The Art of Immunotherapy.

Selection of a patient with rhinitis/conjunctivitis or asthma for allergy immunotherapy (AIT) requires several decisions. First, does the patient's sensitization, pattern of exposure to an allergen, and degree of exposure to that allergen reasonably suggest a causal relationship? Does the level and duration of symptoms warrant the cost and inconvenience of immunotherapy, or is the patient motivated by the disease-modifying potential of AIT? If AIT is selected, is the choice to be greater safety and convenience with sublingual immunotherapy (SLIT) tablets, but with treatment probably limited to 2 or 3 allergens, or for subcutaneous immunotherapy where multiple allergen therapy is the rule and efficacy may be somewhat greater, at least initially, or does the physician go off-label into the unknowns of liquid SLIT? Are there extracts of sufficient potency to achieve likely effective doses? How does the physician deal with large local or systemic reactions, with gaps in treatment, with pollen seasons, and the use of premedication or cautionary prescription of epinephrine autoinjectors? How can adherence to AIT be improved? These and other questions are addressed in this paper.

The Art of Dosing for Subcutaneous Immunotherapy in North America.

Subcutaneous immunotherapy (SCIT) is a long-established treatment option for allergic rhinoconjunctivitis. Proper dosing of the allergens is critical for the efficacy and safety of SCIT. Of the hundreds of liquid allergen extracts in the United States, effective and well-tolerated SCIT dosing has only been established for a small number. Thus, SCIT dosing remains largely empiric and continues to be, by necessity, an art. To highlight the complexity of SCIT dosing, this review summarizes the historical and current landscape of U.S. allergen extracts, differences among U.S. and European allergen extracts, allergen selection for SCIT, considerations for compounding of allergen extract mixtures, and recommended dosing. As of 2021, 18 standardized allergen extracts are available in the United States; all other extracts remain unstandardized without characterization of allergen content or potency. U.S. allergen extracts differ from European extracts in formulation and potency characterization. There is no standardized methodology for SCIT allergen selection, and interpretation of allergen sensitization is not straightforward. Compounding of SCIT mixtures requires consideration of potential dilution effects, allergen cross-reactivity, proteolytic activity, and additives. Probable effective dose ranges for SCIT are recommended in U.S. allergy immunotherapy practice parameters, although there are few studies using U.S. extracts supporting these doses as therapeutic. In contrast, optimized doses of sublingual immunotherapy tablets have been confirmed in North American phase 3 trials. The SCIT dosing for each patient remains an art that requires clinical experience and consideration of polysensitization, tolerability, compounding of allergen extract mixtures, and the range of recommended doses within the context of extract potency variability.

Sublingual immunotherapy tablets in monosensitized and polysensitized adults with allergic rhinoconjunctivitis.

