There is considerable interest in using similar allergen extracts as SLIT as an alternative to SCIT. In the included studies, SLIT specifically refers to allergen extracts administered sublingually in the form of drops. Studies on sublingual tablets are not included here. Allergen extract drops are placed under the tongue for local absorption to desensitize the allergic individual over a period of months to years and to diminish allergic symptoms. SLIT is not currently FDA approved for use in the United States. However, some physicians are using subcutaneous formulations of allergens off-label for sublingual desensitization in the treatment of allergic respiratory conditions. This is largely based on products that have been researched for several years in the United States and Europe and are approved for use by European regulatory authorities.

Conclusions

  • There is sufficient evidence to support the overall effectiveness and safety of both SCIT and SLIT for treating allergic rhinoconjunctivitis and asthma (Tables 1 and 2).
  • 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 (Table 3).
  • Serious, life-threatening reactions are rare, although they can occur (see SCIT, Table 3). SLIT studies mainly include patients with allergic rhinitis and/or mild asthma. Safety outcomes for SLIT should not be extrapolated to more severely affected patients.
  • Most studies use a single allergen for immunotherapy (Table 4). 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 the duration of therapy are unclear.

Clinical Bottom Line

Table 1Efficacy and Comparative Effectiveness of Subcutaneous and Sublingual Immunotherapy for Adult Patients*

OutcomesSCIT vs. Placebo or vs. Standard Therapy (RCTs, No. of Patients) SOESLIT vs. Placebo or vs. Standard Therapy (RCTs, No. of Patients) SOESCIT vs. SLIT (RCTs, No. of Patients) SOE
Improves asthma symptom score17–84% greater improvement vs. controls (16 RCTs, n = 1,178) Image clinallergyfu1.jpgSignificant improvement across all studies vs. controls (13 RCTs, n = 625) Image clinallergyfu1.jpgSCIT may improve asthma symptoms more effectively than SLIT (4 RCTs, n = 171) Image clinallergyfu3.jpg
Decreases use of asthma medicationsDecreased in 42% of studies vs. controls (12 RCTs, n = 1,062) Image clinallergyfu1.jpg Image clinallergyfu4.jpg Image clinallergyfu4.jpg
Improves combined asthma symptom and medication scoreSignificant improvement in 83% of studies vs. placebo (6 RCTs, n = 196) Image clinallergyfu3.jpg Image clinallergyfu4.jpg Image clinallergyfu4.jpg
Improves rhinitis/rhinoconjunctivitis symptomsSignificant improvement in 73% of studies vs. controls (25 RCTs, n = 1,734) Image clinallergyfu1.jpgSignificant improvement in 56% of studies vs. controls (36 RCTs, n = 2,658) Image clinallergyfu2.jpgSCIT is superior to SLIT for improving allergic nasal and/or eye symptoms (6 RCTs, n = 412) Image clinallergyfu2.jpg
Improves conjunctivitis symptomsSignificant improvement in 43% of studies vs. placebo (14 RCTs, n = 1,104) Image clinallergyfu1.jpgSignificant improvement in 46% of studies vs. placebo (13 RCTs, n = 1,074) Image clinallergyfu2.jpg Image clinallergyfu4.jpg
Decreases use of rhinitis/rhinoconjunctivitis medicationsSignificantly decreased in 70% of studies vs. controls (10 RCTs, n = 564) Image clinallergyfu2.jpg Image clinallergyfu4.jpg Image clinallergyfu4.jpg
Improves combined symptoms (nasal, ocular, and bronchial)Significant improvement in 67% of studies vs. placebo (6 RCTs, n = 591) Image clinallergyfu1.jpg Image clinallergyfu4.jpg Image clinallergyfu4.jpg
Improves combined rhinitis/rhinoconjunctivitis symptom and medication scoreSignificant improvement in 83% of studies vs. controls (6 RCTs, n = 400) Image clinallergyfu3.jpg Image clinallergyfu4.jpg Image clinallergyfu4.jpg
Improves asthma plus rhinitis/rhinoconjunctivitis symptoms21–68% greater improvement vs. controls (5 RCTs, n = 175) Image clinallergyfu2.jpgSignificantly improved in 80% of studies vs. controls (5 RCTs, n = 308) Image clinallergyfu2.jpg Image clinallergyfu4.jpg
Decreases use of asthma plus rhinoconjunctivitis medications14–83% greater reduction in asthma-based studies vs. controls (5 RCTs, n = 203); significantly decreased in 91% of rhinitis-based studies vs. controls (11 RCTs, n = 768) Image clinallergyfu1.jpgSignificant improvement in 47% of studies vs. controls (38 RCTs, n = 2,724) Image clinallergyfu2.jpgThere are no consistent differences between SCIT and SLIT (5 RCTs, n = 219) Image clinallergyfu3.jpg
Improves asthma plus rhinitis/rhinoconjunctivitis symptom and medication score Image clinallergyfu4.jpgSignificant improvement in 68% of studies vs. controls (19 RCTs, n = 1,462) Image clinallergyfu2.jpgSCIT is favored in 1 of 2 studies (2 RCTs, n = 65) Image clinallergyfu3.jpg
Improves disease-specific quality of life in patients with rhinitis/rhinoconjunctivitisSignificant improvement by the RQLQ or the SF-36® in 67% of studies vs. placebo (6 RCTs, n = 889) Image clinallergyfu1.jpgSignificant improvement by the RQLQ in 75% of studies vs. controls (8 RCTs, n = 819) Image clinallergyfu2.jpg Image clinallergyfu4.jpg
*

