Allergy Immunotherapy


Continuing Education Activity

Allergy immunotherapy (AIT), which is also termed allergen desensitization or hypo-sensitization was first introduced by Leonard Noon and John Freeman in 1911. They proposed that people with hay fever were sensitive to grass pollen toxins. Desensitization is "a method, to develop a temporary state of tolerance to an agent responsible for an allergic or hypersensitivity reaction." This activity reviews the indications, contraindications, and techniques for allergy immunotherapy and highlights the role of the interprofessional team in the management of patients with allergies.

Objectives:

  • Describe the indications for allergy immunotherapy.
  • Describe how allergy immunotherapy is done.
  • Outline the importance of collaboration and coordination within the interprofessional team in optimizing the care of patients requiring allergy immunotherapy.
  • Discuss future trends in allergy immunotherapy

Introduction

Allergy immunotherapy (AIT),  also referred to as allergen desensitization or hypo-sensitization was first introduced by Leonard Noon and John Freeman in 1911, they proposed that people with hay fever were sensitive to grass pollen toxins. [1]Noon is credited for developing a process involved in the extraction of timothy pollen in distilled water and then boiling it to create an extract. [1] This extract was then injected in increasing doses to alleviate symptoms in patients.  This concept is widely in use today with a modified approach. Currently, the term immunotherapy is used to describe all methods to overcome abnormal immune responses with induction of clonal deletion, anergy, immune tolerance, and immune deviation. [2]However, the term desensitization is "a method, to develop a temporary state of tolerance to an agent responsible for an allergic or hypersensitivity reaction." [3]Furthermore, immunotherapy is a disease-modifying treatment and the effects can last longer even after stopping the treatment, which then provides prophylactic effects.[3][4][5][6][7][8]

Anatomy and Physiology

Several cellular and molecular mechanisms explain the beneficial effects of immunotherapy including allergic specific suppression of inducible CD4(+), CD 25+, forkhead box p3+ T-regulatory cells, and IL-10 secreting T-regulatory cells, preventing their increase in peripheral blood. Other mechanisms include suppression of eosinophils, mast cells, and basophils, and the switching of antibodies from IgE to IgG4 blocking antibodies.[9][10][11]Other mechanisms, including a switch from a TH2 to a THI  immune deviation,  and other changes in humoral/cellular immunity, are still being elucidated.[10][12][13][12]

Indications

Indications for Allergen Immunotherapy[2][3]

  • Moderate-to-severe allergic rhinitis
  • Allergic asthma
  • Allergic conjunctivitis
  • Allergic rhino-conjunctivitis
  • Atopic dermatitis
  • Immune-mediated and IgE-mediated food allergy
  • Insect allergy that causes significant local reaction and anaphylaxis

Note: Allergen immunotherapy is only indicated when there is evidence of an IgE-mediated reaction that correlates with clinical symptoms. These IgE-mediated reactions can be identified via a blood IgE test or the more preferable skin testing.

Other Immunotherapies[3]

  • Vaccination and biological agents in infectious disease and primary immunodeficiencies.
  • Immunosuppressive agents in autoimmune disease and organ transplant
  • Biological and monoclonal agents
  • Food hypersensitivity

Contraindications

There is no evidence to suggest that immunotherapy will be effective if a specific IgE antibody is negative.[3]  Furthermore, if IgE testing results are positive but suspected clinical symptoms and exposure do not correlate, then it is also not likely to work.

The use of concomitant B-blockers is contraindicated with immunotherapy in the rare chance that the patient needs epinephrine to treat anaphylaxis. However, according to the U.S. practice parameters on anaphylaxis, the benefits of Hymenoptera venom immunotherapy (VIT) outweigh the potential risks associated with b-blockers or ACEIs in patients with anaphylaxis to stinging insects who also have cardiovascular disease that requires these medications. [14] As per the EAACI guidelines, the risk/benefit profile also suggests that there should be no contraindication for venom immunotherapy in patients on B-blockers. [15]

If a patient is having an asthma exacerbation, they should not receive an immunotherapy injection [2]

