Research

Granulocyte transfusions in patients with chronic granulomatous disease and refractory infections: the NIH experience.

J Allergy Clin Immunol. 2017 Mar 22;:

Authors: Marciano BE, Allen ES, Cantilena CC, Kristosturyan E, Klein HG, Fleisher TA, Holland SM, Malech HL, Rosenzweig SD

Abstract
Granulocyte transfusions are a relatively safe adjunctive therapeutic option for patients with chronic granulomatous disease and severe/refractory bacterial or fungal infections. Early initiation, high frequency and sustained therapy is associated with significantly better outcomes.

PMID: 28342916 [PubMed – as supplied by publisher]

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Infection Profile in Chronic Granulomatous Disease: a 23-Year Experience from a Tertiary Care Center in North India.

J Clin Immunol. 2017 Mar 22;:

Authors: Rawat A, Vignesh P, Sharma A, Shandilya JK, Sharma M, Suri D, Gupta A, Gautam V, Ray P, Rudramurthy SM, Chakrabarti A, Imai K, Nonoyama S, Ohara O, Lau YL, Singh S

Abstract
PURPOSE: Chronic granulomatous disease (CGD) is an inherited phagocytic disorder characterized by recurrent infections with usually catalase-positive organisms. Infections in CGD from developing countries are expected to be different from those in the Western countries. We report the profile of infections in children diagnosed with CGD from a tertiary care center in North India.
METHODOLOGY: Case records of children diagnosed with CGD at Pediatric Immunodeficiency Clinic, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India, from August 1993 to April 2016 (23 years) were analyzed.
RESULTS: Thirty-eight children were diagnosed to have CGD. Median follow-up of patients was 2 years (interquartile range 0.75, 6.0). Staphylococcus aureus and Pseudomonas spp. were the two most common causative bacteria isolated. Aspergillus was the most common fungus isolated. The most common organ involved was the lung (94.7%). Liver abscesses were identified in 5 patients (13.2%), and 20 (52.6%) patients had lymphadenitis. Infections with Pseudomonas spp. were high in our cohort (15.7%) compared to the other studies. Infections with some unusual organisms (e.g., Fusarium dimerium and Chryseobacterium gleum) were also seen in our cohort. Children with X-linked CGD presented earlier and also had a greater number of infections as compared to autosomal recessive CGD.
CONCLUSIONS: Various socioeconomic factors coupled with the lack of awareness and paucity of readily available diagnostic facilities for primary immunodeficiencies accounted for a late clinical presentation with severe infections and increased mortality (28.9%) in our cohort. However, mortality was similar in X-linked and autosomal recessive CGD as was the number of fungal infections. The incidence of infections and mortality was significantly lower after initiation of antibacterial and antifungal prophylaxis.

PMID: 28332028 [PubMed – as supplied by publisher]

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Limiting Thymic Precursor Supply Increases the Risk of Lymphoid Malignancy in Murine X-Linked Severe Combined Immunodeficiency.

Mol Ther Nucleic Acids. 2017 Mar 17;6:1-14

Authors: Ginn SL, Hallwirth CV, Liao SH, Teber ET, Arthur JW, Wu J, Lee HC, Tay SS, Hu M, Reddel RR, McCormack MP, Thrasher AJ, Cavazzana M, Alexander SI, Alexander IE

Abstract
In early gene therapy trials for SCID-X1, using γ-retroviral vectors, T cell leukemias developed in a subset of patients secondary to insertional proto-oncogene activation. In contrast, we have reported development of T cell leukemias in SCID-X1 mice following lentivirus-mediated gene therapy independent of insertional mutagenesis. A distinguishing feature in our study was that only a proportion of transplanted γc-deficient progenitors were transduced and therefore competent for reconstitution. We hypothesized that reconstitution of SCID-X1 mice with limiting numbers of hematopoietic progenitors might be a risk factor for lymphoid malignancy. To test this hypothesis, in the absence of transduction, SCID-X1 mice were reconstituted with serially fewer wild-type hematopoietic progenitors. A robust inverse correlation between hematopoietic progenitor cell dose and T-lymphoid malignancy was observed, with earlier disease onset at lower cell doses. Malignancies were of donor origin and carried activating Notch1 mutations. These findings align with emerging evidence that thymocyte self-renewal induced by progenitor deprivation carries an oncogenic risk that is modulated by intra-thymic competition from differentiation-committed cells. Although insertional proto-oncogene activation is required for the development of malignancy in humans, failure of γc-deficient thymocytes to effectively compete with this at-risk cell population may have also contributed to oncogenesis observed in early SCID-X1 trials.

PMID: 28325276 [PubMed – in process]

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Neonatal Group B Streptococcal Disease in Otherwise Healthy Infants: Failure of Specific Neonatal Immune Responses.

