Manish Butte

Skewed X-inactivation in a Female Carrier with X-linked Chronic Granulomatous Disease.

Iran J Allergy Asthma Immunol. 2019 Aug 17;18(4):447-451

Authors: López-Hernández I, Deswarte C, Alcantara-Ortigoza MÁ, Saez-de-Ocariz MDM, Yamazaki-Nakashimada MA, Espinosa-Padilla SE, Bustamante J, Blancas-Galicia L

Abstract
Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by defective phagocytic NADPH oxidase, causing a complete lack or significant decrease in the production of microbicidal reactive oxygen metabolites. It mainly affects male children; however, there are scarce reports of adult females diagnosed with X-linked-CGD attributed to an extremely skewed X-chromosome inactivation. This condition is characterized by severe and recurrent infections that usually develop after childhood. In clinical practice, physicians who usually confront these patients should suspect this entity and differentiate it from a secondary immunodeficiency. Here, we report a 38-year-old Mexican female with juvenile-onset X linked-CGD, caused by a de novo mutation and extremely skewed X-inactivation, whose clinical features were similar to those in patients with classic X-linked-CDG.

PMID: 31522453 [PubMed – in process]

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Utilization of high-fidelity simulation to address challenges with the basic science immunology education of preclinical medical students.

BMC Med Educ. 2019 Sep 14;19(1):352

Authors: Cavuoto Petrizzo M, Barilla-LaBarca ML, Lim YS, Jongco AM, Cassara M, Anglim J, Stern JNH

Abstract
BACKGROUND: Immune function and dysfunction are highly complex basic science concepts introduced in the preclinical medical school curriculum. A challenge for early learners is connecting the intricate details and concepts in immunology with clinical manifestations. This impedes relevance and applicability. The impetus in medical education reform is promoting consolidation of basic science and clinical medicine during the first two years of medical school. Simulation is an innovation now widely employed in medical schools to enhance clinical learning. Its use in basic science curriculums is largely deficient. The authors piloted simulation as a novel curricular approach to enhance fundamental immunology knowledge and clinical integration.
METHODS: The authors introduced a Primary Immunodeficiency Disease (PIDD) simulation during a basic science immunology course for second-year medical students at the Zucker School of Medicine at Hofstra/Northwell. The simulation tasked small groups of students with evaluating, diagnosing and managing an infant with previously undiagnosed immunodeficiency. Joint facilitation by clinical and science faculty during terminal debriefings engaged students in Socratic discussion. Debriefing aimed to immerse basic science content in the context of the clinical case. Students completed a post-simulation Likert survey, assessing utility in reinforcing clinical reasoning, integration of basic science and clinical immunology, enhanced knowledge and understanding of immunodeficiency, and enhanced learning. A summative Immunodeficiency Objective Structured Clinical Examination (OSCE) question was created by faculty to assess students’ recognition of a PIDD and clinical reasoning.
RESULTS: The simulation was well received by students with > 90% endorsing each of the objectives on the post-simulation survey. The authors also determined a statistically significant score variance on the summative OSCE question. Higher scores were achieved by the cohort of students completing the OSCE post-simulation versus the cohort completing the OSCE pre-simulation.
CONCLUSIONS: The innovative use of simulation in a highly complex basic science immunology course provides relevance and consolidation for preclinical learners. Additional data will be collected to continuously assess application of concepts and proficiency stemming from this novel curricular intervention. The authors advocate the initiation and/or expansion of simulation in non-clinical basic science courses such as immunology to bridge the gap between theory and practice.

PMID: 31521165 [PubMed – in process]

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Respiratory and allergic disorders in children with severe and partial Immunoglobulin A immunodeficiency.