Equipment

Required Equipment and Procedures[3]

  • All extracts require storage in a refrigerator at 4 C
  • Administration can be done via subcutaneous injection or sublingually
  • Seventy percent isopropanol for sanitization
  • Sterile syringes and vials
  • Mixing log with information on expiration
  • Policy and procedure manual
  • Emergency treatment, i.e epinephrine

Personnel

Because allergy immunotherapy can cause severe reactions, including anaphylaxis, a physician should supervise trained personnel.[2] Required training include:[2]

  • Preparation of allergenic products
  • Successful completion of a written test on aseptic technique and extract preparation and media-fill testing
  • Knowledge of antiseptic hand cleaning and disinfection of mixing surfaces
  • Ability to identify, measure, and mix different allergen extracts
  • Understand who are the appropriate candidates for allergy immunotherapy
  • Review with the patients the risk and benefits of the procedure
  • Learn to identify signs and symptoms of a possible severe reaction
  • Discuss with the patient what are some expectations during the course of treatment and when it will be successfully completed

Preparation

The prescribing physician should select allergen extracts based on IgE results and clinical correlation. The physician should consider several important factors including the quality of allergen extracts, cross-reactivity, and degradation of allergens and immunotherapy doses, for example, the starting dose should be lower than the maintenance dose.[2] Keep in mind that some patients will not be able to achieve the maintenance dose due to possible side effects. There are also ranges of what are considered maintenance doses for standardized and non-standardized extracts.

Technique

Allergenic proteins from pollen, dander, dust mites, insects, mold, among others are the main ingredient of allergen extract. However, the final product is a mixture of diluents or solvents and preservatives. Different extracts including aqueous, glycerinated, lyophilized, acetone precipitated, alum-precipitated are available. Diluents will keep the allergen in liquid form; commonly used agents are glycerin, phenol saline, and HSA. The staff should use measures that include good personal hygiene, hand washing, and antiseptics to clean working areas. These include a water-based disinfectant followed by the application of alcohol on working surfaces for preparing allergen extracts. Alcohol kills organisms by dehydration. Sanitization will prevent bacterial contamination.[2]

Complications

Giving allergy immunotherapy should be given with tremendous care since it involves administering an agent that a patient is already known to be allergic to. Complications due to immunotherapy include systemic reactions such as anaphylaxis, large cutaneous reactions, and a local reaction at the injection site. [2] Although rare, even fatal reactions to subcutaneous allergy immunotherapy can occur.  One of the greatest risk factors for such reactions is asthma, especially uncontrolled or unstable asthma.[16][17]   Another risk factor is an accidental intramuscular injection which can cause an increased risk of systemic reaction due to rapid absorption. Sublingual administration has only shown severe reactions associated with the first dose and subsequent doses cause less severe symptoms of the oral mucosa, throat, or gastrointestinal tract. [18][19]  Due to these complications, patients must be aware of the risk vs benefits associated with immunotherapy. Thus, immunotherapy should be given under the guidance of a specialist trained in the field and informed consent should be gathered.

Management of Complications [2]

  • Topical corticosteroids, antihistamines, or cool compresses for local reaction
  • Epinephrine is the mainstay treatment for anaphylaxis.

The physician should re-visit the benefit versus risk of continuing immunotherapy after systemic reactions.[2]

Clinical Significance

Asthma

Allergen immunotherapy can reduce short-term symptoms in allergic asthma; however, there is a moderate increase in the risk of systemic and local reactions based on a meta-analysis.[6] A 3-year course of either sublingual or subcutaneous immunotherapy prevents asthma for up to 2 years in children and adolescents with grass/birch pollen that triggers moderate to severe allergic rhinitis. However, this still requires further research.[4]

Some studies have shown that giving immunotherapy for allergic rhinitis early can prevent the development of asthma in children. [20][21][22] A study by Grembiale in 2000 showed that allergy immunotherapy to house dust mite helped to prevent the development of asthma.[22]  In the preventative asthma study(PAT) children aged 5 to 12 years were given a subcutaneous injection of grass pollen and/or birch pollen for 3 years and was found to have a decrease in the development of asthma over a 10 year follow up. [20] In the Grass pollen asthma prevention trial (GAP), sublingual treatment with grass pollen also showed reduced asthma symptoms and medication scores.[21]