Front Immunol. 2017;8:215

Authors: Borghesi A, Stronati M, Fellay J

Abstract
Only a small proportion of newborn infants exposed to a pathogenic microorganism develop overt infection. Susceptibility to infection in preterm infants and infants with known comorbidities has a likely multifactorial origin and can be often attributed to the concurrence of iatrogenic factors, environmental determinants, underlying pathogenic processes, and probably genetic predisposition. Conversely, infection occurring in otherwise healthy full-term newborn infants is unexplained in most cases. Microbial virulence factors and the unique characteristics of the neonatal immune system only partially account for the interindividual variability in the neonatal immune responses to pathogens. We here suggest that neonatal infection occurring in otherwise healthy infants is caused by a failure of the specific protective immunity to the microorganism. To explain infection in term and preterm infants, we propose an extension of the previously proposed model of the genetic architecture of infectious diseases in humans. We then focus on group B streptococcus (GBS) disease, the best characterized neonatal infection, and outline the potential molecular mechanisms underlying the selective failure of the immune responses against GBS. In light of the recent discoveries of pathogen-specific primary immunodeficiencies and of the role of anticytokine autoantibodies in increasing susceptibility to specific infections, we hypothesize that GBS disease occurring in otherwise healthy infants could reflect an immunodeficiency caused either by rare genetic defects in the infant or by transmitted maternal neutralizing antibodies. These hypotheses are consistent with available epidemiological data, with clinical and epidemiological observations, and with the state of the art of neonatal physiology and disease. Studies should now be designed to comprehensively search for genetic or immunological factors involved in susceptibility to severe neonatal infections.

PMID: 28326082 [PubMed – in process]

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Staphylococcus aureus bacteremia in patients with rheumatoid arthritis – data from the prospective INSTINCT cohort.

J Infect. 2017 Mar 17;:

Authors: Joost I, Kaasch A, Pausch C, Peyerl-Hoffmann G, Schneider C, Voll RE, Seifert H, Kern WV, Rieg S

Abstract
OBJECTIVES: Patients with rheumatoid arthritis (RA) are considered to be at increased risk of severe infections. We here describe the clinical characteristics, course and outcome of RA patients with Staphylococcus aureus bacteremia (SAB).
METHODS: We conducted a post hoc analysis of data from a German bi-centre prospective SAB cohort study (period 2006-2014). Patients were followed-up for one year. Primary and secondary outcomes were survival time and osteoarticular infection (OAI).
RESULTS: A total of 1069 patients with SAB were analysed, with 31 patients suffering from RA. RA patients showed significantly more often OAI (15/31 patients, 48% vs. 152/1038, 15%), disseminated infection (12/31, 39% vs. 164/1038, 16%) and severe sepsis/septic shock (12/31, 39% vs. 235/1038, 23%). Day-30 mortality in RA patients was 36% (vs. 19% in non-RA patients, p=0.034), and day 90 mortality was 58% (vs. 32%, p=0.003). Multivariate analyses confirmed RA to be an independent risk factor for death (HR 2.3, 95% CI 1.4-3.7) and OAI (OR 4.2, 95% CI 1.8-9.8).
CONCLUSIONS: Patients with RA exhibit a complicated SAB course and a high mortality, their management is challenging. Adequate antibiotic treatment, prompt invasive diagnostic and therapeutic procedures like joint lavage or surgery are of pivotal importance. Joint damage due to RA may confer a higher risk of acquiring OAI than immunosuppression.

PMID: 28322887 [PubMed – as supplied by publisher]

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Early intracellular trafficking of Granulibacter bethesdensis in human macrophages.

Infect Immun. 2017 Mar 20;:

Authors: Chu J, Smelkinson MG, Dorward DW, Zarember KA, Gallin JI

Abstract
Granulibacter bethesdensis is a Gram-negative bacterium that infects patients with Chronic Granulomatous Disease (CGD), a primary immunodeficiency marked by a defect in NOX2, the phagocyte nicotinamide adenine dinucleotide phosphate oxidase. Previous studies have shown that NOX2 is essential for killing of G. bethesdensis by neutrophils and monocytes and that bacteriostatic activity of monocyte derived macrophages (MDM) requires NOX2 and IFNγ-pretreatment. To determine if G. bethesdensis evades phagolysosomal killing, a host defense pathway intact in both normal and CGD MDM, or occupies a distinct intracellular niche in CGD MDM, we assessed the trafficking patterns of this organism. We observed co-localization of G. bethesdensis with an early endosome antigen 1 (EEA1)-positive compartment followed by co-localization with lysosomal-associated membrane protein 1 (LAMP1)-positive and lysotracker-positive late phagosomes that was similar in both normal and CGD MDM. Despite localization to acidified late phagosomes, viable G. bethesdensis were recovered from viable MDM in numbers greater than initial input up to 6 days after infection. G. bethesdensis remains, and in some cases appears to divide, within a membrane-bound compartment for the entire 6-day time course. These findings indicate that this organism resists both oxygen-dependent and oxygen-independent phagolysosomal antimicrobial systems of human macrophages.

PMID: 28320834 [PubMed – as supplied by publisher]

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[Serratia infections, should we think about primary immunodeficiencies?]

