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Allergy/immunology specialists in the US 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 (e.g., polyallergic patients, older patients, patients with asthma, pregnant women), diagnosis topics (e.g., 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 (e.g., optimal dosing for subcutaneous immunotherapy and sublingual immunotherapy tablets, US liquid allergen extract history, duration of treatment, biomarkers of efficacy). In addition, EBM for patient-centered AIT issues (e.g., adherence, use of practice guidelines, pharmacoeconomics) and the approach to implementation of AIT EBM in future clinical practice was also addressed. The EBM for each concept was briefly summarized, and when possible, a practical, concise recommendation was given.

Asthma is a complex syndrome with multiple phenotypes and endotypes. Asthma exacerbations are not only the clearest indictor of the morbidity of asthma and of the risk for mortality due to asthma, but also comprise a significant amount of the cost to care for poorly controlled asthma. There continues to be significant disparity in the prevalence, mortality, and morbidity due to asthma. Patients with asthma who suffer recurrent exacerbations are considered to have exacerbation-prone asthma (EPA). Efforts to characterize patients with frequent exacerbations show that the etiology is likely multifactorial. Research to determine the intrinsic risk factors for EPA include studies of both genetic and inflammatory biomarkers. External factors contributing to exacerbations have been extensively reviewed and include viral infection, environmental exposures, air pollution, and psychosocial and economic barriers to optimizing health. It is likely that EPA occurs when patients who have an increased underlying intrinsic/biological risk are placed in a given exposome (environments with a variety of exposures and triggers including allergens, pollution, stress, barriers, and occupational exposures). It is the social construct combined with underlying biology that frequently drives an EPA phenotype.

Blood eosinophil (EOS) counts are critical to the accurate identification of asthma phenotypes. However, there are few long-term data on intraindividual EOS count variability among patients with eosinophilic asthma.This post hoc analysis of 2 phase III clinical trials from the reslizumab BREATH program explored the variability of blood EOS counts in patients with eosinophilic asthma receiving placebo.Pooled data from study participants receiving placebo (previously randomized 1:1 to receive reslizumab or placebo) were analyzed for blood EOS count variability over 52 weeks. EOS counts were measured up to twice during screening, every 4 weeks from randomization to the end of treatment and at the 90-day follow-up visit.Of 476 included patients, 31 (6.5%), 38 (8.0%), 55 (11.6%), and 352 (73.9%) patients had baseline blood EOS counts of150, ≥150 to300, ≥300 to400, and ≥400 cells/μL, respectively. Patients frequently shifted between EOS count categories during the 52-week treatment period, most often moving to the highest EOS category. Among patients in each of the lower 3 EOS categories, 27% to 56% of patients shifted to the ≥400 cells/μL category at some point during the treatment period.Intraindividual variability in blood EOS count was high among patients with eosinophilic asthma receiving placebo, with shifts to ≥400 cells/μL from lower categories frequently observed. Repeat determinations of blood EOS count may be important to ensure appropriate selection of therapy in patients with severe asthma.

Background Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin (IL)-4 and IL-13 signaling, key drivers of type 2 inflammation. In the phase 3 study (NCT02414854), add-on dupilumab 200mg/300mg every 2 weeks, versus placebo, significantly reduced severe asthma exacerbations and improved pre-bronchodilator forced expiratory volume in 1 second (FEV1) and quality-of-life measures in patients with uncontrolled, moderate-to-severe asthma, with greater efficacy observed in those with a high baseline type 2 phenotype. Objective To assess the efficacy and safety of dupilumab in uncontrolled, moderate-to-severe asthma patients with or without self-reported comorbid chronic rhinosinusitis (CRS or non-CRS). Methods Comorbid CRS was self-reported by patients using an e-diary. Annualized severe exacerbation rates, changes from baseline in pre- and post-bronchodilator FEV1, patient-reported outcomes, type 2 biomarkers, and safety were assessed. Results CRS was self-reported by 382/1902 (20.1%) patients. Dupilumab 200mg/300mg reduced annualized severe exacerbation rates by 63%/61%, respectively, in patients with CRS, and by 42%/40% in patients without CRS (all P≺.001 vs placebo). Dupilumab also improved lung function and patient-reported asthma control and quality of life, and suppressed type 2 biomarkers versus placebo in both subgroups. Clinical responses were rapid, with near-maximal responses observed at the earliest measured timepoints and sustained at week 52. Improvements observed in the CRS subgroup were similar to or numerically greater than those in the non-CRS subgroup. Conclusion Dupilumab showed efficacy and was generally well tolerated in patients with uncontrolled, moderate-to-severe asthma with or without CRS.

Mechanistic studies have improved our understanding of molecular and cellular components involved in asthma and our ability to treat severe patients. An mAb directed against IgE (omalizumab) has become an established add-on therapy for patients with uncontrolled allergic asthma and mAbs specific for IL-5 (reslizumab, mepolizumab), IL-5R (benralizumab), and IL-4R (dupilumab) have been approved as add-on treatments for uncontrolled eosinophilic (type 2) asthma. While these medications have proven highly effective, some patients with severe allergic and/or eosinophilic asthma, as well as most patients with severe non–type-2 disease, have poorly controlled disease. Agents that have recently been evaluated in clinical trials include an antibody directed against thymic stromal lymphopoietin, small molecule antagonists to the chemoattractant receptor-homologous molecule expressed on TH2 cells (CRTH2) and the receptor for stem cell factor on mast cells (KIT), and a DNA enzyme directed at GATA3. Antibodies to IL-33 and its receptor, ST2, are being evaluated in ongoing clinical studies. In addition, a number of antagonists directed against other potential targets are under consideration for future trials, including IL-25, IL-6, TNF-like ligand 1A, CD6, and activated cell adhesion molecule (ALCAM). Clinical data from ongoing and future trials will be important in determining whether these new medications will offer benefits in place of or in addition to existing therapies for asthma.