Allergic Rhinitis

  • Allergen immunotherapy is clinically effective, cost-effective, and disease-modifying in allergic rhinitis compared to standard drugs.[23][24]
  • Sublingual immunotherapy for pediatric allergic rhinitis has shown improvement in symptomatic management and a decreased medication need based on a meta-analysis of the randomized controlled trials. More trials with a larger sample size are underway to assess safety in the pediatric population.[25]

Allergic Rhino-Conjunctivitis

Allergen immunotherapy is beneficial in ameliorating rhino-conjunctivitis symptoms. [26]Some evidence suggests that there is a maintenance effect on reducing symptoms after discontinuation of immunotherapy.[27]

Enhancing Healthcare Team Outcomes

Current and Future Trends in Allergen Immunotherapy

 Recent advances in understanding the mechanism and the long-term effects of immunotherapy are encouraging for future therapies. There are also new approaches being used to improve safety and overcoming the risk of severe adverse allergic reactions during immunotherapy. Newer allergen preparations available include allergoids, recombinant allergens (recA), and modified-recombinant allergens (recA). Studies on virus-like particles and CpG-motifs, adjuvants like MPL, and aluminum hydroxide have been shown to increase immunological response and can improve safety and efficacy.[8]  Other newer approaches to allergen immunotherapy include the application of extract patches on the skin and/or inguinal lymph node injection. Furthermore, recombinant technology or chemicals may alter allergen molecules that make them less reactive; this may be due to suppression of Th2 responses or stimulation of toll-like receptors (approval is pending).[28] The new advances in allergy immunotherapy not only provide disease-modifying treatments but are also cost-effective and improve the quality of life.[29] Yet, with the historical efficacy and safety of immunotherapy, it remains underutilized.

Safety, Doses, Delivery, and Application of Immunotherapy 

  • Comparison of pediatric and adult systemic reactions to subcutaneous immunotherapy shows significant Grade 1 and Grade 2 systemic reactions that are higher in a pediatric population than adults. However, further studies are needed to evaluate the dosing strategy in children.[30]
  • Subcutaneous allergen immunotherapy has shown that SCIT rarely causes any major clinical problems; there is a risk of less than 1.5% in patients who are HIV positive without AIDS, cancer (in remission), severe asthma, transplantation,  and during pregnancy, based on web-based survey.[31]
  • Food immunotherapy has exploded due to numerous studies suggestive of its benefit.  One such study was the LEAP (Learning Early About Peanut Allergy) that showed that high-risk infants with atopic dermatitis and egg allergy were able to build a tolerance to the ingestion of peanut if given early.[32] Studies investigating oral immunotherapy with other foods and various delivery methods are currently being done.

Future trends in allergy immunotherapy support the concept of precision medicine. It should always be individualized and specific for a particular patient. Although it has been shown to prevent the development of asthma and new sensitization, this has only been shown in children. On the other hand, adults should be evaluated differently, and it should be used for the primary objective of bringing relief to their allergic symptoms. Further research is needed to address research gaps in allergy immunotherapy.  Such gaps include which sensitivities should be targeted to prevent disease, timing of immunotherapy, length of treatment, monoallergen vs polyallergen treatment, etc. However, the future is exciting, and with the increasing understanding of the immune system, the age of precision medicine has arrived.

Nursing, Allied Health, and Interprofessional Team Interventions

When using allergy immunotherapy, an interprofessional team including clinicians, mid-level practitioners nursing staff, and pharmacists is the best approach to achieving improved patient outcomes.

Nursing, Allied Health, and Interprofessional Team Monitoring

When administering allergy immunotherapy, an interprofessional team including clinicians, mid-level practitioners, and nursing staff should be vigilant in looking for signs of an allergic reaction. 


