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Immunoglobulin rearrangement analysis from multiple lesions in the same patient using Next Generation Sequencing.

Histopathology. 2015 Apr 18;

Authors: Appenzeller S, Gilissen C, Rijntjes J, Tops BB, Kastner-van Raaij A, Hebeda KM, Nissen L, Dutilh BE, van Krieken JH, Groenen PJ

Abstract
BACKGROUND: For patients who have multiple lymphomas with discordant pathology, it is relevant to determine whether there is one disseminated lymphoma or two unrelated lymphomas. Patients with disseminated, clonally related lymphomas, are usually treated with the most powerful drugs available, while patients with unrelated (primary) lymphomas mostly receive standard first-line therapies.
METHODS: We have used next generation sequencing on the Ion Torrent Personal Genome Machine to characterize the immunoglobulin heavy gene V-D-J rearrangements in two diagnostic tissue samples, including formalin-fixed and paraffin-embedded tissue, of two patients with iatrogenic immunodeficiency-associated Epstein-Barr virus lymphoproliferative disorder, with ulcerative colitis as underlying disease.
RESULTS: The immunoglobulin rearrangement sequences obtained by next generation sequencing revealed undoubtedly clonally related lesions in two tissue biopsies that were taken over time in the first patient, which is concordant with disseminated lymphoma. The other patient showed two clonally unrelated lesions, which is incompatible with clonal dissemination. This information was not inferred from evaluation of the heavy and light chain rearrangements by fragment analysis, which is currently the gold standard.
CONCLUSION: Our study demonstrates the diagnostic application of next generation sequencing of immunoglobulin rearrangement assessment in pathology for clinical decision making in patients with several simultaneous or subsequent lymphoproliferations. This article is protected by copyright. All rights reserved.

PMID: 25891511 [PubMed – as supplied by publisher]

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Association of CLEC16A with human common variable immunodeficiency disorder and role in murine B cells.

Nat Commun. 2015;6:6804

Authors: Li J, Jørgensen SF, Maggadottir SM, Bakay M, Warnatz K, Glessner J, Pandey R, Salzer U, Schmidt RE, Perez E, Resnick E, Goldacker S, Buchta M, Witte T, Padyukov L, Videm V, Folseraas T, Atschekzei F, Elder JT, Nair RP, Winkelmann J, Gieger C, Nöthen MM, Büning C, Brand S, Sullivan KE, Orange JS, Fevang B, Schreiber S, Lieb W, Aukrust P, Chapel H, Cunningham-Rundles C, Franke A, Karlsen TH, Grimbacher B, Hakonarson H, Hammarström L, Ellinghaus E

Abstract
Common variable immunodeficiency disorder (CVID) is the most common symptomatic primary immunodeficiency in adults, characterized by B-cell abnormalities and inadequate antibody response. CVID patients have considerable autoimmune comorbidity and we therefore hypothesized that genetic susceptibility to CVID may overlap with autoimmune disorders. Here, in the largest genetic study performed in CVID to date, we compare 778 CVID cases with 10,999 controls across 123,127 single-nucleotide polymorphisms (SNPs) on the Immunochip. We identify the first non-HLA genome-wide significant risk locus at CLEC16A (rs17806056, P=2.0 × 10(-9)) and confirm the previously reported human leukocyte antigen (HLA) associations on chromosome 6p21 (rs1049225, P=4.8 × 10(-16)). Clec16a knockdown (KD) mice showed reduced number of B cells and elevated IgM levels compared with controls, suggesting that CLEC16A may be involved in immune regulatory pathways of relevance to CVID. In conclusion, the CLEC16A associations in CVID represent the first robust evidence of non-HLA associations in this immunodeficiency condition.

PMID: 25891430 [PubMed – in process]

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Evaluation of four comorbidity indices and Charlson comorbidity index adjustment for colorectal cancer patients.

Int J Colorectal Dis. 2014 Sep;29(9):1159-69

Authors: Marventano S, Grosso G, Mistretta A, Bogusz-Czerniewicz M, Ferranti R, Nolfo F, Giorgianni G, Rametta S, Drago F, Basile F, Biondi A

