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Friday, July 1, 2011

Eosinophilic esophagitis: Updated consensus recommendations

A task force made up of 33 experts from multiple disciplines present updated recommendations for the diagnosis and management of eosinophilic esophagitis (EoE) in this month’s issue (J Allergy Clin Immunol 2011;128:3-20). Liacouras and colleagues performed an exhaustive literature review to inform new clinical recommendations (CR) for 5 categories: diagnostics, genetics, allergy evaluation, therapies, and complications. They also offer recommendations for future critical research areas. Importantly, they provide a concept definition to assist clinicians with framing the clinical presentation of EoE. Liacouras et al. state this concept definition: “Eosinophilic esophagitis represents a chronic, immune/ antigen-mediated esophageal disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation.”

Overview of diagnostic recommendations: The task force makes recommendations in the diagnostic areas of history and physical exam, endoscopy, histology, pH monitoring, and laboratory findings. Among these are a thorough H & P, with emphasis on eating and swallowing symptoms, proximal and distal endoscopic biopsies, and gastric pH and pH impedance testing. Additionally, Liacouras et al. recommend that any and all histological findings be reported until EoE-specific findings are identified. The authors note that very few laboratory tests have been demonstrated to be informative, with the exception of peripheral esosinophil count and skin prick testing.

Overview of genetic studies and recommendation: Noting that the previous consensus report, published in 2007 (Gastroenterology 2007;133:1342–1363), presented a single genotype study, Liacouras et al. provides a substantial review of recent genetic research. Two important genetic findings are the description of an EoE transcriptome with increased expression of eotaxin-3 and IL-13, and the report of a single susceptibility locus, 5q22, for EoE that contains genes encoding thymic stromal lymphopoetin (TSLP), a critical cytokine in TH2 cell commitment. An X-linked variant of TSLP and a common deletion mutation in the filaggrin gene family have also been identified.

Overview of allergic evaluation: Atopic conditions including food allergy, asthma and eczema are known to associate with EoE and the task force emphasizes allergist/immunologist consultation for management of comorbid allergic symptoms. Skin prick testing is necessary to identify reactive allergens and eliminate or mitigate them. Liacouras et al. recommend assessment of allergen-specific IgE to document sensitivity prior to initiating desensitization/tolerance protocols.

Overview of therapeutic options: Liacouras et al. review and recommend a multifocal treatment strategy that includes proton-pump inhibitors (PPI), dietary restrictions, and topical corticosteroids. Oral steroids are recommended only for severe symptom presentations. They also state that alternative therapies, such as cromolyn sodium, LTR antagonists and immunosuppressive drugs, are not recommended based on lack of efficacy data.

Overview of complications: Liacouras et al. point out the common complications, namely, emergent food impaction, esophageal stricture, and non-interventional (“spontaneous”) esophageal perforation. They go on to discuss esophageal dilation for mitigation, but advise that it is best applied as an “add-on” intervention to the recommended clinical management.

Liacouras et al. provide recommendations for the focus of future studies for each of the 5 areas they cover and conclude that the most pressing need is for research to distinguish EoE from gastric esophageal reflux disease (GERD), with several other priorities, such as translational analysis to describe EoE phenotypes, and idenfication of EoE biomarkers and unique histological findings.

We asked lead author Chris Liacouras, from the Children’s Hospital of Philadelphia, to tell us more about our current understanding of EoE and where the research will go from here:

JACI: How has our understanding of EoE changed since the 2007 consensus recommendations were published?

Liacouras: We have been been extremely fortunate that the number of physicians and scientists interested in EoE has grown tremendously since the original Consensus Report in 2007 as noted by the number of additional authors included in the 2011 Updated Guidelines. The most important component of the Updated recommendations continues to be the understanding of the definition which attempts to explain that EoE is an antigen/immune medicated disease process different from acid induced or PPI-responsive esophageal eosinophilia. Additionally, the other most significant advances since 2007 have been made in genetics and with the identification of specific esophageal biochemical tissue markers.

JACI: In your opinion, what is the next priority area in EoE research after the need to distinguish it clinically and pathologically from GERD?

Liacouras: Currently, EoE has become one of the interesting and confusing disorders for both gastroenterologists and allergists. Apart from the need for physicians to identify and accurately diagnose patients with EoE, there are many areas of ongoing research that need to be explored. Clinically, it is essential that we continue to pursue the natural history, non-invasive testing, best treatment options and which patients are likely to develop complications. In addition, scientifically, we need to identify the etiology, pathophysiology, and development of esophageal fibrosis in patients with EoE. We also need to continue to explore the genetics of the disease.

Eating baked cow’s milk products may facilitate resolution of cow’s milk allergy

Kim et al. (J Allergy Clin Immunol 2011;128:125-131.e2) investigate the clinical implications of the empirical observation that 75% of milk-allergic children tolerate extensively heated milk in foods such as baked goods. These children have been observed to have milk-specific IgE directed at conformational epitopes rather than sequential epitopes. Heating (such as baking) disrupts the tertiary structure and consequently, reduces the allergenicity of milk proteins to which these children are sensitive. In contrast, children who are reactive to heated milk products have milk-specific IgE to heat-stable, sequential epitopes.

Kim et al. report on their findings from a clinical study of baked milk tolerant and baked milk reactive subjects, wherein baked milk tolerant subjects were advised to include baked milk food products in their diet on a daily basis, while baked milk reactive subjects were advised to practice complete strict avoidance. A comparison group, not initially challenged to baked milk products, was also observed over the study period.

Overall, Kim et al. report that initially baked milk tolerant subjects were 28 times more likely to become unheated milk tolerant than those initially baked milk reactive subjects, as compared to those subjects who observed strict avoidance. Baked milk tolerant subjects that received active treatment (that is, were able to include baked milk products into their diets) were significantly more likely to develop tolerance to unheated milk compared to the comparison group.

The authors demonstrate two important outcomes of their study: 1) baked milk tolerance is a marker of mild, transient cow’s milk allergy; baked milk reactivity implies a more persistent, severe form of cow’s milk allergy and, 2) the majority of children with baked milk tolerance that routinely eat baked milk food products will develop unheated milk tolerance at an accelerated rate compared to children prescribed a strict avoidance diet.

Kim et al. suggest that ingestion of baked milk products by tolerant patients is a safer, more convenient and cost-effective method of immunotherapy. They also comment that their results might be extrapolated to children with egg allergy in light of reports on heat-related changes in allergenicity of egg proteins.

We asked first author Jennifer Kim, from Mt. Sinai School of Medicine, to tell us about the implications of this work for future research. According to Dr. Kim, “These findings have provided the impetus for a more rigorously designed study that has been developed by our group to determine whether more rapid introduction of increasingly allergenic forms of baked-milk products in baked-milk non-reactive participants shortens the time until they tolerate higher doses of less heated milk and ultimately unheated milk.”

Tell us what you think. Please feel free to post your comments below.