Manish Butte

Percutaneous Lung Biopsy in Immunocompromised Pediatric Patients.

J Vasc Interv Radiol. 2019 Nov 22;:

Authors: Cleveland H, Chau A, Jeng Z, Gardner G, Yoo R, Zhang W, Hernandez J

Abstract
PURPOSE: To determine the diagnostic yield and safety of image-guided lung biopsies in immunocompromised pediatric patients.
MATERIALS AND METHODS: This was a retrospective pediatric cohort study conducted from June 2000 to April 2017. Subjects were 0-17 years of age (median, 10 years of age). There were 46 males (48%). A total of 73 consecutive image-guided lung biopsies were performed in 68 patients (weight range, 4.9-97.3 kg [median, 25.3 kg]). The indication for biopsy was to isolate an organism to tailor medical therapy. All patients were immunocompromised with an underlying history of bone marrow transplantation (n = 50), primary immunodeficiency (n = 14), and solid organ transplantation (n = 4). Patient and technical factors were analyzed for rates of complication.
RESULTS: Overall diagnostic yield was 43 of 73 patients (60%). There were 14 minor (19%) and 8 major (11%) complications. Major complications included pneumothorax or hemoptysis requiring intervention (n = 6), and death (n = 2). The histological diagnosis was an infectious cause in 5 of 8 major complications (63%). There were statistically significant differences between the rates of complications with the imaging modality used (P = .02) and the use of fine needle aspiration (P = .02).
CONCLUSIONS: Image-guided percutaneous lung biopsy can be helpful in isolating an organism to tailor therapy. Biopsies performed in immunosuppressed patients result in an elevated complication risk of up to 30% and demonstrate lower diagnostic yield and increased mortality, which should warrant detailed discussion with the primary team and family.

PMID: 31767410 [PubMed – as supplied by publisher]

Powered by WPeMatico

The Scope for Thalassemia Gene Therapy by Disruption of Aberrant Regulatory Elements.

J Clin Med. 2019 Nov 13;8(11):

Authors: Patsali P, Mussolino C, Ladas P, Floga A, Kolnagou A, Christou S, Sitarou M, Antoniou MN, Cathomen T, Lederer CW, Kleanthous M

Abstract
The common IVSI-110 (G>A) β-thalassemia mutation is a paradigm for intronic disease-causing mutations and their functional repair by non-homologous end joining-mediated disruption. Such mutation-specific repair by disruption of aberrant regulatory elements (DARE) is highly efficient, but to date, no systematic analysis has been performed to evaluate disease-causing mutations as therapeutic targets. Here, DARE was performed in highly characterized erythroid IVSI-110(G>A) transgenic cells and the disruption events were compared with published observations in primary CD34+ cells. DARE achieved the functional correction of β-globin expression equally through the removal of causative mutations and through the removal of context sequences, with disruption events and the restriction of indel events close to the cut site closely resembling those seen in primary cells. Correlation of DNA-, RNA-, and protein-level findings then allowed the extrapolation of findings to other mutations by in silico analyses for potential repair based on the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) 9, Cas12a, and transcription activator-like effector nuclease (TALEN) platforms. The high efficiency of DARE and unexpected freedom of target design render the approach potentially suitable for 14 known thalassemia mutations besides IVSI-110(G>A) and put it forward for several prominent mutations causing other inherited diseases. The application of DARE, therefore, has a wide scope for sustainable personalized advanced therapy medicinal product development for thalassemia and beyond.

PMID: 31766235 [PubMed]

Powered by WPeMatico

Epstein-Barr Virus-Positive Mucocutaneous Ulcer in a Pediatric Patient-Case Report.

Am J Dermatopathol. 2019 Nov 18;:

Authors: Coelho KMPA, Bublitz GS, Condeixa de França PH, Stall J, Hanauer AD, Sangueza JM

Abstract
The Epstein-Barr virus (EBV)-positive mucocutaneous ulcer is a rare entity in the spectrum of lymphoproliferative diseases associated with the EBV. It occurs typically in patients with immunosuppression associated with immunosenescence, as well as due to iatrogenic causes, posttransplant patients and primary immunodeficiency disorders. It is often a benign and self-limited disease that recedes by stopping or reducing the immunosuppressive agents in most of the cases. Histologically, it is characterized by a population of EBV-positive atypical lymphoid cells. Here, we present a rare case of a 5-month-old pediatric patient, born preterm at 24 weeks of gestational age, presenting a lump on the right shoulder, later evolving to EBV-positive mucocutaneous ulcer.

PMID: 31764088 [PubMed – as supplied by publisher]

Powered by WPeMatico

Cutaneous Granulomatosis and Class Switching Defect as a Presenting Sign in Ataxia-Telangiectasia: First Case from the National Iranian Registry and Review of the Literature.

