The burdensome, inflammatory chronic condition is highlighted by difficult diagnoses and screening options. How is research advancing to improve care?
Marc E. Rothenberg, MD, PhD, has seen how eosinophilic esophagitis (EoE) plays out from the beginning.
The director of Division of Allergy and Immunology, as well as the Cincinnati Center for Eosinophilic Disorders at Cincinnati Children’s Hospital Medical Center, has been a direct actor in the research driven to actually understand the pathogenesis of EoE for some time now.
Little is understood of EoE—its exact cause is unexplained, and its prevalence in 1 of every 2000 people is an estimated total. Marketed therapies are limited to none. Yet progress has been made in the disease’s pathogenesis, and from there Rothenberg and colleagues have a path to follow.
From the pathogenesis, EoE’s genetic and environmental basis has been defined; investigators now have an understanding of its molecular steps, Rothenberg told MD Magazine®. As a result, the association to patients’ allergies is better understood, and therapies in development and investigation are fine-tuned, targeted to the correct drivers of symptoms.
There’s bricks being laid from the foundation of research that has made EoE—a burdensome condition which affects the quality of life in patients of all ages—a potentially more managed disease. The development of research is very similar to the pattern set by clinicians who interpreted other chronic conditions that now have targeted therapies: asthma, hepatitis C, even diabetes.
But what still troubles Rothenberg and others is the direct care. Diagnosis capabilities are very limited, and the network of care can reasonably include the primary care physician and at least 3 other specialists.
When Rothenberg envisions the future of EoE care, he speaks confidently on the development of treatment for the disease—but screening and diagnosis improvements will need breakthrough, collaborative efforts. Such is the case for a burdensome, peculiar condition.The Center for Pediatric Eosinophilic Disorders at the Children’s Hospital of Philadelphia (CHOP) currently has about 3100 patients in its database. These patients come from many years apart from one another, presenting EoE symptoms at different times.
But there are some consistencies among this huge swath of patients, Jonathan Spergel, MD, PhD, chief of the Allergy Section at CHOP, told MD Mag. Namely, the symptoms are consistent across each patient age group: infants and toddlers present with vomiting, food refusal, and painful reactions to eating; young to older children present with abdominal pains, refluxes, and occasional swallowing issues; and teenagers to adults present with the greatest issues swallowing.
There’s other tendencies that shape the pattern of the condition—3 times more males than females are diagnosed with EoE, peak diagnoses are in slightly older boys presenting with chronic abdominal pain, and most older patients are compensating for the condition significantly before they end up with specialists at CHOP.
“They typically eat slowly,” Spergel explained. “And if they eat bread, they make sure they have 6 glasses of water with it.”
Though this sort of disease compensation is practiced by patients with the more severe symptoms, other forms of compensation are fairly common. David Katzka, MD, Mayo Clinic professor of Medicine, told MD Mag that many patients eat slowly, carefully, and continuously drink fluids throughout a meal. They may not eat meat or bread at all, and develop anxiety around the idea of eating in a social setting.
“Patients often have to take much longer to eat to perform their compensatory maneuvers which is embarrassing,” Katzka said. “Even more embarrassing is if a piece of food gets stuck in a restaurant and/or with friends and family.”
Rothenberg noted most patients are diagnosed with psychiatric impairments as a result of their condition.The paradox of a rare disease presenting with what’s become patterned, obvious symptoms is driven by what happens between a patient being affected by EoE and actually receiving care for it. It often begins in the emergency department, Spergel said—where patients are being treated for food getting stuck in their esophagus.
They may be immediately referred to a gastroenterologist for a biopsy—the most common form of EoE diagnosis known to Spergel. Because the process toward a biopsy is often unconventional and symptom-driven, there’s no real understanding of EoE’s prevalence.
“There is a big risk of patients being misdiagnosed,” Spergel said. “Other diseases can be screened with blood tests. But you have to do biopsies just to identify eosinophilic esophagitis.”
Just as frustrating for clinicians is that few options look promising to eventually supplant biopsies. Spergel projected that, in the comings years, biopsies done by esophageal samples may eventually serve as a conclusive diagnostic test. Though he hopes risk factors will eventually become identified in patient blood tests, the results are not there yet.
