Background

Asthma is a chronic inflammatory disorder of the airways, characterized by varying degrees of airflow obstruction. Approximately 56 percent of individuals with asthma also have environmental allergies.¹ Allergic asthma and non-allergic asthma generally have the same symptoms; however, allergic asthma is triggered by inhaling airborne allergens (aeroallergens).

There are currently three treatment options for patients with allergic asthma: allergen avoidance, pharmacotherapy including biologics, and allergen immunotherapy (AIT). AIT consists of the repeated administration of one or multiple allergens to which the patient is sensitized. In subcutaneous immunotherapy (SCIT) a solution containing an allergen(s) is injected under the skin. Sublingual immunotherapy (SLIT), which may be dosed at home, consists of exposure to the allergen via an aqueous solution or tablet formulation placed under the tongue.

In 2007, the Expert Panel Report (EPR-3) from The National Heart, Lung, and Blood Institute (NHBLI)² included SCIT as a therapy to be considered in cases of mild to moderate persistent asthma. A working group was convened in 2015 to select the most relevant topics for systematic review to update the EPR-3. This systematic review focuses on one of those high priority topics: expanding the scope of a prior evidence report to assess the efficacy and safety of SCIT and SLIT, in aqueous and tablet forms, in people with allergic asthma.

Key Questions

• Key Question 1. What is the evidence for the efficacy of subcutaneous immunotherapy (SCIT) in the treatment of asthma?
• Key Question 2. What is the evidence for the safety of subcutaneous immunotherapy (SCIT) in the treatment of asthma?
• Key Question 3. What is the evidence for the efficacy of sublingual immunotherapy (SLIT), in tablet and aqueous form, for the treatment of asthma?
• Key Question 4. What is the evidence for the safety of sublingual immunotherapy (SLIT), in tablet and aqueous form, for the treatment of asthma?

Methods

The protocol was registered in PROSPERO (http://www.crd.york.ac.uk/PROSPERO), registration number CRD42016047749, and posted on the AHRQ Web site (http://www.effectivehealthcare.ahrq.gov/).

We rescreened all of the included studies from our prior 2013 evidence report.³ We searched PubMed, Embase®, and the Cochrane Central Register of Controlled Trials (CENTRAL) from January 1, 2005 through May 8, 2017.

As for all evidence reports, our draft report was peer reviewed and posted for public comment.

Results

We identified 31 randomized controlled trials (RCTs) (35 articles) that addressed the efficacy of SCIT (Key Question [KQ] 1), 26 RCTs (31 articles) and 18 non-RCTs that addressed the safety of SCIT (KQ2), 18 RCTs (20 articles) that addressed the efficacy of SLIT (KQ3), and 20 RCTs (23 articles) and 10 non-RCTs that addressed the safety of SLIT (KQ4). We provide details of studies identified per age group in Table A.

Table A

Number of studies included per Key Question, study design, age group, and setting.

Key Question 1. What is the evidence for the efficacy of subcutaneous immunotherapy (SCIT) in the treatment of asthma?

Key Points

• SCIT reduces the need for long-term control medication (moderate strength of evidence [SOE]).
• SCIT may improve asthma-specific quality of life, decrease use of quick-relief medications, decrease use of systemic corticosteroids, and improve FEV₁ (forced expiratory volume) (low SOE).
• There was insufficient evidence regarding the effect of SCIT on asthma symptom control and health care utilization.
• There was insufficient evidence about any differential effect of SCIT in pediatric patients.

Table B

Summary of the strength of evidence for the efficacy of subcutaneous immunotherapy.

Key Question 2. What is the evidence for the safety of subcutaneous immunotherapy (SCIT) in the treatment of asthma?

