Standardizing research food challenges

A pressing need for standards of conduct for research-related double-blind, placebo-controlled, oral food challenges (OFC) provided the impetus for a consensus report by Sampson et al in this month’s issue (J Allergy Clin Immunol 2012;130:1260-1274).

After a brief review of the historical literature on diagnosing food allergy, Sampson et al present topical discussion summaries for major issues in the conduct of research OFC, noting that the guidance and recommendations apply equally to clinically performed challenges. The authors emphasize that patient/subject safety was the pre-eminent consideration. The following are highlights from their discussions:

·      Pre-challenge assessments. The authors cover important evaluations and practices prior to conducting OFC. These include case history, current food avoidance, comorbid conditions that impact safety such as atopic dermatitis and chronic disease, the utility of surrogate test results and their intrinsic problems, and the requirement for an optimal challenge setting. They also discuss the issue of differential severity of allergens as an important safety consideration prior to OFC.

·      Challenge procedures and assessments. Sampson et al discuss dosing schedules and their necessary variability tied to outcomes. General recommendations for dosing include low starting doses, separate active and placebo challenge days, dosing intervals no less than 20 minutes and appropriate, low fat matrices. Recording important, objective clinical parameters, such as respiratory symptoms and other physical reactivity symptoms, is covered. Sampson et al emphasize that scoring and stopping criteria must be pre-specified in light of the critical role of clinical judgment in OFC conduct. Delayed reaction considerations and subjective symptom issues are also reported. Tables of their recommendations are provided for reference.

·      OFC analysis and reporting. To ensure a reliable evidence base, Sampson et al provide guidance and recommendations for statistical analysis and reporting results, particularly from randomized trials. 

Revisiting LABAs with the help of Macbeth

Szefler and Busse provide an entertaining and thoughtful editorial this month on the predicament of LABA step-down by invoking Macbeth’s notorious witches’ ominous chant (J Allergy Clin Immunol 2012;130:1256-1259). Likening the clinician’s dilemma at the FDA recommendation to withdraw LABAs for safety reasons from treatment of well-controlled asthma to the troubling brew of the witches, the authors review the history of long-acting beta 2 agonists’ use and the evidence that supports the safety concerns that prompted the FDA’s action. Szefler and Busse note that a recent evidence review does not concur that LABAs are unsafe when used in combination with ICS and, in fact, concludes that withdrawal of LABAs in that treatment context results in asthma worsening.

At the heart of the controversy are several “Catch-22s”: how and when to step down and, critically, with what to replace LABAs if control is lost. Clinicians and researchers are concerned that the delay in safety reporting will also delay the development of new asthma drugs in the LABA category. Further, the FDA safety trial does not address how to step-down LABAs in the event of a poor safety profile. This would require yet another set of trials, which implies further delays.

Results from the current FDA-mandated safety study are expected to be reported in 2016. Until then, the authors provide approaches for possible step-down in patients on ICS and LABA combination products. Among these, they suggest that clinicians consider the asthma natural history, especially over the previous year, the possibility of adjusting either the ICS or the LABA, and alternative supportive treatments, such as omalizumab or tiotropium, if they decide to step-down the LABA. Szefler and Busse emphasize that there is no current evidence that supports changing the current EPR-3 guidelines, which already advise against LABA monotherapy.

A wart compendium: HPV infections in immunodeficiency diseases

November’s issue features an article from two NIAID researchers, Jennifer Leiding, MD and Steven Holland, MD, who present an inventory of HPV infections associated with primary immunodeficiencies (J Allergy Clin Immunol 2012;130:1030-1048). A short review of HPV immunopathology and epidemiology opens the authors’ discussions of the associated diseases and syndromes.

Beginning with those illnesses with which HPV infection is a predominant clinical presentation, Leiding and Holland present concise information on the symptomatic features, immunogenetic context and treatment approaches of the most common HPV-susceptible immunodeficiencies:

·      EV (epidermodysplasia verruciformis) is characterized by increased susceptibility to cutaneous HPV infection and associated with recurrent, pathological infection and malignant conversion. Autosomal recessive mutations in the genes EVER1 & 2, which code for transmembrane proteins thought to restrict HPV intracellular ingress, result in deficiency that raises HPV susceptibility across many immune cell types. HPV infection in EV is highly resistant to therapies.