Scand J Immunol. 2019 Sep 14;:e12828

Authors: Živković J, Lipej M, Banić I, Bulat Lokas S, Nogalo B, Lulić Jurjević R, Turkalj M

Abstract
BACKGROUND: Immunoglobulin A deficiency (IgAD) is the most common primary immunodeficiency. Although most people with selective IgAD (sIgAD) are asymptomatic, many patients often suffer from recurrent respiratory infections and different allergic disorders. Our aim was to investigate connection between subtypes of sIgAD and incidence of respiratory and allergic disorders, as well as connection with lung function changes in children.
METHODS: Children with IgAD where divided into two groups; severe IgAD in patients was defined as serum IgA level < 7 mg/dL, while partial IgA deficiency diagnosis was made when serum IgA levels was higher than 7 mg/dL but at least two standard deviations (SD) below mean normal concentrations for their age. All patients were evaluated by their clinical and laboratory investigation parameters and compared to control group of children.
RESULTS: Group of children with IgAD, severe as well as partial, showed higher prevalence of allergic diseases and total number of infections, compared to controls. There was a statistically significant difference in lung function for peak expiratory flow (PEF), the maximal expiratory flow at 50 % of the forced vital capacity (MEF50) and fraction of exhaled nitric oxide (FENO) between group of patients with severe as well as partial IgAD and control group, where children with IgAD showed reduced lung function.
CONCLUSIONS: Children with sIgAD are at increased risk for higher number of respiratory infections and developing allergic diseases, resulting in significantly lower pulmonary function which is related with the severity of sIgAD.

PMID: 31520490 [PubMed – as supplied by publisher]

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Primary immunodeficiencies in Central and Eastern Europe-the power of networking Report on the activity of the Jeffrey Modell Foundation Centers Network in Central and Eastern Europe.

Immunol Res. 2019 Sep 12;:

Authors: Sediva A, Bataneant M, Belevtsev M, Blaziene A, Ciznar P, Förster-Waldl E, Kelecic J, Marodi J, Naumova E, Nasrullayeva G, Ress K, Serban M, Sitkaustiene B, Toth B, Modell V, Modell F, Tenembaum V, Marković M, Avcin T

Abstract
Jeffrey Modell Foundation centers’ network activities in Central and Eastern Europe (JMF CEE) have contributed to the development of care for patients with primary immunodeficiencies. On the data continuously collected from individual centers in participating countries since 2011, we demonstrate a steady improvement in a number of aspects concerning complex care for patients with primary immunodeficiencies. The presented data show an improvement of awareness about these rare diseases across the whole Central and Eastern European region, an increase in newly diagnosed patients as well as genetically confirmed cases, earlier establishment of diagnosis, and improved access to clinical treatment. We also present an active patient involvement that is reflected in the expansion of patient organization centers and their activities. The cooperation within the JMF CEE network has also contributed to greater international exposure of participating centers and further to the gradual development of research activities in the rapidly evolving field of primary immunodeficiencies. The improvement of all important aspects of the complex field of primary immunodeficiencies within the JMF CEE network documents the strength and advantages of the joint and coordinated networking.

PMID: 31515711 [PubMed – as supplied by publisher]

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Metastatic colorectal cancer and severe hypocalcemia following irinotecan administration in a patient with X-linked agammaglobulinemia: a case report.

