Vedolizumab therapy in common variable immune deficiency associated enteropathy: A case series.

A number of gastrointestinal complications occur in common variable immunodeficiency (CVID). Infections are one cause, but various forms of severe non-infectious enteropathy also lead to substantial morbidity. The presence of T cell lymphocytic infiltrates in the mucosa have suggested that vedolizumab, a humanized monoclonal antibody which binds to alpha4 beta7 integrin and inhibits the migration of effector T-lymphocytes into gastrointestinal tissues, would be an effective treatment. A previous report of 3 CVID cases suggested benefit in 2 subjects. In this study 7 CVID patients with severe enteropathy were treated with vedolizumab. Four of the 7 completed vedolizumab induction therapy but 3 subjects had acute decompensation during induction and treatment was stopped. While one subject showed improvement, 6 of the 7 patients were withdrawn from therapy. While vedolizumab may be of use in some CVID subjects, it was not ultimately found helpful in most of these patients.

Reticular dysgenesis caused by an intronic pathogenic variant in AK2.

Reticular dysgenesis is a form of severe combined immunodeficiency (SCID) caused by biallelic pathogenic variants in AK2 Here we present the case of a boy diagnosed with SCID following a positive newborn screen (NBS). Genetic testing revealed a homozygous variant: AK2 c.330 + 5G > A. In silico analyses predicted weakened native donor splice site. However, this variant was initially classified as a variant of uncertain significance (VUS) given lack of direct evidence. To determine the impact on splicing, we analyzed RNA from the proband and his parents, using massively parallel RNA-seq of cloned RT-PCR products. Analysis showed that c.330 + 5G > A results in exon 3 skipping, which encodes a critical region of the AK2 protein. With these results, the variant was upgraded to pathogenic, and the patient was given a diagnosis of reticular dysgenesis. Interpretation of VUS at noncanonical splice site nucleotides presents a challenge. RNA sequencing provides an ideal platform to perform qualitative and quantitative assessment of intronic VUS, which can lead to reclassification if a significant impact on mRNA is observed. Genetic disorders of hematopoiesis and immunity represent fruitful areas to apply RNA-based analysis for variant interpretation given the high expression of RNA in blood.

QIPS CURE: Implementing a Quality Improvement and Patient Safety Curriculum and Resident Experience.

BACKGROUND: Resident participation in quality improvement and patient safety (QIPS) programs is an essential training experience and Accreditation Council for Graduate Medical Education requirement. However, the most effective approach to achieve this is unclear. OBJECTIVE: We developed an experiential Quality Improvement and Patient Safety Curriculum and Resident Experience (QIPS CURE) program, which provides internal medicine (IM) residents with foundational QIPS knowledge, and evaluated its effectiveness. METHODS: After reviewing IM residency QIPS curricula and obtaining input from institutional stakeholders in 2013-2014, we launched a longitudinal QIPS curriculum for all 66 postgraduate year 1-3 IM residents in July 2014. The QIPS CURE included 2 major elements: didactics, delivered through a variety of sources, including online modules and workshops, and hands-on projects. We delivered this curriculum annually from 2014 to 2018. We used project completion and an attitude survey of participants to evaluate it. RESULTS: Six projects were completed in 2014-2015, and 10 projects completed yearly for the next 3 academic years. Residents presented all projects at regional meetings. Surveyed residents reported improvement in understanding (M = 5.71, SD = 1.07 pre- to M = 6.38, SD = 0.49 post-curriculum, P = .013) and competence (M = 3.31, SD = 1.18 pre- to M = 6.08, SD = 0.77, post-curriculum, P < .001) when comparing graduates of the curriculum with incoming interns. Qualitative analysis revealed perceived acquisition of skills needed to carry out successful QIPS projects. CONCLUSIONS: This QIPS program was sustainable over 4 years and generally well-received by residents, with many projects completed each year.

Diagnosis of Sesame Allergy: Analysis of Current Practice and Exploration of Sesame Component Ses i 1.

BACKGROUND: Sesame is an allergen of increasing importance. OBJECTIVE: We sought to characterize the outcomes of oral food challenges (OFCs) to sesame and evaluate the diagnostic accuracy of skin prick testing (SPT), sesame, and Ses i 1-specific IgE (sIgE). METHODS: We reviewed sesame OFCs performed at the Mount Sinai pediatric allergy clinic between January 2010 and April 2018. We assessed the accuracy of diagnostic tests by calculating the area under the curve (AUC) of the receiver operating characteristic curves. The association between OFC outcome and sesame sensitization was analyzed using a logistic regression, which was then used to estimate the 95% positive predictive value (PPV) of these tests. RESULTS: We identified 341 patients (69% male, mean age 7.7 years) who underwent sesame OFC. Among 106 (31%) positive OFCs, the median cumulative eliciting dose was 500 mg sesame protein (1/2 teaspoon tahini). Sesame SPT wheal ≥6 mm had sensitivity 54.1% and specificity 87.8%; AUC 0.756 (95% confidence interval [CI], 0.699-0.814). SPT wheal size ≥14 mm had 95% PPV. Sesame-sIgE level did not correlate with OFC outcome. Ses i-sIgE levels were analyzed in 30 patients using the Immuno Solid-phase Allergen Chip (ISAC) microarray and were significantly associated with OFC outcome (AUC: 0.715 [95% CI, 0.541-0.890]). Ses i 1-sIgE ≥0.3 ISAC Standardized Units had sensitivity 58.3% and specificity 83.3%. CONCLUSIONS: This is the largest study of sesame allergy to date. Sesame SPT is a more accurate predictor of sesame allergy compared with sesame sIgE. Ses i 1-sIgE appears promising but requires further study regarding diagnostic accuracy.

Signaling pathways for B cell-activating factor (BAFF) and a proliferation-inducing ligand (APRIL) in human placenta.

The tumor necrosis superfamily (TNFSF) contains two soluble ligands that are involved in B lymphocyte development, BAFF (B cell activating factor, BlyS, TALL-1, CD257, TNFSF13B) and APRIL (a proliferation inducing ligand, CD256, TNFSF13). These two ligands signal through three receptors: the exclusive BAFF receptor (BAFF-R, CD268, TNFRSF17) and two receptors that recognize both BAFF and APRIL, TACI (transmembrane-activator-1 and calcium-modulator- and cyclophilin ligand-interactor CD267, TNFRSF13B) and BCMA (B cell maturation antigen, CD269, TNFRSF13C). All but BAFF-R are known to be synthesized in term placentas. In this study, expression of the ligands and receptors were distinguished in two embryologically discrete subpopulations of placental cells, villous cytotrophoblast (vCTB) cells and mesenchymal cells (MCs). Real-Time PCR showed that vCTB cells contain low levels of BAFF and APRIL transcripts whereas MCs contain high levels. Both Real-Time PCR and immunohistochemistry identified BAFF-R and BCMA mRNA and proteins in vCTB cells but essentially no TACI. By contrast, MCs contained readily detectable levels of all three receptors. These results illustrating potential autocrine and paracrine pathways for BAFF and APRIL signaling in human placentas suggest that lineage-specific regulation of placental cell viability, differentiation and/or other activities may be novel functions of these proteins.