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.

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.

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.

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.

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.

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.

Ragweed allergy immunotherapy tablet MK-3641 (Ragwitek®) for the treatment of allergic rhinitis.

INTRODUCTION: Allergic rhinitis (AR) is among the most common chronic conditions affecting both children and adults. It is the cause of significant morbidity from the symptoms and interference with sleep. It results in major impairment of performance both at school and at work. In the U.S. and certain parts of Europe, ragweed pollen is a major cause of seasonal AR. In 2014, the U.S. Food and Drug Administration (FDA) approved a sublingual ragweed tablet (MK-3641) for use in adults with ragweed-induced AR. Areas covered: This paper will review the impact of ragweed-induced AR and available treatments including subcutaneous immunotherapy and studies with MK-3641. The principal search method was PubMed. Expert commentary: One dosing finding, two 28-day safety and two 52-week safety and efficacy studies have been conducted with MK-3641. The 12-U (12µg Amb a 1) tablet was the most effective. Local application site reactions were common but usually not serious. Only one, non-serious systemic reaction was reported in four safety studies. MK-3641 is a safe and effective treatment for ragweed-pollen-induced AR when treatment is initiated ≥ 12 weeks prior to the onset of the ragweed pollen season.

Allergen immunotherapy (AIT) for the multiple-pollen sensitive patient.

INTRODUCTION: The majority of allergic subjects are polysensitized. In Europe, allergy immunotherapy (AIT) in these patients is usually limited to their single clinically most troublesome allergy while in the U.S. the immunotherapy prescription usually includes all allergen extracts to which the patient has evidence of clinical sensitivity. Areas covered: This article will review the evidence supporting the U.S. practice. It will also review the major new development in the management of polysensitized patients, the introduction of component-resolved diagnosis (CRD). Expert commentary: This allows, in many cases, distinguishing in polysensitized patients between sensitization to the major allergens of several unrelated allergen extracts and to panallergens that cause broad patterns of cross-reactivity.

Allergen immunotherapy now and in the future.

BACKGROUND: Subcutaneous (SCIT) and sublingual (SLIT) immunotherapy provide effective treatment for allergic rhinitis and allergic asthma with clinical improvement following an adequate course of therapy persisting in most patients for years after treatment is discontinued. However, both require prolonged courses of therapy and many or most patients either do not begin or stop long before they have completed the prescribed course of treatment. METHODS: Based on review of the recent medical literature, the current status of SCIT and SLIT was reviewed as well as new approaches to allergy immunotherapy (AIT) that have promise to overcome the safety and inconvenience concerns of both the current approaches. RESULTS: New approaches to AIT include application of extracts to the skin with patches, injection into inguinal lymph nodes, alterations in the allergen molecules by chemical treatment or recombinant technology to make them less reactive with specific IgE, shifting the immune response by stimulation of toll-like receptors or suppression of Th2 responses, and finally by adjuvants such as probiotics and vitamin D. CONCLUSIONS: Current forms of immunotherapy require years of treatment. New approaches, although differing markedly in their approach to AIT, all offer marked reduction in the required period of treatment. Hopefully, some of these new approaches will prove safe and effective and obtain approval for general use. If approved, they should make AIT more widely utilized to the benefit of the allergic population.

SQ grass sublingual allergy immunotherapy tablet for disease-modifying treatment of grass pollen allergic rhinoconjunctivitis.

BACKGROUND: Allergy immunotherapy is a treatment option for allergic rhinoconjunctivitis (ARC). It is unique compared with pharmacotherapy in that it modifies the immunologic pathways that elicit an allergic response. The SQ Timothy grass sublingual immunotherapy (SLIT) tablet is approved in North America and throughout Europe for the treatment of adults and children (≥5 years old) with grass pollen-induced ARC. OBJECTIVE: The clinical evidence for the use of SQ grass SLIT-tablet as a disease-modifying treatment for grass pollen ARC is discussed in this review. METHODS: The review included the suitability of SQ grass SLIT-tablet for patients with clinically relevant symptoms to multiple Pooideae grass species, single-season efficacy, safety, adherence, coseasonal initiation, and cost-effectiveness. The data from the long-term SQ grass SLIT-tablet clinical trial that evaluated a clinical effect 2 years after a continuous 3-year treatment period were presented in the context of regulatory criteria that define a clinically meaningful effect. RESULTS: This trial demonstrated that the clinical effect of the SQ grass SLIT-tablet is maintained, which is also supported by the immunologic findings. CONCLUSION: Therefore, the SQ grass SLIT-tablet has an indication as a disease-modifying therapy in Europe, and a sustained effect is recognized in the United States.

