IRF2BP2 mutation with autoimmune enteropathy, immune deficiency, and respiratory failure

Case history: We present the case of a 31-year-old Hispanic male with history of recurrent bronchiectasis, invasive aspergillosis, and severe persistent asthma, who is now status post lung transplant for end-stage lung disease. He initially presented at 7 years of age with diarrhea, failure to thrive, and nearly absent immunoglobulin levels (IgG < 33 mg/dL, IgA < 7 mg/dL, IgM = 11 mg/dL, IgE = 4 IU/dL) necessitating IVIG treatment. Small intestinal biopsy showed villous atrophy consistent with autoimmune enteropathy. Sweat chloride was reported as indeterminate (44 me/dL). Initial WBC, platelet, and T- and NK-cell counts were within normal range, and B-cell count and percentage were borderline low. Most recently, he was found to have increased immature B-cell count (CD21low), decreased memory B-cells, and poor pneumococcal vaccine antibody response. Patient has been hospitalized numerous times with increasingly severe bronchiectasis, pneumonitis, and COVID-19 infections twice despite vaccination, leading to respiratory failure and lung transplantation. Family history is negative for immune deficiency and lung diseases. Discussion(s): Of these 3 VUSs (see the table), the one in IRF2BP2 has the most pathogenic potential due to its autosomal dominant inheritance, its location in a conserved domain (Ring), and previous case reports of pathogenic variants at the same or adjacent alleles 1-3. Baxter et al reported a de novo truncating mutation in IRF2BP2 at codon 536 (c.1606CinsTTT), which is similar to our patient's mutation. This patient was noted to have an IPEX-like presentation, with chronic diarrhea, hypogammaglobulinemia, and recurrent infections. Variant Functional Prediction Score for our variant predicts a potentially high damage effect. There are 2 other case reports of heterozygous mutations in loci adjacent to this allele;one (c.1652G>A)2 with a similar clinical phenotype to our patient and the other (C.625-665 del)3 with primarily inflammatory features and few infections. Impact: This case highlights a variant in IRF2BP2 associated with severe hypogammaglobulinemia, recurrent pulmonary infections, and autoimmune enteropathy. [Table presented]Copyright © 2023 Elsevier Inc.

Whipple's Disease, An Overlooked Diagnosis

Whipple disease is a rare multisystem inflammatory disease. Because fewer than 1000 reported cases have been described, clinical experience with this disorder is sparse. We are reporting a case of a 46-year-old man who presented with fever, weight loss, and polyarthralgia for 2 months, and 1 month of diarrhea. The patient was thoroughly investigated for collagen diseases and COVID-19, with no definite diagnosis. A therapeutic trial by immunosuppressive drugs provided partial remission followed by a marked rebound of the symptoms. His occult blood in stool was positive and subsequent upper endoscopy with proximal small intestinal biopsies showed the pathological features of Whipple's disease. The patient showed a dramatic improvement following treatment with ceftriaxone and trimethoprim-sulfamethoxazole. Despite the rarity of Whipple's disease, its course mimics many rheumatological diseases, inflammatory bowel disease, and COVID-19 disease. It should always be a part of the differential diagnosis of obscure polyarthralgia and chronic diarrhea.Copyright © 2023 The Author(s).

Early Diagnosis of Coeliac Disease by Case-Finding at the Preventive Youth Health Care Centres in the Netherlands (Glutenscreen)

Introduction: Objectives: Coeliac disease (CD) occurs in 1% of the population, but is severely underdiagnosed. Secondary prevention by early diagnosis may be achieved by case-finding. Aims & Methods: To prospectively assess whether case-finding at the Preventive Youth Health Care Centres (YHCCs) in the Netherlands is a feasible and effective strategy for early CD-diagnosis. We analyzed data from the case-finding study GLUTENSCREEN from its start at 4th February 2019 till 4th January 2022 (with interruption of 5 months due to COVID19). Parents of all symptomatic children aged 1-4 years attending the YHCC in the Kennemerland-region for a regular visit, were asked if their child has >=1 CD-related symptoms. If so, a point-of-caretest (POCT) to assess CD-specific antibodies against tissue transglutaminase (TGA), was performed onsite the YHCCs. If the POCT was positive, the child was referred to our hospital for definitive diagnosis according to the ESPGHAN guideline. Result(s): 36.9% (5706/15466) of the children had >=1 CD-related symptoms. Parents of 3104 (54.4%) children gave informed consent for a POCT (47% female;median age 2.8years). In 61 children the POCT was positive: CD was confirmed in 55 children (2.0% of the tested children) and ruled out in 5 children. Of them two children had negative HLA-DQ2/8 and TGA (ELISAtest) and in 3 children with TGA <10xULN small bowel biopsies showed Marsh 0-1 lesions. From one child who was referred to the hospital, parents refused additional investigation. Conclusion(s): Case-finding for CD using a POCT is effective and feasible and it detects a high CD prevalence of 1.8%. Before implementation of the case-finding strategy cost-effectiveness and acceptability analyses are needed. .

