Manish Butte

[Histoplasmosis of the central nervous system in an immunocompetent patient].

Biomedica. 2014 Dec;34(4):506-13

Authors: Osorio N, López Y, Jaramillo JC

Abstract
Histoplasmosis is a multifaceted condition caused by the dimorphic fungi Histoplasma capsulatum whose infective spores are inhaled and reach the lungs, the primary organ of infection. The meningeal form, considered one of the most serious manifestations of this mycosis, is usually seen in individuals with impaired cellular immunity such as patients with acquired immunodeficiency syndrome, systemic lupus erythematous or solid organ transplantation, and infants given their immunological immaturity. The most common presentation is self-limited and occurs in immunocompetent individuals who have been exposed to high concentrations of conidia and mycelia fragments of the fungi. In those people, the condition is manifested by pulmonary disorders and late dissemination to other organs and systems. We report a case of central nervous system histoplasmosis in an immunocompetent child.

PMID: 25504238 [PubMed – in process]

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Diagnostics of Primary Immunodeficiency Diseases: A Sequencing Capture Approach.

PLoS One. 2014;9(12):e114901

Authors: Moens LN, Falk-Sörqvist E, Asplund AC, Bernatowska E, Smith CI, Nilsson M

Abstract
Primary Immunodeficiencies (PID) are genetically inherited disorders characterized by defects of the immune system, leading to increased susceptibility to infection. Due to the variety of clinical symptoms and the complexity of current diagnostic procedures, accurate diagnosis of PID is often difficult in daily clinical practice. Thanks to the advent of “next generation” sequencing technologies and target enrichment methods, the development of multiplex diagnostic assays is now possible. In this study, we applied a selector-based target enrichment assay to detect disease-causing mutations in 179 known PID genes. The usefulness of this assay for molecular diagnosis of PID was investigated by sequencing DNA from 33 patients, 18 of which had at least one known causal mutation at the onset of the experiment. We were able to identify the disease causing mutations in 60% of the investigated patients, indicating that the majority of PID cases could be resolved using a targeted sequencing approach. Causal mutations identified in the unknown patient samples were located in STAT3, IGLL1, RNF168 and PGM3. Based on our results, we propose a stepwise approach for PID diagnostics, involving targeted resequencing, followed by whole transcriptome and/or whole genome sequencing if causative variants are not found in the targeted exons.

PMID: 25502423 [PubMed – as supplied by publisher]

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Specific antibody deficiency with normal immunoglobulin concentration in children with recurrent respiratory infections.

Allergol Immunopathol (Madr). 2014 Dec 10;

Authors: Quezada A, Norambuena X, Inostroza J, Rodríguez J

Abstract
BACKGROUND: Response to polysaccharide antigens is a test to evaluate the immunological competence of children with recurrent respiratory infections (RRI) of unknown cause and no other immune system abnormality. In order to detect specific antibody deficiency (SAD), a group of children with RRI without other immunodeficiency were prospectively studied.
METHODS: We included 20 children (12 male), age range 3-14 years, with six or more annual episodes of respiratory infections (RI); one or more monthly episodes of RI during the winter months; or three or more annual episodes of lower RI. The children were immunised with 23-valent polysaccharide anti-pneumococcal vaccine, and ELISA was used to measure anti-polysaccharide IgG antibody levels for 10 pneumococcal serotypes at baseline (T0), and 45 days (T1) and one year post-immunisation (T2). Post-immunisation response above 1.3μg/ml for more than 50% of the serotypes was considered normal for children 2-5 years, and for more than 70% of the serotypes in children older than 5 years.
RESULTS: At T1 19/20 children showed a normal response for their age, and only one patient showed a deficient response, suggestive of classic moderate SAD. At T2, 8/20 patients showed deficient responses, suggestive of impaired persistence of specific antibodies. There was a noteworthy association between deficient response and asthma and allergic rhinitis.
CONCLUSIONS: We propose first ruling out local or systemic causes, then performing serum immunoglobulin IgM, IgG, IgA, IgE and IgG subclass levels, and finally measuring response to polysaccharide pneumococcal antigens for detection of SAD.

PMID: 25498324 [PubMed – as supplied by publisher]

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Is there evidence for recommending specific intravenous immunoglobulin formulations? A systematic review of head-to-head randomized controlled trials.