Key Points

• Local reactions to SCIT were frequent; however, reactions also commonly occurred with placebo injections (risk differences ranged from -0.317 to 0.4), and local reactions infrequently required a change in the SCIT dosing.
• Systemic allergic reactions to SCIT were reported frequently (risk differences ranged from 0 to 0.319). The majority of systemic allergic reactions were mild, and only a small number was consistent with anaphylaxis and required treatment with injectable epinephrine.
• There was insufficient evidence to draw conclusions regarding the effect of SCIT on anaphylaxis or death.
• Serious adverse events such as anaphylaxis and death were not reported in the included studies in the pediatric population (total of 462 patients in 4 RCTs).
• None of the studies reported providing patients SCIT in the home setting.

Table C

Summary of the strength of evidence for the safety of subcutaneous immunotherapy.

Key Question 3. What is the evidence for the efficacy of sublingual immunotherapy (SLIT), in tablet and aqueous form, for the treatment of asthma?

Key Points

• SLIT improves asthma symptoms, as measured by validated instruments (high SOE).
• SLIT improves disease-specific quality of life and decreases use of long-term control medications (specifically, ICS), and improves FEV₁ (moderate SOE).
• SLIT may decrease quick-relief medication use (short-acting bronchodilators) and may improve disease-specific quality of life (low SOE).
• There is insufficient evidence on the effect of SLIT on systemic corticosteroid use or health care utilization.
• There is insufficient evidence about the efficacy of SLIT in children.

Table D

Summary of the strength of evidence for the efficacy of sublingual immunotherapy.

Key Question 4. What is the evidence for the safety of sublingual immunotherapy (SLIT) in the treatment of asthma?

Key Points

• Local reactions to SLIT were frequent (some reactions occurring in up to 80% of patients in RCTs); however, reactions also commonly occurred with placebo (risk differences ranged from -0.03 to 0.765).
• Systemic allergic reactions to SLIT were frequent (some reactions occurring in up to 22% of patients in RCTs), with only a few reports of anaphylaxis and no reports of deaths (risk differences ranged from -0.03 to 0.06).
• Although rates of anaphylaxis with SLIT compared to no treatment could not be determined (no cases reported in RCTs, insufficient evidence), three case reports suggest that rare cases may occur with SLIT treatment. Two of the three reports of anaphylaxis secondary to SLIT were in patients who received multiple-allergen therapy.
• No deaths secondary to SLIT therapy were reported (moderate SOE).

Table E

Summary of the strength of evidence for the safety of sublingual Immunotherapy.

Discussion

Our findings are consistent with our prior JHU EPC evidence report and other prior systematic reviews and support the efficacy of SCIT and SCIT for asthma in the allergic patient. The Cochrane review of SCIT concluded that it resulted in significant reduction in asthma symptoms and the need for asthma medications, as well as improvement in allergen-specific bronchial hyper-reactivity.⁴⁵ Our prior evidence report similarly concluded that there was high strength of evidence that SCIT reduces asthma symptoms and medication use.³ Both of these reviews noted the significant heterogeneity between the studies, as we found. In contrast, we could not draw conclusions about the effect of SCIT on asthma symptoms, as we limited our review to studies that used validated tools to measure asthma symptoms and identified none. A 2015 Cochrane review found there was low-quality evidence supporting the use of SLIT in changing ICS use and very low quality evidence regarding bronchial provocation.⁴⁶ This Cochrane review further noted that the largely non-validated asthma symptom scores, medications scores, and available data for quality of life precluded meaningful synthesis of these outcomes. Our prior evidence report examined SLIT in aqueous form only, and concluded that SLIT reduced asthma symptoms.³ This review expanded our scope to consider SLIT in tablet form and came to similar conclusions.

Future Research Needs

We were limited in our ability to synthesize results owing to lack of studies for specific populations, interventions, and outcomes; substantial heterogeneity; and limited reporting. We detail below specific areas for future research.

Conclusion

SCIT reduces the need for long-term control medication and may improve asthma-specific quality of life, use of quick-relief medications, systemic corticosteroids use, and FEV₁. SLIT improves asthma symptoms, reduces long-term control medication use, improves disease-specific quality of life, and may reduce the need for quick-relief medication and improve FEV₁. Local and systemic allergic reactions to SCIT and SLIT are common but infrequently required changes in treatment. Life-threatening events (such as anaphylaxis) are reported rarely. There is insufficient evidence on the comparative effectiveness of SCIT versus SLIT or for differential effects by patient age, type of allergen, or setting.

