Huaibin M. Ko

Eosinophilic Gastritis in Children: Clinicopathological Correlation, Disease Course, and Response to Therapy

OBJECTIVES:Eosinophilic gastritis (EG), defined by histological criteria as marked eosinophilia in the stomach, is rare, and large studies in children are lacking. We sought to describe the clinical, endoscopic, and histopathological features of EG, assess for any concurrent eosinophilia at other sites of the gastrointestinal (GI) tract, and evaluate response to dietary and pharmacological therapies.METHODS:Pathology files at our medical center were searched for histological eosinophilic gastritis (HEG) with ≥70 gastric eosinophils per high-power field in children from 2005 to 2011. Pathology slides were evaluated for concurrent eosinophilia in the esophagus, duodenum, and colon. Medical records were reviewed for demographic characteristics, symptoms, endoscopic findings, comorbidities, and response to therapy.RESULTS:Thirty children with severe gastric eosinophilia were identified, median age 7.5 years, 14 of whom had both eosinophilia limited to the stomach and clinical symptoms, fulfilling the clinicopathological definition of EG. Symptoms and endoscopic features were highly variable. History of atopy and food allergies was common. A total of 22% had protein-losing enteropathy (PLE). Gastric eosinophilia was limited to the fundus in two patients. Many patients had associated eosinophilic esophagitis (EoE, 43%) and 21% had eosinophilic enteritis. Response to dietary restriction therapy was high (82% clinical response and 78% histological response). Six out of sixteen patients had persistent EoE despite resolution of their gastric eosinophilia; two children with persistent HEG post therapy developed de novo concurrent EoE.CONCLUSIONS:HEG in children can be present in the antrum and/or fundus. Symptoms and endoscopic findings vary, highlighting the importance of biopsies for diagnosis. HEG is associated with PLE, and with eosinophilia elsewhere in the GI tract including the esophagus. The disease is highly responsive to dietary restriction therapies in children, implicating an allergic etiology. Associated EoE is more resistant to therapy.

Expansion of inflammatory innate lymphoid cells in patients with common variable immune deficiency.

BACKGROUND Common variable immunodeficiency (CVID) is an antibody deficiency treated with immunoglobulin; however, patients can have noninfectious inflammatory conditions that lead to heightened morbidity and mortality. OBJECTIVES Modular analyses of RNA transcripts in whole blood previously identified an upregulation of many interferon-responsive genes. In this study we sought the cell populations leading to this signature. METHODS Lymphoid cells were measured in peripheral blood of 55 patients with CVID (31 with and 24 without inflammatory/autoimmune complications) by using mass cytometry and flow cytometry. Surface markers, cytokines, and transcriptional characteristics of sorted innate lymphoid cells (ILCs) were defined by using quantitative PCR. Gastrointestinal and lung biopsy specimens of subjects with inflammatory disease were stained to seek ILCs in tissues. RESULTS The linage-negative, CD127(+), CD161(+) lymphoid population containing T-box transcription factor, retinoic acid-related orphan receptor (ROR) γt, IFN-γ, IL-17A, and IL-22, all hallmarks of type 3 innate lymphoid cells, were expanded in the blood of patients with CVID with inflammatory conditions (mean, 3.7% of PBMCs). ILCs contained detectable amounts of the transcription factors inhibitor of DNA binding 2, T-box transcription factor, and RORγt and increased mRNA transcripts for IL-23 receptor (IL-23R) and IL-26, demonstrating inflammatory potential. In gastrointestinal and lung biopsy tissues of patients with CVID, numerous IFN-γ(+)RORγt(+)CD3(-) cells were identified, suggesting a role in these mucosal inflammatory states. CONCLUSIONS An expansion of this highly inflammatory ILC population is a characteristic of patients with CVID with inflammatory disease; ILCs and the interferon signature are markers for the uncontrolled inflammatory state in these patients.

Tertiary lymphoid neogenesis is a component of pulmonary lymphoid hyperplasia in patients with common variable immunodeficiency

BACKGROUND Despite reducing pneumonia and other infections, antibody replacement does not appear to treat pulmonary lymphoid hyperplasia (PLH) in patients with common variable immunodeficiency (CVID). The pathogenesis and optimal treatments remain to be clarified. OBJECTIVE We aimed to better understand the pathology of CVID-associated lung disease. Tertiary lymphoneogenesis, although a component of interstitial lung disease associated with autoimmune diseases, has not previously been explored in patients with CVID. METHODS We examined the clinical characteristics and pathologic findings of 6 patients with CVID with nodular/infiltrative lung disease who had biopsy specimens demonstrating PLH. RESULTS In these subjects regions of PLH contained distinct B- and T-cell zones, with B-cell predominance in 1 patient and T-cell predominance in the others. Colocalization of Ki67, Bcl6, and CD23 within this ectopic lymphoid architecture demonstrated tertiary lymphoneogenesis with active centers of cellular proliferation. One patient received rituximab with improved pulmonary radiologic findings. CONCLUSION Ectopic lymphoid tissue forming germinal centers suggest tertiary lymphoneogenesis in CVID-associated lung disease. B cell-targeted therapy might disrupt CVID-associated lymphoid hyperplasia.