COVID-19 in the gut and liver

Coronavirus disease 2019 (COVID-19) is known to result in gastrointestinal symptoms and liver damage. Consideration needs to be given to COVID-19 as a potential cause of new-onset gastrointestinal symptoms. Awareness of special issues affecting patients with chronic gastrointestinal and liver diseases in a pandemic is important. © 2021 Medicine Today Pty Ltd. All rights reserved.

EXPRESSION OF EPITHELIAL PROTEASES PREDICTS SARS-COV-2 ENTRY IN HUMAN ENTEROIDS

Introduction: Coronavirus Disease 2019 (COVID-19) is an ongoing public health crisis that has sickened or precipitated death in millions. The etiologic agent of COVID-19, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), infects the intestinal epithelium and can persist long after the respiratory infection has cleared. We previously observed that intestinal SARS-CoV-2 infection levels varied by individual donors and did not correlate positively with ACE2, the cognate SARS-CoV-2 receptor. Therefore we aimed to delineate host factors that influence viral infection in the intestine. Methods: Published dataset GSE75214 was downloaded and expression levels of select genes were querried. Primary human ileal spheroids (enteroids), derived from healthy donors and patients with Crohn's disease (CD), were grown on 2D transwells until confluent. Cells were differentiated for 3d before infection with a modified vesicular stomatitis virus expressing the SARS-CoV-2 spike protein (VSV-SARS-CoV-2) and GFP for 1h at a multiplicity of infection of ~0.5. Cells were harvested pre-infection and 24h after infection and expression of select genes was performed by qRT-PCR. Expression data were fit to a linear regression model to predict viral RNA levels. Results: Small intestine biopsy samples from CD patients demonstrated a reduction in ACE and an increase in CTSB and CTSL expression during active inflammation compared to healthy controls. Viral RNA expression did not correlate with ACE2 expression in CD enteroids. A subset of CD enteroids exhibited enhanced protease expression (TMPRSS2, TMPRSS4, CTSL), each of which correlated with higher viral RNA levels (P=0.04, P=0.002, P=0.006, respectively). Expression of these proteases was higher in the pre-infection for the sample subset. Principle component analysis of uninfected expression data demonstrated these samples clustered separately from the others, with the difference driven by TMPRSS2, TMPRSS4, and CTSL. Modeling viral RNA levels based on gene expression revealed expression levels of these proteases are a predictive expression signature. Conclusions: Host protease expression can predict SARS-CoV-2 infection and represent potential therapeutic targets for COVID-19. This is consistent with the recent report showing that cathepsin inhibition reduces SARS-CoV-2 spike-mediated syncytia formation. High expression of these proteases in the intestine may also be a novel biomarker for the risk of intestinal complications associated with COVID-19.(Figure Presented)RNA data from dataset GSE75214 demonstrating reduced ACE2 and increased CTSB and CTSL in patients with Crohn's disease during active inflammation compared to healthy controls. (Figure Presented) Enteroids from healthy control donors and patients with Crohn's disease were grown in 2D transwells and expression of indicated genes was assessed in pre-infection (A) and after infection with VSV-SARS-CoV-2 (B)

No decrease in number of new Inflammatory Bowel Disease diagnoses in children in the Netherlands during the Covid-19 pandemic: A nationwide retrospective cohort study

