Research

Impact of Site of Care on Infection Rates Among Patients with Primary Immunodeficiency Diseases Receiving Intravenous Immunoglobulin Therapy.

J Clin Immunol. 2017 Feb 03;:

Authors: Wasserman RL, Ito D, Xiong Y, Ye X, Bonnet P, Li-McLeod J

Abstract
PURPOSE: Patients with primary immunodeficiency diseases (PIDD) are at increased risk of infection and may require lifelong immunoglobulin G (IgG) replacement. Infection incidence rates were determined for patients with PIDD receiving intravenously administered IgG (IGIV) in a home or hospital outpatient infusion center (HOIC).
METHODS: Data were extracted from a large, US-based, employer-sponsored administrative database. Patients were eligible for analysis if they had ≥1 inpatient or emergency room claim or ≥2 outpatient claims with a PIDD diagnosis between January 2002 and March 2013, 12 months of continuous health plan enrollment prior to index date (i.e., first IGIV infusion date), and 6 months of continuous IGIV at the same site of care after the index date. Incidences of pneumonia (bacterial or viral) and bronchitis (all types) within 7 days of IGIV infusion were retrospectively determined and compared between sites of care.
RESULTS: A total of 1076 patients were included in the analysis; 51 and 49% received IGIV at home and at an HOIC, respectively. The event/patient-year of pneumonia was significantly lower in patients receiving IGIV at home compared to an outpatient hospital (0.102 vs. 0.216, p = 0.0071). Similarly, the event/patient-year of bronchitis was significantly lower among patients infusing at home compared to an HOIC (0.150 vs. 0.288, p < 0.0001).
CONCLUSIONS: PIDD patients experienced incidence rates for pneumonia and bronchitis that were lower for patients receiving home-based IGIV treatment versus HOIC-based IGIV treatment. The lower infection rates in the home setting suggest that infection risk may be an important factor in site of care selection.

PMID: 28160239 [PubMed – as supplied by publisher]

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Bacillus Calmette-Guérin vaccine complications in Iranian children at a University Hospital.

Allergol Immunopathol (Madr). 2017 Feb 01;:

Authors: Bolursaz MR, Lotfian F, Velayati AA

Abstract
BACKGROUND: Although the BCG vaccine remains the only available vaccine, a number of complications from local to systemic adverse reactions can occur.
OBJECTIVE: The aim of the study was to review the clinical features and treatment of Bacillus Calmette-Guérin (BCG) complications in children.
METHODS: Children with clinical and laboratory findings compatible with a diagnosis of local complication and disseminated disease at Masih Daneshvari Medical Center were enrolled from March 2013 to September 2015.
RESULTS: Among 49 children with BCG complications, 35 (71%) had local complications and 14 (29%) had disseminated disease. The mean age at presentation was nine months (range: 1m-13y). The male to female ratio was 1.7:1. Suppurative lymphadenitis was seen in 25 of 35 (71%) cases. Among cases with disseminated disease, primary immunodeficiency (PID) was identified in nine (64%) cases. All cases with non-suppurative lymphadenitis were managed conservatively. Twenty (80%) cases with suppurative lymphadenitis were managed differently with medical treatment or surgery. In disseminated cases, three (43%) were treated with only medical treatment and eight (57%) with both medical and surgical treatment.
CONCLUSIONS: Most children with BCG complications had a local disease in our study. A higher rate of disseminated disease was also observed. In addition, PID was identified in most children with disseminated disease. Development of more appropriate BCG vaccines and changing the current vaccination programme in cases with suspected PID are required in our country.

PMID: 28161281 [PubMed – as supplied by publisher]

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Identifying functional defects in patients with immune dysregulation due to LRBA and CTLA-4 mutations.