Reported scales or scoring systems were not uniform across studies. Followup 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.

RCT = randomized controlled trial; RQLQ = Rhinoconjunctivitis Quality of Life Questionnaire; SCIT = subcutaneous immunotherapy; SF-36® = Short Form (36) Health Survey; SLIT = sublingual immunotherapy; SOE = strength of evidence

Table 2Efficacy and Comparative Effectiveness of Subcutaneous and Sublingual Immunotherapy for Pediatric Patients*

OutcomesSCIT vs. Placebo or vs. Standard Therapy (RCTs, No. of Patients) SOESLIT vs. Placebo or vs. Standard Therapy (RCTs, No. of Patients) SOESCIT vs. SLIT (RCTs, No. of Patients) SOE
Improves asthma symptom scoreSignificant improvement in 50% of studies vs. controls (6 RCTs, n = 550) Image clinallergyfu2.jpgSignificant improvement in all studies vs. controls (9 RCTs, n = 471) Image clinallergyfu1.jpgSCIT is favored in 67% of studies vs. SLIT (3 RCTs, n = 135) Image clinallergyfu3.jpg
Decreases use of asthma medicationsSignificant reduction in 50% of studies (4 RCTs, n = 470) Image clinallergyfu3.jpg Image clinallergyfu4.jpg Image clinallergyfu4.jpg
Improves rhinitis/rhinoconjunctivitis symptomsSignificant improvement in 67% of studies vs. placebo (3 RCTs, n = 285) Image clinallergyfu2.jpgSignificant improvement in 42% of studies vs. controls (12 RCTs, n = 1,065) Image clinallergyfu2.jpg Image clinallergyfu4.jpg
Improves conjunctivitis symptomsSignificant improvement in 67% of studies vs. placebo (3 RCTs, n = 285) Image clinallergyfu3.jpgSignificant improvement in 40% of studies vs. placebo (5 RCTs, n = 513) Image clinallergyfu2.jpg Image clinallergyfu4.jpg
Improves asthma plus rhinitis/rhinoconjunctivitis symptoms Image clinallergyfu4.jpgSignificant improvement with high-dose and low-dose SLIT vs. placebo (1 RCT, n = 98) Image clinallergyfu2.jpgSCIT may be favored over SLIT for reducing nasal and/or eye symptoms (3 RCTs, n = 135) Image clinallergyfu3.jpg
Decreases use of asthma plus rhinoconjunctivitis medicationsDecreased in both studies vs. controls (2 RCTs, n = 80) Image clinallergyfu3.jpgSignificantly reduced in 42% of studies vs. controls (13 RCTs, n = 1,078) Image clinallergyfu2.jpgSLIT may decrease medication use more than SCIT, but results are inconsistent (3 RCTs, n = 135) Image clinallergyfu3.jpg
Improves combined asthma or asthma plus rhinitis/rhinoconjunctivitis symptom and medication scoreSignificant improvement in both studies vs. placebo (2 RCTs, n = 85) Image clinallergyfu3.jpgSignificant improvement in 50% of studies vs. controls (2 RCTs, n = 329) Image clinallergyfu3.jpg Image clinallergyfu4.jpg
Improves disease-specific quality of life in patients with rhinitis/rhinoconjunctivitisSignificant improvement measured by RQLQ in both studies vs. controls (2 RCTs, n = 350) Image clinallergyfu3.jpg Image clinallergyfu4.jpg Image clinallergyfu4.jpg
*

Reported scales or scoring systems were not uniform across studies. Followup 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.

