Allergen Immunotherapy  

Allergen Immunotherapy – 6 Interesting Facts

1. •Allergen immunotherapy is the term used to describe a prolonged process of repeated administration of allergen extracts to reduce symptoms in patients with allergic disease and confirmed relevant allergic sensitization. It is also termed desensitization, referring to the process of attenuating the allergic response over time.
2. •Immunotherapy is a disease-modifying treatment and is a key therapeutic option for several allergic diseases, along with allergen avoidance and symptomatic drug therapy.
3. •Desensitization refers to a diminished state of clinical reactivity dependent on continued allergen exposure. Although the term tolerance has been used to refer to the more enduring hyporesponsive clinical and immunologic state induced by treatment, sustained unresponsiveness may be a more accurate term, in that the duration of this state is largely unknown and may vary according to allergen, disease state, and host. ¹
4. •Clinical effectiveness in allergen immunotherapy is antigen specific and dose dependent. A patient’s response to treatment depends on proper identification of relevant allergens based on history, exposure, and presence of specific immunoglobulin E (IgE). A certain minimal dose of allergen extract must be administered to produce effective symptomatic control or reduced risk of systemic allergic reaction. ¹
5. •Clinical benefit increases for several years after the maximal doses of antigens are achieved. It is important to note, however, that single-dose sublingual immunotherapy has a more rapid onset of action, likely because no build-up phase is required, and is efficacious when given only part of the year, before and during the relevant pollen season.
6. •For clinicians, it is also important to recognize that there is a significant and powerful placebo effect associated with the repeated injections and frequent visits with sympathetic physicians and nurses. In clinical trials when symptom scores are compared with those in untreated patients, a placebo effect is consistently seen. The placebo effect is especially easy to see in the asthma trials, in which most placebo-treated patients improve and 25% to 30% improve significantly. ²

Pathophysiology

• •The precise mechanism of action of immunotherapy remains unknown.
• •Suppression of mast cell and basophil activity is seen early in treatment, followed by the appearance of regulatory T and B cells and suppression of T _H 1 and T _H 2 responses. Specific IgE levels initially increase and gradually decrease late in treatment in some patients. Allergen-specific IgG and IgG4 levels increase early in treatment and continue to rise throughout treatment. Late changes include decreased numbers of tissue mast cells and eosinophils, reflected in decreased skin test reactivity. ³
• •There is an early and prolonged increase in allergen-specific IgE, with a slow decline months to years after starting immunotherapy. In contrast, allergen-specific IgG levels increase within months of starting immunotherapy and remain elevated, with allergen-specific IgG4 becoming more prominent than other isotypes. ¹
• •Allergen immunotherapy also induces a shift toward a regulatory B cell phenotype, resulting in suppression of proinflammatory cytokines via production of interleukin-10 (IL-10) and induction of IgG4 production. ³ It has been suggested that allergen-specific IgG acts as a blocking antibody by either blocking antigen binding by IgE or preventing aggregation of the high-affinity IgE receptor (FcεRI) at the cell surface.
• Although allergen-specific IgG levels do not correlate with clinical efficacy, the functional blocking activity of allergen-specific IgG does appear to correlate with clinical efficacy, and the absence of allergen-specific IgG is associated with lack of clinical response. ⁴
• •Because a T _H 2 phenotype has been associated with allergic disease and a T _H 1 phenotype with protection against allergic disease, it has been hypothesized that immunotherapy exerts its effects through modulation of the T helper phenotype. There also is evidence that immunotherapy affects mast cells, basophils, and eosinophils. ³