Background: Most patients with allergic rhinitis/conjunctivitis (AR/C) are sensitized to more than one allergen. An ongoing question is the efficacy of single-allergen immunotherapy in patients who are polysensitized. Objective: To evaluate the efficacy and safety of grass, ragweed, tree, and house-dust mite (HDM) sublingual immunotherapy (SLIT) tablets in adults with AR/C who are mono- or polysensitized. Methods: Data from adults (ages ≥ 18 years) with AR/C who participated in phase III double-blind, placebo controlled field trials (four grass, two ragweed, two HDM, one tree) were included in the post hoc analyses. Efficacy was assessed by the total combined score (TCS) (sum of AR/C daily symptom and medication scores) during the entire pollen season for grass and tree trials, and peak pollen season for ragweed trials versus placebo. Efficacy for the HDM SLIT-tablet was assessed by the total combined rhinitis score (TCRS) (sum of rhinitis daily symptom and medication scores) during the last 8 weeks of treatment versus placebo. Results: For the grass SLIT-tablet, TCS improved by 20% (mean difference 1.33 [95% confidence interval {CI}, 0.44-2.22]) in the subjects who were monosensitized (n = 442) and 20% (mean difference 1.28 [95% CI, 0.90-1.67]) in the subjects who were polysensitized (n = 1857). For the ragweed SLIT-tablet, TCS improved by 19% (mean difference 1.72 [95% CI, -0.20 to 3.63]) in the subjects who were monosensitized (n = 115) and 27% (mean difference 2.27 [95% CI, 1.28-3.27]) in the subjects who were polysensitized (n = 528). For the tree SLIT-tablet, TCS improved by 54% (mean difference 4.65 [95% CI, 2.48-6.82]) in the subjects who were monosensitized (n = 138) and 34% (mean difference 2.51 [95% CI, 1.34-3.69]) in the subjects who were polysensitized (n = 437). For the HDM SLIT-tablet, TCRS improved by 20% (mean difference 1.24 [95% CI, 0.48-1.99]) in the subjects who were monosensitized (n = 468) and 17% (mean difference 0.85 [95% CI, 0.43-1.28]) in the subjects who were polysensitized (n = 1294). The overall safety profile was not qualitatively different between the subjects who were monosensitized and the subjects who were polysensitized. Conclusion: Grass, ragweed, tree, or HDM SLIT-tablet treatment is effective for the specific allergen in question in adults with AR/C and who are monosensitized or polysensitized. Targeting one relevant allergen with SLIT-tablets induces a clinical effect for that allergen in patients who were polysensitized.

Allergy immunotherapy for allergic fungal respiratory diseases.

Background: Allergy immunotherapy (AIT) with fungal extracts is not as straight forward as that with other inhalants. The complexities relate to the number of airborne fungal spores, the limited data on the exposure to the spores of individual species of fungi and their clinical importance, the poor quality of the fungal allergen extracts that are available for the diagnosis and treatment, and the lack of controlled studies establishing dosing and efficacy of AIT with fungal extracts except for Alternaria. Objective: The objective was to review what is known with regard to the role of fungi in causing allergic respiratory diseases as well as the evidence that exists for the role of AIT as a treatment for these conditions. Methods: A search was conducted of PubMed, textbooks, known articles on immunotherapy with fungal extracts, and references derived from these primary sources. Results: Nine immunotherapy studies that used Alternaria or its major allergen Alt a 1 and two studies that used Cladosporium herbarum were identified. When a good quality extract was administered in adequate doses, immunotherapy with Alternaria was as effective as that with other inhalant allergens. There was a suggestion of efficacy with a specially prepared Cladosporium extract, but systemic reactions were common and limited the tolerated dose. The use of immunotherapy as an adjunct treatment for allergic fungal sinusitis is briefly reviewed, but controlled trials are lacking. Conclusion: Fungal immunotherapy should largely be limited to Alternaria alternata and perhaps C. herbarum. Under conditions of demonstrated exposure to a particular species of fungus and with symptoms that correlate with that exposure as well as availability of an apparently potent extract of that fungus to which the patient is sensitive that fungus may be considered for immunotherapy. Fungal (mold) mixes should not be used for diagnosis or therapy.

Extrapolating Evidence-Based Medicine of AIT Into Clinical Practice in the United States.

Allergy/immunology specialists in the United States prescribing allergy immunotherapy (AIT) have placed a heavy value on practical experience and anecdotal evidence rather than research-based evidence. With the extensive research on AIT conducted in the last few decades, the time has come to better implement evidence-based medicine (EBM) for AIT. The goal of this review was to critically assess EBM for debated concepts in US AIT practice for respiratory allergies in the context and quality of today's regulatory standards. Debated topics reviewed were the efficacy and safety of AIT in various subgroups (eg, polyallergic patients, older patients, patients with asthma, and pregnant women), diagnosis topics (eg, skin prick test vs allergen-specific serum IgE, factors affecting skin prick tests, use of nasal or conjunctival allergen challenges, and telemedicine for diagnosis), and dosing topics (eg, optimal dosing for subcutaneous immunotherapy and sublingual immunotherapy tablets, US liquid allergen extract history, duration of treatment, and biomarkers of efficacy). In addition, EBM for patient-centered AIT issues (eg, adherence, use of practice guidelines, and pharmacoeconomics) and the approach to implementation of AIT EBM in future clinical practice were addressed. The EBM for each concept was briefly summarized, and when possible, a practical, concise recommendation was given.