·      WHIM (warts, hypogammaglobulinemia, infection and myelokathexis) syndrome, an autosomal dominant immunodeficiency, presents with pulmonary, gastrointestinal, and cutaneous infections and neutropenia. Dysplastic and malignant warts are the characteristic features. A gain-of-function mutation of the chemokine receptor CXCR4 results in impaired myeloid and dendritic cell signaling that permits greater HPV infection. Patients have good response to IVIg and bone marrow growth factors.

·      DOCK8 (dedicator of cytokinesis 8) deficiency is one of the combined immunodeficiencies in which infection by HPV and herpetic viruses are chronic and comorbid. Presentation is similar to STAT3-associated hyper-IgE syndrome.

Leiding and Holland also cover rare immunodeficiencies, such as idiopathic CD4 lymphopenia, severe combined immunodeficiency disease, GATA2 deficiency, Wiskott-Aldrich syndrome and Netherton syndrome, with which there have been a few reports of HPV infection. The authors provide an excellent table summarizing the immunodeficiency diseases that have associated HPV infection. Leiding and Holland wrap up noting that physicians should suspect immunodeficiency in their patients with recurrent, pervasive, and/or treatment refractory HPV infections.

Says first author Jennifer Leiding, from the National Institute of Allergy and Infectious Diseases: “Investigation of patients with susceptibility to HPV will lead to further understanding of host defense toward viruses as well as cutaneous and systemic immunity.”

Modeling asthma-related utilization

In the current socioeconomic climate, evaluating healthcare utilization in the context of chronic disease outcomes and intervention is vital. Think Framingham. Wu et al. in this month’s issue (J Allergy Clin Immunol 2012;130:1065-1070) step up to this challenge for asthma, designing and testing a prediction model that draws on data from the Childhood Asthma Management Program (CAMP). The authors use data on changes in prebronchodilator FEV₁ % predicted in subjects treated with ICS to simulate prediction of hospitalization, ED visits, and oral CS therapy associated with exacerbations. The simulated results are then compared with the actual data from CAMP to assess the model’s reliability.

Wu et al. report remarkable consistency between the simulation predictions and the CAMP data. As one example, their model predicted a 48% decrease in hospitalizations with ICS therapy compared to placebo. The observed decrease in the CAMP data was 49%. The authors comment that further testing with data not involved in developing the model is required and they invite other asthma investigators to collaborate. 

The allergenicity of “hypoallergenic” dogs

It’s a primitive social urge in humans to interact with dogs. So much so that many people found to be clinically sensitive to dogs will own them anyway. In this context, it is not surprising that the search for dogs that elicit a minimal allergic response would claim so much energy, but are there such things as “hypoallergenic” dogs? Vredegoor et al. look at that question in this month’s issue (J Allergy Clin Immunol 2012;130:904-909.e7).

The authors examine levels of the primary dog allergen, Can f 1, in samples from dog fur and skin, and settled and airborne dust from “hypoallergenic” dogs (Labradoodles, Poodles, Spanish water dogs, and Airedale terriers), normal allergenic dogs (Labrador retrievers), and a variety of breeds and mixed breeds that made up the control group. Their results are paradoxical and even ironic.

Poodles and Labradoodles had the highest levels of Can f 1 in their coat and skin; Labrador retrievers had the lowest. Hair and dander shedding was highest from Airedale terriers. Vredegoor et al. report that environmental levels of Can f 1 were not significantly different between “hypoallergenic” dogs and their allergenic counterparts, though homes with covered floors had overall lower environmental levels than homes with exposed floors. The authors note that other identified canine allergens, such as Can f 2 and 3, were not screened due to lack of available methods for analyzing large sample sizes. 

The authors also collected information from owners by administering questionnaires. Dog-allergic owners reported much fewer symptoms with the breeds thought to be hypoallergenic and did not report having different house-cleaning practices than non-allergic owners. It was noted that recent swimming by the dogs had an overall effect of lowering allergen levels and Vredegoor et al. speculated that this could contribute to the lower levels found in Labrador retrievers, which are frequent swimmers.