Patient Selection

• •Patient selection must take into account several different variables, including medical criteria, patient/family preference, adherence, medication requirement and response, adverse effects of medications versus immunotherapy, and desire to reduce need for medications.
• Other aspects of the patient’s history should be taken into consideration.
• For example, successful immunotherapy requires that a patient be able to visit a physician’s office weekly and spend a minimum of 30 minutes there. Certain medications, such as β-blockers and angiotensin-converting enzyme inhibitors, put a patient at higher risk for systemic reactions to immunotherapy. ⁵
• •Although allergen immunotherapy (AIT) was initially administered by the subcutaneous route, sublingual immunotherapy (SLIT) has proved to be efficacious, and direct comparisons suggest comparable reductions in symptom scores and drug reductions.
• Subcutaneous immunotherapy must be administered by a physician who is experienced in its use, and there is a small risk of systemic reactions.
• Therefore, the office needs to be set up to deal with the management of adverse allergic reactions, including anaphylaxis. The time of application varies by the individual product. The sequence of immunologic events is characterized by a typical sequence of events. Initially desensitization takes place.
• Moreover, a transient expansion of the type 2 responses kicks in that is paralleled by the generation of allergen-specific regulatory T cells, the exhaustion of effector cells, and the generation of blocking antibodies of an IgA, IgG, and specifically IgG4 type. At a later stage, allergen sIgE tends to decline. The standard duration of AIT is 3 yr. The improvement in symptoms persists for several years after the treatment is discontinued. ¹
• •It is also important to detail response rate and timeline to response, namely the delayed effect of immunotherapy, so patients have realistic expectations.
• Although immunotherapy is highly effective with careful patient selection, for most patients symptomatic improvement is partial and immunotherapy serves to decrease the severity of symptoms without totally eliminating them.
• In addition, a significant number of allergic patients, perhaps as many as 25%, do not benefit from immunotherapy regardless of the potency of the antigen or the length of therapy.
• The reasons why certain patients are “nonresponders” are unclear, but the point is an important one to bear in mind when discussing immunotherapy with patients. ¹

Allergen Extracts for Immunotherapy

• •Allergen extracts are prepared by extracting bulk source materials (e.g., pollens, mite cultures, fungal cultures) in aqueous buffers; typically the potency of these extracts is expressed in a ratio of the weight of source material extracted to the extraction volume, such as 1:10 weight to volume (wt/v).
• Variations in the bulk sources and in the manufacturing process have led to vast differences in the quantity of active allergens in these extracts.
• A second approach to labeling is based on the total protein content of the extract and is expressed in protein nitrogen units (PNUs); this method has little relationship to allergenic potency but is still commonly used in the United States. ¹

Indications for Immunotherapy

Allergic Rhinitis:

• •Immunotherapy should be considered for patients with clear evidence of IgE-mediated symptoms who have not been adequately controlled with first-line medical therapy, including antihistamines, nasal corticosteroids, and ocular antihistamines or antiinflammatory medications. ¹
• •Subcutaneous immunotherapy has been demonstrated to be quite effective in both seasonal and perennial allergic rhinitis. Immunotherapy also has been shown to be effective for mite-induced perennial allergic rhinitis and also may be effective in mold-induced rhinitis. ⁶ 
• Sublingual immunotherapy tablets have also been approved for treatment of allergic rhinitis with or without allergic conjunctivitis in pediatric patients with allergy to northern pasture grasses.

Asthma:

• •Patients must have demonstrable IgE to allergens to which they are exposed and a clinical history of exacerbation of asthma symptoms with exposure to the allergens.
• However, IgE-mediated mechanisms are only part of the underlying pathophysiology of asthma, making the rationale for immunotherapy as a treatment option in allergic asthma less straightforward.
• •Immunotherapy may be appropriate for treating asthma that has been difficult to control and is recommended as add-on therapy in the current asthma guidelines, but it should not be prescribed for patients with unstable asthma and an FEV ₁ less than 70% of predicted because of safety concerns. ⁵ 
• The most recent National Asthma Education and Prevention Program Coordinating Committee (NASEPPCC) Expert Panel recommendations state that in individuals ages 5 yr and older with mild to moderate allergic asthma the use of subcutaneous immunotherapy (SLIT) as an adjunct treatment to standard pharmacotherapy is appropriate in those individuals whose asthma is controlled.
• However, in individuals with persistent allergic asthma, the Expert Panel did not find that SLIT reduced asthma symptoms or improved asthma control or asthma quality of life. ⁷

Stinging Insect:

• •Immunotherapy for venom allergy is highly efficacious, affording protection for more than 95% of individuals undergoing treatment. ⁸
• •Although VIT is indicated in adults with evidence of IgE to Hymenoptera venom and a history of a systemic reaction to Hymenoptera , the indications in children are somewhat different. VIT has been reserved for those children who have had symptoms beyond systemic cutaneous reactions to Hymenoptera and evidence of IgE to Hymenoptera venom, though it may be considered if requested by the child’s parents or if frequent stings are anticipated. ⁹
• •Immunotherapy also can be considered in children with generalized cutaneous reactions to fire ant stings because less is known about the natural history of fire ant allergy and risk of reexposure is generally high in endemic areas. ⁹

