Manish Butte

Colonic Basidiobolomycosis-An Unusual Presentation of Eosinophilic Intestinal Inflammation.

Front Pediatr. 2020;8:142

Authors: Kurteva E, Bamford A, Cross K, Watson T, Owens C, Cheng F, Hartley J, Harris K, Johnson EM, Lindley K, Levine S, Köglmeier J

Abstract
Basidiobolomycosis is a rare fungal disease caused by Basidiobolus ranarum. Involvement of the gastrointestinal tract is unusual and poses both a diagnostic and therapeutic challenge, as clinical signs are non-specific and predisposing risk factors are lacking. It can mimick inflammatory bowel disease, primary immunodeficiency, or a malignancy and should be considered in patients who do not respond to standard therapy. We present the case of a 22 months old boy with confirmed colonic Basidiobolomycosis, who presented with severe eosinophilic inflammation of the gastrointestinal tract. Panfungal PCR performed on DNA extracted directly from a tissue sample confirmed the presence of Basidiobolus. He made a full recovery with a combination of surgery and prolonged targeted antifungal medication.

PMID: 32373558 [PubMed]

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Rapid Low-Cost Microarray-Based Genotyping for Genetic Screening in Primary Immunodeficiency.

Front Immunol. 2020;11:614

Authors: Suratannon N, van Wijck RTA, Broer L, Xue L, van Meurs JBJ, Barendregt BH, van der Burg M, Dik WA, Chatchatee P, Langerak AW, Swagemakers SMA, Goos JAC, Mathijssen IMJ, Dalm VASH, Suphapeetiporn K, Heezen KC, Drabwell J, Uitterlinden AG, van der Spek PJ, van Hagen PM, South East Asia Primary Immunodeficiencies (SEAPID) Consortium

Abstract
Background: Genetic tests for primary immunodeficiency disorders (PIDs) are expensive, time-consuming, and not easily accessible in developing countries. Therefore, we studied the feasibility of a customized single nucleotide variant (SNV) microarray that we developed to detect disease-causing variants and copy number variation (CNV) in patients with PIDs for only 40 Euros. Methods: Probes were custom-designed to genotype 9,415 variants of 277 PID-related genes, and were added to the genome-wide Illumina Global Screening Array (GSA). Data analysis of GSA was performed using Illumina GenomeStudio 2.0, Biodiscovery Nexus 10.0, and R-3.4.4 software. Validation of genotype calling was performed by comparing the GSA with whole-genome sequencing (WGS) data of 56 non-PID controls. DNA samples of 95 clinically diagnosed PID patients, of which 60 patients (63%) had a genetically established diagnosis (by Next-Generation Sequencing (NGS) PID panels or Sanger sequencing), were analyzed to test the performance of the GSA. The additional SNVs detected by GSA were validated by Sanger sequencing. Results: Genotype calling of the customized array had an accuracy rate of 99.7%. The sensitivity for detecting rare PID variants was high (87%). The single sample replication in two runs was high (94.9%). The customized GSA was able to generate a genetic diagnosis in 37 out of 95 patients (39%). These 37 patients included 29 patients in whom the genetic variants were confirmed by conventional methods (26 patients by SNV and 3 by CNV analysis), while in 8 patients a new genetic diagnosis was established (6 patients by SNV and 2 patients suspected for leukemia by CNV analysis). Twenty-eight patients could not be detected due to the limited coverage of the custom probes. However, the diagnostic yield can potentially be increased when newly updated variants are added. Conclusion: Our robust customized GSA seems to be a promising first-line rapid screening tool for PIDs at an affordable price, which opens opportunities for low-cost genetic testing in developing countries. The technique is scalable, allows numerous new genetic variants to be added, and offers the potential for genetic testing not only in PIDs, but also in many other genetic diseases.

PMID: 32373116 [PubMed – in process]

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Exome-first Approach Identified Novel Homozygous Dedicator of Cytokinesis 8 (DOCK8) Mutations in Three Unrelated Iranian Pedigrees Suspected with Hyper-IgE Syndrome.