References

1.

Arbes SJJ, F. GPJ, Vaughn B, et al. Asthma cases attributable to atopy: results from the Third National Health and Nutrition Examination Survey. 2007(1097-6825 [Electronic]). [PMC free article: PMC2291202] [PubMed: 17889931]

2.

EPR-3. Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma-National Asthma Education and Prevention Program, Third Expert Panel on the Diagnosis and Management of Asthma. Washington, DC: National Heart, Lung, and Blood Institute; 2007. [PubMed: 17983880]

3.

Lin SY, Erekosima N, Suarez-Cuervo C, Ramanathan M, Kim JM, Ward D, Chelladurai Y, Segal JB. 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.) AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality. March 2013. Errata added May and August 2013. www​.effectivehealthcare​.ahrq.gov/reports/final.cfm. [PubMed: 23638484]

4.

Kilic M, Altintas DU, Yilmaz M, et al. Evaluation of efficacy of immunotherapy in children with asthma monosensitized to Alternaria. Turk J Pediatr. 2011 May-Jun;53(3):285-94. PMID: 21980810. [PubMed: 21980810]

5.

Lozano J, Cruz MJ, Piquer M, et al. Assessing the efficacy of immunotherapy with a glutaraldehyde-modified house dust mite extract in children by monitoring changes in clinical parameters and inflammatory markers in exhaled breath. Int Arch Allergy Immunol. 2014;165(2):140-7. doi: 10.1159/000368832. PMID: 25471080. [PubMed: 25471080] [CrossRef]

6.

Garcia-Robaina JC, Sanchez I, de la Torre F, et al. Successful management of mite-allergic asthma with modified extracts of Dermatophagoides pteronyssinus and Dermatophagoides farinae in a double-blind, placebo-controlled study. J Allergy Clin Immunol. 2006 Nov;118(5):1026-32. doi: 10.1016/j.jaci.2006.07.043. PMID: 17088125. [PubMed: 17088125] [CrossRef]

7.

Ameal A, Vega-Chicote JM, Fernandez S, et al. Double-blind and placebo-controlled study to assess efficacy and safety of a modified allergen extract of Dermatophagoides pteronyssinus in allergic asthma. Allergy. 2005 Sep;60(9):1178-83. doi: 10.1111/j.1398-9995.2005.00862.x. PMID: 16076305. [PubMed: 16076305] [CrossRef]

8.

Olsen OT, Larsen KR, Jacobsan L, et al. A 1-year, placebo-controlled, double-blind house-dust-mite immunotherapy study in asthmatic adults. Allergy. 1997 Aug;52(8):853-9. PMID: 9284985. [PubMed: 9284985]

9.

Baris S, Kiykim A, Ozen A, et al. Vitamin D as an adjunct to subcutaneous allergen immunotherapy in asthmatic children sensitized to house dust mite. Allergy. 2014 Feb;69(2):246-53. doi: 10.1111/all.12278. PMID: 24180595. [PubMed: 24180595] [CrossRef]

10.

Hui Y, Li L, Qian J, et al. Efficacy analysis of three-year subcutaneous SQ-standardized specific immunotherapy in house dust mite-allergic children with asthma. Exp Ther Med. 2014 Mar;7(3):630-4. doi: 10.3892/etm.2014.1469. PMID: 24520258. [PMC free article: PMC3919950] [PubMed: 24520258] [CrossRef]

11.

Adkinson NF, Jr., Eggleston PA, Eney D, et al. A controlled trial of immunotherapy for asthma in allergic children. N Engl J Med. 1997 Jan 30;336(5):324-31. doi: 10.1056/nejm199701303360502. PMID: 9011784. [PubMed: 9011784] [CrossRef]

12.

