CEGIR Presentation Q&A

• Are access to healthcare and socioeconomic factors being studied in EGIDs?

  • Existing data is limited, but some tools :are available to evaluate how socioeconomic factors and access to healthcare affect EGID care.
  • The Childhood Opportunity Index (COI) measures and maps the quality of resources and conditions that maner for children to develop in a healthy way in the neighborhoods where they live.
  • The COI has been used to study pediatric asthma.
    • Factors including high foreclosure rates and low levels of education may increase the risk for asthma-related hospitalization and need for healthcare.
    • Living closer to a healthcare facility may decrease the risk for asthma-related hospitalization and need for healthcare.
  • The COI may be a tool that can help us understand how access to healthcare, education, and socioeconomic status affect patients with EGIOs in the US.
  • CEGIR is actively researching how these factors influence care of patients with EoE who go to the emergency room for a food impaction.

• Are there different types of EoE and how do they differ?

  • Yes, EoE can be classified based on different clinical features, endoscopic findings, response to treatment, and molecular markers. 
  • Currently, there are three main types of EoE:
    • EoE 1- normal appearing endoscopy, pediatric-onset, steroid-sensitive, associated with other allergic conditions.
    • EoE 2 – inflammatory appearance, pediatric-onset, steroid-refractory.
    • EoE 3- scarring and narrowing seen on endoscopy, adult-onset, not associated with allergic conditions.
  • As of yet, these different clinical presentations do not necessarily predict response to treatment or natural history.

• Are there other rare diseases that coexist with EGIDs?

  • Yes, EGIDs are associated with several other rare diseases.
  • These include but are not limited to the following:
    • Hypereosinophilic syndromes (HIES)
    • Netherton syndrome
    • Common variable immunodeficiency (CVID)
    • Hyper lgE syndrome
    • SAM: Severe dermatitis, multiple allergies, and metabolic wasting syndrome
    • Connective tissue disorders (e.g. Loeys Dietz syndrome)
    • PTEN hamartoma tumor syndrome
  • Some of these conditions may compromise the barrier function of the lining of the esophagus or predispose to eosinophilic inflammation.

• Can biologics used for the treatment of inflammatory bowel disease be used to treat EGIDs?

  • There are several different biologic medications used for the treatment of inflammatory bowel disease. Some of these include the following:
    • Anti-TNFα agents (e.g., infliximab (Remicade), adalimumab (Humira)]
    • Anti-a4137 integrin agents (e.g., vedolizumab (Entyvio))
    • JAKl/3 inhibtors (e.g., tofacitinib (Xeljanz))
  • Data supporting the use of anti-TNFα agents, anti-a4β7 integrin agents, and JAK 1/3 inhibitors for EGIDs is limited.
  • A handful of small case series and case reports suggest these medications may be helpful depending on the individual and the parts of the gastrointestinal tract affected. Others have not been as supportive.
  • None of these medications are approved by the FDA for the treatment of EGIDs. Additional studies are needed to evaluate the safety and efficacy of these medications.

• Can EGID's progress into Hypereosinophilic Syndrome (HES) or Eosinophilic Granulomatosis with Polyangitis (EGPA)?

  • Progression of EGID to hypereosinophilic syndrome (HES) or eosinophilic granulomatosis with polyangiitis (EGPA) is rare but has been reported.
  • Patients with eosinophilic gastritis/gastroenteritis and blood eosinophil counts ≥ 1,500 may be at increased risk for eosinophilic inflammation in other organs.

• Can EoE cause chronic fatigue even when it is in remission?

  • Fatigue is common in individuals with EoE.
  • The underlying mechanisms connecting fatigue and EoE are unclear; however, patients with EoE may be at risk for nutritional deficiencies, medication side effects, and sleep disruption.
  • Patients with EoE may also experience feelings of depression, anxiety, and isolation, which can contribute to fatigue.
  • There is limited data on fatigue in well-controlled EoE.

• Can EoE cause speech delay?

  • We don’t know of any associations between EoE and speech delay. 
  • Speech delay can be diagnosed alone or caused by something else (e.g. hearing loss, autism, intellectual disability).
  • Patients with autism are more likely to have EoE.

• Can you grow out of EoE or other EGIDs?