Abstract
INTRODUCTION: Cancer survival is related not only to primary malignancy but also to concomitant nonmalignant diseases. The aim of this study was to investigate the prognostic capacity of four comorbidity indices [the Charlson comorbidity index (CCI), the Elixhauser method, the National Institute on Aging (NIA) and National Cancer Institute (NCI) comorbidity index, and the Adult Comorbidity Evaluation-27 (ACE-27)] for both cancer-related and all-cause mortality among colorectal cancer patients. A modified version of the CCI adapted for colorectal cancer patients was also built.
METHODS: The study population comprised 468 cases of colorectal cancer diagnosed between 1 January 2000 and 31 December 2010 at a community hospital. Data were prospectively collected and abstracted from patients’ clinical records. Kaplan-Meier method and multivariate logistic regression models were performed for survival and risk of death analysis.
RESULTS: Only moderate or severe renal disease [hazard ratio (HR) 2.71, 95% confidence interval (CI) 1.11-6.63] and AIDS (HR 3.27, 95% CI 1.23-8.68) were independently associated with cancer-specific mortality, with a population attributable risk of 5.18 and 4.36%, respectively. For each index, the highest comorbidity burden was significantly associated with poorer overall survival (NIA/NCI: HR 2.14, 95% CI 1.14-4.01; Elixhauser: HR 1.98, 95% CI 1.09-1.42; ACE-27: HR 1.78, 95% CI 1.07-1.23; CCI: HR 1.68, 95% CI 1.05-1.42) and cancer-specific survival. The modified version of the CCI resulted in a higher predictive power compared with other indices studied (cancer-specific mortality HR = 2.37, 95% CI 1.37-4.08).
CONCLUSIONS: The comorbidity assessment tools provided better prognostic prevision of prospective outcome of colorectal cancer patients than single comorbid conditions.

PMID: 25064390 [PubMed – indexed for MEDLINE]

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Novel primary immunodeficiency candidate genes predicted by the human gene connectome.

Front Immunol. 2015;6:142

Authors: Itan Y, Casanova JL

Abstract
Germline genetic mutations underlie various primary immunodeficiency (PID) diseases. Patients with rare PID diseases (like most non-PID patients and healthy individuals) carry, on average, 20,000 rare and common coding variants detected by high-throughput sequencing. It is thus a major challenge to select only a few candidate disease-causing variants for experimental testing. One of the tools commonly used in the pipeline for estimating a potential PID-candidate gene is to test whether the specific gene is included in the list of genes that were already experimentally validated as PID-causing in previous studies. However, this approach is limited because it cannot detect the PID-causing mutation(s) in the many PID patients carrying causal mutations of as yet unidentified PID-causing genes. In this study, we expanded in silico the list of potential PID-causing candidate genes from 229 to 3,110. We first identified the top 1% of human genes predicted by the human genes connectome to be biologically close to the 229 known PID genes. We then further narrowed down the list of genes by retaining only the most biologically relevant genes, with functionally enriched gene ontology biological categories similar to those for the known PID genes. We validated this prediction by showing that 17 of the 21 novel PID genes published since the last IUIS classification fall into this group of 3,110 genes (p < 10(-7)). The resulting new extended list of 3,110 predicted PID genes should be useful for the discovery of novel PID genes in patients.

PMID: 25883595 [PubMed]

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The Association Between Colonization With Carbapenemase-Producing Enterobacteriaceae and Overall ICU Mortality: An Observational Cohort Study.

Crit Care Med. 2015 Apr 16;

Authors: Dautzenberg MJ, Wekesa AN, Gniadkowski M, Antoniadou A, Giamarellou H, Petrikkos GL, Skiada A, Brun-Buisson C, Bonten MJ, Derde LP, Mastering hOSpital Antimicrobial Resistance in Europe Work Package 3 Study Team