Oral/sublingual Phleum pretense grass tablet (Grazax/Grastek) to treat allergic rhinitis in the USA.

With the approval of two grass tablets and one ragweed tablet for sublingual immunotherapy (SLIT) by the US FDA in April 2014, the practice of allergy immunotherapy (AIT) in the USA has dramatically changed. Until this time, there were no approved allergen extracts for sublingual administration and physicians who prescribed SLIT for their patients did so without full knowledge of proper dosing or assurance of its safety. Now sublingual allergen tablets are available that have proven safe and effective doses. This article describes, in detail, the studies that have been conducted with a timothy grass SLIT tablet and draws some comparisons to the alternative 5-grass SLIT tablet. It also attempts to predict what will be the impact of the introduction of these tablets on the practice of AIT in the USA over the next few years.

Allergen-specific immunotherapy.

Specific immunotherapy was introduced for the treatment of grass pollen-induced hay fever in 1911. The treatment was soon extended to other pollens as well as perennial allergens, and to the treatment of bronchial asthma. Definitive studies of its efficacy for both rhinitis and asthma came only many decades later. Understanding gradually emerged of the underlying immunologic mechanisms that include the generation of regulatory T lymphocytes, immune deviation from allergen-specific Th2 to Th1 responses, and a shift in allergen-specific antibody production from immunoglobulin (Ig) E to IgG4. Along with understanding of the immune basis came an appreciation that immunotherapy modifies allergic disease expression, producing protection against disease progression and symptomatic improvement that persists for years after the treatment is discontinued. Recent new directions for immunotherapy include sublingual administration of inhalant allergens and use of the oral route to treat food allergy.

Response to sublingual immunotherapy with grass pollen extract: monotherapy versus combination in a multiallergen extract.

BACKGROUND: To date, there have been no randomized, double-blind studies showing the effectiveness of sublingual immunotherapy with multiple allergens. OBJECTIVE: The purpose of this study was to examine whether the efficacy of sublingual immunotherapy (SLIT) with standardized timothy extract was reduced by combination with other allergen extracts. METHODS: A single-center, randomized, double-blind, placebo-controlled trial with SLIT was conducted. After an observational grass season, SLIT was administered for 10 months to 54 patients randomized to 1 of 3 treatment arms: placebo, timothy extract (19 microg Phl p 5 daily) as monotherapy, or the same dose of timothy extract plus 9 additional pollen extracts. Symptom and medication scores were collected and titrated nasal challenges, titrated skin prick tests, specific IgE, IgG4 and cytokines release by timothy-stimulated lymphocyte proliferation were performed. RESULTS: Perhaps because of a very low grass pollen season in 2008, there were no significant differences in medication or symptom scores in either treatment group compared with placebo. Compared with placebo, in the timothy monotherapy group, thresholds for titrated nasal challenge and skin prick tests (P = .03 and P = .001, respectively), and serum-specific IgG4 levels (P = .005) significantly increased, and IFN- gamma levels decreased (P = .02), whereas in the multiallergen group, there was significant improvement only in the titrated skin prick tests (P = .04) which was less than in the monotherapy group. There were no significant differences between the 2 active groups in any outcome measure, and both active groups experienced more adverse events than placebo. There were no systemic reactions. CONCLUSION: Improvement in multiple relevant outcomes strongly suggests that SLIT with timothy extract alone was effective; however, the results for symptom and medication scores were not significant. The differences between multiple allergen SLIT and placebo only in skin sensitivity to timothy suggest a reduction in SLIT efficacy in this group. However, further studies are required to confirm these observations.

How ill the wind? Issues in aeroallergen sampling.

The effective size of bioaerosols is the principal determinant of their behavior during takeoff, transport, and deposition. Collection methods involving impaction, impingement, and filtration allow recovery of increasingly small aerosol units and do so "per unit volume of processed air" with more or less well-defined efficiency. These principles offer direction in choosing sampling devices for specific applications; similarly, a particle's appearance, growth potential, and assayability define the scope of relevant analyses. Where a variety of aerosol types occur, multiple collection and/or analytic approaches might be required. The development of a sampling grid in North America makes possible studies of distribution, transport, and climatic effects in ways never previously possible; however, some directive planning and oversight are essential to realize these goals. Methods sensitive to paucimicronic and submicronic particles should be included increasingly in new and ongoing survey protocols. Similarly, available means now facilitate study of aerosols at specific sites, both indoors and outdoors, with estimates of personal exposure during defined events. Resulting data describing airborne prevalence gain special value in light of competent inspection of implicated venues and consideration of alternative sources, such as incursion of bioaerosols into enclosed spaces.