Vredegoor et al. conclude that there is no evidence that supports the label “hypoallergenic” with respect to dogs, so we asked the authors to comment on a possible explanation for the number of dog-allergic owners who reported experiencing fewer symptoms with certain dogs: Senior author Esmeralda J.M. Seegers-Krop replies, “We believe the health effects can be a kind of placebo effect in these people. It has been seen in cat allergic people as well (they report not to be allergic to their own cat but only to other cats).”

Asthma therapies targeting Il-13

This month’s clinical review article by Ingram and Kraft (J Allergy Clin Immunol 2012;130: 829-842) presents exhaustive and timely coverage of a complex issue in asthma treatment, namely, the interface of IL-13 pathophysiology, asthma phenotypes, and IL-13 targeted therapies. The authors take the discussion to foundations of IL-4/IL-13 signaling in asthma before delving into the clinical and investigative implications associated with IL-13 dominance in atopic asthma. The review comprehensively covers current knowledge on the clinical and genetic heterogeneity of asthma, emerging phenotypes and subtypes, biomarker diagnostics, and systemic and targeted therapy responses in well-characterized asthma phenotypes.


Review highlights include:

• Cluster analysis of clinical asthma phenotypes by several research groups, including the consistent finding of eosinophilic, high TH2 cytokine profile asthma and non-eosinophilic, low TH2 cytokine profile asthma.

• Evidence confirming therapeutic efficacy of systemic and targeted therapies in eosinophilic, high TH2 asthma.

• Reports of the successful use of biomarkers in characterizing response to therapy, including recent research involving omalizumab, mepolizumab, and lebrikizumab for patients with severe and/or uncontrolled asthma characterized using clinical and biomarker indices.

• Specific evidence for applying FENO, induced sputum, IgE, and periostin to treatment decision making.

Ingram and Kraft note that traditional and targeted therapies are effective only for eosinophilic, TH2 high asthma patients, leaving a gap in our knowledge about how to effectively manage the low TH2 profile patients. They also remark that TH2 inflammation in asthma patients may be more effectively assessed through the use of combinations of inflammatory and molecular markers, rather than relying on observations of single biomarkers. They conclude by commenting that application of the molecular features of asthma phenotypes, in combination with clinical evidence, is being used to predict response to intervention. They follow by pointing out that the current knowledge base has defined a gap in managing asthma that does not present with a TH2 dominant signature.

A collaborative model for drug development for rare diseases

This month’s issue holds an article by Fiorentino et al. putting forward a model for rare disease drug development and the first realization of this model (J Allergy Clin Immunol 2012;130:613-616). Fiorentino and colleagues at the FDA in CDER’s Division of Gastroenterology and Inborn Error Products chose the rare disease eosinophilic esophagitis (EoE) as the focus of their efforts to establish this new paradigm.

Noting the rise in prevalence and incidence of EoE, the authors discuss the knowledge gaps that create obstacles to effective clinical interventions. They use this information to construct their model of “rational” drug development, which includes defining the disease in clinical, research and sociocultural terms, evaluating the natural history of the disease using the definitions identified, and reliably assessing clinical and patient-reported outcomes.

Fiorentino et al. describe their efforts to date implementing this model. They tapped critical research groups, such as The International Gastrointestinal Eosinophil Researchers (TIGERs), North American Society of Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) to open discussions on disease definition and urge the inclusion of disease and patient advocacy groups in this early process. Advocacy groups are identified as critical to the success of the model because they bring strong interest in the long-term success of research into the disease.

Early progress is reported for the determination of a functional disease definition and appropriate terminology. The authors note that findings from graduate student research supported by the EoE project demonstrate that inconsistent and vague terminology is impeding research efforts. Additionally, they comment that research is underway to understand the relationship between positive clinical outcomes and the esophageal mucosal eosinophilia that is diagnostic for EoE. They point out that there is a pressing need to define and characterize the EoE patient population in order to develop appropriate patient-reported outcome measures.

An editorial in this issue by Rothenberg et al. presents additional perspectives and considerations (pp#). Dr. Rothenberg notes that an upcoming meeting (Sept. 19) provides an opportunity for more information and exchange of opinion about the subject. For further information: https://www.signup4.net/public/ap.aspx?EID=20123759E&OID=50