Serrated colorectal polyps in inflammatory bowel disease.

Serrated colorectal polyps, which, besides hyperplastic polyps, comprise sessile serrated adenomas/polyps and traditional serrated adenomas, are presumptive precursors of at least 20% of sporadic colorectal carcinomas; however, their significance in patients with inflammatory bowel disease is unclear. We retrospectively evaluated 78 serrated polyps, removed over a 14-year period from 6602 inflammatory bowel disease patients undergoing endoscopic surveillance, with respect to morphologic, clinicopathologic, and molecular features, and compared rates of advanced neoplasia (high-grade dysplasia and carcinoma) development following the index serrated polyp diagnosis to reference inflammatory bowel disease cohorts without serrated polyps. Serrated polyps negative for dysplasia, which morphologically resembled sporadic sessile serrated adenoma/polyps, occurred mainly in females, in the proximal colon, and contained BRAF mutations. Serrated polyps with low-grade dysplasia resembled sporadic traditional serrated adenomas and occurred mainly in males, in the distal colon, and contained KRAS mutations. Serrated polyps indefinite for dysplasia were morphologically heterogeneous, but similar to serrated polyps positive for low-grade dysplasia with respect to male predominance, left-sided location, and KRAS mutation rates. Rates of prevalent neoplasia associated with serrated polyps positive for low-grade dysplasia, indefinite for dysplasia, and negative for dysplasia were 76, 39, and 11%, respectively (P<0.001). Actuarial 10-year rates of incident advanced neoplasia after an initial diagnosis of serrated polyp positive for low-grade dysplasia, indefinite for dysplasia, and negative for dysplasia were 17, 8, and 0%, respectively, the first and last being significantly different (P=0.02) and comparable to those of corresponding reference populations of inflammatory bowel disease patients with and without low-grade dysplasia at baseline, respectively. We conclude that in serrated polyps from inflammatory bowel disease patients, dysplasia grade correlates with morphology, sex, anatomic location, BRAF and KRAS mutation status, prevalent conventional neoplasia, and rates of advanced neoplasia development.

Anti-{alpha}4{beta}7 therapy targets lymphoid aggregates in the gastrointestinal tract of HIV-1 infected individuals

Herein, we present the first human study of anti-α4β7 therapy in a cohort of HIV-1 infected subjects with mild inflammatory bowel disease. α4β7+ gut homing CD4+ T cells are early viral targets and contribute to HIV-1 pathogenesis, likely by seeding the gastrointestinal (GI) tract with HIV. Although, simianized anti-α4β7 monoclonal antibodies (Mab) have shown promise in preventing or attenuating the disease course of SIV in Non-Human Primate studies, the mechanisms of drug action remain elusive and the impact on HIV-1 persistence remains unanswered. By sampling the immune inductive and effector sites of the GI tract, we have discovered that anti-α4β7 therapy led to a significant and unexpected attenuation of lymphoid aggregates, most notably in the terminal ileum. Given that lymphoid aggregates serve as important sanctuary sites for establishing and maintaining viral reservoirs, their attrition by anti-α4β7 therapy has important implications for HIV-1 therapeutics and eradication efforts, and defines a rational basis for the continued evaluation of anti-α4β7 therapy in HIV-1 infection. One Sentence Summary Anti-α4β7 integrin therapy results in attrition of lymphoid aggregates within the gastrointestinal tract of HIV-1 infected individuals

Anti-α4β7 therapy targets lymphoid aggregates in the gastrointestinal tract of HIV-1–infected individuals

Anti-α4β7 integrin therapy results in attrition of lymphoid aggregates within the gastrointestinal tract of HIV-1–infected individuals with IBD. Gut check for a promising HIV treatment Eradicating HIV in infected patients likely requires disrupting the reservoir of infected T cells in the gastrointestinal tract. One way to accomplish this is by targeting cells expressing the α4β7, which has been tested in SIV models and is an approved therapy for inflammatory bowel disease. Uzzan and colleagues studied a small cohort of HIV-infected individuals on antiretroviral therapy that began anti-α4β7 treatment for their mild inflammatory bowel disease. The investigators performed colonoscopies before and several months after the anti-integrin treatment, allowing them to assess lymphoid populations and HIV prevalence before and after treatment. They saw that treatment disrupted local lymphoid aggregates and also affected peripheral immune populations. As with non–HIV-infected IBD patients, treatment was well tolerated. Their results are sure to draw interest from scientists and clinicians who believe targeting this integrin could possibly help cure HIV. Gut homing CD4+ T cells expressing the integrin α4β7 are early viral targets and contribute to HIV-1 pathogenesis, likely by seeding the gastrointestinal (GI) tract with HIV. Although simianized anti-α4β7 monoclonal antibodies have shown promise in preventing or attenuating the disease course of simian immunodeficiency virus in nonhuman primate studies, the mechanisms of drug action remain elusive. We present a cohort of individuals with mild inflammatory bowel disease and concomitant HIV-1 infection receiving anti-α4β7 treatment. By sampling the immune inductive and effector sites of the GI tract, we have discovered that anti-α4β7 therapy led to a significant and unexpected attenuation of lymphoid aggregates, most notably in the terminal ileum. Given that lymphoid aggregates serve as important sanctuary sites for maintaining viral reservoirs, their attrition by anti-α4β7 therapy has important implications for HIV-1 therapeutics and eradication efforts and defines a rational basis for the use of anti-α4β7 therapy in HIV-1 infection.