The return of the mixed respiratory bacterial vaccine.

Background: Orally or sublingually administered lysates of mixed respiratory pathogenic bacteria have been used in Europe, Asia, and other parts of the world, but not the United States, since the mid 1950s, first to prevent recurrent respiratory tract infections, later to prevent wheezing and asthma exacerbations associated with respiratory infections, and, more recently, for the treatment of allergic rhinitis. The apparent success of this treatment contrasts with the negative experience of treating with injections of similar mixed respiratory bacterial vaccines (MRBV or BV) to prevent asthma exacerbations associated with respiratory infections that was once common practice but abandoned ∼50 years ago. Methods: Textbooks and articles on the use of injected BVs to prevent asthma exacerbations associated with respiratory infections were reviewed, including a number of, randomized, double-blind, placebo controlled (RDBPC) studies the results of which were predominantly negative that contributed to the abandonment of this treatment. Also reviewed were more recent articles from Europe and China, which report both clinical and immunologic support for the use of the orally and sublingually administered mixed respiratory bacterial lysates (MRBL or BL). Results: A review of five RDBPC studies of the parenteral use of BVs for prevention of asthma exacerbations conducted by leading international allergists in the 1950s and 1960s showed, in a combined 532 patients, an overall reduction of asthma attacks by 4.9% over placebo. However, in five studies in 1126 patients of oral or sublingual treatment with BLs, the reduction in respiratory infections, wheezing episodes, and asthma exacerbations was 42.6% over placebo. Conclusion: Reported results with oral and sublingual BLs are far superior to the historical performance of injected BVs. Possible reasons for this difference are discussed, but none is clearly responsible for the difference in clinical results.

Curcumin does not significantly affect immediate skin tests.

Background: Curcumin has been shown to decrease allergic symptoms and biomarkers in some animal and human studies. Objective: Our study aimed to determine if curcumin affects immediate skin-prick testing. Methods: We enrolled 34 participants sensitized to select antigens. The participants were randomized to treatment with curcumin or placebo in a double-blind fashion. The participants underwent titrated skin-prick testing before and after 1 week of treatment, and the pre- and posttreatment skin test wheals and flares were compared. Results: Curcumin did not have a statistically significant effect on immediate skin-prick test wheal or flare size. Conclusion: Although curcumin may attenuate allergic symptoms and biomarkers, it does not have a significant effect on immediate skin-prick test results and does not need to be discontinued before testing.

Standardized allergen extracts for allergen immunotherapy.

Nineteen U.S. allergen extracts were standardized by the U.S. Food and Drug Administration (FDA) between 1987 and 1998, including of two house-dust mites, short ragweed, cat hair and cat pelt, seven temperate and one southern grass, and six Hymenoptera venom preparations. Relevant literature was reviewed. For each allergen, a "representative" extract was established; the potency of each representative extract was determined by measurement of the total protein content (Hymenoptera venom), radial diffusion measurement of the dominant allergen (short ragweed and cat), or, if there was no dominant allergen, then by quantitative skin testing by using the ID50EAL (intradermal dilution for 50 mm sum of erythema determines the bioequivalent allergy units) method. In vitro tests were developed to allow the manufacturer to demonstrate that each lot of its extract was statistically identical, within defined limits, to the FDA reference extract. These tests included radial immunodiffusion, competitive enzyme-linked immunosorbent assay, and isoelectric focusing. The standardized extracts offer the advantage of consistent potency from lot to lot for each manufacturer and also from manufacturer to manufacturer, and assure the presence of recognized significant allergens within the extract. Therefore, standardized extracts offer improved safety and efficacy over their nonstandardized predecessors.

