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Intravenous and subcutaneous immunoglobulin replacement: a two-way road. Optimizing healthcare quality in patients with primary immunodeficiencies.

J Clin Immunol. 2014 Nov;34(8):1015-7

Authors: Soler-Palacín P, Gasó-Gago I, Fernández-Polo A, Martín-Nalda A, Oliveras M, Martinez-Cutillas J, Figueras C

Abstract
PURPOSE: To evaluate the alternate use of subcutaneous immunoglobulin (SCIG) and intravenous immunoglobulin (IVIG) in patients with primary immunodeficiencies (PID) in a third-level Pediatric University Hospital.
METHODS: Retrospective study of all patients receiving SCIG from 2006 to 2012. Data collected included demographics, date SCIG was started, date of switch to IVIG and reasons, administration tolerance, and related adverse events. Effectiveness was defined as the lack of severe infections.
RESULTS: Twenty-three patients (15 male, 8 female) with PID were studied. SCIG was initiated at a median age of 14.2 years (8.4 months-25.7 years) and median duration on SCIG treatment was 41 months (4-68). Nine patients (39.1%) temporarily switched from SCIG to IVIG for the following reasons: vacation (8), administration issues (1), and transient need for immunomodulatory therapy (1). A mean of 5.2 IVIG infusions/patient (SD=2.86) was administered while on SCIG. IVIG-related adverse events were documented in 3 patients with 6 infusions. Eight (34.8%) patients definitively discontinued SCIG use for the following reasons: convenience (5), adverse effects (1), coagulopathy (1), and autoimmune thrombocytopenia (1). There were no severe infections requiring hospital admission in any patient during the study period.
CONCLUSIONS: Alternating SCIG and IVIG use in patients with PID was associated with considerable advantages in terms of convenience for the patients and their caregivers, while maintaining the effectiveness and safety of this therapy. Healthcare units treating these patients should show flexibility with this dual therapy in order to optimize patients’ quality of life.

PMID: 25190197 [PubMed – indexed for MEDLINE]

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Altered chemotactic response to CXCL12 in patients carrying GATA2 mutations.

J Leukoc Biol. 2015 Dec 28;

Authors: Maciejewski-Duval A, Meuris F, Bignon A, Aknin ML, Balabanian K, Faivre L, Pasquet M, Barlogis V, Fieschi C, Bellanné-Chantelot C, Donadieu J, Schlecht-Louf G, Marin-Esteban V, Bachelerie F

Abstract
GATA2 deficiency-formerly described as MonoMAC syndrome; dendritic cells, monocytes, B cells, and natural killer cell deficiency; familial myelodysplastic syndrome/acute myeloid leukemia; or Emberger syndrome-encompasses a range of hematologic and nonhematologic anomalies, mainly characterized by monocytopenia, B lymphopenia, natural killer cell cytopenia, neutropenia, immunodeficiency, and a high risk of developing acute myeloid leukemia. Herein, we present 7 patients with GATA2 deficiency recruited into the French Severe Chronic Neutropenia Registry, which enrolls patients with all kinds of congenital neutropenia. We performed extended immunophenotyping of their whole blood lymphocyte populations, together with the analysis of their chemotactic responses. Lymphopenia was recorded for B and CD4(+) T cells in 6 patients. Although only 3 patients displayed natural killer cell cytopenia, the CD56(bright) natural killer subpopulation was nearly absent in all 7 patients. Natural killer cells from 6 patients showed decreased CXCL12/CXCR4-dependent chemotaxis, whereas other lymphocytes, and most significantly B lymphocytes, displayed enhanced CXCL12-induced chemotaxis compared with healthy volunteers. Surface expression of CXCR4 was significantly diminished in the patients’ natural killer cells, although the total expression of the receptor was found to be equivalent to that of natural killer cells from healthy individual controls. Together, these data reveal that GATA2 deficiency is associated with impaired membrane expression and chemotactic dysfunctions of CXCR4. These dysfunctions may contribute to the physiopathology of this deficiency by affecting the normal distribution of lymphocytes and thus potentially affecting the susceptibility of patients to associated infections.

PMID: 26710799 [PubMed – as supplied by publisher]

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The requirement of iron transport for lymphocyte function.

Nat Genet. 2015 Dec 29;48(1):10-1

Authors: Lo B

Abstract
Iron is essential in multiple cellular processes and is especially critical for cellular respiration and division. A new study identified a mutation affecting the iron import receptor TfR1 as the cause of a human primary immunodeficiency, illuminating the importance of iron in immune cell function.

PMID: 26711111 [PubMed – in process]

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Magnetic Resonance Imaging May Be a Valuable Radiation-Free Technique for Lung Pathologies in Patients with Primary Immunodeficiency.