Eur J Pharmacol. 2014 Dec 10;

Authors: Buehler AM, Flato UP, Ferri CP, Fernandes JG

Abstract
Intravenous immunoglobulins (IVIG) have been used for several licensed and off-label indications. Each IVIG product is a unique formulation of IgG and excipients, making them distinct products. How these differences impact on individual IVIG product efficacy and safety are not well established but can be investigated by head-to-head randomized controlled trials (RCT). A systematic review of head-to-head RCT comparing different formulations of IVIG, regardless of the target condition and outcomes investigated. Two reviewers screened 4,084 citations retrieved from MEDLINE, Embase, Cochrane and LILACS, and 23 citations were fully-text evaluated. Eight trials were included. The clinical conditions, outcomes and risk of bias were assessed. Of the eight trials included only two investigated products that are currently on the market. One evaluated two Grifols brands used in patients with primary immunodeficiency and another evaluated two Baxter brands used in patients with chronic inflammatory demyelinating polyradiculoneuropathy. There were no differences between the formulations for the outcomes evaluated. In the other trials, either the manufacturers were acquired by other companies or the formulation was withdrawn from the market. As consequence, evidence concerning these products could not be considered. The quality of the studies was low, showing high risk of bias. Direct evidence about the different IVIGs is scarce and, at present, there is no scientific evidence that can be applied for a specific brand or formulation. Further comparative effectiveness studies are highly desirable for a better understanding of the differences in safety and efficacy of IVIGs.

PMID: 25496751 [PubMed – as supplied by publisher]

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A coding IRAK2 protein variant compromises Toll-like receptor (TLR) signaling and is associated with colorectal cancer survival.

J Biol Chem. 2014 Aug 15;289(33):23123-31

Authors: Wang H, Flannery SM, Dickhöfer S, Huhn S, George J, Kubarenko AV, Lascorz J, Bevier M, Willemsen J, Pichulik T, Schafmayer C, Binder M, Manoury B, Paludan SR, Alarcon-Riquelme M, Bowie AG, Försti A, Weber AN

Abstract
Within innate immune signaling pathways, interleukin-1 receptor-associated kinases (IRAKs) fulfill key roles downstream of multiple Toll-like receptors and the interleukin-1 receptor. Although human IRAK4 deficiency was shown to lead to severe immunodeficiency in response to pyogenic bacterial infection during childhood, little is known about the role of human IRAK2. We here identified a non-synonymous IRAK2 variant, rs35060588 (coding R214G), as hypofunctional in terms of NF-κB signaling and Toll-like receptor-mediated cytokine induction. This was due to reduced ubiquitination of TRAF6, a key step in signal transduction. IRAK2 rs35060588 occurs in 3-9% of individuals in different ethnic groups, and our studies suggested a genetic association of rs35060588 with colorectal cancer survival. This for the first time implicates human IRAK2 in a human disease and highlights the R214G IRAK2 variant as a potential novel and broadly applicable biomarker for disease or as a therapeutic intervention point.

PMID: 24973222 [PubMed – indexed for MEDLINE]

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Secondary antibody deficiency.

Expert Rev Clin Immunol. 2014 May;10(5):583-91

Authors: Duraisingham SS, Buckland MS, Grigoriadou S, Longhurst HJ

Abstract
Secondary antibody deficiencies are defined by a quantitative or qualitative decrease in antibodies that occur most commonly as a consequence of renal or gastrointestinal immunoglobulin loss, hematological malignancies and corticosteroid, immunosuppressive or anticonvulsant medications. Patients with hematological malignancies or requiring immunosuppressive medications are known to be at increased risk of infection, but few studies directly address this relationship in the context of antibody deficiency. Immunoglobulin replacement therapy has been shown to be effective in reducing infections in primary and some secondary antibody deficiencies. The commonly encountered causes of secondary antibody deficiencies and their association with infection-related morbidity and mortality are discussed. Recommendations are made for screening and clinical management of those at risk.

PMID: 24684706 [PubMed – indexed for MEDLINE]

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Role of dendritic cells in innate and adaptive immune response in human aging.

Exp Gerontol. 2014 Jun;54:47-52

Authors: Gupta S

Abstract
Aging is associated with a progressive decline in T cell function, chronic inflammation, hyperimmunoglobulinemia, autoimmunity, poor response to vaccines, and increased susceptibility to infection as well as diseases associated with chronic inflammation. DCs in aging appear to be functionally impaired with regard to response to uptake of antigens, phagocytosis of apoptotic cells, migration, priming of CD4+ and CD8+ T cells, and production of IFN-I and IFN-III. In this review I have discussed various mechanisms, which may be responsible for impaired functions of DCs.