Immunol Invest. 2019 Nov 25;:1-14

Authors: Amirifar P, Yazdani R, Moeini Shad T, Ghanadan A, Abolhassani H, Lavin M, Sotoudeh S, Aghamohammadi A

Abstract
Ataxia-telangiectasia (A-T) is a rare autosomal recessive syndrome characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia, immunodeficiency and cancer predisposition, caused by mutations in the ataxia telangiectasia mutated (ATM) gene. The clinical and immunological manifestations of A-T are very heterogeneous, especially at an early age, leading to frequent misdiagnosis. Cutaneous granulomas with unknown pathogenesis occur uncommonly in a minority of A-T patients. We herein report an unusual case of a 13-year-old girl with A-T who presented severe clinical manifestations, including multiple granulomatous lesions of the skin and a class switch defect phenotype. This patient is the first Iranian A-T case with cutaneous granulomatosis and immunodeficiency. In addition, the literature on skin granulomas in all previously reported A-T patients is reviewed indicating an increased frequency of elevated IgM level and female dominancy in this selected group of patients.

PMID: 31762358 [PubMed – as supplied by publisher]

Powered by WPeMatico

How I Manage Natural Killer Cell Deficiency.

J Clin Immunol. 2019 Nov 22;:

Authors: Orange JS

Abstract
Natural killer (NK) cell deficiency (NKD) is a subset of primary immunodeficiency disorders (PID) in which an abnormality of NK cells represents a major immunological defect resulting in the patient’s clinical immunodeficiency. This is distinct from a much larger group of PIDs that include an NK cell abnormality as a minor component of the immunodeficiency. Patients with NKD most frequently have atypical consequences of herpesviral infections. There are now 6 genes that have been ascribed to causing NKD, some exclusively and others that also cause other known immunodeficiencies. This list has grown in recent years and as such the mechanistic and molecular clarity around what defines an NKD is an emerging and important field of research. Continued increased clarity will allow for more rational approaches to the patients themselves from a therapeutic standpoint. Having evaluated numerous individuals for NKD, I share my perspective on approaching the diagnosis and managing these patients.

PMID: 31754930 [PubMed – as supplied by publisher]

Powered by WPeMatico

Electrochemical selection of a DNA aptamer, and an impedimetric method for determination of the dedicator of cytokinesis 8 by self-assembly of a thiolated aptamer on a gold electrode.

Mikrochim Acta. 2019 Nov 21;186(12):828

Authors: Eissa S, Siddiqua A, Chinnappan R, Zourob M

Abstract
The autosomal recessive-hyper immunoglobulin E syndromes (AR-HIES) are inherited inborn primary immunodeficiency disorders caused mainly by mutations in the dedicator of cytokinesis 8 (DOCK8) gene. A method is described for the selection of DNA aptamers against DOCK8 protein. The selection was performed by using a gold electrode as the solid matrix for immobilization of DOCK8. This enables voltammetric monitoring of the bound DNA after each selection cycle. After eight rounds of selection, high affinity DNA aptamers for DOCK8 were identified with dissociation constants (Kds) ranging from 3.3 to 66 nM. The aptamer which a Kd of 8.8 nM was used in an aptasensor. A gold electrode was modified by self-assembly of the thiolated aptamer, and the response to the DOCK8 protein was detected by monitoring the change in the electron transfer resistance using the ferro/ferricyanide system as a redox probe. The aptasensor works in the 100 pg.mL-1 to 100 ng.mL-1 DOCK8 concentration range, has a detection limit of 81 pg.mL-1 and good selectivity over other proteins in the serum. Graphical abstractSchematic representation of an electrochemical screening protocol for the selection of DNA aptamer against dedicator of cytokinesis 8 protein using electrode as solid support for target immobilization.

PMID: 31754797 [PubMed – in process]

Powered by WPeMatico

X-linked lymphoproliferative syndrome in mainland China: review of clinical, genetic, and immunological characteristic.

Eur J Pediatr. 2019 Nov 21;:

Authors: Xu T, Zhao Q, Li W, Chen X, Xue X, Chen Z, Du X, Bai X, Zhao Q, Zhou L, Tang X, Yang X, Kanegane H, Zhao X

