Research

Accelerated Loss of TCR Repertoire Diversity in Common Variable Immunodeficiency.

J Immunol. 2016 Aug 1;

Authors: Wong GK, Millar D, Penny S, Heather JM, Mistry P, Buettner N, Bryon J, Huissoon AP, Cobbold M

Abstract
Although common variable immunodeficiency (CVID) has long been considered as a group of primary Ab deficiencies, growing experimental data now suggest a global disruption of the entire adaptive immune response in a segment of patients. Oligoclonality of the TCR repertoire was previously demonstrated; however, the manner in which it relates to other B cell and T cell findings reported in CVID remains unclear. Using a combination approach of high-throughput TCRβ sequencing and multiparametric flow cytometry, we compared the TCR repertoire diversity between various subgroups of CVID patients according to their B cell immunophenotypes. Our data suggest that the reduction in repertoire diversity is predominantly restricted to those patients with severely reduced class-switched memory B cells and an elevated level of CD21(lo) B cells (Freiburg 1a), and may be driven by a reduced number of naive T cells unmasking underlying memory clonality. Moreover, our data indicate that this loss in repertoire diversity progresses with advancing age far exceeding the expected physiological rate. Radiological evidence supports the loss in thymic volume, correlating with the decrease in repertoire diversity. Evidence now suggests that primary thymic failure along with other well-described B cell abnormalities play an important role in the pathophysiology in Freiburg group 1a patients. Clinically, our findings emphasize the integration of combined B and T cell testing to identify those patients at the greatest risk for infection. Future work should focus on investigating the link between thymic failure and the severe reduction in class-switched memory B cells, while gathering longitudinal laboratory data to examine the progressive nature of the disease.

PMID: 27481850 [PubMed – as supplied by publisher]

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Prospective evaluation of Streptococcus pneumoniae serum antibodies in patients with primary immunodeficiency on regular intravenous immunoglobulin treatment.

Allergol Immunopathol (Madr). 2016 Jul 29;

Authors: Simão-Gurge RM, Costa-Carvalho BT, Nobre FA, Gonzalez IG, de Moraes-Pinto MI

Abstract
BACKGROUND: This is a prospective study that assessed pneumococcal antibody levels in PID patients under intravenous immunoglobulin (IVIG) treatment using different brands.
METHODS: Twenty-one patients receiving regular IVIG every 28 days were invited to participate: 12 with common variable immunodeficiency, six with X-linked agammaglobulinaemia and three with hyper-IgM syndrome. One blood sample was collected from each patient just prior to IVIG administration at a three-month time interval during one year. A questionnaire was filled in with patient’s demographic data and history of infections during the study period. Streptococcus pneumoniae antibodies against six serotypes (1, 5, 6B, 9V, 14 and 19F) were assessed by ELISA both in patients’ serum (trough levels) and in IVIG samples.
RESULTS: Median total IgG trough serum levels were 7.91g/L (range, 4.59-12.20). All patients had antibody levels above 0.35μg/mL to the six serotypes on all four measurements. However, only 28.6% of patients had pneumococcal antibodies for the six analysed serotypes above 1.3μg/mL on all four evaluations during the one-year period. No correlation was found between IgG trough levels and pneumococcal specific antibodies. Eighteen of the 21 patients (85.7%) had infections at some point during the 12-month follow-up, 62/64 (96.9%) clinically classified in respiratory tract infections, four of which were pneumonia.
CONCLUSIONS: Pneumococcal antibodies are present in a high range of concentrations in sera from PID patients and also in IVIG preparations. Even maintaining a recommended IgG trough level, these patients can be susceptible to these bacteria and that may contribute to recurrent respiratory infections.

PMID: 27480789 [PubMed – as supplied by publisher]

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Primary immune deficiency in bronchiectasis.

Nurs Times. 2016 Apr 13-19;112(15):16-9

Authors: Ozerovitch L

Abstract
The primary purpose of the immune system is to protect the body from infection. Failure of the immune system can lead to repeated infections. The aim of this review is to discuss primary immune deficiency (PID) and its relationship with bronchiectasis in adults. It examines treatment options for patients with PID and provides practical details of how nurses can empower these patients to reduce their risk of respiratory infections.

PMID: 27400622 [PubMed – indexed for MEDLINE]

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Recombinant human hyaluronidase facilitated subcutaneous immunoglobulin treatment in pediatric patients with primary immunodeficiencies: long-term efficacy, safety and tolerability.