RCT = randomized controlled trial; RQLQ = Rhinoconjunctivitis Quality of Life Questionnaire; SCIT = subcutaneous immunotherapy; SLIT = sublingual immunotherapy; SOE = strength of evidence

Table 3Adverse Effects*

StudyAdultsPediatric Patients
SCIT
  • Local reactions (such as redness, swelling, pruritus, or induration at injection site) were usually mild and occurred in 5 to 58 percent of patients and in 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 (n = 205 immunotherapy patients). No deaths were reported.
  • Local reactions were the most common adverse reactions in the pediatric population receiving SCIT.
  • There were no reports of anaphylaxis or deaths.
SLIT
  • 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 SLIT.
  • Systemic reactions occurred more frequently in the SLIT arm 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.
  • 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.
SCIT vs. SLIT
  • The recording and reporting of the adverse events were 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 SCIT.
  • There were no reported deaths.
  • Local reactions were reported in both patient groups.
  • No systemic reactions were reported in patients receiving SLIT.
  • In the pediatric population taking SCIT, one anaphylaxis event and three respiratory systemic reactions were reported.
*

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.

SCIT = subcutaneous immunotherapy; SLIT = sublingual immunotherapy

Table 4Included Studies by Type of Allergen for Subcutaneous Immunotherapy (SCIT), Sublingual Immunotherapy (SLIT), and SCIT Versus SLIT

AllergenSCITSLITSCIT vs. SLIT
Dust mitea21146
Grassb1115-
Weedsc97-
Cat52-
Dog1--
Moldd62-
Treee6132
Multiple allergens157-
a

Dust mites could include Dermatophagoides pteronyssinus or D. farinae or unspecified dust mites.

b

Grass could include Bermuda grass, cocksfoot, meadow fescue, orchard grass, rye (Secale cereale or unspecified), Timothy grass, unspecified grass, or grass mix.

c

Weeds could include English plantain, Kochia, mugwort, Parietaria, ragweed (short, Western, or unspecified), Russian thistle, or sagebrush.

d

Mold could include Alternaria, Aspergillus, or Cladosporium.

e

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.

Strength of Evidence Scale

High: Image clinallergyfu1.jpgHigh confidence that the evidence reflects the true effect. Further research is very unlikely to change our confidence in the estimate of effect.
Moderate: Image clinallergyfu2.jpgModerate 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: Image clinallergyfu3.jpgLow confidence that the evidence reflects the true effect. Further research is likely to change our confidence in the estimate of effect and is likely to change the estimate.
Insufficient: Image clinallergyfu4.jpgEvidence is either unavailable or does not permit a conclusion.

Gaps in Knowledge

  • Additional studies are needed on the efficacy and safety of multiple-allergen SCIT and SLIT
  • 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
  • Additional studies directly comparing SCIT to SLIT in pediatric and adult patients
  • Optimizing allergen standardization for subcutaneous and sublingual regimens

Ordering Information

For electronic copies of Allergy Shots and Allergy Drops for Adults and Children, A Review of the Research, this clinician research summary, and the full systematic review, visit www.effectivehealthcare.ahrq.gov/allergy-asthma-immunotherapy.cfm. To order free print copies, call the AHRQ Publications Clearinghouse at 800-358-9295.

What To Discuss With Your Patients

  • The benefits and adverse effects of SCIT or SLIT 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

Resource for Patients

Allergy Shots and Allergy Drops for Adults and Children, A Review of the Research is a free companion to this clinician research summary. It 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
  • 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

Source

The information in this summary is based on 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. 290-2007-10061-I for the Agency for Healthcare Research and Quality, March 2013. Available at www.effectivehealthcare.ahrq.gov/allergy-asthma-immunotherapy.cfm. This summary was prepared by the John M. Eisenberg Center for Clinical Decisions and Communications Science at Baylor College of Medicine, Houston, TX.