  • Most patients require ongoing, life-long treatment for EoE to control inflammation and prevent scarring.
  • The absence of symptoms does not necessarily mean that inflammation is controlled.
  • EoE may be outgrown in a small subset of patients(< 5%)
  • Eosinophilic inflammation affecting the stomach or intestines may be more likely to resolve.
  • The factors that may lead to long-term remission in EGIDs are unknown.
  • CEGIR is investigating the natural history of EGIDs through an ongoing cohort study.

• Do you believe glutathione deficiencies play a role in EoE?

  • We don’t know if glutathione deficiency plays a role in EoE.
  • We do know the following about glutathione:
    • Glutathione is an important anti-oxidant.
    • Glutathione deficiency may be associated with increased inflammation in inflammatory bowel disease (180).
    • Glutathione deficiency is associated with an increased risk for cancer.
    • In contrast, glutathione may be necessary to produce leukotrienes (inflammatory molecule) in EoE.

• Does maternal antibiotic exposure cause food allergies and EoE?

  • We aren’t sure if maternal antibiotics cause food allergies and EoE.
  • A new study suggests that a baby’s risk for EoE may increase the more an expectant mother takes antibiotics.
  • The risk for EoE appears to increase the closer the antibiotic exposure occurs to the time of delivery.
  • Other risk factors for EoE include: 
    • Infant antibiotic exposure
    • Cesarean delivery
    • Antacid use

• Have changes in farming practices or food manufacturing, processing, and packaging increased the number of EGIDs?

  • The incidence and prevalence of EoE has increased in the last 30 years.
  • Several changes have been introduced in farming practices and food production since the 1950’s:
    • Mechanization, fertilizers, pesticides (e.g., glyphosates), and genetically modified seeds have been used more.
    • Antibiotic use has increased and there are more animals in feedlots.
    • Preservatives and plastics (e.g., phthalates) have been introduced to preserve and package foods.
  • It is is unknown whether any of these changes have contributed to the increase in EGIDs.
  • Environmental exposure to some pesticides may be associated with increases in food allergy, but additional research is needed to identify causal relationships between chemical and antibiotic exposures in the food supply and EGIDs.

• If I have EoE, are my family members at risk of developing EoE too?

  • The overall prevalence of EoE in the general population is low
    (approximately 0.06%).
  • Individuals with an immediate family member (parent/child, sibling) with EoE are at increased risk of EoE compared to the general population, but the risk is modest based on existing studies.
  • The increased risk of developing EoE in families is due to both genetic and environmental factors (lack of breastfeeding, geographic location, infections, absence of pets, etc.).
  • Additional studies are needed to understand how genetic and environmental factors combine to increase the risk of developing EoE in families.

• If IL-5 has been linked to EoE, will there be recommendations for genetic testing specifically for it?

  • lnterleukin-5 (IL-5) is a biologically relevant protein which contributes to EoE that been targeted for treatment.
  • Currently, there is no evidence that variation in the IL5 gene contributes to EoE.
  • Given the complex regulatory network driving IL5 expression, it is possible that we are not looking for the variation in the right place. 
  • Right now, there is not clinical genetic testing for EoE – but that could change in the future.

• If someone has EoE and asthma, does it mean they have eosinophilic asthma?

  • Not necessarily as there are multiple different subtypes of asthma and EoE. Eosinophilic asthma is a subtype of asthma that may be more severe and harder to treat. It can be diagnosed by a lung biopsy, fluid or mucus from the lungs, blood eosinophil counts, or a breath test (feNO).
  • In patient$ with EoE and other allergic diseases, the risk for eosinophilic asthma is likely increased because both arise from a shared pathophysiology.
  • Patients with EoE may have more severe asthma (more persistent with decreased lung function).
  • Conversely, patients with asthma may have more severe EoE based on eosinophil counts in the esophagus.
  • Treatment approaches for eosinophilic asthma are likely to complement one another and treating one condrtion is likely to benefit/improve the other.
  • Systemic biologics targeting allergic inflammation (IL-4, IL-5, IL-13) may improve both diseases simultaneously.

• Is it possible to biopsy tissue from an EoE patient's esophagus, grow that tissue in a lab setting and then test it for eosinophilic triggers?