PMID: 24370374 [PubMed – indexed for MEDLINE]

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primary immunodeficiency NOT human immunodeficiency virus

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The etiologies of non-CF bronchiectasis in childhood: a systematic review of 989 subjects.

BMC Pediatr. 2014 Dec 10;14(1):299

Authors: Brower KS, Del Vecchio MT, Aronoff SC

Abstract
BackgroundWhile cystic fibrosis (CF) is the most common cause of bronchiectasis in childhood, non-CF bronchiectasis is associated with a wide variety of disorders. The objective of this study was to determine the relative prevalence and specific etiologies on non-CF bronchiectasis in childhood.MethodsEMBASE, Medline, OVID Cochrane Reviews, Directory of Open Access Journals, Open Science Directory, EPSCO information services, and OAlster were searched electronically and the bibliographies of selected studies were searched manually. The search was conducted independently by 2 authors. Study Selection: (1) any clinical trial, observational study or cross-sectional case series of 10 or more patients with a description of the conditions associated with bronchiectasis; (2) subjects aged 21 years or younger; (3) cystic fibrosis was excluded and; (4) the diagnosis was confirmed by computed tomography of the chest. Data Extraction: Patient number, age range, inclusion criteria, diagnostic criteria, patient source, and categorical and specific etiology.ResultsFrom 491 studies identified, 12 studies encompassing 989 children with non-CF bronchiectasis were selected. Sixty-three percent of the subjects had an underlying disorder. Infectious (17%), primary immunodeficiency (16%), aspiration (10%), ciliary dyskinesia (9%), congenital malformation (3%), and secondary immunodeficiency (3%) were the most common disease categories; 999 etiologies were identified. Severe pneumonia of bacterial or viral etiology and B cell defects were the most common disorders identified.ConclusionsThe majority of children with non-CF bronchiectasis have an underlying disorder. A focused history and laboratory investigated is recommended.

PMID: 25492164 [PubMed – as supplied by publisher]

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Incidence, Presentation, and Prognosis of Malignancies in Ataxia-Telangiectasia: A Report From the French National Registry of Primary Immune Deficiencies.

J Clin Oncol. 2014 Dec 8;

Authors: Suarez F, Mahlaoui N, Canioni D, Andriamanga C, d’Enghien CD, Brousse N, Jais JP, Fischer A, Hermine O, Stoppa-Lyonnet D

Abstract
PURPOSE: Biallelic mutations in ATM cause ataxia-telangiectasia (AT), a rare inherited disease with a high incidence of cancer. Precise estimates of the risk, presentation, and outcomes of cancer in patients with AT need to be addressed in large series.
PATIENTS AND METHODS: In this large retrospective cohort, 69 patients with cancers (24.5%) were identified among 279 patients with AT. Centralized review was performed on 60% of the lymphomas. Incidence rates were compared with the French population, and risk factors were analyzed.
RESULTS: Eight patients developed acute leukemias (including four T-cell acute lymphoblastic leukemias), 12 developed Hodgkin lymphoma (HL), 38 developed non-Hodgkin lymphoma (NHL), three developed T-cell prolymphocytic leukemia (T-PLL), and eight developed carcinoma at a median age of 8.3, 10.6, 9.7, 24.2, and 31.4 years, respectively (P < .001). The majority of NHLs were aggressive B-cell NHL. Epstein-Barr virus was associated with all of the HLs and 50% of the NHLs. Overall survival was shorter in patients with AT who developed cancer compared with those who did not develop cancer (15 v 24 years, respectively; P < .001). Survival was improved in patients who achieved a major response to treatment (3.46 v 0.87 years for major v minor responses, respectively; P = .011). Immunodeficiency was associated with increased risk of cancer. ATM mutation type was associated with a difference in survival in the entire cohort but not with cancer incidence or cancer survival.
CONCLUSION: B-cell NHL, HL, and acute lymphoblastic leukemia occur at a high rate and earlier age than carcinomas in AT. T-PLLs are rarer than initially reported. Prognosis is poor, but patients may benefit from treatment with an improved survival.

PMID: 25488969 [PubMed – as supplied by publisher]

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