Immunotherapy. 2016 Jul 28;

Authors: Wasserman RL, Melamed I, Kobrynski L, Puck J, Gupta S, Doralt J, Sharkhawy M, Engl W, Leibl H, Gelmont D, Yel L

Abstract
AIM: To assess the long-term efficacy, safety and tolerability of recombinant human hyaluronidase-facilitated subcutaneous infusion of immunoglobulin (Ig) (fSCIG; HYQVIA(®); IGHy) in children aged <18 years.
PATIENTS & METHODS: Patients with primary immunodeficiency diseases were included in the studies. IGHy was administered every 3 or 4 weeks.
RESULTS: Validated acute serious bacterial infections were reported at 0.08/patient-year (four pneumonia episodes in three patients). No serious adverse drug reaction (ADR) was reported, and rates of local and systemic ADRs were low (0.09/infusion and 0.1/infusion). Infection rates were low (3.02/patient-year) with sustained Ig trough levels (median: 1009 mg/dl). Of 674 IGHy infusions, 97.2% required no change of administration due to ADR, in most (82.5%) with one infusion site. No patient developed neutralizing anti-rHuPH20 antibodies. Postpivotal study, 100% of patients aged <14 years or their caregivers and 85.7% of patients aged 14 to <18 years expressed preference for IGHy compared with Ig administered intravenously or Ig administered subcutaneously.
CONCLUSION: These studies, with the longest (maximum: 3.3 years) duration of any reported Ig replacement trials in children with primary immunodeficiency diseases, showed low infection, local and systemic reaction rates along with well-tolerated infusions given in a single site.

PMID: 27468136 [PubMed – as supplied by publisher]

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Pneumocystis jirovecii pneumonia in pediatric patients: an analysis of 15 confirmed consecutive cases during 14 years.

Korean J Pediatr. 2016 Jun;59(6):252-5

Authors: Kim KR, Kim JM, Kang JM, Kim YJ

Abstract
PURPOSE: Pneumocystis jirovecii pneumonia occurs in various immunocompromised patients. Despite the prophylaxis strategies in clinical practice, certain patients develop P. jirovecii pneumonia. This study was performed to investigate pediatric cases with P. jirovecii pneumonia in a single center.
METHODS: We identified pediatric patients younger than 19 years with microbiologically confirmed P. jirovecii pneumonia from January 2000 to February 2014. A retrospective chart review was performed.
RESULTS: Fifteen episodes of P. jirovecii pneumonia in 14 patients were identified with median age of 8.3 years (range, 0.4-18.6 years). Among these patients, 11 patients had hematology-oncology diseases, 2 had primary immunodeficiency disorders (one with severe combined immunodeficiency and the other with Wiskott Aldrich syndrome), 1 had systemic lupus erythematosus and 1 received kidney transplant. Four patients were transplant recipients; 1 allogeneic and 2 autologous hematopoietic cell transplant and 1 with kidney transplant. The median absolute lymphocyte count at the diagnosis of P. jirovecii pneumonia was 5,156 cells/mm(3) (range, 20-5,111 cells/mm(3)). In 13 episodes (13 of 15, 86.7%), patients were not receiving prophylaxis at the onset of P. jirovecii pneumonia. For treatment, trimethoprim/sulfamethoxazole was given as a main therapeutic agent in all 15 episodes. Steroid was given in 9 episodes (60%). Median treatment duration was 15 days (range, 4-33 days). Overall mortality at 60 days was 35.7% (5 of 14).
CONCLUSION: Majority of our patients developed P. jirovecii pneumonia while not on prophylaxis. Continuous efforts and more data are needed to identify high risk patients who may get benefit from P. jirovecii pneumonia prophylaxis.

PMID: 27462353 [PubMed]

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The B-cell compartment in antibody-deficient infants and young children – developing common variable immunodeficiency or transient immune maturation?

Ital J Pediatr. 2016;42(1):71

Authors: Szczawinska-Poplonyk A, Tapolska-Jozwiak K, Samara H

Abstract
BACKGROUND: Hypogammaglobulinemia in early childhood is a common feature characterized by distinct intrinsic and extrinsic factors leading to disturbed peripheral blood lymphocyte homeostasis. Detailed flow cytometric immunophenotyping of the peripheral blood B cell compartment is an informative tool for delineating disturbed generation of B cell subpopulations crucial for the diagnosis of hypogammaglobulinemia in young children.
METHODS: We analyzed by flow cytometry the proportions and absolute values of total, naïve, memory – non-switched and switched, transitional and immature B lymph cells as well as plasmablasts in the peripheral blood of 50 hypogammaglobulinemic children aged from 3 to 50 months.
RESULTS: Beyond physiological, age-related changes within the B cell pool, a proportion of children manifested defective differentiation into switched memory and accumulation of CD21lo immature B cells.
CONCLUSIONS: Dynamic shifts within B cell subpopulations of the immature immune system being most prominent during the first two years of life contribute to the age-related developmental abnormalities of the B cell compartment. Therefore, a reliable diagnosis of common variable immunodeficiency (CVID) in young hypogammaglobulinemic children cannot yet be established despite their clinical and immunological phenotypes sharing common features with this primary immunodeficiency.