Blood. 2017 Feb 03;:

Authors: Hou TZ, Verma N, Wanders J, Kennedy A, Soskic B, Janman D, Halliday N, Rowshanravan B, Worth A, Qasim W, Baxendale H, Stauss H, Seneviratne S, Neth O, Olbrich P, Hambleton S, Arkwright PD, Burns SO, Walker LS, Sansom DM

Abstract
Heterozygous CTLA-4 deficiency has been reported as a monogenic cause of common variable immune deficiency (CVID) with features of immune dysregulation. Direct mutation in CTLA-4 leads to defective regulatory T cell function associated with impaired ability to control levels of the CTLA-4 ligands, CD80 and CD86. However, additional mutations affecting the CTLA-4 pathway, such as those recently reported for LRBA, indirectly affect CTLA-4 expression resulting in clinically similar disorders. Robust phenotyping approaches sensitive to defects in the CTLA-4 pathway are therefore required to inform understanding of such immune dysregulation syndromes. Here we describe assays capable of distinguishing a variety of defects in the CTLA-4 pathway. Assessing total CTLA-4 expression levels was found to be optimal when restricting analysis to the CD45RA-negative Foxp3+ fraction. CTLA-4 induction following stimulation, and the use of lysosomal blocking compounds, distinguished CTLA-4 from LRBA mutations. Short term T cell stimulation improved the capacity for discriminating the Foxp3+ Treg compartment, clearly revealing Treg expansions in these disorders. Finally, we developed a functionally orientated assay to measure ligand uptake by CTLA-4, which is sensitive to ligand-binding or trafficking mutations, that would otherwise be difficult to detect and that is appropriate for testing novel mutations in CTLA-4 pathway genes. These approaches are likely to be of value in interpreting the functional significance of mutations in the CTLA-4 pathway identified by gene sequencing approaches.

PMID: 28159733 [PubMed – as supplied by publisher]

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The diagnosis of bilateral primary renal paragangliomas in a cat.

J S Afr Vet Assoc. 2017 Jan 24;88(0):e1-e6

Authors: Friedlein RB, Carter AJ, Last RD, Clift S

Abstract
A 9-year-old sterilised female domestic short-hair cat was referred with a history of vomiting and anorexia of 3 months’ duration. Biochemistry, full-blood counts, thoracic radiographs, feline pancreatic-specific lipase, abdominal ultrasonography and feline immunodeficiency virus/feline leukaemia virus (FIV/FeLV) SNAP tests had been performed. Mild hypochloraemia and moderate hypokalaemia were evident on initial presentation. Abdominal ultrasonography initially revealed unilateral renal nodules on the left side. These were subjected to fine-needle aspiration and cytological evaluation. A neuroendocrine tumour was suspected, and biopsies via midline coeliotomy were taken to confirm the diagnosis. Initial histopathology diagnosed primary renal carcinomas or neuroendocrine neoplasia; however, the definitive diagnosis became renal paragangliomas after immunohistochemistry and transmission electron microscopy were performed. The cat was regularly monitored with serum biochemistry parameters, blood pressure determinations, thoracic radiographs and subsequent abdominal ultrasonography. Biochemistry, radiography and blood pressures remained normal over a 24-week follow-up period, while subsequent ultrasonography revealed tumour progression in both number and size in both kidneys. Primary neuroendocrine tumours of the kidney are frequently incorrectly diagnosed as other renal tumours such as renal cell carcinoma, mesonephric tumours or undifferentiated carcinomas. This case report highlights the importance of additional testing, including immunohistochemistry and transmission electron microscopy, to obtain a definitive diagnosis of paragangliomas.

PMID: 28155290 [PubMed – in process]

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Functional analysis for gut microbes of the brown tree frog (Polypedates megacephalus) in artificial hibernation.

