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Tuesday, August 11, 2015

Measuring the corticosteroid responsiveness endophenotype in asthmatic patients

Inhaled corticosteroids (ICSs) constitute the most commonly prescribed therapies for asthma. They are effective, but there are up to 24% of asthma patients who do not achieve significant improvement with them. ICSs produce treatment responses in six clinical phenotypes: lung function, bronchodilator response, airway responsiveness, symptoms, need for oral steroids, and frequency of emergency department visits or need for hospitalization. For the past 15 years and in an escalating prevalence of asthma, researchers have considered these phenotypes to be guided by separate mechanisms.

Clemmer et al propose a move away from the focus on single phenotypes to a more holistic approach. They suggest that there is a corticosteroid responsiveness endophenotype that modulates the asthma disease process, is latent in ICS-untreated patients, and is active in ICS-treated patients. Under this hypothesis, the corticosteroid responsiveness endophenotype influences the asthma disease process to produce the treatment effect observed in all the clinical phenotypes (J Allergy Clin Immunol 2015; 136(2): 274-281).

As such, the authors present a composite phenotype responsiveness model that combines the six clinical phenotypes and measures the endophenotype. They used principal component analysis (PCA) to determine the model in a study population of both ICS-treated and non-ICS-treated patients with mild to moderately severe asthma. The model was then tested in four replication populations. Using treatment effect area under the receiver operating characteristic curve (AUC), they demonstrate that a composite phenotype measures corticosteroid responsiveness with greater accuracy and stability across populations than the individual clinical phenotypes do.

The potential applications of the composite phenotype are many. It should enable asthma pharmacogenetic studies with more power for a given sample size or that require a smaller sample to achieve a given power. Given that it collapses multiple longitudinal clinical observations into a corticosteroid response metric and that it is easily implemented in a single computer program, it could allow a clinical practitioner to more accurately estimate ICS response. Finally, the model could be used to characterize the many asthma patients who do not respond to ICS treatment with better accuracy.

Report from the National Institute of Allergy and Infectious Disease Workshop on Drug Allergy

Allergic reaction to drugs is a serious and often underserved public health concern. In 2013, the National Institute of Allergy and Infectious Diseases (NIAID) Division of Allergy, Immunology and Transplantation convened a workshop on the issue. Representatives from several NIH institutes and from the FDA joined experts in drug allergy for a day-long discussion. Wheatley et al present a summary of the topics and recommendations (J Allergy Clin Immunol 2015; 136(2): 262-271).

The authors define “drug allergy” as any adverse drug reaction (ADR) that has a proven immunologic mechanism, including but not limited to IgE-mediated disease. There are currently no systematic epidemiologic studies of drug allergy. Most of the epidemiologic data on adverse drug reactions (ADRs) at this point relies on clinical diagnosis. With few specific diagnostic tests, physician-based assessment remains the gold standard for phenotyping the reactions.

ADRs are categorized as type A or type B. Type A reactions result from known pharmacologic/toxic effects of the drug often related to dosage. Mechanisms other than pharmacologic toxicity mediate type B reactions, which constitute approximately 20% of ADRs. The majority of type B reactions have an immunological basis. In particular, IgE-mediated reactions, whether immediate or delayed, often occur with a single encounter with the allergen. The mechanisms underlying both immediate-onset and delayed-onset reactions remain elusive. In no small part, this is due to a lack of appropriate reagents and reliable tests to detect drug-specific IgE antibodies and an absence of model systems.

While drug desensitization has a risk of inducing an allergic reaction, it is the only currently available approach that appears to provide clinical benefit. There is a need for valid, rapid, and inexpensive screening tests. While immunologically mediated ADRs are common, there will be few patients with the same reaction to the same drug in the same clinical context in any one institution. The authors call for multi-center clinical networks and communication between investigators, funding and regulatory agencies, and the pharmaceutical industry as the field grows.

Consensus communication on early peanut introduction and the prevention of peanut allergy in high-risk infants

While means of measurement and estimates differ, in the past ten to fifteen years the prevalence of peanut allergy may have as much as tripled in countries such as the United States. This translates to nearly 100,000 new cases a year in the United States and United Kingdom. Fleischer et al. highlight emerging evidence that supports early, rather than delayed, peanut introduction in the period of complementary food introduction in infants, including many of those considered to be at high risk for peanut allergy. (J Allergy Clin Immunol 2015; 136(2): 258-261)

In the Learning Early About Peanut Allergy (LEAP) trial, 640 infants between the ages of four and eleven months, who were considered to be at high-risk because of egg allergy and/or severe eczema, were randomized to consume peanut at least 6 grams of peanut protein three times a week or to completely avoid peanut for the first five years of life. Five hundred and forty-two of these infants had a negative skin prick test (SPT) response to peanut at study entry, and ninety-eight of them had a minimally positive SPT response to peanut (1-4 mm; children with a SPT response to peanut of ≥5 mm were presumed peanut-allergic and excluded from the trial.)

In an intention-to-treat analysis, 17.2% of the children in the peanut-avoidance group had food-challenged-proven peanut allergy by the age of five years; 3.2% of the children in the consumption group did by the same age. This corresponds to a 14% absolute risk reduction, a number needed to treat (NNT) of 7.1, and a relative risk reduction of 80%. Overall, the risk of early peanut introduction in this group was low: 7 of the 319 children randomized to the consumption group reacted to peanut at the baseline food challenge, suggesting that peanut food challenges and introduction, even in children with other risk factors or with minimally positive peanut SPT responses, are safe and feasible.

Six children in the consumption group developed peanut allergy during the study, which indicates allergy can still develop despite primary intervention. In addition, this study focused only on infants considered to be at high-risk and did not extend to the general infant population. Still, the study is the first prospective, randomized trial for early peanut intervention, which its results suggest may reduce the risk of peanut allergy in this patient population by as much as 80%.

Existing guidelines from 2013, which recommended not delaying the introduction of any highly allergenic food beyond 4-6 months of age, did not actively recommend peanut introduction between four and six months of age in high-risk infants. Based on the data presented above, the authors suggest the following interim guidelines to aid in clinical decision-making for early peanut introduction. First, providers should recommend the introduction of peanut into the diets of high-risk infants between four and eleven months of age, as an association has been identified between delaying the introduction and the development of peanut allergy. Second, the evaluation by an allergist or appropriately-trained physician can assess the appropriateness of peanut introduction for a given high-risk infant that has severe eczema or egg allergy, and whether possible allergy testing and observed peanut ingestion would be recommended first. Finally, the outcomes of the LEAP regimen do not address the effects of alternative doses of peanut protein, the minimum length of treatment necessary to induce tolerance, or potential risks of premature discontinuation or sporadic feeding of peanut. More specific guidelines are expected later this year from an Expert Panel sponsored by the NIAID.