Research

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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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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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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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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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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Related Articles

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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Lymphomatoid granulomatosis associated with azathioprine therapy in Crohn disease.

BMC Gastroenterol. 2014;14:127

Authors: Connors W, Griffiths C, Patel J, Belletrutti PJ

Abstract
BACKGROUND: Lymphomatoid granulomatosis (LYG) is a rare Epstein-Barr virus-associated lymphoproliferative disorder. It most often occurs in patients with immunodeficiency and the clinical course ranges from indolent behavior to that of an aggressive malignancy. Pulmonary, central nervous system and dermatological manifestations are most common. To our knowledge this is the first reported case of LYG related to azathioprine therapy in Crohn disease.
CASE PRESENTATION: A twenty-six year old Caucasian woman with colonic Crohn disease on maintenance azathioprine therapy presented with right upper quadrant pain and fever. Diagnostic imaging revealed extensive liver, pulmonary and cerebral lesions. A diagnosis of LYG was made based on the pattern of organ involvement and the immunohistochemical features on liver and lung biopsy.
CONCLUSIONS: Thiopurine therapy for inflammatory bowel disease is associated with an increased incidence of lymphoproliferative disorders. This report highlights the diagnostic challenges associated with LYG. As long-term thiopurine therapy remains central to the management of inflammatory bowel diseases it is essential that both patients and clinicians are aware of this potential adverse outcome.

PMID: 25022612 [PubMed – indexed for MEDLINE]

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Subcutaneous immunoglobulin in lymphoproliferative disorders and rituximab-related secondary hypogammaglobulinemia: a single-center experience in 61 patients.

Haematologica. 2014 Jun;99(6):1101-6

Authors: Compagno N, Cinetto F, Semenzato G, Agostini C

Abstract
Intravenous immunoglobulin replacement therapy represents the standard treatment for hypogammaglobulinemia secondary to B-cell lymphoproliferative disorders. Subcutaneous immunoglobulin infusion is an effective, safe and well-tolerated treatment approach in primary immunodeficiencies but no extensive data are available on their use in secondary hypogammaglobulinemia, a frequent phenomenon occurring after treatment with anti-CD20 monoclonal antibodies in lymphoproliferative disorders. In this retrospective study we evaluated efficacy (serum IgG trough levels, incidence of infections per year, need for antibiotics) and safety (number of adverse events) of intravenous (300 mg/kg/4 weeks) versus subcutaneous (75 mg/kg/week) immunoglobulin replacement therapy in 61 patients. In addition, the impact of the infusion methods on quality of life was compared. All patients were treated with subcutaneous immunoglobulin, and 33 out of them had been previously treated with intravenous immunoglobulin. Both treatments appeared to be effective in replacing Ig production deficiency and in reducing the incidence of infectious events and the need for antibiotics. Subcutaneous immunoglobulin obtained a superior benefit when compared to intravenous immunoglobulin achieving higher IgG trough levels, lower incidence of overall infection and need for antibiotics. The incidence of serious bacterial infections was similar with both infusion ways. As expected, a lower number of adverse events was registered with subcutaneous immunoglobulin, compared to intravenous immunoglobulin, with no serious adverse events. Finally, we observed an improvement in health-related quality of life parameters after the switch to subcutaneous immunoglobulin. Our results suggest that subcutaneous immunoglobulin is safe and effective in patients with hypogammaglobulinemia associated to lymphoproliferative disorders.

PMID: 24682509 [PubMed – indexed for MEDLINE]

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NK cell tolerance as the final endorsement of prenatal tolerance after in utero hematopoietic cellular transplantation.

Front Pharmacol. 2015;6:51

Authors: Alhajjat AM, Lee AE, Strong BS, Shaaban AF

Abstract
The primary benefits of in utero hematopoietic cellular transplantation (IUHCT) arise from transplanting curative cells prior to the immunologic maturation of the fetus. However, this approach has been routinely successful only in the treatment of congenital immunodeficiency diseases that include an inherent NK cell deficiency despite the existence of normal maternal immunity in either setting. These observations raise the possibility that fetal NK cells function as an early barrier to allogeneic IUHCT. Herein, we summarize the findings of previous studies of prenatal NK cell allospecific tolerance in mice and in humans. Cumulatively, this new information reveals the complexity of the fetal immune response in the setting of rejection or tolerance and illustrates the role for fetal NK cells in the final endorsement of allospecific prenatal tolerance.

PMID: 25852555 [PubMed]

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