Diagnosis of eosinophilic esophagitis in patients with dysphagia during the Coronavirus Disease 2019 (COVID-19) pandemic.

Background: The coronavirus disease 2019 (COVID-19) pandemic posed restrictions to many standard practices. Dysphagia is a common presentation of eosinophilic esophagitis (EoE) in adults, and biopsy via esophagogastroduodenoscopy (EGD) is required for diagnosis. We hypothesized that a diagnosis of EoE has declined during the pandemic. Objective: To investigate whether the COVID-19 pandemic influenced the likelihood of an EGD and an EoE diagnosis in patients with dysphagia. Methods: In this retrospective matched cohort study, we used the TriNetX US Collaborative Network to identify adult patients who presented with dysphagia to the emergency department (ED) during the year of and the year preceding the pandemic. Patients with a previous EoE diagnosis were excluded. The two cohorts were balanced for demographics, gastroesophageal reflux disease (GERD) diagnosis, obesity, H2 blockers and proton-pump inhibitors use, anemia, smoking, and alcohol use. The proportion of patients who received an EGD, and an EoE and a GERD diagnosis were contrasted up to 90 days from ED evaluation. Results: We identified 16,942 adult patients during the pandemic, and 16,942 adult patients the year preceding the pandemic who presented to the ED with a concern of dysphagia. During the 30-day follow-up period, no significant difference was observed in the proportion of patients who received an EGD during the pandemic versus the prepandemic period at 1, 7, and 30 days from ED evaluation. The proportion of patients who received an EoE diagnosis was not different, but slightly more patients received a GERD diagnosis during the pandemic versus prepandemic that was evident by day 30 (31.2% versus 30%; p ≤ 0.05). Conclusion: Our results revealed that the COVID-19 pandemic did not significantly impact diagnostic EGD and an EoE diagnosis.

Development of a core outcome set for therapeutic studies in eosinophilic esophagitis (COREOS).

BACKGROUND: End points used to determine treatment efficacy in eosinophilic esophagitis (EoE) have evolved over time. With multiple novel therapies in development for EoE, harmonization of outcomes measures will facilitate evidence synthesis and appraisal when comparing different treatments. OBJECTIVE: We sought to develop a core outcome set (COS) for controlled and observational studies of pharmacologic and diet interventions in adult and pediatric patients with EoE. METHODS: Candidate outcomes were generated from systematic literature reviews and patient engagement interviews and surveys. Consensus was established using an iterative Delphi process, with items voted on using a 9-point Likert scale and with feedback from other participants to allow score refinement. Consensus meetings were held to ratify the outcome domains of importance and the core outcome measures. Stakeholders were recruited internationally and included adult and pediatric gastroenterologists, allergists, dieticians, pathologists, psychologists, researchers, and methodologists. RESULTS: The COS consists of 4 outcome domains for controlled and observational studies: histopathology, endoscopy, patient-reported symptoms, and EoE-specific quality of life. A total of 69 stakeholders (response rate 95.8%) prioritized 42 outcomes in a 2-round Delphi process, and the final ratification meeting generated consensus on 33 outcome measures. These included measurement of the peak eosinophil count, Eosinophilic Esophagitis Histology Scoring System, Eosinophilic Esophagitis Endoscopic Reference Score, and patient-reported measures of dysphagia and quality of life. CONCLUSIONS: This interdisciplinary collaboration involving global stakeholders has produced a COS that can be applied to adult and pediatric studies of pharmacologic and diet therapies for EoE and will facilitate meaningful treatment comparisons and improve the quality of data synthesis.

MiR-4668 as a Novel Potential Biomarker for Eosinophilic Esophagitis.