Pifferi M, Baldini G, Marrazzini G, et al. Benefits of immunotherapy with a standardized Dermatophagoides pteronyssinus extract in asthmatic children: a three-year prospective study. Allergy. 2002 Sep;57(9):785-90. PMID: 12169173. [PubMed: 12169173]

13.

Tsai TC, Lu JH, Chen SJ, et al. Clinical efficacy of house dust mite-specific immunotherapy in asthmatic children. Pediatr Neonatol. 2010 Feb;51(1):14-8. doi: 10.1016/s1875-9572(10)60004-6. PMID: 20225533. [PubMed: 20225533] [CrossRef]

14.

Wang H, Lin X, Hao C, et al. A double-blind, placebo-controlled study of house dust mite immunotherapy in Chinese asthmatic patients. Allergy. 2006 Feb;61(2):191-7. doi: 10.1111/j.1398-9995.2005.00913.x. PMID: 16409195. [PubMed: 16409195] [CrossRef]

15.

Bousquet J, Calvayrac P, Guerin B, et al. Immunotherapy with a standardized Dermatophagoides pteronyssinus extract. I. In vivo and in vitro parameters after a short course of treatment. J Allergy Clin Immunol. 1985 Nov;76(5):734-44. PMID: 4056259. [PubMed: 4056259]

16.

Alzakar RH, Alsamarai AM. Efficacy of immunotherapy for treatment of allergic asthma in children. Allergy Asthma Proc. 2010 Jul-Aug;31(4):324-30. doi: 10.2500/aap.2010.31.3353. PMID: 20819323. [PubMed: 20819323] [CrossRef]

17.

Zielen S, Kardos P, Madonini E. Steroid-sparing effects with allergen-specific immunotherapy in children with asthma: a randomized controlled trial. J Allergy Clin Immunol. 2010 Nov;126(5):942-9. doi: 10.1016/j.jaci.2010.06.002. PMID: 20624650. [PubMed: 20624650] [CrossRef]

18.

Casanovas M, Sastre J, Fernandez-Nieto M, et al. Double-blind study of tolerability and antibody production of unmodified and chemically modified allergen vaccines of Phleum pratense. Clin Exp Allergy. 2005 Oct;35(10):1377-83. doi: 10.1111/j.1365-2222.2005.02343.x. PMID: 16238799. [PubMed: 16238799] [CrossRef]

19.

Creticos PS, Reed CE, Norman PS, et al. Ragweed immunotherapy in adult asthma. N Engl J Med. 1996 Feb 22;334(8):501-6. doi: 10.1056/nejm199602223340804. PMID: 8559203. [PubMed: 8559203] [CrossRef]

20.

Confino-Cohen R, Goldberg A. Allergen immunotherapy-induced biphasic systemic reactions: incidence, characteristics, and outcome: a prospective study. Ann Allergy Asthma Immunol. 2010 Jan;104(1):73-8. doi: 10.1016/j.anai.2009.11.001. PMID: 20143649. [PubMed: 20143649] [CrossRef]

21.

Quiralte J, Justicia JL, Cardona V, et al. Is faster safer? Cluster versus short conventional subcutaneous allergen immunotherapy. Immunotherapy. 2013 Dec;5(12):1295-303. doi: 10.2217/imt.13.133. PMID: 24283840. [PubMed: 24283840] [CrossRef]

22.

Rank MA, Bernstein DI. Improving the safety of immunotherapy. J Allergy Clin Immunol Pract. 2014 Mar-Apr;2(2):131-5. doi: 10.1016/j.jaip.2013.09.017. PMID: 24607038. [PubMed: 24607038] [CrossRef]

23.

Sana A, Ben Salem C, Ahmed K, et al. Allergen specific immunotherapy induced multi-organ failure. Pan Afr Med J. 2013;14:155. doi: 10.11604/pamj.2013.14.155.1891. PMID: 23785560. [PMC free article: PMC3683521] [PubMed: 23785560] [CrossRef]

24.