Food:

• •Although immunotherapy is not currently an approved treatment for food allergy, it is an area of active investigation, with evidence suggesting that first-generation treatments may be available for clinical use in the near future.
• Large phase 3 studies of oral ¹⁰ and epicutaneous ¹¹ immunotherapy for peanut allergy have demonstrated desensitization in approximately 67% and 35% of subjects, respectively.
• These studies and others indicate immunotherapy shows promise, though several important questions remain, including optimal dose, frequency, and length of treatment. ¹²

Reactions to Immunotherapy

• The risks of immunotherapy are not trivial.
• The American Academy of Asthma, Allergy and Immunology and the American College of Asthma, Allergy, and Immunology initiated a surveillance program of immunotherapy reactions in 2008, and the most recent results indicate a rate of 1 in 1 million injections for near-fatal reactions and 1 in 1000 injections for systemic reactions. ¹³

References

1. Varshney P., Matsui E.C.: Immunotherapy for allergic disease . In Leung D.Y.M., et al. (eds): 2021. Elsevier , Philadelphia
2. Warner J.O., Price J.F., Soothill J.F., Hey E.N.: Controlled trial of hyposensitisation to Dermatophagoides pteronyssinus in children with asthma . Lancet (London, England) 1978; 2 (8096): pp. 912-915.
3. Akdis M., Akdis C.A.: Mechanisms of allergen-specific immunotherapy: multiple suppressor factors at work in immune tolerance to allergens . J Allergy Clin Immunol 2014; 133 (3): pp. 621-631.
4. Eifan A.O., Shamji M.H., Durham S.R.: Long-term clinical and immunological effects of allergen immunotherapy . Curr Opin Allergy Clin Immunol 2011; 11 (6): pp. 586-593.
5. Cox L., Nelson H., Lockey R., et al.: Allergen immunotherapy: a practice parameter third update . J Allergy Clin Immunol 2011; 127 (Suppl 1): pp. S1-S55.
6. Calderon M.A., Alves B., Jacobson M., Hurwitz B., Sheikh A., Durham S.: Allergen injection immunotherapy for seasonal allergic rhinitis . Cochrane Database Syst Rev 2007; 1: pp. CD001936.
7. NAEPPCC Expert Panel Working Group : Focused updates to the asthma management guidelines: a report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group . J Allergy Clin Immunol 2020; 146: pp. 1217-1270.
8. Hunt K.J., Valentine M.D., Sobotka A.K., Benton A.W., Amodio F.J., Lichtenstein L.M.: A controlled trial of immunotherapy in insect hypersensitivity . N Engl J Med 1978; 299 (4): pp. 157-161.
9. Golden D.B., Moffitt J., Nicklas R.A., et al.: Stinging insect hypersensitivity: a practice parameter update 2011 . J Allergy Clin Immunol 2011; 127 (4): pp. 852-854.
10. Vickery B.P., Vereda A., Casale T.B., et al.: AR101 oral immunotherapy for peanut allergy . N Engl J Med 2018; 379 (21): pp. 1991-2001.
11. Fleischer D.M., Greenhawt M., Sussman G., et al.: Effect of epicutaneous immunotherapy vs placebo on reaction to peanut protein ingestion among children with peanut allergy: the PEPITES randomized clinical trial . JAMA 2019; 321 (10): pp. 946-955. 30794314 .
12. Burks A.W., Sampson H.A., Plaut M., Lack G., Akdis C.A.: Treatment for food allergy . J Allergy Clin Immunol 2018; 141 (1): pp. 1-9.
13. Epstein T.G., Liss G.M., Murphy-Berendts K., Bernstein D.I.: AAAAI/ACAAI surveillance study of subcutaneous immunotherapy, years 2008–2012: an update on fatal and nonfatal systemic allergic reactions . J Allergy Clin Immunol Pract 2014; 2 (2): pp. 161-167.