BMC Genomics. 2016 Dec 22;17(Suppl 13):1024

Authors: Weng FC, Yang YJ, Wang D

Abstract
BACKGROUND: Annual hibernation is an adaptation that helps many animals conserve energy during food shortage in winter. This natural cycle is also accompanied by a remodeling of the intestinal immune system, which is an aspect of host biology that is both influenced by, and can itself influence, the microbiota. In amphibians, the bacteria in the intestinal tract show a drop in bacterial counts. The proportion of pathogenic bacteria is greater in hibernating frogs than that found in nonhibernating frogs. This suggests that some intestinal gut microbes in amphibians can be maintained and may contribute to the functions in this closed ecosystem during hibernation. However, these results were derived from culture-based approaches that only covered a small portion of bacteria in the intestinal tract.
METHODS: In this study, we use a more comprehensive analysis, including bacterial appearance and functional prediction, to reveal the global changes in gut microbiota during artificial hibernation via high-throughput sequencing technology.
RESULTS: Our results suggest that artificial hibernation in the brown tree frog (Polypedates megacephalus) could reduce microbial diversity, and artificially hibernating frogs tend to harbor core operational taxonomic units that are rarely distributed among nonhibernating frogs. In addition, artificial hibernation increased significantly the relative abundance of the red-leg syndrome-related pathogenic genus Citrobacter. Furthermore, functional predictions via PICRUSt and Tax4Fun suggested that artificial hibernation has effects on metabolism, disease, signal transduction, bacterial infection, and primary immunodeficiency.
CONCLUSIONS: We infer that artificial hibernation may impose potential effects on primary immunodeficiency and increase the risk of bacterial infections in the brown tree frog.

PMID: 28155661 [PubMed – in process]

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[Pulmonary manifestations in adult patients with a defect in humoral immunity].

Ter Arkh. 2016;88(8):127-34

Authors: Latysheva TV, Latysheva EA, Martynova IA, Aminova GE

Abstract
Primary immunodeficiencies (PIDs) are a group of congenital diseases of the immune system, which numbers more than 230 nosological entities associated with lost, decreased, or wrong function of its one or several components. Due to the common misconception that these are extremely rare diseases that occur only in children and lead to their death at an early age, PIDs are frequently ruled out by physicians of related specialties from the range of differential diagnosis. The most common forms of PIDs, such as humoral immunity defects, common variable immune deficiency, X-linked agammaglobulinemia, selective IgA deficiency, etc., are milder than other forms of PID, enabling patients to attain their adult age, and may even manifest in adulthood. Bronchopulmonary involvements are the most common manifestations of the disease in patients with a defect in humoral immunity. Thus, a therapist and a pulmonologist are mostly the first doctors who begin to treat these patients and play a key role in their fate, since only timely diagnosis and initiation of adequate therapy can preserve not only the patient’s life, but also its quality, avoiding irreversible complications. Chest computed tomography changes play a large role in diagnosis. These are not specific for PID; however, there are a number of characteristic signs that permit this diagnosis to be presumed.

PMID: 27636936 [PubMed – indexed for MEDLINE]

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Ruxolitinib reverses dysregulated T helper cell responses and controls autoimmunity caused by a novel signal transducer and activator of transcription 1 (STAT1) gain-of-function mutation.

J Allergy Clin Immunol. 2017 Jan 23;:

Authors: Weinacht KG, Charbonnier LM, Alroqi F, Plant A, Qiao Q, Wu H, Ma C, Torgerson TR, Rosenzweig SD, Fleisher TA, Notarangelo LD, Hanson IC, Forbes LR, Chatila TA

Abstract
BACKGROUND: Gain-of-function (GOF) mutations in the human signal transducer and activator of transcription 1 (STAT1) manifest in immunodeficiency and autoimmunity with impaired TH17 cell differentiation and exaggerated responsiveness to type I and II interferons. Allogeneic bone marrow transplantation has been attempted in severely affected patients, but outcomes have been poor.
OBJECTIVE: We sought to define the effect of increased STAT1 activity on T helper cell polarization and to investigate the therapeutic potential of ruxolitinib in treating autoimmunity secondary to STAT1 GOF mutations.
METHODS: We used in vitro polarization assays, as well as phenotypic and functional analysis of STAT1-mutated patient cells.
RESULTS: We report a child with a novel mutation in the linker domain of STAT1 who had life-threatening autoimmune cytopenias and chronic mucocutaneous candidiasis. Naive lymphocytes from the affected patient displayed increased TH1 and follicular T helper cell and suppressed TH17 cell responses. The mutation augmented cytokine-induced STAT1 phosphorylation without affecting dephosphorylation kinetics. Treatment with the Janus kinase 1/2 inhibitor ruxolitinib reduced hyperresponsiveness to type I and II interferons, normalized TH1 and follicular T helper cell responses, improved TH17 differentiation, cured mucocutaneous candidiasis, and maintained remission of immune-mediated cytopenias.
CONCLUSIONS: Autoimmunity and infection caused by STAT1 GOF mutations are the result of dysregulated T helper cell responses. Janus kinase inhibitor therapy could represent an effective targeted treatment for long-term disease control in severely affected patients for whom hematopoietic stem cell transplantation is not available.