J Clin Immunol. 2015 Dec 28;

Authors: Arslan S, Poyraz N, Ucar R, Yesildag M, Yesildag A, Caliskaner AZ

Abstract
PURPOSE: In some primary immunodeficiency (PID) patients, especially in the subgroup with common variable immunodeficiency (CVID), radiosensitivity is a concern and avoidance of repeated radiation exposure has been recommended. To investigate the use of lung Magnetic resonance imaging (MRI) instead of Computed Tomography (CT) for the diagnosis and follow-up of various lesions in the lung parenchyma and airways, especially in PID patients in whom x-ray exposure should be limited.
METHODS: The study enrolled 23 patients with PID who underwent thorax CT within the last 3 months and/or who will undergo initial radiological assessment. Lung MRI was performed in all patients to compare the pulmonary findings with CT images.
RESULTS: MRI performance was weaker at detecting bronchiectasis extension, and a low concordance was found between MRI and CT in the assessment of the number of bronchial generations. CT better identified peripheral airway abnormalities, while CT and MRI gave similar results for detecting the presence and extension of consolidation, bullae, mucus plugging, bronchial wall thickening, bronchiectasis severity and nodules.
CONCLUSIONS: Despite the low spatial resolution, higher cost, and low availability, we suggest MRI as a possible radiation-free alternative to CT in selected patients with PID.

PMID: 26707785 [PubMed – as supplied by publisher]

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Clinical Features, Non-Infectious Manifestations and Survival Analysis of 161 Children with Primary Immunodeficiency in Mexico: A Single Center Experience Over two Decades.

J Clin Immunol. 2015 Dec 28;

Authors: Lugo Reyes SO, Ramirez-Vazquez G, Cruz Hernández A, Medina-Torres EA, Ramirez-Lopez AB, España-Cabrera C, Hernandez-Lopez CA, Yamazaki-Nakashimada MA, Espinosa-Rosales FJ, Espinosa-Padilla SE, Murata C

Abstract
PURPOSE: The hallmark of Primary immunodeficiencies (PID) is unusual infection, although other immunological non-infectious manifestations such as autoimmunity, allergy and cancer are often present. Most published reports focus on one disease or defect groups, so that a global prevalence of non-infectious manifestations of PID is hard to find. We aimed to describe the clinical features of our pediatric patients with PID, as well as the frequency and evolution of allergy, cancer and autoimmunity.
METHODS: We reviewed all the available charts of patients being followed for PID from 1991 to the spring of 2012 at the National Institute of Pediatrics, Mexico City, to describe their demographic, clinical and laboratory features. Their diagnoses were established by pediatric immunologists in accordance to ESID criteria, including routine immunological workup and specialized diagnostic assays. We divided patients by decade of diagnosis to analyze their survival curves.
RESULTS: There were 168 charts available, from which we excluded one duplicate and six equivocal diagnoses. We studied the charts of 161 PID patients (68 % male, 86 % alive), mostly from the center of the country, with a positive family history in 27 % and known consanguinity in 11 %. Eighty percent of the patients were diagnosed during the last decade. Current median age was 124 months; median age at onset of infections, 12 months; median age at diagnosis, 52 months; median age at death, 67.5 months. Severe infection and bleeding were the cause of 22 deaths. Eighty-six percent of all patients had at least one infection, while non-infectious manifestations had a global prevalence of 36 %, namely: autoimmunity 19 %, allergies 17 %, and cancer 2.4 %. Survival curves were not significantly different when compared by decade of diagnosis.
CONCLUSIONS: Compared to other registry reports, we found a lower prevalence of antibody defects, and of associated allergy and cancer. We could only locate two isolated IgA deficiencies and four cases of cancer among our PID patients. Although antibody defects are the most prevalent group (30 %), the distribution we found is similar to that reported in Iran, Kuwait, Egypt and Taiwan, with a close 27 % share for phagocyte defects, and 26 % for the formerly called “well-defined” syndromes. Of note, autoimmune and inflammatory complications are high among our patients with chronic granulomatous disease, as has been reported in both the United States and Japan, but not in Europe.

PMID: 26707787 [PubMed – as supplied by publisher]

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Spectrum of Phenotypes Associated with Mutations in LRBA.

J Clin Immunol. 2015 Dec 28;

Authors: Alkhairy OK, Abolhassani H, Rezaei N, Fang M, Andersen KK, Chavoshzadeh Z, Mohammadzadeh I, El-Rajab MA, Massaad M, Chou J, Aghamohammadi A, Geha RS, Hammarström L

Abstract
To date, several germline mutations have been identified in the LRBA gene in patients suffering from a variety of clinical symptoms. These mutations abolish the expression of the LRBA protein, leading to autoimmunity, chronic diarrhea, B-cell deficiency, hypogammaglobulinemia, functional T-cell defects and aberrant autophagy. We review the clinical and laboratory features of patients with LRBA mutations and present five novel mutations in eight patients suffering from a multitude of clinical features.

PMID: 26707784 [PubMed – as supplied by publisher]

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STAT5B deficiency: Impacts on human growth and immunity.

