International consensus on allergen immunotherapy-II: Mechanisms, standardization, and pharmacoeconomics

This month, JACI presents the second portion of the comprehensive international consensus (ICON) statement on allergen immunotherapy. The ICON statement is an effort of the International Collaboration in Asthma, Allergy and Immunology (iCALL) that includes the European Academy of Allergy and Clinical Immunology (EAACI), the American Academy of Allergy, Asthma and Immunology (AAAAI), the American College of Allergy, Asthma and Immunology (ACAAI) and the World Allergy Organization (WAO). Jutel et al. review the evidence on how allergen immunotherapy (AIT) works and summarize what lies on the horizon (J Allergy Clin Immunol 2016; 137(2): 358-368).

A number of mechanisms underlie an allergic response to a substance such as grass pollen, house dust mites, or bee venom. Allergen immunotherapy involves slowly increasing exposure to an allergen over time, ideally resulting in a patient’s increased tolerance and clinical improvement. The literature indicates that administration of AIT leads to early decreases in the susceptibility of mast cells and basophils to respond to environmental proteins, even in the presence of elevated allergen-specific immunoglobulin (Ig)E. Desensitization is followed by allergen-specific T-regulatory (Treg) and B-regulatory (Breg) cell generation and regulation of allergen-specific IgE and IgG₄. In the longer term, changes in memory T- and B-cell compartments and shift in the balance of type 1 T-helper (Th1) and type 2 T-helper (Th2) cells result in sustained improvement.

There are a number of barriers to the use of AIT worldwide. One such barrier is a low awareness of its potential, in the context of patient welfare and improved pharmaco-economics. AIT is currently the only therapy with the capacity to alter the course of allergic disease. Further, standardization of the potency, consistency, and stability of allergen extracts used in AIT is essential, as is the standardization of the practices of regulatory agencies from different parts of the world. Potential facilitators for acceptance and increased use of AIT include validation and consensus on outcome measures for clinical trials; validated methods of assessing AIT’s impact; and post-marketing studies demonstrating the positive impact of AIT on the quality of life of its recipients.

Sublingual grass and ragweed immunotherapy: Clinical considerations—a PRACTALL consensus report

In early 2014, the Food and Drug Administration approved three sublingual allergen immunotherapy (SLIT) products for use in the United States: a 5-grass tablet, a timothy grass tablet, and a ragweed tablet. The approval was based on multicenter clinical trials with large patient populations and supported by decades of real-life use in Europe. Li et al. have provided a consensus report of the experts of the American Academy of Allergy, Asthma and Immunology (AAAAI) and European Academy of Allergy and Clinical Immunology (EAACI) for the prescribing clinician (J Allergy Clin Immunol 2016; 137(2): 369-376).

The decision to use SLIT depends on practical considerations, cost, convenience, and patient preference. Within the current therapeutic options for allergic rhinitis, SLIT offers a therapy that can be self-administered at home and has the potential to permanently alter the course of allergic disease. In addition to those patients who prefer a disease-modifying approach, SLIT may work well for those with disease that does not respond to standard pharmacotherapy. While preliminary studies suggest it has a beneficial effect on asthma, asthma alone is not a clinical indication.

There is currently insufficient evidence to make a meaningful comparison between SLIT and subcutaneous immunotherapy (SCIT), but the current data suggests both routes reduce symptom scores and rescue medication use. Systemic reviews and meta-analyses suggest the clinical effect size may be greater for SCIT than SLIT, but the findings are not definitive. There have also been no head-to-head comparisons of SLIT with as-needed medications such as second generation antihistamine or nasal corticosteroids, but indirect comparisons suggest SLIT’s efficacy can be as good as SCIT. An important addition is that SLIT can provide sustained benefits for up to two years after discontinuation of three years of treatment as previously observed for SCIT.

The most common adverse events associated with SLIT are local reactions, such as gastrointestinal symptoms, which affect up to 75% of patients. Most occur shortly after treatment initiation and cease without medical intervention. Patients often also experience irritation in the lips, tongue, or throat. The incidence rate of fatal and near-fatal systemic reactions is low, likely lower than that of SCIT; and severe anaphylaxis is rare. Data from three large, pivotal European trials have indicated SLIT is efficacious and safe for children. Evidence also suggests that in children with allergic rhinitis, SLIT may decrease the rate of future asthma development.

Predictive value of nonspecific bronchial responsiveness in occupational asthma

The diagnosis of occupational asthma (OA) poses challenges to the clinician and requires a stepwise approach. The American College of Chest Physicians has recently published a consensus on this approach, also providing guidelines that indicate “the absence of airway hyper-responsiveness on challenge testing has a fairly high negative predictive value (NPV) for current symptomatic asthma, and can generally be used to rule out active disease.” Pralong et al. have verified this statement, evaluating the sensitivity, specificity, and positive and negative predictive values of the methacholine challenge in the diagnosis of occupational asthma (J Allergy Clin Immunol 2016; 137(2): 412-416).

The authors used a Canadian database to review 1012 cases of workers who, between the years of 1983 and 2011, were referred for suspicion of having occupational asthma and who underwent a specific inhalation challenge (SIC). SIC is considered the gold standard for diagnosing OA. It entails a first day of testing during which a patient is exposed to a control substance followed by a methacholine challenge. The patient is then exposed to the suspected causative occupational agent and undergoes another methcholine challenge. Among the 1012 patients reviewed, the median exposure duration was seven years, the median symptom duration was one year, and the median delay between exposure cessation and testing was two months. SIC confirmed OA in 27.5% of the cases.

Results presented here are the first to confirm two current recommendations. First, a negative methacholine challenge during the time in which the patient is still working at the exposure site makes the diagnosis of OA highly unlikely, as the negative predictive value (NPV) of the test in this population while at the workplace was 95.2%. Second, the NPV rose to 97.7% when considering all patients who had undergone a methacholine challenge at least once while at work at the exposure site, and it fell to 82.2% among patients who were tested off-site. The data demonstrate the utility of the methacholine challenge and indicates that, when possible, an OA diagnostic workup is best done when the patient is still working at the location of exposure.