Lim CE, Sison CP, Ponda P. Comparison of Pediatric and Adult Systemic Reactions to Subcutaneous Immunotherapy. J Allergy Clin Immunol Pract. 2017 Mar 21 doi: 10.1016/j.jaip.2017.01.014. PMID: 28341172. [PubMed: 28341172] [CrossRef]

25.

Virchow JC, Backer V, Kuna P, et al. Efficacy of a House Dust Mite Sublingual Allergen Immunotherapy Tablet in Adults With Allergic Asthma: A Randomized Clinical Trial. JAMA. 2016 Apr 26;315(16):1715-25. doi: 10.1001/jama.2016.3964. PMID: 27115376. [PubMed: 27115376] [CrossRef]

26.

de Blay F, Kuna P, Prieto L, et al. SQ HDM SLIT-tablet (ALK) in treatment of asthma--post hoc results from a randomised trial. Respir Med. 2014 Oct;108(10):1430-7. doi: 10.1016/j.rmed.2014.07.017. PMID: 25135744. [PubMed: 25135744] [CrossRef]

27.

Devillier P, Fadel R, de Beaumont O. House dust mite sublingual immunotherapy is safe in patients with mild-to-moderate, persistent asthma: a clinical trial. Allergy. 2016 Feb;71(2):249-57. doi: 10.1111/all.12791. PMID: 26465232. [PubMed: 26465232] [CrossRef]

28.

Marogna M, Braidi C, Bruno ME, et al. The contribution of sublingual immunotherapy to the achievement of control in birch-related mild persistent asthma: a real-life randomised trial. Allergol Immunopathol (Madr). 2013 Jul-Aug;41(4):216-24. doi: 10.1016/j.aller.2012.07.004. PMID: 23141837. [PubMed: 23141837] [CrossRef]

29.

Marogna M, Spadolini I, Massolo A, et al. Long-term comparison of sublingual immunotherapy vs inhaled budesonide in patients with mild persistent asthma due to grass pollen. Ann Allergy Asthma Immunol. 2009 Jan;102(1):69-75. doi: 10.1016/s1081-1206(10)60111-1. PMID: 19205289. [PubMed: 19205289] [CrossRef]

30.

Marogna M, Colombo F, Spadolini I, et al. Randomized open comparison of montelukast and sublingual immunotherapy as add-on treatment in moderate persistent asthma due to birch pollen. J Investig Allergol Clin Immunol. 2010;20(2):146-52. PMID: 20461969. [PubMed: 20461969]

31.

Niu CK, Chen WY, Huang JL, et al. Efficacy of sublingual immunotherapy with high-dose mite extracts in asthma: a multi-center, double-blind, randomized, and placebo-controlled study in Taiwan. Respir Med. 2006 Aug;100(8):1374-83. doi: 10.1016/j.rmed.2005.11.016. PMID: 16403616. [PubMed: 16403616] [CrossRef]

32.

Gómez VJ, Flores SG, Orea SM, et al. Safety and efficacy of specific sublingual immunotherapy in patients with asthma and allergy to Dermatophagoides pteronyssinus. Revista alergia Mexico (Tecamachalco, Puebla, Mexico: 1993). 2004;52(6):231-6. [PubMed: 16568708]

33.

Pham-Thi N, Scheinmann P, Fadel R, et al. Assessment of sublingual immunotherapy efficacy in children with house dust mite-induced allergic asthma optimally controlled by pharmacologic treatment and mite-avoidance measures. Pediatr Allergy Immunol. 2007 Feb;18(1):47-57. doi: 10.1111/j.1399-3038.2006.00475.x. PMID: 17295799. [PubMed: 17295799] [CrossRef]

34.

Lue KH, Lin YH, Sun HL, et al. Clinical and immunologic effects of sublingual immunotherapy in asthmatic children sensitized to mites: a double-blind, randomized, placebo-controlled study. Pediatr Allergy Immunol. 2006 Sep;17(6):408-15. doi: 10.1111/j.1399-3038.2006.00443.x. PMID: 16925685. [PubMed: 16925685] [CrossRef]

35.