Abstract
OBJECTIVES: Infections caused by carbapenemase-producing Enterobacteriaceae are increasing worldwide, especially in ICUs, and have been associated with high mortality rates. However, unequivocally demonstrating causality of such infections to death is difficult in critically ill patients because of potential confounding and competing events. Here, we quantified the effects of carbapenemase-producing Enterobacteriaceae carriage on patient outcome in two Greek ICUs with carbapenemase-producing Enterobacteriaceae endemicity.
DESIGN: Observational cohort study.
SETTING: Two ICUs with carbapenemase-producing Enterobacteriaceae endemicity.
PATIENTS: Patients admitted to the ICU with an expected length of ICU stay of at least 3 days were included.
INTERVENTIONS: None.
MEASUREMENTS AND MAIN RESULTS: Carbapenemase-producing Enterobacteriaceae colonization was established through screening in perineum swabs obtained at admission and twice weekly and inoculated on chromogenic plates. Detection of carbapenemases was performed phenotypically, with confirmation by polymerase chain reaction. Risk factors for ICU mortality were evaluated using cause-specific hazard ratios and subdistribution hazard ratios, with carbapenemase-producing Enterobacteriaceae colonization as time-varying covariate. One thousand seven patients were included, 36 (3.6%) were colonized at admission, and 96 (9.5%) acquired carbapenemase-producing Enterobacteriaceae colonization during ICU stay, and 301 (29.9%) died in ICU. Of 132 carbapenemase-producing Enterobacteriaceae isolates, 125 (94.7%) were Klebsiella pneumoniae and 74 harbored K. pneumoniae carbapenemase (56.1%), 54 metallo-β-lactamase (40.9%), and four both (3.0%). Carbapenemase-producing Enterobacteriaceae colonization was associated with a statistically significant increase of the subdistribution hazard ratio for ICU mortality (subdistribution hazard ratio = 1.79; 95% CI, 1.31-2.43), not explained by an increased daily hazard of dying (cause-specific hazard ratio for death = 1.02; 95% CI, 0.74-1.41), but by an increased length of stay (cause-specific hazard ratio for discharge alive = 0.73; 95% CI, 0.51-0.94). Other risk factors in the subdistribution hazard model were Acute Physiology and Chronic Health Evaluation II score (subdistribution hazard ratio = 1.13; 95% CI, 1.11-1.15), female gender (subdistribution hazard ratio = 1.29; 95% CI, 1.02-1.62), presence of solid tumor (subdistribution hazard ratio = 1.54; 95% CI, 1.15-2.06), hematopoietic malignancy (subdistribution hazard ratio = 1.61; 95% CI, 1.04-2.51), and immunodeficiency (subdistribution hazard ratio = 1.59; 95% CI, 1.11-2.27).
CONCLUSIONS: Patients colonized with carbapenemase-producing Enterobacteriaceae have on average a 1.79 times higher hazard of dying in ICU than noncolonized patients, primarily because of an increased length of stay.

PMID: 25882764 [PubMed – as supplied by publisher]

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Longitudinal Evaluation of Immune Reconstitution and B-cell Function After Hematopoietic Cell Transplantation for Primary Immunodeficiency.

J Clin Immunol. 2015 Apr 15;

Authors: Scarselli A, Di Cesare S, Capponi C, Cascioli S, Romiti ML, Di Matteo G, Simonetti A, Palma P, Finocchi A, Lucarelli B, Pinto RM, Rana I, Palumbo G, Caniglia M, Rossi P, Carsetti R, Cancrini C, Aiuti A

Abstract
PURPOSE: Hematopoietic cell transplantation (HCT) provides a curative therapy for severe forms of primary immunodeficiencies (PID). While the timing and extent of T-cell reconstitution following transplant for PID has been studied in depth, less is known about the kinetics of B-cell development and long-term restoration of humoral functions, which been often reported to be suboptimal after HCT.
METHODS: We studied longitudinally B-cell development and function in a cohort of 13 PID patients transplanted between 1997 and 2010, with a follow-up ranging from 0.7 to 15 years. Flow cytometric analysis of naïve and antigen-experienced B-cell subsets and in vitro functional responses to CpG were compared with data from healthy children and correlated with the degree of B-cell chimerism and in vivo antibody production.
RESULTS: We found that total memory B-cells count remained below normal levels for the first 2 years of follow up and progressively normalized. Switched memory B-cells (CD19+CD27+IgD-IgM-) were restored early and better than IgM memory B-cells (CD19+CD27+IgD+IgM+), which remained significantly reduced long-term. The recovery of memory B-cells correlated with good in vivo humoral function and normalization of CpG-response. A complete B-cell reconstitution was usually associated with donor B-cells chimerism and pre-transplant conditioning. Donor source and the underlying genetic defect represented also important variables.
CONCLUSION: Monitoring of phenotypic and functional changes on B-cells following HCT may prove clinically relevant to tailor patients’ care. In particular the analysis of IgM memory and switched memory B-cells in addition to in vitro B-cells stimulation are recommended before Ig replacement therapy (IgRT) discontinuation.

PMID: 25875698 [PubMed – as supplied by publisher]

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Overview of 15-year severe combined immunodeficiency in the Netherlands: towards newborn blood spot screening.