INTRODUCTION: Eosinophilic esophagitis (EoE) is a clinico-pathological diagnosis characterized by esophageal dysfunction and eosinophilic infiltration of the esophagus. Demonstration of esophageal eosinophilia (more than 15 eosinophils/hpf) in biopsy specimen obtained by esophagogastroduodenoscopy (EGD) continues to be the gold standard for diagnosis and monitoring of response to therapy. There is a growing necessity for non-invasive biomarkers that can accurately diagnose this condition and assess response to therapy. While microRNAs (miRNA) are being investigated in allergic diseases, including EoE, not many studies have explored the role of salivary miRNAs in EoE. MiR-4668-5p is a particularly interesting candidate, as it is predicted to regulate TGF-beta signaling and has not previously been identified as a target in any allergy disease. We sought to further investigate the role of miR-4668 as a biomarker to characterize and monitor response to treatment with swallowed topical glucocorticoids. METHODS: After IRB approval, twenty-two adult patients with EoE were randomly enrolled to provide a saliva sample before and after 2 months of swallowed fluticasone therapy. Differences of miRNA expression before and after treatment were analyzed by paired T-test. A significance cutoff of <0.05 was used for all analyses. RESULTS: Expression of miR-4668 was higher in EoE vs. non-EoE subjects. The level of miR-4668 decreased in all subjects except one, with a mean fold change 0.49 ± 0.25. There was an association between miRNA expression and number of positive aeroallergens. The miR-4668 high group had a higher number of positive aeroallergen tests, while the miR-4668 low group had a greater number of subjects with drug allergies. CONCLUSIONS: In this study, we identified that salivary miRNAs may serve as biomarkers to characterize EoE and response to topical corticosteroids. We specifically identified miR-4668 as a novel potential biomarker, which was not previously discovered as a target in EoE or any other allergic disease.

Challenges in managing patients referred for eosinophilic esophagitis: A telephone survey and retrospective review.

Background: Eosinophilic esophagitis (EoE) in patients referred to allergists can be difficult to manage. This is due to multiple factors, including overlaps in presentation with gastroesophageal reflux disease and proton-pump inhibitor responsive eosinophilia, remaining uncertainties regarding the role of different forms of allergy testing, and a variety of patient adherence issues. Objective: To highlight, in an objectively studied fashion, complications that can be faced when managing patients referred for EoE. Methods: We conducted a telephone survey of 78 patients (pediatric and adult) who were referred to our academic allergy clinic for EoE. The survey focused on patients' perspectives regarding their symptoms and treatments. We then conducted a chart review to determine if there had been a proton-pump inhibitor (PPI) trial before diagnosis, and we compared patient responses with documented allergy test results, treatment plans, and biopsy results. Results: Only 22 of 78 patients (28%) had a ≥8-week PPI trial before diagnosis and/or referral. There was considerable variability in the type of allergy testing done for patients, and how the results were used to guide therapy. More than one-third of the patients reported being on a different treatment regimen (PPI, swallowed steroid, and/or diet) than planned, and the majority of patients on dietary therapy reported being on a different diet than planned. Also, nearly half of the adult patients did not have follow-up biopsies done despite recommendations for this. Conclusion: We identified several challenges in EoE management, including potential misdiagnosis or overtreatment, lack of standardization in testing and dietary recommendations, and patient adherence issues. We hope this information will prompt increased vigilance for these issues and promote solutions when needed.

A Novel STAT3 Gene Mutation Related Hyper-IgE Syndrome Misdiagnosed as Hidradenitis Suppurativa.

Although Hyper-IgE Syndrome (HIES) is a rare immunodeficiency disorder, presenting symptoms may be as common as lung and skin infections. Symptoms are usually nonspecific such as recurrent abscesses, folliculitis, and pneumonias along with skeletal abnormalities. Careful history of susceptibility to skin and lung infections, thorough family history, and findings on physical exam can guide towards the diagnosis of this often-eluded condition. Early optimization of therapy with prophylactic antibiotics can prevent recurrent infections and future complications and improve quality of life and longevity of survival. We present a case of a young female with Hyper-IgE Syndrome with a novel mutation in STAT 3 gene who initially presented with long standing history of intractable skin abscesses being managed as Hidradenitis Suppurativa.

Effect of topical beclomethasone on inflammatory markers in adults with eosinophilic esophagitis: A pilot study.