Ippoliti F, De Santis W, Volterrani A, et al. Immunomodulation during sublingual therapy in allergic children. Pediatr Allergy Immunol. 2003 Jun;14(3):216-21. PMID: 12787302. [PubMed: 12787302]

36.

Calderon M, Essendrop M. Specific immunotherapy with high dose SO standardized grass allergen tablets was safe and well tolerated. J Investig Allergol Clin Immunol. 2006;16(6):338-44. PMID: 17153880. [PubMed: 17153880]

37.

Stelmach I, Kaczmarek-Wozniak J, Majak P, et al. Efficacy and safety of high-doses sublingual immunotherapy in ultra-rush scheme in children allergic to grass pollen. Clin Exp Allergy. 2009 Mar;39(3):401-8. doi: 10.1111/j.1365-2222.2008.03159.x. PMID: 19134016. [PubMed: 19134016] [CrossRef]

38.

Maloney J, Prenner BM, Bernstein DI, et al. Safety of house dust mite sublingual immunotherapy standardized quality tablet in children allergic to house dust mites. Ann Allergy Asthma Immunol. 2016 Jan;116(1):59-65. doi: 10.1016/j.anai.2015.10.024. PMID: 26553448. [PubMed: 26553448] [CrossRef]

39.

Shao J, Cui YX, Zheng YF, et al. Efficacy and safety of sublingual immunotherapy in children aged 3-13 years with allergic rhinitis. Am J Rhinol Allergy. 2014 Mar-Apr;28(2):131-9. doi: 10.2500/ajra.2014.28.4006. PMID: 24717951. [PubMed: 24717951] [CrossRef]

40.

Mosges R, Graute V, Christ H, et al. Safety of ultra-rush titration of sublingual immunotherapy in asthmatic children with tree-pollen allergy. Pediatr Allergy Immunol. 2010 Dec;21(8):1135-8. PMID: 21121080. [PubMed: 21121080]

41.

Blazowski L. Anaphylactic shock because of sublingual immunotherapy overdose during third year of maintenance dose. Allergy. 2008 Mar;63(3):374. doi: 10.1111/j.1398-9995.2007.01563.x. PMID: 18076729. [PubMed: 18076729] [CrossRef]

42.

Vovolis V, Kalogiros L, Mitsias D, et al. Severe repeated anaphylactic reactions to sublingual immunotherapy. Allergol Immunopathol (Madr). 2013 Jul-Aug;41(4):279-81. doi: 10.1016/j.aller.2012.05.012. PMID: 23253689. [PubMed: 23253689] [CrossRef]

43.

Dunsky EH, Goldstein MF, Dvorin DJ, et al. Anaphylaxis to sublingual immunotherapy. Allergy. 2006 Oct;61(10):1235. doi: 10.1111/j.1398-9995.2006.01137.x. PMID: 16942576. [PubMed: 16942576] [CrossRef]

44.

Bufe A, Eberle P, Franke-Beckmann E, et al. Safety and efficacy in children of an SQ-standardized grass allergen tablet for sublingual immunotherapy. J Allergy Clin Immunol. 2009 Jan;123(1):167-73 e7. doi: 10.1016/j.jaci.2008.10.044. PMID: 19130937. [PubMed: 19130937] [CrossRef]

45.

Abramson MJ, Puy RM, Weiner JM. Injection allergen immunotherapy for asthma. Cochrane Database Syst Rev. 2010(8):CD001186. doi: 10.1002/14651858.CD001186.pub2. PMID: 20687065. [PubMed: 20687065] [CrossRef]

46.

Normansell R, Kew KM, Bridgman AL. Sublingual immunotherapy for asthma. Cochrane Database Syst Rev. 2015(8):CD011293. doi: 10.1002/14651858.CD011293.pub2. PMID: 26315994. [PMC free article: PMC6769158] [PubMed: 26315994] [CrossRef]