  • Yes, there are model systems in place to study the esophagus in the laboratory setting. It may be possible to use these systems to determine food triggers in the future.
  • The esophagus is a complex organ supplied by a series of blood vessels that has multiple layers (e.g. mucosa, submucosa, muscle, and connective tissue).
  • Responses to triggers foods are determined by interactions between esophageal cells and immune cells within the esophagus and the lymph nodes.
  • There are several types of models we use to study EoE in the lab:
    • In vitro (in test tube/petri dish) – submerged esophageal cell cultures, air-liquid interface cell cultures.
    • In vivo (in living body) – animal models.
    • Ex vivo (outside living body) – esophageal tissue removed (e.g. biopsy, explant) and grown in the lab.
    • Organoids (organs in petri dish) – 3-D culture systems that recreate multiple layers of the esophagus.

• Is there a connection between EGIDs, dysautonomia, and connective tissue disease?

  • Dysautonomia (also called “autonomic dysfunction”): occurs when the autonomic nervous system is not able to regulate itself properly. The autonomic nervous system is part of the nervous system that controls things that are not usually in our control (e.g., heart rate, breathing, and digestion).
    • Postural Orthostatic Tachycardia Syndrome (“POTS”): a common form of dysautonomia.
  • Connective Tissue Diseases: are a group of diseases that affect parts of the body that hold structures together (e.g. ligaments, skin, blood vessels, etc.).
  • While there are only a few studies on this subject, there does seem to be a link between all these diseases.
    • People with EGIDS are more likely to have dysautonomia and connective tissue diseases (particularly women), but we don’t know why yet.
    • Treatment of EGIOs does not seem to improve dysautonomia or connective tissue disease.

• Is there a link between EGIDs and headaches?

  • We don’t know of a link between EGIDs and headaches.
  • Headaches are common.
  • Migraine headaches may be more common in other allergic diseases (asthma and allergic rhinitis).
  • More research is needed to directly address this question.

• What are some of the risk factors that contribute to developing EGID?

  • Studies of identical vs. fraternal twins with EoE suRgest that environmental factors are important for the development of EoE.
  • Early life exposures may influence the microbes that colonize the infant gut.
  • Antibiotic and antacid exposure are risk factors for EoE. For antibiotics:
    • We see a higher risk of EoE if a mother takes antibiotics during the third trimester.
    • After birth, the risk for EoE increases the earlier and the more antibiotics are prescribed in infancy.
  • For acid suppressants:
    • We see increased risk for EoE if either a pregnant mother or infant has been prescribed antacids.
  • Future studies are needed to understand the mechanisms whereby these risk factors contribute to EoE development.

• What causes eosinophilic colitis? Is it autoimmune or caused by foods?

  • We do not know the cause of eosinophilic colitis (EoC).
  • EoC is an inflammatory disease characterized by the presence of eosinophils that presents with abdominal pain and diarrhea.
  • It is important to distinguish between different causes of increased eosinophils in the colon.
  • Several diseases/exposures can increase eosinophils in the colon (e.g. allergies, medications, infections, autoimmune and connective tissue disorders, hypereosinophilic syndromes and graft vs. host disease).
  • In addition to eosinophils, tissue mast cells are increased in EoC.
  • Recognition of EoC as a distinct disease category has increased recent efforts to better understand this disease.

• What causes esophageal ulcers? How common are they in patients with EoE?

  • Esophageal ulcers are most often caused by severe reflux.
  • Patients with ulcers usually have more pain with swallowing. 
  • Ulcerations are not a typical endoscopic feature of EoE but can be seen:
    • after a food impaction or dilation procedure
    • if a pill gets stuck in the esophagus and erodes the lining of the esophagus (pill esophagitis}
    • in rare cases of esophageal infection (e.g., candida, herpes simplex virus {HSV), cytomegalovirus (CMV), HIV: histoplasmosis, and tuberculosis)
  • Treatment should be focused on the source of the ulcer.

• What research is being done to prevent EGIDs?