BACKGROUND: Topical corticosteroids have proven efficacy in the treatment of eosinophilic esophagitis (EoE) and are considered the cornerstone of therapy. OBJECTIVE: To evaluate the effect of topical beclomethasone dipropionate (BDP) therapy on clinical outcomes, esophageal eosinophilia, and other markers of inflammation in patients with EoE. METHODS: Nine subjects with a biopsy-proven diagnosis of EoE were enrolled. In a cross-over design, the subjects were randomly assigned to a sequence of BDP and placebo. Treatment periods were 8 weeks, with a 4-week washout period. The subjects had endoscopic biopsies and blood tests at baseline and after each treatment period. They were instructed to maintain a diary of symptoms. Immuno-histochemical studies were performed for interleukins IL-4, IL-5, IL-13, granulocyte-macrophage colony-stimulating factor (GM-CSF), and transforming growth factor (TGF) beta. Reverse transcription polymerase chain reaction was performed for IL-3, IL-4, IL-5, IL-10, IL-13, IL-17F, IL-25, IL-33, chemokine ligands (CCL)2, CCL5, CCL11, GM-CSF, and TGF-beta levels. The mast cell tryptase (MCT) level was measured in esophageal tissues. RESULTS: BDP led to a significantly larger decrease in esophageal eosinophilia compared with placebo, but there was no significant change in peripheral eosinophilia and high-sensitivity C-reactive protein between the two groups. The study was not powered enough for us to report a significant improvement in clinical symptoms. There was a significant decrease in tissue IL-13 and MCT levels from baseline to the end of treatment between the treatment and placebo groups. Mean fold decreases in cytokine expression between the baseline and treatment groups were observed for IL-17F, IL-25, CCL2, and CCL5. CONCLUSION: Treatment with topical BDP was associated with significant decrease in esophageal eosinophilia, MCT and IL-13. BDP is a potential alternative to fluticasone propionate and budesonide for treatment of EoE. Larger studies are needed to validate these findings.

Idiopathic CD4 lymphocytopenia.

BACKGROUND: Idiopathic CD4 lymphocytopenia (ICL) is a rare disorder of unknown etiology. Diagnostic criteria include a persistent CD4 T-cell lymphopenia with no underlying primary or secondary immune deficiencies and a CD4 T-cell count of 300 cells/mL or 20% total lymphocyte on multiple occasions. OBJECTIVE: To increase awareness of ICL and to provide a review of the clinical characteristics, diagnosis, and management of this disease process. Presently, many of these patients receive prophylactic treatment similar to other T-cell deficient conditions, most notably patients with human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome; however, the same indications may not necessarily apply to this patient population because the T cells are not affected by a virus as in HIV. METHODS: A literature search of salient articles that describe case reports and case series of ICL and their management were analyzed. RESULTS: A case of ICL with a literature review is presented with emphasis on clinical pearls and pitfalls. The patients with ICL are usually identified with a CD4 count of 200 cells/mL when complications develop. Opportunistic infections are the most common initial manifestations. Current therapies used to increase CD4 levels include interleukin 2, interferon gamma, interleukin 7, and allogeneic hematopoietic stem cell transplantation, with variable results. CONCLUSION: ICL is a diagnosis of exclusion when there is no identifiable underlying cause for a low CD4 count. Although the nature of the T-cell problem is not the same in ICL and HIV, in the absence of specific guidelines, patients receive the same prophylactic treatment as patients with HIV.

Tongue necrosis as an initial manifestation of giant cell arteritis: case report and review of the literature.

Giant cell arteritis (GCA) is a systemic vasculitis of medium and large arteries that mainly affects the external carotid artery. It is a diagnosis of the elderly that typically presents as low-grade fever, temporal tenderness, claudication of the jaw, and in some patients vision loss. In cases where GCA presents with atypical manifestations, the diagnosis may be more difficult, causing a delay in both diagnosis and treatment and ultimately leading to irreversible complications. In this paper, we present an atypical presentation of GCA with symptoms of neck swelling and lingual pain in an elderly female. These symptoms progressed to bilateral necrosis and eventual dislodgement of the tongue. Lingual necrosis is a severe potential complication in GCA. In patients presenting with lingual swelling, pain, and discoloration, GCA should be suspected and prompt therapy should be initiated to avoid irreversible complications.

A review of the evidence linking eosinophilic esophagitis and food allergy.