BMC Med Genet. 2019 Sep 12;20(1):157

Authors: Li M, Chen W, Sun X, Wang Z, Zou X, Wei H, Wang Z, Chen W

Abstract
BACKGROUND: X-linked agammaglobulinemia (XLA) is a primary immunodeficiency disorder caused by germline mutations in the Bruton tyrosine kinase (BTK) gene on X chromosome. These mutations disturb B-cell development, decrease immunoglobulin levels, increase susceptibility to infection or neoplasms, and increase the risk of developing colorectal cancer (CRC). For occasional cases of CRC have been reported in XLA patients, low levels of B lymphocytes and immunoglobulins induced by congenital immune disorder make them more susceptible to drug-related toxicities (DRT). Therefore, gene sequencing, therapeutic drug monitoring and any possible measurement to predict DRT should be considered before determining the course of chemotherapy for XLA patients with CRC.
CASE PRESENTATION: In this study, we reported a 21-year-old male who developed metastatic CRC in the context of XLA. Since the whole exome sequencing and therapeutic drug monitoring did not reveal any predictive markers of DRT, we applied standard first-line chemotherapy to the patient. However, progressive disease occurred after the fifth treatment cycle. Therefore, the administration of oxaliplatin was changed to irinotecan as second-line therapy. After that, the patient firstly suffered from severe hypocalcemia and eventually died due to metastatic CRC after the eighth treatment cycle. The overall survival time was 7.5 months.
CONCLUSIONS: This study reported the first written record of a Chinese XLA patient with metastatic CRC and severe hypocalcemia. Whole exome sequencing and bioinformatic analysis indicated the somatic mutations in ABCA6, C6 and PAX3 genes might contribute to the early-onset and metastasis CRC. Besides, a number of germline mutations in genes related to calcium metabolism (CACNA2D4, CD36, etc.) and the administration of irinotecan were speculated to be the causes of severe hypocalcemia. We therefore suggested that in order to avoid severe DRT, clinicians should take genetic background and therapeutic drug monitoring into consideration while planning chemotherapy treatment for XLA patients with CRC.

PMID: 31510946 [PubMed – in process]

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Inborn Errors of Immunity With Immune Dysregulation: From Bench to Bedside.

Front Pediatr. 2019;7:353

Authors: Delmonte OM, Castagnoli R, Calzoni E, Notarangelo LD

Abstract
Inborn errors of immunity are genetic disorders with broad clinical manifestations, ranging from increased susceptibility to infections to significant immune dysregulation, often leading to multiple autoimmune phenomena, lymphoproliferation, and malignancy. The treatment is challenging as it requires careful balancing of immunosuppression in subjects at increased risk of infections. Recently, the improved ability to define inborn errors of immunity pathophysiology at the molecular level has set the basis for the development of targeted therapeutic interventions. Such a “precision medicine” approach is mainly bases on the use of available small molecules and biologics to target a specific cell function. In this article, we summarize the clinical and laboratory features of various recently described inborn errors of immunity associated with immune dysregulation and hyperinflammation in which mechanism-based therapeutic approaches have been implemented.

PMID: 31508401 [PubMed]

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Subcutaneous Immunoglobulin Twenty Percent Every Two Weeks in Pediatric Patients with Primary Immunodeficiencies: Subcohort Analysis of the IBIS Study.

Pediatr Allergy Immunol Pulmonol. 2019 Jun 01;32(2):70-75

Authors: Canessa C, Gallo V, Pignata C, Trizzino A, Graziani S, Martire B, Moschese V, Palladino V, Boggia GM, Matucci A, Pecoraro A, Spadaro G, Vultaggio A, Azzari C

Abstract
Background: Subcutaneous immunoglobulin G (SCIG) may be a better option than intravenous immunoglobulin G (IVIG) for patients with primary immunodeficiencies (PID) due to reduced systemic and serious adverse reactions and easier administration. The Infusione Bimensile di Immunoglobuline Sottocute (IBIS) study investigated the effects of Hizentra®, a 20%-concentrated SCIG, administered biweekly in patients with PID. This subanalysis aimed to evaluate clinical and laboratory outcomes in the IBIS pediatric subcohort. Methods: Thirteen children with PID were observed for 12 months retrospectively (with previous IVIG/SCIG) and prospectively with biweekly Hizentra. Results: Mean ± standard deviation serum IG levels during the retrospective (833.8 ± 175.7 mg/dL) and the prospective (842.0 ± 188.0 mg/dL) phases were comparable; there were also no differences in the number of infections. Conclusions: Biweekly Hizentra is a noninferior option with respect to previous IVIG/SCIG-based treatment.

PMID: 31508259 [PubMed]

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