Future directions in allergen immunotherapy.

Both subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) are effective clinically against allergic rhinitis and allergic asthma, and modify the underlying immunologic abnormalities. Despite this, many patients who could benefit from receiving SCIT and SLIT do not because of concerns about safety and the inconvenience in receiving SCIT, and the long duration of treatment with both, 3-4 years being required for lasting benefit. Attempts to improve the efficacy and safety, and to shorten the course of allergen immunotherapy have taken many approaches. Some approaches have generated great enthusiasm, only to fail in larger trials and be discarded. Other approaches show some promise but perhaps not enough to achieve regulatory approval. Those approaches that seem to have the best chance of becoming available in the next few years include the following: intralymphatic and epicutaneous immunotherapy, vitamin D in patients with insufficient serum 25 hydroxy vitamin D, probiotics, and allergoids, but all require further studies before being ready for nonexperimental use or, where necessary, for regulatory approval.

To mix or not to mix in allergy immunotherapy vaccines.

PURPOSE OF REVIEW: European and US allergists generally do not agree on the approach to subcutaneous allergy immunotherapy in patients with multiple allergies. The North American approach is to treat with a mixture that contains all the allergen extracts to which the patient has evident clinical sensitivity, whereas the European approach is to select for treatment the one or at the most two allergens that are clinically most important for the patient. RECENT FINDINGS: Recent society guidelines continue to recommend these differing practices of treating the polyallergic patient and reviews of prescribing practices indicate these divergent recommendations are followed in Europe and the USA. SUMMARY: The objections by European allergists to the practice by US allergists are that multiallergen immunotherapy leads to dilution of allergens to less than effective doses, that proteases in some extracts can degrade allergens in other extracts, that there is a problem of safety and inability to determine which component extract caused a systemic reaction, and finally that there is alack of convincing studies demonstrating efficacy of multiallergen mixtures. Each of these contentions is addressed.

How important is proper dosing for subcutaneous and sublingual allergy immunotherapy?

Background: Results of surveys report that allergists use a wide range of doses for allergy immunotherapy; however, results of randomized, double-blind, placebo controlled studies suggest that the range of the optimum effective dosing is relatively narrow. Objective: To review studies that established effective or less than fully effective doses for allergy immunotherapy. Methods: Studies were reviewed that established effective and ineffective subcutaneous and sublingual immunotherapy doses. Only those studies that expressed dosing in terms of the content of a major allergen in the maintenance doses were included in defining effective and ineffective doses. Results: Studies were identified that showed effective doses for subcutaneous injection, established in randomized, double-blind, placebo controlled trials, for short ragweed, timothy grass, house-dust mites, cat and dog dander, birch, and Alternaria. For short ragweed, timothy grass, Dermatophagoides pteronyssinus, and cat and dog dander, less-effective doses were determined, along with effective doses; the less-effective doses were only one-fifth to one-tenth less in allergen content than were the effective doses. Effective doses of cockroach and all fungal extracts except Alternaria have not been established. Information is available on the mean major allergen content of U.S. standardized and a few nonstandardized extracts, which allows the information on effective and ineffective dosing to be used in prescribing subcutaneous allergy immunotherapy. With sublingual allergy immunotherapy, all the approved tablets had multidose studies that determined the optimal dose. For the U.S. liquid extracts, to my knowledge, there are no studies to define effective doses except for ragweed. Conclusions: Although a wide range of doses are prescribed by U.S. allergists, analysis of available data suggests that effective doses fall within a narrow range and that use of doses one-fifth or one-tenth of the effective doses may sacrifice most or all of the potential efficacy of the treatment.

The evolution of allergy immunotherapy.