Eosinophilic esophagitis (EoE) is a chronic inflammation of the esophagus that has been considered an allergic phenomenon based on its similarities to other allergic conditions. More specifically, EoE has been considered a form of food allergy because of patient sensitizations to foods and improvements in symptoms and inflammation after food eliminations. This article presents the currently available evidence regarding the classification of EoE as an allergic condition, the involvement of foods in disease pathogenesis, and the value of different types of allergy testing and elimination diets in management of EoE. Using the search engines PubMed and Ovid, English literature in the past 10 years was reviewed with the use of the following key words: eosinophilic esophagitis, EoE epidemiology, EoE pathophysiology, food allergy, eosinophils, skin-prick testing, atopy patch testing, elemental diet, test directed elimination diet, six food elimination diet. Studies of EoE epidemiology and pathophysiology support the link between EoE and allergy in general, and studies of food allergy testing and elimination diets have supported a link between EoE and food allergy. Although food elimination diets cause resolution of symptoms and pathology in pediatric EoE, the results of testing and diet elimination studies are not as clear in adults, and aeroallergen sensitizations may play a larger role in adult EoE pathophysiology. Although several studies in children and adults support considering EoE a form of food allergy, the usefulness of skin-prick testing and atopy patch testing for food allergies and the optimal elimination diet for disease management are still uncertain.

Comparison of atopic features between children and adults with eosinophilic esophagitis.

Eosinophilic esophagitis (EoE) is a clinicopathological diagnosis seen in children as well as adults. Growing evidence suggests that EoE is strongly associated with atopic disorders. Presenting symptoms differ in children and adults and it is not known whether atopic features vary by age. This study was designed to compare atopic features and allergic sensitization between children and adults with EoE. We conducted a retrospective analysis of demographic and clinical data from 50 children (aged 2-18 years) and 50 adults (aged 21-75 years) with a biopsy-proven diagnosis of EoE referred to our allergy clinic. Data regarding patient characteristics, history of atopic diseases, and allergy test results were collected for analysis. The majority of children and adults were white and male patients. When compared with adults, a higher percentage of children had a history of asthma (52% versus 24%; p < 0.05). There was no statistically significant difference between adults and children regarding history of allergic rhinitis, atopic dermatitis, immunoglobulin E-mediated food allergy, and family history of atopy. There was no statistically significant difference between children and adults regarding immediate-type sensitization to foods and aeroallergens. Compared with adults, a higher percentage of children showed a positive reaction to one or more foods on patch testing (62% versus 31%; p = 0.01). A high prevalence of comorbid atopic diseases and sensitizations to food and environmental allergens was seen in both children and adults. Children had a significantly higher rate of asthma and positive patch test to foods compared with adults.

Aseptic splenic abscess as precursory extraintestinal manifestation of inflammatory bowel disease.

Splenic abscesses are most often secondary to aerobic bacterial infections due to Streptococcus, Staphylococcus, and Enterococcus species of organisms. Sterile splenic abscesses rarely occur and diagnosis and treatment of those are challenging. We report a case of a previously healthy young female presenting with aseptic splenic abscesses as the initial manifestation of Crohn's disease along with a review of the literature on aseptic splenic abscess as an extraintestinal manifestation of Crohn's disease.

Esophageal rupture as a primary manifestation in eosinophilic esophagitis.

Eosinophilic esophagitis (EoE) is a chronic inflammatory process characterized by symptoms of esophageal dysfunction and, histologically, by eosinophilic infiltration of the esophagus. In adults, it commonly presents with dysphagia, food impaction, and chest or abdominal pain. Chronic inflammation can lead to diffuse narrowing of the esophageal lumen which may cause food impaction. Endoscopic procedures to relieve food impaction may lead to complications such as esophageal perforation due to the friability of the esophageal mucosa. Spontaneous transmural esophageal rupture, also known as Boerhaave's syndrome, as a primary manifestation of EoE is rare. In this paper, we present two adult patients who presented with esophageal perforation as the initial manifestation of EoE. This rare complication of EoE has been documented in 13 other reports (11 adults, 2 children) and only 1 of the patients had been previously diagnosed with EoE. A history of dysphagia was present in 1 of our patients and in the majority of previously documented patients. Esophageal perforation is a potentially severe complication of EoE. Patients with a history of dysphagia and patients with spontaneous esophageal perforation should warrant an evaluation for EoE.