Abstract
X-linked lymphoproliferative syndrome (XLP) is a rare primary immunodeficiency disease that can be divided into two types: SAP deficiency (XLP1) and XIAP deficiency (XLP2), caused by mutations in the SH2D1A and XIAP genes, respectively. Few cases of XLP (particularly XIAP deficiency) have been reported in mainland China; hence, little is known about the characteristics of Chinese patients with XLP. We identified 13 and 7 patients with SAP and XIAP deficiency, respectively, in our center. Of our 20 patients, 19/20 (95%) presented with disease symptoms at a very early age: six in infancy and 13 in childhood. One XIAP- and three SAP-deficient patients died, while 3/7(42.9%) and 4/13(30.8%), respectively, developed hemophagocytic lymphohistiocytosis (HLH). Epstein-Barr virus (EBV) infection was significantly more common in SAP-deficient 10/13 (76.9%) than XIAP-deficient 2/7 (28.6%) patients, as was hypogammaglobulinemia (10/13 (76.9%) vs. 1/7 (14.3%)). None of the seven XIAP-deficient patients had colitis or lymphoma. Nine SAP-deficient patients and five XIAP-deficient patients showed markedly deficient SAP and XIAP expression, respectively, in lymphocytes. Significantly reduced levels of switched memory B cells were observed in six SAP-deficient patients with persistent hypogammaglobulinemia. One of 13 (7.7%) SAP-deficient patients and 1 of 7 (12.3%) XIAP-deficient patients have received HSCT treatment and are now alive and well; the other alive patients were waiting for HSCT. We also summarized clinical, genetic, and immunological characteristics of all 55 patients (including our 20 patients) reported in the literature in mainland China today.Conclusion: The overall characteristics of SAP deficiency in mainland China were consistent with those in previous reports, whereas manifestations of XIAP deficiency varied significantly. None of inflammatory bowel disease (IBD) has been reported among XIAP-deficient patients in our center; however, whether Chinese XIAP-deficient patients will develop colitis in the future warrants further investigation. HSCT is the only curative therapy for XLP and this therapy should be urgently considered.What is Known:• SAP and XIAP deficiencies share common clinical feature, HLH, whereas they also have their own specific manifestations.• IBD affects 25-30% of XIAP-deficient patients, which has been reported in other countries especially in European country and Japan.What is New:• This is the largest patient cohort study of XLP in China.• We firstly summarized the clinical features and outcomes of Chinese XIAP-deficient patients and found only 1 in 22 patients developed IBD and diet background may contribute to it; Asian SAP-deficient patients carrying SH2D1A R55X mutation were more prone to HLH.

PMID: 31754776 [PubMed – as supplied by publisher]

Powered by WPeMatico

Wiskott-Aldrich Syndrome (WAS) and Dedicator of Cytokinesis 8- (DOCK8) Deficiency.

Front Pediatr. 2019;7:451

Authors: Albert MH, Freeman AF

Abstract
Both Wiskott-Aldrich syndrome (WAS) and dedicator of cytokinesis 8 (DOCK8) deficiency are primary immunodeficiency diseases caused by mutations in genes that result in defective organization of the cytoskeleton in hematopoietic tissues. They share some overlapping features such as a combined immunodeficiency, eczema and a predisposition to autoimmunity and malignancy, but also have some unique features that make them relatively easy to diagnose by clinical means. Both diseases can be cured by HSCT in a large proportion of patients. In WAS it is sometimes difficult to establish an indication for HSCT due to the large variability of disease severity, while HSCT is probably indicated in all patients affected by DOCK8 deficiency. There is considerably more published HSCT experience for WAS than for DOCK8 deficiency, but many open questions remain, which will be discussed in this review.

PMID: 31750279 [PubMed]

Powered by WPeMatico

Focusing on Good Responders to Pneumococcal Polysaccharide Vaccination in General Hospital Patients Suspected for Immunodeficiency. A Decision Tree Based on the 23-Valent Pneumococcal IgG Assay.

Front Immunol. 2019;10:2496

Authors: Janssen LMA, Heron M, Murk JL, Leenders ACAP, Rijkers GT, de Vries E

Abstract
Background and Aim: Recently, the 23-valent IgG-assay was suggested as screening assay to identify poor responders to pneumococcal polysaccharide (PnPS)-vaccination with the serotype-specific assay as a second-line test. However, in a low pre-test probability general hospital setting predicting good responders could be more valuable to reduce the number of samples needing serotyping. Methods: Serotype-specific PnPS antibody-assays were performed for suspected immunodeficiency in two Dutch general hospitals (Jeroen Bosch Hospital, ‘s-Hertogenbosch; Elisabeth Tweesteden Hospital, Tilburg). 23-Valent PnPS antibody-assays were subsequently performed in archived material. Data were analyzed using receiver operating characteristic curves (AUC) and agreement indices (ICC). Results: Sera of 284 patients (348 samples) were included; 23-valent IgG-titres and the corresponding sum of PnPS-serotype specific antibodies showed moderate correlation (ICC = 0.63). In 232 conjugated-pneumococcal-vaccine-naïve patients (270 samples), a random 23-valent IgG-titer could discriminate between samples with and without ≥7/11, ≥7/13, or ≥6/9 pneumococcal serotypes when both cut-off values 0.35 and 1.0 μg/ml were used (AUC 0.86 and 0.92, respectively). All patients with a pre-immunization-titer ≥38.2 μg/ml and/or post-immunization-titer ≥96.1 μg/ml and none with a post-immunization-titer ≤38.5 μg/ml exhibited a good response to PnPS vaccination. Using these breakpoints as screening test to predict good responders, only 24% of patients would require further serotyping, as opposed to 68% if breakpoints to predict poor responders would have been used. Conclusion: In a low pre-test probability setting, the 23-valent IgG-assay proved to be a reliable screening test for good responders in conjugated-pneumococcal-vaccine-naïve patients, reducing the overall number of patient samples needing further serotyping, thus reducing overall costs of pneumococcal vaccination response assessment.

PMID: 31749801 [PubMed – in process]

Powered by WPeMatico