Efficient long‐term depletion of CD20+ B cells by rituximab does not affect gut‐resident plasma cells

The vast majority of antibody‐producing B cells are located within the gastrointestinal tract and are key players in maintaining homeostasis. The failure of rituximab, a potent B cell–depleting agent, to ameliorate ulcerative colitis in a single clinical trial has dampened enthusiasm to study B cells in patients with inflammatory bowel disease (IBD). However, several lines of evidence suggest that intestinal B cells may be affected in IBD. Additionally, the pathophysiological mechanisms underlying rituximabs lack of efficacy in IBD remain unclear. Here, on the basis of detailed immunophenotyping of a patient who underwent a colonoscopy 6 months after the end of rituximab‐based therapy, we observed that rituximab did not deplete colon‐resident plasma cells (PCs) while ablating all CD20+ B cells in tissues and in the circulation. On the basis of these observations, we propose that one factor underlying the lack of efficacy of rituximab relates to the fact that it does not affect the entire B cell compartment in tissues, sparing the intestinal‐resident PCs while effectively depleting CD20+ B cell populations. Thus, we contend that, despite the results of the Rituximab study, there is a need for more intensive B cell–oriented research in inflammatory disorders, including IBD.

Su1121 IgG4 Reactivity Characterizes a Subpopulation of Patients With Esophageal Eosinophilia

Relationship of Quality of Life With Symptom Severity, Endoscopy, and Histology in Adults With Eosinophilic Esophagitis Ekaterina Safroneeva, Michael Coslovsky, Claudia Kuehni, Radoslaw Panczak, Marcel Zwahlen, Nadine Haas, Tiffany Taft, Evan S. Dellon, Nirmala Gonsalves, Ikuo Hirano, John Leung, Christian Bussmann, John T. Woosley, Pu Yan, Guang-Yu Yang, Yvonne Romero, Glenn Furuta, Sandeep K. Gupta, Seema Aceves, Mirna Chehade, Alex Straumann, Alain Schoepfer

Su1287 Anal Neoplasia in Inflammatory Bowel Disease Is Associated With HPV and Perianal Disease

Background: Patients with inflammatory bowel disease (IBD) may develop anal squamous cell carcinoma. Little is known about predisposing factors. Design: We retrospectively reviewed the records of IBD patients diagnosed with anal neoplastic lesions presenting at our Center between March 1st 1994 and September 9th 2014. Histological specimens were reviewed to classify anal neoplastic lesions. Presence of HPV was assessed using immunohistochemical staining in combination with global and type-specific molecular PCR for HPV16 and 18. Lesions with p16 block-positive staining (p16+) and negative PCR for HPV underwent additional immunostaining for p53. Results: We identified 17 IBD patients with anal neoplastic lesions (8M/9F, 9 ulcerative colitis/7 Crohns disease/1 indeterminate colitis). Invasive squamous cell carcinomas (SCCs), high grade anal intraepithelial neoplasms (ASIN-H) and low grade anal intraepithelial neoplasm (ASIN-L) were identified respectively in 6, 8 and 3 patients. In the SCC group, 5/6 patients had Crohns disease with perianal involvement compared to 2/8 and 0/3 in the ASIN-H and ASIN-L group, respectively. Information regarding medical therapy at the time of anal cancer diagnosis was available in 10 patients, of which 5, 2 and 2 were on thiopurine, steroids and biological therapy, respectively. In patients with SCC, 3/6 and 1/6 were HPV 16+ and 18+ respectively. The patient who was HPV18+ had more than a 10 year history of UC and underwent proctocolectomy with ileo-anal pouch anastomosis 11 years before development of anal cancer. Eight out of 8 patients with ASIN-H lesions were HPV16 but not 18 positive. One out of 3 patients with ASIN-L was HPV16+. Conclusion: In our experience, anal neoplasia in IBD is associated with HPV infection and perianal Crohns disease. Prospective studies are needed to confirm these results.