The Association between Autoimmune Disorders and Chronic Granulomatous Disease.

Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by recurrent bacterial and fungal infections, as well as dysregulated granuloma formation. It results from functional defect of the phagocytic nicotinamide adenine dinucleotide phosphate oxidase (NADPH). Autoimmune disorders have been reported more commonly in CGD patients than in the general population. Early diagnosis and management of autoimmune disorders may affect the course of CGD. We present a case of CGD with type 1 diabetes mellitus, a literature review reporting association of CGD and autoimmune diseases, and proposed mechanisms for the pathogenesis of autoimmune diseases in CGD.

Eosinophilic esophagitis: review of nonsurgical treatment modalities.

Eosinophilic esophagitis (EoE) is a clinicopathological condition characterized by the combination of upper gastrointestinal symptoms such as dysphagia and even food impaction in association with histological findings of >15 eosinophils/high-powered field found in endoscopic biopsy specimens. EoE is considered an atopic disease with food and aeroallergen sensitivity. Current treatment options include elemental and elimination diets and topical corticosteroids. This study was designed to provide a review of the literature on the nonsurgical treatment modalities for EoE to understand the therapeutic challenges. A Medline and PubMed search was conducted using the key words eosinophilic esophagitis and treatment. EoE guidelines, randomized controlled trials, case studies, and evidence-based treatment articles in the English literature were selected. EoE patients can have symptomatic and pathological resolutions with dietary modifications and topical swallowed corticosteroids with continued therapy. However, these effects are not long-lasting and adverse reactions, both local and systemic, are possible. Newer targeted therapies using monoclonal antibodies against interleukin-5 (IL-5) appear to be well tolerated but various studies have not consistently shown symptomatic or histological improvement. Current therapies for EoE including specific diets and topical corticosteroids have shown only short-term symptomatic relief. Biological therapies such as anti-IL-5 agents are still under investigation. Long-term effects of treatments are not known and studies regarding safety of these therapies and specific dosing regimens are needed. Therapies targeting the molecules involved in the pathogenesis of EoE may be future options. Treatment should be individualized with careful consideration of patient's age, allergen sensitivity, lifestyle, and compliance.

Biomarkers for eosinophilic esophagitis: a review.

BACKGROUND: The complex pathophysiology of eosinophilic esophagitis (EoE) provides several candidate biomarkers that could be used to establish diagnosis, assess response to therapy, and document disease recurrence. OBJECTIVE: To review the literature on various biomarkers of EoE, with respect to their correlation to disease activity and response to treatment. DATA SOURCES: A literature search was performed using PubMed and OVID with keyword combinations of EoE and various potential biomarkers. STUDY SELECTIONS: Between 2006 and 2012, 26 studies that investigated the correlation of various tissue and serum biomarkers with EoE were identified. RESULTS: The markers investigated included eotaxins-1,-2, and -3, interleukin-5 (IL-5), interleukin-13 (IL-13), eosinophil-derived neurotoxin, mast cell markers, absolute eosinophil count, and micro-RNAs. Several studies have shown a positive correlation between eotaxin-3, IL-5, and IL-13 messenger RNA (mRNA) expression in esophageal tissue and disease activity. Eotaxin-3 mRNA staining was found to have 89% sensitivity for diagnosing EoE. Staining for mast cells and their products has also shown promise. More recently, a microRNA signature that can potentially distinguish EoE from non-EoE esophagitis has been identified. CONCLUSION: The studies are quite heterogeneous with respect to their methodology and the biomarker(s) studied, but most have investigated tissue biomarkers. Eotaxin-3 and IL-13 have emerged as the most promising ones with respect to sensitivity and degree of positive correlation to disease process. Future research on biomarkers for EoE should include longitudinal studies, establishment of normal values, effects of concomitant atopic diseases, age and gender, and validation of methodology of the tests.

International survey on evaluation and management of eosinophilic esophagitis.