Article Details

Article Author

Yudy Persaud

Article Author

Ruba Memon

Article Editor:

Mohammedi Savliwala

Updated:

5/12/2021 11:12:45 AM

PubMed Link:

Allergy Immunotherapy

References

[1]

NOON L, Prophylactic inoculation against hay fever (historical document). Annals of allergy. 1955 Nov-Dec     [PubMed PMID: 13268980]

[2]

Cox L,Nelson H,Lockey R,Calabria C,Chacko T,Finegold I,Nelson M,Weber R,Bernstein DI,Blessing-Moore J,Khan DA,Lang DM,Nicklas RA,Oppenheimer J,Portnoy JM,Randolph C,Schuller DE,Spector SL,Tilles S,Wallace D, Allergen immunotherapy: a practice parameter third update. The Journal of allergy and clinical immunology. 2011 Jan     [PubMed PMID: 21122901]

[3]

Tanno LK,Calderon MA,Papadopoulos NG,Sanchez-Borges M,Rosenwasser LJ,Bousquet J,Pawankar R,Sisul JC,Cepeda AM,Li J,Muraro A,Fineman S,Sublett JL,Katelaris CH,Chang YS,Moon HB,Casale T,Demoly P, Revisiting Desensitization and Allergen Immunotherapy Concepts for the International Classification of Diseases (ICD)-11. The journal of allergy and clinical immunology. In practice. 2016 Jul-Aug     [PubMed PMID: 26969269]

[4]

Halken S,Larenas-Linnemann D,Roberts G,Calderón MA,Angier E,Pfaar O,Ryan D,Agache I,Ansotegui IJ,Arasi S,Du Toit G,Fernandez-Rivas M,Geerth van Wijk R,Jutel M,Kleine-Tebbe J,Lau S,Matricardi PM,Pajno GB,Papadopoulos NG,Penagos M,Santos AF,Sturm GJ,Timmermans F,van Ree R,Varga EM,Wahn U,Kristiansen M,Dhami S,Sheikh A,Muraro A, EAACI guidelines on allergen immunotherapy: Prevention of allergy. Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology. 2017 Dec     [PubMed PMID: 28902467]

[5]

Di Lorenzo G,Leto-Barone MS,La Piana S,Plaia A,Di Bona D, The effect of allergen immunotherapy in the onset of new sensitizations: a meta-analysis. International forum of allergy     [PubMed PMID: 28544523]

[6]

Dhami S,Kakourou A,Asamoah F,Agache I,Lau S,Jutel M,Muraro A,Roberts G,Akdis CA,Bonini M,Cavkaytar O,Flood B,Gajdanowicz P,Izuhara K,Kalayci Ö,Mosges R,Palomares O,Pfaar O,Smolinska S,Sokolowska M,Asaria M,Netuveli G,Zaman H,Akhlaq A,Sheikh A, Allergen immunotherapy for allergic asthma: A systematic review and meta-analysis. Allergy. 2017 Dec     [PubMed PMID: 28543086]

[7]

Kristiansen M,Dhami S,Netuveli G,Halken S,Muraro A,Roberts G,Larenas-Linnemann D,Calderón MA,Penagos M,Du Toit G,Ansotegui IJ,Kleine-Tebbe J,Lau S,Matricardi PM,Pajno G,Papadopoulos NG,Pfaar O,Ryan D,Santos AF,Timmermanns F,Wahn U,Sheikh A, Allergen immunotherapy for the prevention of allergy: A systematic review and meta-analysis. Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology. 2017 Feb     [PubMed PMID: 27653623]

[8]

Klimek L,Pfaar O,Bousquet J,Senti G,Kündig T, Allergen immunotherapy in allergic rhinitis: current use and future trends. Expert review of clinical immunology. 2017 Sep     [PubMed PMID: 28532268]

[9]

Jutel M,Akdis CA, Immunological mechanisms of allergen-specific immunotherapy. Allergy. 2011 Jun     [PubMed PMID: 21466562]

[10]

James LK,Durham SR, Update on mechanisms of allergen injection immunotherapy. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. 2008 Jul     [PubMed PMID: 18691292]