Iran J Allergy Asthma Immunol. 2020 Apr 16;19(2):193-199

Authors: Aghebati-Maleki A, Shahani T, Momen T, Alyasin S, Changi-Ashtiani M, Biglari A, Shahrooei M, Javanian AS, Amini S, Bossuyt X, Rokni-Zadeh H

Abstract
The prevalence of primary immunodeficiency (PID) is rather high in Iran compared to the world average, mainly due to the high rate of consanguineous marriage. Despite that, little genetic information is available about primary immunodeficiencies in Iran. Autosomal recessive hyper IgE syndrome (AR-HIES) is a severe type of immunodeficiency, mainly caused by mutations in the dedicator of cytokinesis 8 (DOCK8). Rapid and precise diagnoses of patients suffering from AR-HIES can help to manage the patients and reach properly the treatment decision. However, in regions with low financial resources and limited expertise, deep phenotyping is uncommon. Therefore, an exome-first approach is helpful to make a genetic-based diagnosis. In the present study, whole-exome sequencing (WES) was applied to detect causative mutations in three unrelated primary immunodeficient patients with poor clinical information. One of the cases was a deceased patient with suspected hyper IgE syndrome (HIES) whose parents were subjected to WES. As a result, three novel pathogenic variants were detected in the DOCK8 gene, including two splicing sites (c.4241+1G>T and c.4886+1G>T) and one-stop-gain (c.4201G>T, p.Glu1401Ter) variants. Sanger sequencing confirmed the mutations’ segregation in corresponding families. Further immunological investigations confirmed that HIES in the studied probands. The presence of frontal bossing and broad nose in one of the studied cases, in addition to the typical clinical presentation of DOCK8-AR-HIES, is notable. This work suggests that an exome-first approach can be a valuable alternative strategy for precise diagnosis of primary immunodeficiency patients.

PMID: 32372632 [PubMed – in process]

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Primary immunodeficiency disorders in children with Non-Cystic Fibrosis Bronchiectasis.

Eur Ann Allergy Clin Immunol. 2020 May 06;:

Authors: Cagdas D, Pehlivanturk Kyzylkan M, Tagiyev A, Emiralioglu N, Keleþ A, Yalcyn E, Dogru D, OzCelik U, Kiper N, Tezcan Y

Abstract
Summary: Introduction.Primary Immunodeficiency diseases(PID) are common in patients with non-cystic fibrosis bronchiectasis(NCFB). Our objective was to determine ratio/types of PID in NCFB. Patients.Seventy NCFB patients followed up in a two-year period were enrolled. Results.Median age was 14 years (min.-max., 6-30). Patients had their first pulmonary infection at a median age of 6 months(min.-max., 0.5-84), were diagnosed with bronchiectasis at about 9 years(114 months)(min.-max., 2-276)). Male/female ratio was 39/31; parental consanguinity, 38.6%. PID, primary ciliary dyskinesis (PCD), bronchiolitis obliterans, rheumatic/autoimmune diseases, severe congenital heart disease and tuberculosis were evaluated as the most common causes of NCFB. About 40% of patients (n=16) had bronchial hyperreactivity(BH) and asthma. Twenty-nine patients(41.4%) had a PID, and nearly all (n=28) had primary antibody deficiency, including patients with combined T and B cell deficiency. PID and non-PID groups did not differ according to gender, parental consanguinity, age at first pneumonia, age of onset of chronic pulmonary symptoms, bronchiectasis, presence of gastroesophageal reflux disease(GERD), bronchial hyperreactivity(BH) and asthma (p>0.05). Admission to immunology clinic was about 3 years later in PID compared with non-PID group(p less than 0.001). Five patients got molecular diagnosis, X-linked agammaglobulinemia(n=2), LRBA deficiency(n=1), RASGRP1 deficiency(n=1), MHC Class II deficiency(n=1). They were given monthly IVIG and HSCT was performed for three patients. Conclusions.PID accounted for about 40% of NCFB. Early diagnosis/appropriate treatment have impact on clinical course of a PID patient. Thus, follow-up in also immunology clinics should be a routine for patients who experience pneumonia in the first year of their lives and those with NCFB. Most patients with NCFB (84.28%) had their first pulmonary infection within the first year of their lives.

PMID: 32372587 [PubMed – as supplied by publisher]

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HSCT provides effective treatment for lymphoproliferative disorders in children with primary immunodeficiency.

J Allergy Clin Immunol. 2020 May 01;:

Authors: Prunotto G, Offor UT, Samarasinghe S, Wynn R, Vora A, Carpenter B, Gowdy C, McHugh K, Windebank KP, Rovelli AM, Slatter MA, Gennery AR, Veys P, Bacon CM, Bomken S, Lucchini G

Abstract
In a national cohort, we demonstrate the safety and efficacy of tailored chemo-immunotherapy followed by RIC HSCT for PID-associated lymphoproliferative disorders in children.

