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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.

Thursday, July 9, 2015

Respiratory allergy caused by house dust mites: What do we really know?

The house dust mite (HDM) is present in human habitats around the globe, and it is a significant factor in allergic rhinitis and allergic asthma. Sensitization to mite allergens in early life compromises lung function and leads to wheezing in children, and it associates with poorer outcomes in a patient’s respiratory health in the long term. Calderón et al review the epidemiology of HDM allergy and the effect of HDM allergens on the human immune system (J Allergy Clin Immunol 2015; 136(1): 38-48).

Both assessing prevalence of HDM sensitivity and controlling a patient’s exposure to the allergen pose challenges. Prevalence data for HDM sensitization vary according to targeted population: from estimating 65 million to 130 million people in the global general population may be affected to as many as 50% of those with asthma. In addition, results vary within geographic locations, meaning studies have found significant differences in prevalence within a given country or region. In terms of a patient’s exposure, house dust mites are ubiquitous. Humidity levels have been shown to affect HDM propagation, and a recent practice parameter recommends the use of a hygrometer in the home. Studies indicate that HDM allergen levels should be maintained at less than 2 μg/g to decrease the likelihood of sensitization, yet measures to decrease HDM exposure have shown little benefit on symptoms in sensitized patients. Finally, the quantitative relationship between exposure to HDM and symptoms in asthmatic patients is complicated, as many of these patients are sensitized to more than one allergen.

Allergenic effects in HDM allergy are thought to be orchestrated via two main routes: through the CD4+ TH2 cells that induce and drive the IgE-dependent allergic response and through the innate immune system. It is this combined effect of adaptive and innate immune reactions that makes the allergen so powerful. Current guidelines for allergic rhinitis and allergic asthma classify disease based on severity of symptoms. That HDM is often the underlying cause is an important step in managing clinical control, as well as potentially preventing disease progression.

Thursday, July 2, 2015

Anti–IL-23A mAb BI 655066 for treatment of moderate-to-severe psoriasis: Safety, efficacy, pharmacokinetics, and biomarker results of a single-rising-dose, randomized, double-blind, placebo-controlled trial

Psoriasis is a chronic immune-mediated inflammatory skin disease with a global incidence of approximately 2%. The extent of the affected body surface area and degree of erythema, induration, and scaling in four areas define its severity, and approximately 25% of patients have moderate-to-severe disease. Genome-wide association studies have linked variants in the gene for the IL-23 receptor and the p19 subunit of IL-23 to psoriasis susceptibility. IL-23 induces differentiation of TH17 cells and TH22 cells. The former are a primary cellular source of proinflammatory cytokines, including IL-17, and the latter are a primary source of IL-22. Both interleukins can mediate the development of the epidermal hyperplasia and tissue inflammation that occurs in psoriasis.

Krueger et al present the first-in-human proof-of-concept study to evaluate the clinical and biological effects of BI 655066 in patients with moderate-to-severe psoriasis. BI 655066 is a novel, fully human IgG1 mAb selective for IL-23A. It binds to IL-23A with high affinity and blocks the biologic activity of IL-23 (J Allergy Clin Immunol 2015; 136(1):116-124).

Thirty-nine patients received single-dose BI 655066 intravenously, subcutaneously, or placebo. The patients who received the antibody showed clinical improvement after two weeks that, in a subset of those treated, was maintained for up to 66 weeks after treatment. After 12 weeks, 87% of treated patients experienced a decrease in the Psoriasis Area and Severity Index of at least 75% (PASI75). The three groups reported adverse events with similar frequency.  The authors measured strong inhibition of IL-17 and disease-related genes related to the IL-23/Th17 axis, in addition to a significant correlation between treatment-associated molecular changes and improvement in PASI scores. The results support a new model for treating psoriasis and raise the possibility of attaining long-term remission from a single drug intervention. 

Persistence of asthma requires multiple feedback circuits involving type 2 innate lymphoid cells and IL-33

Little is known about the mechanisms regulating the persistence of chronic asthma. Because many allergens are perennially present, it has been difficult to ascertain whether persistence depends on this proximity. Studies of patients with occupational asthma have shown they experience symptoms for years after occupational exposure has ended. Christianson et al developed a mouse model in which asthma persisted for six months after allergen exposure ceased. They then used a combination of immunologic, genetic, microarray, and pharmacologic approaches to identify the factors contributing to symptom persistence (J Allergy Clin Immunol 2015; 136(1):59-68).

The authors found increased ILC2 levels characterize chronic asthma. In addition, IL-33-driven ILC2s prove to be an essential factor. The blockade of epithelial IL-33 led to a complete resolution of airway hyperactivity and a significant reduction of airway inflammation. They found IL-13, a product of ILC2s, can induce production of IL-33. It also generates a forward-feed mechanism on IL-33R expression, creating a positive feedback loop. Elimination of any component of the circuit resulted in disease resolution. They found finally that elimination of T-cells resolved airway inflammation but not airway hyperactivity or remodeling.

While previous studies have shown increased IL-33 in bronchoalveolar lavage (BAL) fluid, here the authors demonstrate an increase in ILC2 numbers. The results have implications for the treatment of chronic illnesses in general, suggesting that they depend on feedback and feed-forward circuits, interconnected systems that fail if a component is removed, and that it is these circuits that transition a disease from an acute condition to a chronic one.

The mechanism or mechanisms driving atopic asthma initiation: The infant respiratory microbiome moves to center stage

It is acknowledged that key events that determine risk for the development of allergic disease frequently occur years before manifestation of symptoms. Recent culture-based studies, in combination with population-wide bacterial metagenomic data, suggest that parallel bacterial interactions may contribute to disease development. Holt reviews these and related issues of immune competence in infancy (J Allergy Clin Immunol 2015; 136(1): 15-22).

A number of factors specific to  infancy can contribute to disease development. Prospective tracking of postnatal IgE titres in serum samples collected over the first five years of life strongly suggests IgE antibody production against aeroallergens rarely begins before the age of six months. Airway mucosal dendritic cells (AMDC) transmit aeroallergen-specific signals from the airway mucosal surface to the central immune system and program the balance between the Th2 and T regulatory cell components of the immunological memory that results. The immaturity of this network in infants is likely a risk factor for early respiratory infection, itself a risk factor for early atopic asthma.

The focus on respiratory pathogens that contribute to the immunopathogenesis of atopic asthma has in the past been almost exclusively on viral pathogens: respiratory syncitial virus (RSV) and human rhinovirus (HrV). Emerging studies include consideration of the role of bacterial pathogens. Data suggests qualitative and quantitative differences in the lower airway bacterial populations of asthmatic children, including the mix of the strains present and the overall bacterial burden. The findings call for an accurate understanding of the full spectrum of strains that constitute the respiratory tract microbiome, particularly  nasopharyngeal microbial populations which function as a resevoir from which seeding into the lower airways occurs, in terms of population level and dynamics, across the average age range for asthma onset. The Perth CAS cohort study of 234 infants has provided the first foundation for this work. Questions, such as whether the replacement of commensal bacteria species in the nasopharyngeal microbiome of infants with known pathogens precede or result from local viral infection, remain to be answered.