  • There are four stages of disease prevention:
    • Reducing risk factors for all patients.
    • Preventing EGIOs in healthy, but susceptible patients.
    • Identifying patients who have early signs of EGIDs without symptoms.
    • Reducing disease severity in patients diagnosed with EGIOs.
  • The increase in EGIOs is likely due to a combination of factors including specific exposures, patient characteristics, and the environment.
  • Potential early life exposures may include prematurity, cesarean section delivery, lack of breastfeeding, and acid blocker or antibiotic use in infancy.
  • Patient factors include other allergic diseases, poor esophageal barrier function, and increased susceptibility to inflammation and scarring.
  • Potential environmental factors include cold, arid climates.
  • Future studies are needed to identify cause and effect relationships between these factors and the development of EGIDs.

• What role does mold exposure play in EoE?

  • There is very little evidence to suggest that mold plays any role in EoE in patients.
  • Some researchers have used the mold Aspergillus fumigatus to model EoE in mice.
  • White blood cells isolated from patients with EoE may produce more of the cytokine IL-5 in response to .stimulation with Aspergillus.
  • The rate of EoE diagnosis does not increase with increased mold counts in the air.
  • Some patients who are allergic to mold may be more difficult to treat.
  • More studies are needed to determine the role of mold exposure in EoE.

• Why are some active EoE patients asymptomatic whlle others are symptomatic?

  • When the esophagus doesn’t function normally it can cause difficulty swallowing.
  • Many patients mask the symptoms of EoE with the following adaptive behaviors:
    • Drinking liquids to help swallow.
    • Cutting foods into small pieces, puree foods. Avoiding hard textures.
    • Eating slowly.
    • Chewing excessively.
  • Some patients can have eosinophilic inflammation in the esophagus without symptoms.
  • More research is needed to determine if truly asymptomatic patients with eosinophils in the esophagus have a distinct disease or an early form of EoE.

• Why is EoE treatment for children different than adults?

  Although most EoE treatments for children and adults should be the same, differences may stem from several factors:

  • Adults usually present, with difficulty swallowing while children often present with less-specific symptoms including vomiting, abdominal pain, and poor weight gain.
  • Adults are more likely to have structures or narrowing of the esophagus; therefore, esophageal dilation is performed more frequently in adults.
  • Treatments (e.g., food elimination diets, topical steroids) may be perceived differently in the context of growth, nutrition, and chronicity of disease.
  • Families may have more stress an.d concern about repeated anesthesia and endoscopies in children.
  • Some medications are currently only approved for teens and adults (e.g., dupilumab).

• How can we better identify EGIDs early, so we are not waiting for symptoms to arise before we know there is a problem?

  • Currently, there are no widely accepted screening tests for EGIOs.
  • EoE is a chronic disease that progresses from inflammation to scarring over time.
  • The ideal screening test for an EGIO should:
    • Be inexpensive and easy to administer.
    • Cause minimal discomfort or harm to the patient.
    • Give valid results.
    • Detect the disease early.
  • Several screening tests for EoE are in development including the esophageal string test, transnasal endoscopy, Cytosponge, nuclear medicine studies, and blood tests.
  • The medical history, family history, and clinical symptoms may help identify patients at higher risk for EoE and scarring.

• Is someone with MCAS more likely to have EGIDs and do the two relate?

  • Mast cell activation syndrome (MCAS) is generally diagnosed by:
    • Rapid onset symptoms involving multiple organ systems.
    • A favorable response to antihistamines or mast cell stabilizing medications.
    • Laboratory evidence of mast cell involvement.
  • MCAS may be more common in individuals with autonomic dysfunction and hypermobility.
  • There is limited evidence suggesting patients with connective tissue diseases, autonomic dysfunction, and hypermobility may be more likely to have EGIDs.
  • More research is needed to determine the meaning of elevated mast cell numbers, shape, and location within the gastrointestinal tract.

• Should someone with EoE and autoimune disease be seen by a gastroenterologist and an immunologist?

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  • Autoimmune disease are classically defined as harmful immune reactions directed against our own bodies. 
  • EoE is not considered an autoimmune disease because the immune reactions causing inflammation are directed against food or environmental allergens.
  • Patients with EoE are at increased risk for autoimmune diseases. (These may include autoimmune diseases of the gastrointestinal tract (e.g. celiac disease, inflammatory bowl disease) but also rheumatologic and neurologic diseases. 
  • Often patients with EoE benefit from treatment by a gastroenterologist and an allergist/immunologist. 
  • Additional specialists (e.g. rheumatologist, neurologist)  may be helpful depending on clinical signs, symptoms, or other medical diagnoses.