When Food Is the Enemy: Understanding Eosinophilic Esophagitis
Better understanding of the immune dysfunction causing EoE will lead to additional treatment options for this disease that is on the rise.
Eosinophilic esophagitis (referred to as EoE) involves an atypical allergic response to food in the esophagus. In some patients, the response can be triggered by simply the smell of the problematic food. The disease does not involve an inappropriate reaction to self molecules. So, although it is an immune disease, it is not an autoimmune disease. EoE is diagnosed by the presence of >15 eosinophils per high power field (∼60 eosinophils/mm2) in biopsy samples of the esophagus, inflammatory changes to the esophagus, and the presence of other digestive system symptoms.
The major symptoms are gastroesophageal reflux (GERD), difficulty swallowing, food impaction in the esophagus, or recurrent vomiting. Weight loss (or failure to gain weight in children) and “finicky” eating are also common.
The diagnosis of EoE has increased in the past few decades. Some of the increase relates to the increased use of endoscopy with biopsies to diagnose upper GI conditions. Some of the increase relates to changes in the classification of the disease. Unfortunately, the treatment options for this condition are limited.
Not only is food necessary for survival, but many social interactions involve food. A diagnosis of EoE can explain food restrictions and self-imposed dietary limitations someone has had for a long time. This diagnosis can also create an enormous amount of stress and anxiety if the triggering foods have not been figured out. For someone newly diagnosed, this can present real challenges, because identifying the triggering foods can be a long difficult process.
By identifying the foods that cause the reaction and removing them from the diet, the condition can be managed. Unlike food allergies that cause the throat to swell immediately, the food allergies that cause EoE cannot typically be identified through skin tests. Instead, elimination diets tend to be required. However, this can be challenging, especially in a very active person or an athlete. The full elimination diet, which can be required to clear the system before introducing foods in a controlled way, can result in a reduction in calories that causes rapid weight loss. Foods have to be slowly re-introduced, and the definitive method to know if a food does not cause symptoms is to have the esophagus checked through endoscopy and a biopsy. With each new food requiring several weeks to confirm no reaction or to recover if there is a reaction, it can be many months before the patient’s dietary requirements to minimize EoE are determined.
The only available medications for treating EoE are proton pump inhibitors (PPIs) and synthetic glucocorticoids. PPIs reduce acid production in the stomach and thus reduce GERD, which can alleviate some symptoms. Indeed, a subset of patients, referred to as patients with proton pump inhibitor-responsive eosinophilic esophagitis (PPI-REE), have complete resolution of their symptoms and normalization of the number of eosinophils in their esophagus in response to PPI treatment. However, they may need to take these medications intermittently if the condition flares or regularly for the rest of their lives to maintain this healthy state.
- Nexium (esomeprazole)
- Prevacid (lansoprazole)
- Prilosec and Zegerid (omeprazole)
- Protonix (pantoprazole)
- Aciphex (rabeprazole)
- Dexilant and Kapidex (dexlansoprazole)
Synthetic glucocorticoids can be administered orally to suppress the entire immune response, or they can be administered to the esophagus. None of the currently used medicines are prepared in a formulation for targeted administration to the esophagus. Instead, these medicines (fluticasone or budesonide) are prescribed as preparations for treating asthma. One improvement to treating this condition would be to provide an EoE formulation for patients, rather than requiring them to prepare their own by either “swallowing” medicine from the inhaler sprayed into the mouth (fluticasone) or removing the medicine from asthma inhalers (budesonide), mixing it with a thick liquid (such as honey, sucralose, or agave syrup), and swallowing the mixture. Clinical trials are underway to develop such properly formulated glucorticoids that can be swallowed and act on the esophagus.
Glucocorticoids do not cure the condition, but they do limit the inflammation associated with it and can even permit the patient to eat the triggering foods. Unfortunately, the swallowed glucocorticoids can lead to the development of thrush in the mouth and throat, resulting from overgrowth of the naturally occurring yeast that are present. When this occurs, treatment must stop to allow the immune system to fight the yeast overgrowth, which can let the inflammation from the eosinophil response recur or become worse, especially if the symptoms are not adequately controlled through dietary restriction.
Although the cells that define this condition clinically are eosinophils, other cells in the immune system contribute. In particular, a type of T cell called T helper type 2 (Th2) cells release signals (called cytokines) that promote maturation of eosinophils in the bone marrow and also stimulate their release from the bone marrow and recruitment to the esophagus. Th2 cells are components of the adaptive immune system and are the cells that specifically respond to the molecules called antigens that are in the food and trigger the allergy. Indeed, it may be abnormal activity of Th2 cells is the underlying problem in EoE. Consistent with this idea, increased amounts of Th2 cytokines (IL-4, IL-5, and IL-13) have been found in esophageal biopsies from EoE patients.
Clinical trials are testing medications that interfere with the Th2 cytokines or the receptor for these cytokines. The available data from clinical trials suggest that reslizumab, mepolizumab, and benralizumab, which are antibodies targeting IL-5, reduce eosinophils in the esophagus but do not provide clinical improvement in symptoms or for the damage to the esophageal tissue. Dupilumab is the antibody that interferes with a protein that is part of the receptor for IL-4 and IL-13. RCP4046 is an experimental antibody-based drug that targets IL-13. With the exception of RCP4046, the others are approved for the treatment of eosinophilic asthma, and some are approved for other eosinophilic diseases. However, the apparent difference in the responsiveness of patients with eosinophilic diseases in different tissues suggests that the underlying biological basis for the diseases may be different.
Additional therapeutic opportunities relate to esophageal-targeted interference with the signaling pathways of Th2 cells or eosinophils or inhibiting the proteins that the epithelial cells produce that promote the damaging tissue remodeling or that help recruit the eosinophils into the esophagus.
For most types of therapy, the ideal strategy would be to deliver the treatment to the esophagus rather than having to administer the drugs systemically. Such targeted delivery would limit the possibility of systemic immune suppression or other adverse effects.
Although it is not good news that the frequency of EoE and other GI eosinophilic diseases is increasing, it should spark research and encourage development of treatments for these conditions.
Also of Interest
N. R. Gough, Attack of the Eosinophil. BioSerendipity (3 September 2019). https://www.bioserendipity.com/attack-of-the-eosinophil
N. R. Gough, Eosinophilic Esophagitis: When Food Is the Enemy. BioSerendipity (14 September 2019) https://www.bioserendipity.com/eosinophilic-esophagitis-when-food-is-the-enemy
Eosinophilic Esophagitis. Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/eosinophilic-esophagitis/symptoms-causes/syc-20372197 (accessed 13 September 2019)
Cincinnati Center for Eosinophilic Disorders. Cincinnati Children’s Hospital Medical Center. https://www.cincinnatichildrens.org/service/c/eosinophilic-disorders/about (accessed 13 September 2019)
Eosinophilic Gastrointestinal Disorders Q & A with Marc Rothenberg, MD, PhD. https://www.youtube.com/watch?v=aiVuzeyCTEw (viewed on 13 September 2019)
Eosinophilic Esophagitis (EOE). American Academy of Allergy Asthma & Immunology. https://www.aaaai.org/conditions-and-treatments/related-conditions/eosinophilic-esophagitis (accessed 13 September 2019)