[11]

van de Veen W,Stanic B,Yaman G,Wawrzyniak M,Söllner S,Akdis DG,Rückert B,Akdis CA,Akdis M, IgG4 production is confined to human IL-10-producing regulatory B cells that suppress antigen-specific immune responses. The Journal of allergy and clinical immunology. 2013 Apr     [PubMed PMID: 23453135]

[12]

Shamji MH,Durham SR, Mechanisms of allergen immunotherapy for inhaled allergens and predictive biomarkers. The Journal of allergy and clinical immunology. 2017 Dec     [PubMed PMID: 29221580]

[13]

Gold MJ,Antignano F,Halim TY,Hirota JA,Blanchet MR,Zaph C,Takei F,McNagny KM, Group 2 innate lymphoid cells facilitate sensitization to local, but not systemic, TH2-inducing allergen exposures. The Journal of allergy and clinical immunology. 2014 Apr     [PubMed PMID: 24679471]

[14]

Lieberman P,Nicklas RA,Randolph C,Oppenheimer J,Bernstein D,Bernstein J,Ellis A,Golden DB,Greenberger P,Kemp S,Khan D,Ledford D,Lieberman J,Metcalfe D,Nowak-Wegrzyn A,Sicherer S,Wallace D,Blessing-Moore J,Lang D,Portnoy JM,Schuller D,Spector S,Tilles SA, Anaphylaxis--a practice parameter update 2015. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology. 2015 Nov     [PubMed PMID: 26505932]

[15]

Sturm GJ,Varga EM,Roberts G,Mosbech H,Bilò MB,Akdis CA,Antolín-Amérigo D,Cichocka-Jarosz E,Gawlik R,Jakob T,Kosnik M,Lange J,Mingomataj E,Mitsias DI,Ollert M,Oude Elberink JNG,Pfaar O,Pitsios C,Pravettoni V,Ruëff F,Sin BA,Agache I,Angier E,Arasi S,Calderón MA,Fernandez-Rivas M,Halken S,Jutel M,Lau S,Pajno GB,van Ree R,Ryan D,Spranger O,van Wijk RG,Dhami S,Zaman H,Sheikh A,Muraro A, EAACI guidelines on allergen immunotherapy: Hymenoptera venom allergy. Allergy. 2018 Apr     [PubMed PMID: 28748641]

[16]

Reid MJ,Lockey RF,Turkeltaub PC,Platts-Mills TA, Survey of fatalities from skin testing and immunotherapy 1985-1989. The Journal of allergy and clinical immunology. 1993 Jul     [PubMed PMID: 8335856]

[17]

Bernstein DI,Wanner M,Borish L,Liss GM,Immunotherapy Committee, American Academy of Allergy, Asthma and Immunology., Twelve-year survey of fatal reactions to allergen injections and skin testing: 1990-2001. The Journal of allergy and clinical immunology. 2004 Jun;     [PubMed PMID: 15208595]

[18]

Bernstein DI,Bardelas JA Jr,Svanholm Fogh B,Kaur A,Li Z,Nolte H, A practical guide to the sublingual immunotherapy tablet adverse event profile: implications for clinical practice. Postgraduate medicine. 2017 Aug;     [PubMed PMID: 28326906]

[19]

Nolte H,Casale TB,Lockey RF,Fogh BS,Kaur A,Lu S,Nelson HS, Epinephrine Use in Clinical Trials of Sublingual Immunotherapy Tablets. The journal of allergy and clinical immunology. In practice. 2017 Jan - Feb     [PubMed PMID: 27838323]

[20]

Jacobsen L,Niggemann B,Dreborg S,Ferdousi HA,Halken S,Høst A,Koivikko A,Norberg LA,Valovirta E,Wahn U,Möller C,(The PAT investigator group)., Specific immunotherapy has long-term preventive effect of seasonal and perennial asthma: 10-year follow-up on the PAT study. Allergy. 2007 Aug     [PubMed PMID: 17620073]

[21]