Eur J Pediatr. 2015 Apr 1;

Authors: de Pagter AP, Bredius RG, Kuijpers TW, Tramper J, van der Burg M, van Montfrans J, Driessen GJ, Dutch Working Party for Immunodeficiencies

Abstract
Severe combined immune deficiency (SCID) is a fatal primary immunodeficiency usually presenting in the first months of life with (opportunistic) infections, diarrhea, and failure to thrive. Hematopoietic stem cell transplantation (HSCT) and gene therapy (GT) are curative treatment options. The objective of the study was to assess the morbidity, mortality, and diagnostic and therapeutic delay in children with SCID in the Netherlands in the last 15 years. These data may help to judge whether SCID should be considered to be included in our national neonatal screening program. In the period 1998-2013, 43 SCID patients were diagnosed in the Netherlands, 11 of whom were atypical SCID (presentation beyond the first year). The median interval between the first symptom and diagnosis was 2 months (range 0-1173 months). The total mortality was 42 %. In total, 32 patients were treated with HSCT of whom 8 were deceased. Nine patients died due to severe infectious complications before curative treatment could be initiated.
CONCLUSION: Because of a high mortality of patients with SCID before HSCT could be initiated, only a national newborn screening program and pre-emptive HSCT or GT will be able to improve survival of these patients. “What is known” • SCID is a fatal disease if a curative hematopoietic stem cell transplantation cannot be performed in time. • Newborn screening for SCID enables early diagnosis in the asymptomatic phase. “What is new” • Nine out of 43 SCID patients in the Netherlands died due to severe infectious complications before curative treatment could be initiated. • Only newborn screening and pre-emptive curative therapy will improve survival of children with SCID in the Netherlands.

PMID: 25875249 [PubMed – as supplied by publisher]

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Intravenous immunoglobulin for hypogammaglobulinemia after lung transplantation: a randomized crossover trial.

PLoS One. 2014;9(8):e103908

Authors: Lederer DJ, Philip N, Rybak D, Arcasoy SM, Kawut SM

Abstract
BACKGROUND: We aimed to determine the effects of treatment with intravenous immunoglobulin on bacterial infections in patients with hypogammaglobulinemia (HGG) after lung transplantation.
METHODS: We performed a randomized, double-blind, placebo-controlled two-period crossover trial of immune globulin intravenous (IVIG), 10% Purified (Gamunex, Bayer, Elkhart, IN) monthly in eleven adults who had undergone lung transplantation more than three months previously. We randomized study participants to three doses of IVIG (or 0.1% albumin solution (placebo)) given four weeks apart followed by a twelve week washout and then three doses of placebo (or IVIG). The primary outcome was the number of bacterial infections within each treatment period.
RESULTS: IVIG had no effect on the number of bacterial infections during the treatment period (3 during IVIG and 1 during placebo; odds ratio 3.5, 95% confidence interval 0.4 to 27.6, p = 0.24). There were no effects on other infections, use of antibiotics, or lung function. IVIG significantly increased trough IgG levels at all time points (least square means, 765.3 mg/dl during IVIG and 486.3 mg/dl during placebo, p<0.001). Four serious adverse events (resulting in hospitalization) occurred during the treatment periods (3 during active treatment and 1 during the placebo period, p = 0.37). Chills, flushing, and nausea occurred during one infusion of IVIG.
CONCLUSIONS: Treatment with IVIG did not reduce the short-term risk of bacterial infection in patients with HGG after lung transplantation. The clinical efficacy of immunoglobulin supplementation in HGG related to lung transplantation over the long term or with recurrent infections is unknown.
TRIAL REGISTRATION: Clinicaltrials.gov NCT00115778.

PMID: 25090414 [PubMed – indexed for MEDLINE]

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Immune deficiency disorders involving neutrophils.

J Clin Pathol. 2008 Sep;61(9):1001-5

Authors: Spickett GP

Abstract
This review addresses current thinking on the diagnosis, causation and management of common and rare primary disorders of granulocytes. The genetic basis of many of these disorders is now understood. Increased awareness is necessary to ensure that these disorders are identified promptly and treated appropriately.

PMID: 18755725 [PubMed – indexed for MEDLINE]

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Successful renal transplantation in a patient with a Wiskott-Aldrich syndrome protein (WASP) gene mutation.

Transpl Int. 2015 Apr 11;

Authors: Chovancova Z, Kuman M, Vlkova M, Litzman J

Abstract
Wiskott-Aldrich syndrome (WAS) is a rare primary immunodeficiency disorder caused by mutations in the WAS protein (WASP) gene. Renal disease progressing to renal failure is a well-recognised complication in patients with WAS. Only a few case reports of renal transplantation have been reported to date. Here, we present a patient with a WASP mutation who suffered from severe atopic eczema, mild thrombocytopenia and only a slightly increased frequency of infections, who then developed IgA nephropathy and consequently underwent renal transplantation, which was successful. This study demonstrates that renal transplantation is possible in patients with WAS, regardless of conceivable complications. This article is protected by copyright. All rights reserved.

PMID: 25864580 [PubMed – as supplied by publisher]

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