OBJECTIVE: The objective of this review is to trace the evolution of the art and science of allergy immunotherapy (AIT). DATA SOURCES: Original reports relating to the evolution of the concept of respiratory allergy and its specific treatment were identified by following references in journal articles, review articles, and allergy textbooks from the mid-20th century to the present. STUDY SELECTIONS: Studies highlighting substantial milestones in the evolution of the practice of allergy immunotherapy were included. RESULTS: The story of AIT begins with the recognition of hay fever as a distinct entity and subsequent studies that established grass pollen as one of the causes. This knowledge led several investigators, most notable Leonard Noon and John Freeman who worked at St. Mary's Hospital in London, to attempt to induce tolerance giving grass pollen extract by injection to their patients. After the publication of the work of Noon and Freeman in 1911, the practice of AIT spread rapidly and was applied to many other pollen allergens besides grass and for perennial rhinitis and asthma. The early studies were largely anecdotal, but over the past 60 to 70 years, studies of AIT have been conducted with increasingly sophisticated scientific methods. Nowadays, not only is the practice of AIT based on carefully conducted studies, but the underlying immunologic basis of allergy and the response to AIT have also been and still are being firmly established. CONCLUSION: Both the art and the science behind the practice of AIT have been established by a solid base of clinical and immunologic studies.

Allergy immunotherapy: Future directions for the 2020s.

Allergy immunotherapy (AIT), whether administered as subcutaneous immunotherapy or as sublingual immunotherapy (SLIT), is an effective treatment for sensitization to inhalant allergens. There remain, however, some important unresolved issues, such as the need for compelling evidence for or against the efficacy of treatment with multiple unrelated allergen extracts and optimal dosing with SLIT-liquid preparations. Both methods of AIT involve prolonged periods of treatment to achieve persisting benefit. This can be inconvenient and expensive, and failure to complete the period of prescribed treatment is common with both methods. New approaches are being developed and studied to make AIT more effective, safer, or more convenient. Among these approaches are using alternative routes of administration; using adjuvants, including vitamin D, Toll-like receptor ligand agonists, biologics, or probiotics; introducing additional SLIT tablets; defining the patterns of major and minor allergen sensitivity of patients and the content of allergen extracts to better match sensitization with treatment; and treating cats to reduce their allergen release. The allergen molecules themselves are being altered to make them less reactive with specific immunoglobulin E, both by creating allergoids and by using recombinant technology to produce modified allergen molecules. Which, if any, of these new approaches will become part of AIT practice in the next decade depends in part on their efficacy and in part on the availability of the resources to adequately study them.

Clinical Practice of Allergen Immunotherapy for Allergic Rhinoconjunctivitis and Asthma: An Expert Panel Report.

Allergen immunotherapy (AIT) reduces symptoms and medication use associated with allergic rhinitis with or without conjunctivitis and allergic asthma. Although several AIT guidelines exist, there remain unanswered questions about AIT that are relevant to everyday practice. Our objective was to prepare an evidence-based overview addressing the practical aspects of AIT in clinical practice based on published evidence and the experience of international experts in the field. Topics covered include interpretation and translation of clinical trial data into everyday clinical practice (eg, allergen doses and treatment duration), assessment of risk and treatment of local and systemic allergic reactions, recommendations for improvement of AIT guidelines, and identification of appropriate data for seeking regulatory approval, to name a few. Many informational gaps in AIT practice need further evaluation as products and practices evolve.

Efficacy and Safety of Ragweed SLIT-Tablet in Children with Allergic Rhinoconjunctivitis in a Randomized, Placebo-Controlled Trial.