Growth Horm IGF Res. 2015 Dec 10;

Authors: Hwa V

Abstract
Growth hormone (GH) promotes postnatal human growth primarily by regulating insulin-like growth factor (IGF)-I production through activation of the GH receptor (GHR)-signal transducer and activator of transcription (STAT)-5B signaling cascade. The critical importance of STAT5B in human IGF-I production was confirmed with the identification of the first homozygous, autosomal recessive, STAT5B mutation in a young female patient who phenotypically resembled patients with classical growth hormone insensitivity (GHI) syndrome (Laron syndrome) due to mutations in the GHR gene, presenting with severe postnatal growth failure and marked IGF-I deficiency. Of note, the closely related STAT5A, which shares >95% amino acid identity with STAT5B, could not compensate for loss of functional STAT5B. To date, 7 homozygous, inactivating, STAT5B mutations in 10 patients have been reported. STAT5B deficient patients, unlike patients deficient in GHR, can also present with a novel, potentially fatal, primary immunodeficiency, which can manifest as chronic pulmonary disease. STAT5B deficiency may be underestimated in endocrine, immunology and pulmonary clinics.

PMID: 26703237 [PubMed – as supplied by publisher]

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IRAK-4 deficiency as a cause for familial fatal invasive infection by steptococcus pneumoniae.

Clin Immunol. 2015 Dec 14;

Authors: Grazioli S, Hamilton SJ, McKinnon ML, Del Bel KL, Hoang L, Cook VE, Hildebrand KJ, Junker AK, Turvey SE

Abstract
In this Letter to the Editor we report the case of two siblings with fatal pneumococcal meningitis as the initial manifestation of IRAK-4 deficiency caused by previously undescribed mutations in IRAK4. The letter also highlights the importance of invasive pneumococcal infection as a critical ‘red flag’ warning of the potential for an underlying primary immunodeficiency and identifies some of the challenges in making the clinical diagnosis of IRAK-4 deficiency.

PMID: 26698383 [PubMed – as supplied by publisher]

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Efficacy and safety of Gammaplex® 5% in children and adolescents with primary immunodeficiency diseases.

Clin Exp Immunol. 2015 Dec 22;

Authors: Melamed IR, Gupta S, Bobbitt MS, Hyland N, Moy JN

Abstract
This open-label multicentre study evaluated Gammaplex(®) 5%, a human intravenous immunoglobulin (IVIG) 5% liquid, in 25 children and adolescent patients (aged 3-16 years) with primary immunodeficiency diseases (PIDs). Subjects received Gammplex 5% (at doses of 300-800 mg/kg/infusion) for 12 months, with a 3-month follow up. The primary efficacy endpoint was the incidence of serious acute bacterial infections (SABIs) during the 12-month treatment period. Secondary objectives assessed safety and tolerability. Nineteen males and 6 females were treated using the same infusion schedule as their prior IVIG treatment (14 and 11 subjects on 21- and 28-day dosing schedules, respectively). Two SABIs of pneumonia were reported, resulting in an annual SABI event rate of 0·09 (upper one-sided 99% CI, 0·36). Twenty-one subjects (84%) experienced ≥1 infection during the study, with a median infective episode per subject/year of 3·08 (range, 0-10·4). Sixteen subjects (64%) missed ≥1 day of nursery or school because of infection or other illness. All trough immunoglobulin G levels exceeded 7·00 g/L after 15 weeks (mean, 9·69 g/L; range, 7·04-15·35 g/L). Product-related adverse events occurred in 14 subjects (56%); none were serious. Of 368 total infusions, 97 (26%) were temporally associated with an adverse event (≤72 hours after infusion), regardless of causality. Laboratory test results and adverse-reaction data showed no evidence of product-related haemolysis or thromboembolic events. These data demonstrate that Gammplex 5% is effective in preventing SABIs and well-tolerated in children and adolescents with PID. This article is protected by copyright. All rights reserved.

PMID: 26696596 [PubMed – as supplied by publisher]

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Three faces of recombination activating gene 1 (RAG1) mutations.

Acta Microbiol Immunol Hung. 2015 Dec;62(4):393-401

Authors: Patiroglu T, Akar HH, Van Der Burg M

Abstract
Severe combined immune deficiency (SCID) is a group of genetic disorder associated with development of T- and/or B-lymphocytes. Recombination-activating genes (RAG1/2) play a critical role on VDJ recombination process that leads to the production of a broad T-cell receptor (TCR) and B-cell receptor (BCR) repertoire in the development of T and B cells. RAG1/2 genes mutations result in various forms of primary immunodeficiency, ranging from classic SCID to Omenn syndrome (OS) to atypical SCID with such as granuloma formation and autoimmunity. Herein, we reported 4 patients with RAG1 deficiency: classic SCID was seen in two patients who presented with recurrent pneumonia and chronic diarrhoea, and failure to thrive. OS was observed in one patient who presented with chronic diarrhoea, skin rash, recurrent lower respiratory infections, and atypical SCID was seen in one patient who presented with Pyoderma gangrenosum (PG) and had novel RAG1 mutation.

PMID: 26689875 [PubMed – in process]

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