Valovirta E,Petersen TH,Piotrowska T,Laursen MK,Andersen JS,Sørensen HF,Klink R,GAP investigators., Results from the 5-year SQ grass sublingual immunotherapy tablet asthma prevention (GAP) trial in children with grass pollen allergy. The Journal of allergy and clinical immunology. 2018 Feb     [PubMed PMID: 28689794]

[22]

Grembiale RD,Camporota L,Naty S,Tranfa CM,Djukanovic R,Marsico SA, Effects of specific immunotherapy in allergic rhinitic individuals with bronchial hyperresponsiveness. American journal of respiratory and critical care medicine. 2000 Dec     [PubMed PMID: 11112112]

[23]

Cox L, The role of allergen immunotherapy in the management of allergic rhinitis. American journal of rhinology     [PubMed PMID: 26867530]

[24]

Nelson HS,Makatsori M,Calderon MA, Subcutaneous Immunotherapy and Sublingual Immunotherapy: Comparative Efficacy, Current and Potential Indications, and Warnings--United States Versus Europe. Immunology and allergy clinics of North America. 2016 Feb     [PubMed PMID: 26617224]

[25]

Feng B,Wu J,Chen B,Xiang H,Chen R,Li B,Chen S, Efficacy and safety of sublingual immunotherapy for allergic rhinitis in pediatric patients: A meta-analysis of randomized controlled trials. American journal of rhinology     [PubMed PMID: 28234149]

[26]

Pfaar O,Demoly P,Gerth van Wijk R,Bonini S,Bousquet J,Canonica GW,Durham SR,Jacobsen L,Malling HJ,Mösges R,Papadopoulos NG,Rak S,Rodriguez del Rio P,Valovirta E,Wahn U,Calderon MA, Recommendations for the standardization of clinical outcomes used in allergen immunotherapy trials for allergic rhinoconjunctivitis: an EAACI Position Paper. Allergy. 2014 Jul     [PubMed PMID: 24761804]

[27]

Dhami S,Nurmatov U,Arasi S,Khan T,Asaria M,Zaman H,Agarwal A,Netuveli G,Roberts G,Pfaar O,Muraro A,Ansotegui IJ,Calderon M,Cingi C,Durham S,van Wijk RG,Halken S,Hamelmann E,Hellings P,Jacobsen L,Knol E,Larenas-Linnemann D,Lin S,Maggina P,Mösges R,Oude Elberink H,Pajno G,Panwankar R,Pastorello E,Penagos M,Pitsios C,Rotiroti G,Timmermans F,Tsilochristou O,Varga EM,Schmidt-Weber C,Wilkinson J,Williams A,Worm M,Zhang L,Sheikh A, Allergen immunotherapy for allergic rhinoconjunctivitis: A systematic review and meta-analysis. Allergy. 2017 Nov     [PubMed PMID: 28493631]

[28]

Nelson HS, Allergen immunotherapy now and in the future. Allergy and asthma proceedings. 2016 Jul     [PubMed PMID: 27401313]

[29]

Reisacher WR,Schwanke T, New advances in allergy immunotherapy. Current opinion in otolaryngology     [PubMed PMID: 26926847]

[30]

Lim CE,Sison CP,Ponda P, Comparison of Pediatric and Adult Systemic Reactions to Subcutaneous Immunotherapy. The journal of allergy and clinical immunology. In practice. 2017 Sep - Oct     [PubMed PMID: 28341172]

[31]

Larenas-Linnemann DE,Hauswirth DW,Calabria CW,Sher LD,Rank MA, American Academy of Allergy, Asthma & Immunology membership experience with allergen immunotherapy safety in patients with specific medical conditions. Allergy and asthma proceedings. 2016 Sep     [PubMed PMID: 27657518]

[32]

Du Toit G,Sayre PH,Roberts G,Sever ML,Lawson K,Bahnson HT,Brough HA,Santos AF,Harris KM,Radulovic S,Basting M,Turcanu V,Plaut M,Lack G,Immune Tolerance Network LEAP-On Study Team., Effect of Avoidance on Peanut Allergy after Early Peanut Consumption. The New England journal of medicine. 2016 Apr 14     [PubMed PMID: 26942922]