PMID: 32371070 [PubMed – as supplied by publisher]

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Frequency of HLA Class I and Class II Alleles in Patients with CVID from Turkey.

Immunol Invest. 2020 May 05;:1-9

Authors: Ozbek B, Tan C, Yaz I, Kosukcu C, Esenboga S, Cetinkaya PG, Cagdas D, Tezcan I

Abstract
BACKGROUND: Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency. Certain gene loci are pointed out in several studies in CVID patients. Until now, monogenic defects have been identified in only 2-10% of CVID patients; therefore, association of the disease with HLA alleles may be important for elucidating immunological and genetic mechanisms behind CVID. The aim of this study is to investigate the relationship between CVID and HLA alleles.
METHODS: HLA class I/II alleles were analyzed in 65 patients with CVID and alleles that may be related to disease susceptibility were determined by comparing with 300 healthy controls. We also evaluated HLA allele frequencies in CVID patients with gastrointestial system (GIS) involvement and autoimmune manifestations.
RESULTS: When compared with controls, frequencies of B*27, B*35, C*04, and DRB1*04 alleles were significantly different in patients with CVID (p < .05). Frequencies of C*12, DRB1*13, and DRB1*15 alleles were more frequent in controls, indicating protective alleles (p < .05). There was a statistically significant difference for DQ2 and DQ8 haplotypes between patients with GIS involvement and controls.
CONCLUSION: In comparison with literature, distinctive HLA alleles found in our study may originate from the diversity in gene pool between the populations. These data may provide clues for disease susceptibility.

PMID: 32370566 [PubMed – as supplied by publisher]

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Patient experience with subcutaneous immunoglobulin 20%, Ig20Gly, for primary immunodeficiency diseases: a prespecified post hoc analysis of combined data from 2 pivotal trials.

BMC Immunol. 2020 May 04;21(1):24

Authors: Meckley LM, Wu Y, Ito D, Berner T, McCoy B, Yel L

Abstract
BACKGROUND: Often, patients with primary immunodeficiency diseases (PID), which are marked by the absence or loss of functional antibodies, require lifelong treatment with immunoglobulin (IG) replacement therapy administered either intravenously (intravenous immunoglobulin [IVIG]) or subcutaneously (subcutaneous immunoglobulin [SCIG]). In patients with PID, the 20% SCIG product, Ig20Gly, was shown to be efficacious and well tolerated in 2 phase 2/3 trials conducted in North America and Europe. This analysis evaluated patient satisfaction with Ig20Gly therapy and treatment preferences.
METHODS: This prespecified post hoc analysis showed combined data from 2 Ig20Gly pivotal trials. Treatment satisfaction was assessed in the pre-Ig20Gly period and after ≥11 months of Ig20Gly treatment using the Life Quality Index (LQI; both studies) and the Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9; North American study only). Treatment preference was assessed using a survey at the end of the European study. Median within-patient differences in LQI and TSQM-9 scores between the pre-Ig20Gly period and the end of the Ig20Gly treatment period were assessed using the Wilcoxon signed-rank test.
RESULTS: A total of 113 patients (n = 68 [North American]; n = 45 [Europe]) with PID were included in the analysis. In the combined LQI analysis (n = 110), significant improvements were observed in the treatment interference (median ∆: + 2.8; P = 0.006) and therapy setting (median ∆: + 5.6; P < 0.0001) domains, and in the item-level scores for convenience (median ∆: + 1.0; P < 0.0001) and interference with work/school (median ∆: + 1.0; P = 0.0001) categories. In the subgroup analyses, significant improvements in the treatment interference and therapy setting domains and the convenience and interference with work/school items were observed for those who had previously received treatment outside the home, those who had previously received IVIG, and those in the North American study. Significant improvements were observed in the TSQM-9 treatment convenience domain (median ∆: + 11.1; P < 0.0001) and selected item-level scores in the North American study. In the European study, most (88.9%) patients preferred to continue Ig20Gly versus other IG treatments.
CONCLUSIONS: After ≥11 months of taking Ig20Gly, patients reported high levels of treatment satisfaction, convenience, and preference for Ig20Gly, with consistent results across studies and use of multiple patient-reported outcome measures.

PMID: 32366233 [PubMed – in process]

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