BACKGROUND: : Recommendations regarding evaluation and management of eosinophilic esophagitis (EoE) remain incompletely defined. This survey assesses: how providers across the world diagnose, evaluate, and treat EoE and how educational activities affect management. METHODS: : A web-based survey was sent to the members of World Allergy Organization, American College of Allergy, Asthma, and Immunology, and American Academy of Allergy, Asthma, and Immunology. A χ analysis compared responses based on personal and practice demographics and participation in educational activities. RESULTS: : Of the 200 respondents, 68.5% were from the United States. The majority were allergists, who require biopsy to diagnose EoE, perform allergy testing, and obtain follow-up biopsy after treatment. The following variables had significant differences: (1) US practitioners were more likely to test for immediate-type hypersensitivity to foods and obtain follow-up endoscopic biopsies after the initial treatment; (2) Practitioners encountering patients with EoE more frequently were more likely to ask about personal and family history of atopy, test for immediate-type hypersensitivity to aeroallergens and foods, and recommend follow-up biopsy after treatment; and (3) Practitioners who participate more often in EoE workshops were more likely to perform patch testing for foods, while attendance at EoE lectures increased EoE management confidence. CONCLUSIONS: : Diagnostic and management strategies differ based on practice location, EoE patient load, and participation in educational activities. Practitioners who attend more EoE lectures are more confident managing EoE.

A sixty-five-year-old man with rash, fever, and generalized weakness.

Diffuse erythematous rash accompanied by high-grade fever, eosinophilia, and facial edema can be caused by a variety of infective, allergic, or systemic etiologies. We present a case of 65-year-old man with septic arthritis, who had a vancomycin antibiotic spacer placed in his infected knee and was also started on intravenous (i.v.) vancomycin. After 2 weeks he presented with sudden onset of fever and generalized weakness. Physical examination was significant for tachycardia and hypotension, facial edema, diffuse erythematous rash, and bilateral wheezing. Laboratory values indicated acute renal insufficiency associated with eosinophiluria and significant peripheral eosinophilia. Septic shock was highly suspected and he was treated with i.v. fluids and broad-spectrum antibiotics. Despite aggressive management his condition rapidly deteriorated with persistent of shock state, increase in facial edema, and rash. Other suspected etiologies included hypersensitivity reactions to i.v. antibiotics (piperacillin/tazobactam) or vancomycin, systemic vasculitis, or idiosyncratic reactions to medications such as Stevens-Johnson syndrome. The patient was started on high-dose i.v. steroids, which led to improvement of his clinical condition. Clinical presentation of adverse drug reactions is highly variable and may present as potentially life-threatening multiorgan failure. Early recognition of the etiology and removing the offending agent is important to improve the outcome.

The perceived obstacles in performing patch test to detect allergic contact dermatitis: a comparison between community allergists and directors of allergy training programs.

BACKGROUND: Patch testing (PT) is the gold standard test to detect allergic contact dermatitis. Despite its usefulness, it is not universally performed in allergy practices. OBJECTIVES: To determine obstacles in performing PT and to evaluate the differences in perception of these obstacles between community allergists and directors of training programs. METHODS: Two anonymous Web-based questionnaires were distributed to 65 program directors (PDs) across the United States and to 200 community allergists in the mid-Atlantic region. Program directors and community allergists were categorized based on PT performance. Community allergists were categorized based on type of practice. Comparisons between categories were made using the chi2 test. RESULTS: Perceived obstacles among community allergists and PDs were similar; this remained unchanged regardless of performing PT. When community allergists in solo practice were compared with those in group private practice, the difference in perception was significant (P < .01). Previous training in PT among PDs and community allergists was associated with a higher likelihood of performing PT. CONCLUSIONS: Previous training in PT among PDs and community allergists was associated with a higher likelihood of performing PT. We recommend that training in the application and interpretation of PT for diagnosis of allergic contact dermatitis should be an integral part of the curriculum of allergy fellowship training programs and should also be incorporated into the continuing medical education program of practicing allergists. Furthermore, although allergists may continue to rely on dermatologists for more comprehensive PT, use of the thin-layer rapid use epicutaneous test is a simple screening tool that should be available to all allergy practices.