Katzka has an eye set toward other non-invasive testing options. Along with blood tests, he highlighted buccal swaps and esophageal impedance as potential diagnostic tools. He also stressed the evidenced need for “silent or subtle symptom” monitoring in patients, as well as the use of scoring systems and scales such as the Eosinophilic Esophagitis Endoscopic Reference score (EREFS).
Eventually, improved esophageal tissue sampling could become beneficial to monitor therapies’ effects on diet strategies.
“One of the key areas of opportunity to diagnostic testing avoids endoscopy,” Katzka said. “We are hopeful our work on the Cytosponge as an easy and less invasive esophageal mucosal sampling advice will facilitate monitoring of therapy.”For better or worse, patients need to follow a team-based approach to diagnosis and care, Spergel said.
“It’s an allergic disease of the esophagus,” he explained. “You may end up in the ER, or with an internist or primary care physician, then to the gastroenterologist—and depending on individual thoughts on therapy and measures, you may need to see an allergist.”
Though Spergel isn’t sure if any shortcuts exist, Katzka sees the referral process becoming optimized. He observed the landscape of EoE care shifting from specialty centers to the offices of general gastroenterologists and allergists. Specialty centers are now more likely to treat refractory EoE patients, not primary.
That said, the presence of type 2 inflammation—a characteristic similarly identified in patients with asthma, chronic obstructive pulmonary disease (COPD), atopic dermatitis (AD), and others—require the presence of allergists frequently. About more than half of all patients with EoE suffer from seasonal allergies, Spergel said, and another one-third have asthma, one-fourth have food allergies, and even AD is common as well.
“I often see these very allergic patients in my office,” Spergel said. “If you see an atopic person with a lot of gastroenterological symptoms, I’d really worry a lot about EoE.”
At least, in those cases, therapies are more established.Since the approval of omalizumab (Xolair) about 15 years ago, non-steroid therapy options for inflammation have been limited, Rothenberg said. That said, he, Spergel, and Katzka all have stock in the development of biologics such as dupilumab and benralizumab for EoE.
“Biologic therapy is also emerging and some of the trial results are encouraging,” Katzka said. “Where this will fit in ultimately with treatment is unclear.”
Currently, Spergel has 2 go-to therapy options: patient avoidance to allergy-triggering foods, and off-label topical steroids. Both have major pitfalls, however: the major allergen associated with EoE is milk, which is a broadly prevalent drink and ingredient in most people’s diets, and topical steroids’ greatest benefit for EoE is that they have any benefit at all.
Spergel and his team at CHOP recently completed a phase 2 immunotherapy trial which observed the use of epicutaneous immunotherapy (EPIT) to desensitize EoE patient allergies—with the hope that the disease process could eventually be reversed due to intolerance reduction.
Though EPIT benefitted approximately 40% of patients, Spergel said further studies are necessary.
Such plans fit into the shift Katzka has observed from acute to chronic medical care. Among most of their patients, Katzka noted, it’s become clear “that some type of therapy that maintains normal esophageal mucosa in these patients is critical.”Rothenberg foresees 4 facets of EoE care to change in the following decade.
First, he believes diagnostic tools will improve to mirror the molecular-based testing prominent in oncology. From there, clinicians will be able to identify patient subpopulations and apply individualized therapy.
There will also be marketed therapies for EoE, he predicted—targeted drugs that will dramatically improve patients’ diets, life quality, with a reduction in morbidity and mortality.
Next, there will be increased awareness, through patient advocacy organizations like the CURED Foundation and the increase of media coverage surrounding EoE advances. With that increased awareness comes better education in Rothenberg’s field, he said, and this will drive rapid diagnoses and evidence-based medicine.
All 3 of these predictions would likely be caused by Rothenberg’s final prognosis: that the genetics of EoE will become mastered—leading to early disease recognition, and different interventions designed to stop its development. This could shape better understanding of patient microbiome exposure risks, protocol for behavioral therapy, and a possible blueprint to stop the condition altogether.
“The genetics will be determining of the cure,” he said.
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