BACKGROUND: Ragweed sublingual immunotherapy (SLIT) tablet reduces symptoms and symptom-relieving medication use in adults with allergic rhinitis with or without conjunctivitis (AR/C) but has not been evaluated in children. OBJECTIVE: This international, multicenter, double-blind, placebo-controlled trial evaluated the efficacy and safety of ragweed SLIT-tablet in children with AR/C. METHODS: Children (N = 1025; 77.7% polysensitized) aged 5 to 17 years with ragweed pollen-induced AR/C with or without asthma (FEV1 ≥80% predicted) were randomized 1:1 to daily ragweed SLIT-tablet (12 Amb a 1-Unit) or placebo for up to 28 weeks (NCT02478398). The primary end point was the average total combined score (TCS; sum of rhinoconjunctivitis daily symptom score [DSS] and daily medication score [DMS]) during peak ragweed pollen season (RPS). Key secondary end points were TCS during the entire RPS, and DSS and DMS during the peak RPS. RESULTS: Relative TCS (95% CI) improvements with ragweed SLIT-tablet versus placebo were -38.3% (-46.0% to -29.7%; least square [LS] mean difference, -2.73; P < .001) during peak RPS and -32.4% (-40.7% to -23.3%; LS mean difference, -1.86; P < .001) during the entire RPS. DSS and DMS during peak RPS improved with SLIT-tablet versus placebo by -35.4% (-43.2% to -26.1%; LS mean difference, -1.40; P < .001) and -47.7% (-59.8% to -32.5%; LS mean difference, -1.84; P < .001), respectively. Asthma DSS, short-acting ß-agonist use, and nocturnal awakenings during peak RPS improved with SLIT-tablet versus placebo by -30.7%, -68.1%, and -75.1%, respectively (all nominal P ≤ .02). No events of anaphylaxis, airway compromise, or severe treatment-related systemic allergic reactions were reported. CONCLUSIONS: Ragweed SLIT-tablet significantly improved symptoms and decreased symptom-relieving medication use in children with ragweed pollen-induced AR/C and was well tolerated.

Allergy immunotherapy for inhalant allergens: Strategies to improve efficacy.

Background: Allergy immunotherapy (AIT), both subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT), is an effective and safe treatment for allergic rhinitis and allergic asthma due to inhalant allergens. However, there are many variables in how it is administered. Objective: To review the evidence that suggests the optimum practices to enhance the efficacy of AIT. Methods: Articles that reported the results of various approaches to the practice of AIT and evidence-based guidelines were consulted for guidance on what approaches would enhance the efficacy of AIT. Results: Evidence is presented that supports optimum dosing for SCIT, a discussion of dosing with liquid SLIT, the management of the patient who is polyallergic, considerations in mixing allergen extracts, advantages and disadvantages of different up-dosing regimens with SCIT, the optimum duration of AIT, the comparative efficacy of SCIT and SLIT, and improving adherence to AIT. Also reviewed were two approaches, the use of adjuvants and of alternative routes of administration of currently available extracts, which may be useful in the future after further studies have defined their effectiveness. Conclusion: Although there is still controversy about some aspects of AIT, there is literature to support approaches that enhance the efficacy of both SCIT and SLIT.

Allergy immunotherapy for inhalant allergens: Strategies to minimize adverse reactions.

Background: Allergy immunotherapy (AIT), both subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT), is an effective and safe treatment for allergic rhinitis and allergic asthma due to inhalant allergens. However, there are many variables in how it is administered. Objective: To review the evidence that suggests the optimal practice(s) to minimize adverse reactions to AIT. Methods: Articles that reported the results of various approaches to the practice of AIT and evidence-based guidelines were consulted for guidance about approaches that would minimize adverse reactions to AIT. Results: Evidence is presented that supports care in the preparation of allergy extracts for treatment; use of modified extracts; location for administration of SCIT and SLIT; risk factors for systemic reactions; AIT in patients on adrenergic blocking agents and angiotensin-converting enzyme inhibitors; use of premedication; the need for prescription of epinephrine autoinjectors; adjustments in dose for pollen seasons, interruptions in treatment, and for local and systemic reactions; and the safety in patients with autoimmune diseases and during pregnancy. Conclusion: Although some of these variables have not been adequately studied, there are many studies that indicate practices that minimize the risk of adverse reactions for both SCIT and SLIT.