Background: The COVID-19 pandemic has had a large impact on regular healthcare provision in the Netherlands. During the first wave, healthcare in children was strongly reduced due to safety regulations and reduced hospital capacity for non-COVID care. This, and fear of COVID-19 could have led to delayed inflammatory bowel disease (IBD) healthcare, and delayed or even missed diagnoses. This has already been demonstrated in adult IBD patients in the Netherlands1, but not yet in the paediatric population. This is of importance, as in children, diagnostic delay is associated with higher rates of strictures, fistulising complications, and growth delay2. Therefore, this study aims to determine the impact of COVID-19 on IBD-related procedures and new IBD diagnoses in children in the Netherlands. Methods: In this nationwide retrospective cohort study, a search was conducted in the nationwide pseudonymized pathology registry of the Netherlands (PALGA), with complete national coverage. Using retrieval terms for ulcerative colitis, Crohn's disease, IBD unclassified and corresponding synonyms, all IBD related pathology reports (resection specimens or intestinal biopsies) from January 2018 to December 2020 in children age 1-18 were selected. Patients with a recognized diagnosis of IBD were eligible for inclusion, which was scored independently by two authors based on all reports. All IBD-related procedures (endoscopies and intestinal resections) were identified. Monthly frequencies of procedures and new IBD diagnoses during the COVID-19 pandemic in the Netherlands (March 11, 2020 - December 31, 2020) were compared to the average monthly frequencies of 2018-2019. Results: After exclusion of non-IBD related reports, 2161 IBD-related procedures were identified between January 2018 and December 2020. The average number of monthly IBD procedures in 2018-2019 was 59.8, whereas in 2020 this was 60.6 procedures per month, reflecting a 0.8% increase (Figure 1). In 2020, the number of new IBD diagnoses was 456, similar to the 458 new IBD diagnoses in 2018-2019. During the COVID-19 pandemic the weekly number of new diagnoses was 8.8, while between January 2018 and March 2020 this was 8.5 (Figure 2). A slight reduction in monthly IBD-related resections was observed (2.7 vs. 3.5). Conclusion: Despite the reduction in regular healthcare in children in the Netherlands due to the COVID-19 pandemic, no reduction was observed in IBD-related endoscopies and surgeries during the pandemic in the Netherlands. This reassuring evidence demonstrates that pediatric IBD healthcare remained unchanged, thus not delaying diagnosis of new IBD patients or treatment of severe disease flares.

FIRST HIGH DIMENSIONAL EXAMINATION OF INTESTINAL BIOPSIES IN PATIENTS WITH COVID-19

Introduction: SARS-CoV-2, the causative pathogen for COVID-19, engages host ACE2 receptor for cellular entry. The brush border of the small intestines express high levels of ACE2. Gastrointestinal (GI) manifestations are common among COVID-19 patients. However, to date, there is limited information regarding intestinal response to SARS-CoV-2 infection. Methods: Intestinal biopsies were obtained from 17 COVID-19 patients (17.3 ± positive nasal swab) for cellular and transcriptomic analyses using mass cytometry and RNA-sequencing, respectively. Ten uninfected individuals served as compartment (EC) and lamina propria (LP) were analyzed separately. Results: The cellular profiles from LP of COVID-19 patients showed reduced frequencies of CD206+ conventional dendritic cells (CDC2s) and plasmacytoid (CD123+) dendritic cells Effector T cell (PD1+CD38+) frequency was increased in the LP and Intraepithelial lymphocytes (IEL) were increased in the EC of COVID-19 patients, with a concomitant decrease in CD206+ CDC2s. RNA sequencing active downregulation of genes involved in inflammatory pathways including IBD-associated pathways, while an upregulation of intestinal barrier function Gene expression of Neuropilin-1 (NRP-1), a putative SARS-CoV-2 receptor as well as key inflammatory cytokines (IL-1b, IFN-g, CCL24 and CXCL8) were significantly reduced in controls. A low intensity antiviral host response signature was observed predominantly in EC as opposed to LP suggesting viral localization to epithelium. Conclusions: Epithelial, myeloid and lymphoid cell alterations characterize intestinal response to SARS-CoV-2 infection with an unanticipated downregulation of key inflammatory pathways that have been implicated in adverse outcomes associated with These data stand in contrast to the inflammatory response reported in the systemic compartments and identify a potential mitigating role of the GI

EUROMEDLAB 2021

The proceedings contain 823 papers. The topics discussed include: where, when, and how? the quest for extra-terrestrial life;high-sensitivity cardiac troponin i: central lab or POC - the choice is yours;comparison of reference values for small extracellular particles in a healthy study cohort using nanoparticle tracking analysis (NTA) before and after particle isolation by different isolation methods;highly fluorescent 360 nm excitable europium(III) label for time-resolved-fluorescence immunoassays;use of a machine learning, deep profiler network to predict disease progression and patient outcome in hospitalized patients with COVID-19;interaction between homocysteine, some antioxidants, lipids and d-dimer in patients with carotid atherosclerosis;implementation of ISO 15189 standard in a certified laboratory. key points for success;and relation between specific antibody tests for celiac disease and grade of enteropathy of intestinal biopsy in adults.