PMID: 27461226 [PubMed – in process]

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Lentiviral vector gene therapy protects XCGD mice from acute Staphylococcus aureus pneumonia and inflammatory response.

Mol Ther. 2016 Jul 26;

Authors: Farinelli G, Hernandez RJ, Rossi A, Ranucci S, Sanvito F, Migliavacca M, Brombin C, Pramov A, Serio CD, Bovolenta C, Gentner B, Bragonzi A, Aiuti A

Abstract
Chronic Granulomatous Disease (CGD) is a primary immunodeficiency due to a deficiency in one of the subunits of the NADPH oxidase complex. CGD patients are characterized by an increased susceptibility to bacterial and fungal infections, and to granuloma formation due to the excessive inflammatory responses. Several gene therapy approaches with lentiviral vectors (LVs) have been proposed but there is a lack of in vivo data on the ability to control infections and inflammation. We set up a mouse model of acute infection that closely mimic the airway infection in CGD patients. It involved an intratracheal injection of a methicillin-sensitive reference strain of S. aureus. Gene therapy, with hematopoietic stem cells transduced with regulated lentiviral vectors, restored the functional activity of NADPH oxidase complex (with 20-98% of dihydrorhodamine positive granulocytes and monocytes) and saved mice from death caused by S. aureus, significantly reducing the bacterial load and lung damage, similarly to WT mice even at low vector copy number (VCN). When challenged, gene therapy- treated XCGD mice showed correction of pro-inflammatory cytokines and chemokine imbalance at levels that were comparable to WT. Examined together, our results support the clinical development of gene therapy protocols using lentiviral vectors for the protection against infections and inflammation.

PMID: 27456061 [PubMed – as supplied by publisher]

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The Use of Immunoglobulin Therapy in Primary Immunodeficiency Diseases.

Endocr Metab Immune Disord Drug Targets. 2016 Jul 24;

Authors: Azizi G, Abolhassani H, Rezaei N, Aghamohammadi A, Asgardoon MH, Rahnavard J, Dizaji MZ, Yazdani R

Abstract
Immunoglobulin therapy represents a lifesaving intervention for many patients with primary immunodeficiency (PID). Antibody defects represent approximately half of the well-known PIDs requiring immunoglobulin replacement therapy. Following immunoglobulin therapy in PID patients, protection against serious upper and lower respiratory tract infections and pulmonary function improves which leads to an increase in the quality of life of these patients. Successful treatment of PID patients depends on the type of immunodeficiency, regular monitoring of the patient, co-morbidities of the patient, and the availability of the products.

PMID: 27456825 [PubMed – as supplied by publisher]

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Subcutaneous Immunoglobulin Therapy for Hypogammaglobulinemia Secondary to Malignancy or Related Drug Therapy.

Transfus Med Rev. 2016 Jul 2;

Authors: Windegger TM, Lambooy CA, Hollis L, Morwood K, Weston H, Fung YL

Abstract
Immunoglobulin replacement therapy (IRT) has an important role in minimizing infections and improving the health-related quality of life (HRQoL) in patients with immunodeficiency, who would otherwise experience recurrent infections. These plasma-derived products are available as intravenous immunoglobulin (IVIg) or subcutaneous immunoglobulin (SCIg). The global demand for these products is growing rapidly and has placed pressure on supply. Some malignancies and their treatment (as well as other medical therapies) can lead to secondary hypogammaglobulinemia or secondary immunodeficiency (SID) requiring IRT. Although IVIg use in this cohort has well-established therapeutic benefits, little is known about SCIg use. A literature search in July 2015 found only 7 published articles on SCIg use. These articles found that both IRT modes had equivalent efficacy in regard to reduction of bacterial infections. In addition, SCIg was reported to produce higher serum IgG trough levels compared with IVIg on equivalent dosage with the added benefit of fewer adverse effects. Patient HRQoL reports demonstrate preference for SCIg because of reduced adverse effects and hospital visits. There are no health economic models published on SCIg use in SID, but models on primary immunodeficiency disease and IRT conclude that SCIg provided greater economic benefits than IVIg. The findings of this small number of reports suggest that SCIg therapy for patients with SID is likely to be beneficial for both the patient and health care providers. To substantiate wider use of SCIg in SID, larger and more detailed studies are needed to accurately quantify the effectiveness of SCIg.

PMID: 27450021 [PubMed – as supplied by publisher]

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