PMID: 28139313 [PubMed – as supplied by publisher]

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Respiratory Complications Lead to the Diagnosis of Chronic Granulomatous Disease in Two Adult Patients.

J Clin Immunol. 2017 Jan 27;:

Authors: Colin de Verdière S, Noel E, Lozano C, Catherinot E, Martin M, Rivaud E, Couderc LJ, Salvator H, Bustamante J, Martin T

Abstract
Chronic granulomatous disease (CGD) is a primary immunodeficiency associated to multiple life-threatening bacterial and fungal infections, beginning in childhood. There are rare cases of diagnosis in adulthood. We describe here two cases of late diagnosis in adults: a 45-year-old woman and 59-year-old-man. CGD diagnosis should be considered in adult patients with unexplained infectious diseases with tissue granuloma.

PMID: 28130637 [PubMed – as supplied by publisher]

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Activation of compensatory pathways via Rac2 in the absence of the Cdc42 effector Wiskott-Aldrich syndrome protein in Dendritic cells.

Small GTPases. 2017 Jan 27;:0

Authors: Baptista MA, Westerberg LS

Abstract
There is extensive crosstalk between different Rho GTPases, including Cdc42, Rac1, and Rac2, and they can activate or inhibit the activity of each other. Dendritic cells express both Rac1 and Rac2. Due to posttranslational modification of lipid anchors, Rac1 localizes mainly to the plasma membrane whereas Rac2 localizes to the phagosomal membrane where it assembles the NADPH complex. Our recent study of primary immunodeficiency disease caused by mutations in the Cdc42 effector Wiskott-Aldrich syndrome protein (WASp) has shed light on the compensatory mechanisms between Rho GTPases and their effector proteins. WASp-deficient dendritic cells have increased localization and activity of Rac2 to the phagosomal membrane and this allows antigen to be presented on MHC class I molecules to activate cytotoxic CD8(+) T cells. This study reveals an intricate balance between Rac2 and WASp signaling pathways and provides an example of compensatory pathways in cells devoid of the Cdc42 effector WASp.

PMID: 28129089 [PubMed – as supplied by publisher]

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Ataxia-telangiectasia: Immunodeficiency and survival.

Clin Immunol. 2017 Jan 23;:

Authors: van Os NJ, Jansen AF, van Deuren M, Haraldsson A, van Driel NT, Etzioni A, van der Flier M, Haaxma CA, Morio T, Rawat A, Schoenaker MH, Soresina A, Taylor AM, van de Warrenburg BP, Weemaes CM, Roeleveld N, Willemsen MA

Abstract
Ataxia-telangiectasia (AT) is a neurodegenerative disorder characterized by ataxia, telangiectasia, and immunodeficiency. An increased risk of malignancies and respiratory diseases dramatically reduce life expectancy. To better counsel families, develop individual follow-up programs, and select patients for therapeutic trials, more knowledge is needed on factors influencing survival. This retrospective cohort study of 61 AT patients shows that classical AT patients had a shorter survival than variant patients (HR 5.9, 95%CI 2.0-17.7), especially once a malignancy was diagnosed (HR 2.5, 95%CI 1.1-5.5, compared to classical AT patients without malignancy). Patients with the hyper IgM phenotype with hypogammaglobulinemia (AT-HIGM) and patients with an IgG2 deficiency showed decreased survival compared to patients with normal IgG (HR 9.2, 95%CI 3.2-26.5) and patients with normal IgG2 levels (HR 7.8, 95%CI 1.7-36.2), respectively. If high risk treatment trials will become available for AT, those patients with factors indicating the poorest prognosis might be considered for inclusion first.

PMID: 28126470 [PubMed – as supplied by publisher]

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