Arch Argent Pediatr. 2017 Apr 01;115(2):e108-e111

Authors: Montaner Ramón A, Murillo Sanjuán L, Martínez Faci C, Guerrero Laleona C, Rodríguez-Vigil Iturrate C

Abstract
Chronic granulomatous disease (CGD) is a primary immunodeficiency with an incidence of 1/200,000-250,000 live births. CGD affects mainly male patients, most of the mutations being X-linked, and autosomal recessive forms occur more frequently in communities with greater numbers of consanguineous marriages. CGD is characterized by sensitivity to recurrent and severe bacterial and fungal infections, with formation of granulomas due to the inability of phagocytes to generate reactive oxygen compounds, necessary for the intracellular death of phagocytic microorganisms. We report three cases of CGD in which Serratia marcescens was isolated, and after detailed anamnesis and performance of neutrophil function tests, a molecular diagnosis of the disease was reached. CGD can be manifested in a wide variety of ways, so that high suspicion and a meticulous anamnesis are essential to reach a diagnosis.

PMID: 28318195 [PubMed – in process]

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Good Laboratory Practice Preclinical Safety Studies for GSK2696273 (MLV Vector-Based Ex Vivo Gene Therapy for Adenosine Deaminase Deficiency Severe Combined Immunodeficiency) in NSG Mice.

Hum Gene Ther Clin Dev. 2017 Mar;28(1):17-27

Authors: Carriglio N, Klapwijk J, Hernandez RJ, Vezzoli M, Chanut F, Lowe R, Elena D, Nord M, Albertini P, Cristofori P, Richards J, Staton H, Appleby J, Aiuti A, Sauer AV

Abstract
GSK2696273 (autologous CD34+ cells transduced with retroviral vector that encodes for the human adenosine deaminase [ADA] enzyme) is a gamma-retroviral ex vivo gene therapy of bone marrow-derived CD34+ cells for the treatment of adenosine deaminase deficiency severe combined immunodeficiency (ADA-SCID). ADA-SCID is a severe monogenic disease characterized by immunologic and nonimmunologic symptoms. Bone-marrow transplant from a matched related donor is the treatment of choice, but it is available for only a small proportion of patients. Ex vivo gene therapy of patient bone-marrow CD34+ cells is an alternative treatment. In order to prepare for a marketing authorization application in the European Union, preclinical safety studies in mice were requested by the European Medicines Agency (EMA). A pilot study and a main biodistribution study were performed according to Good Laboratory Practice (GLP) at the San Raffaele Telethon Institute for Gene Therapy test facility. In the main study, human umbilical cord blood (UCB)-derived CD34+ cells were transduced with gamma-retroviral vector used in the production of GSK2696273. Groups of 10 male and 10 female NOD-SCID gamma (NSG) mice were injected intravenously with a single dose of transduced- or mock-transduced UCB CD34+ cells, and they were observed for 4 months. Engraftment and multilineage differentiation of blood cells was observed in the majority of animals in both groups. There was no significant difference in the level of chimerism between the two groups. In the gene therapy group, vector was detectable in lymphohemopoietic and nonlymphohemopoietic tissues, consistent with the presence of gene-modified human hematopoietic donor cells. Given the absence of relevant safety concerns in the data, the nonclinical studies and the clinical experience with GSK2696273 supported a successful application for market authorization in the European Union for the treatment of ADA-SCID patients, for whom no suitable human leukocyte antigen-matched related donor is available.

PMID: 28319446 [PubMed – in process]

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Evaluation of the Safety, Tolerability, and Pharmacokinetics of Gammaplex(®) 10% Versus Gammaplex(®) 5% in Subjects with Primary Immunodeficiency.

J Clin Immunol. 2017 Mar 18;:

Authors: Wasserman RL, Melamed IR, Stein MR, Jolles S, Norton M, Moy JN, GMX07 Study Group

Abstract
PURPOSE: This phase 3, multicenter, open-label, randomized, two-period, crossover bioequivalence trial evaluated the safety, tolerability, and pharmacokinetics of intravenous immunoglobulins (IVIGs) Gammaplex 5% and Gammaplex 10% in 33 adults and 15 children with primary immunodeficiency diseases (PIDs).
METHODS: Eligible adults received five Gammaplex 5% infusions followed by five Gammaplex 10% infusions, or vice versa, stratified by a 21- or 28-day dosing regimen. Pediatric subjects received five Gammaplex 10% infusions only.
RESULTS: The primary objective, to demonstrate the bioequivalence of Gammaplex 10% and Gammaplex 5% at the 28-day dosing interval, was met based on the Gammaplex 10%/Gammaplex 5% ratio of area under the concentration versus time curve (AUC0-28) values. Throughout the study, total immunoglobulin G trough levels were well maintained, with total values generally ≥600 mg/dL (minimum level for study inclusion). At the dosing schedules and infusion rates used in this study, safety and tolerability were comparable and acceptable in adult and pediatric PID subjects treated with Gammaplex 10% and 5%.
CONCLUSIONS: In this study, the first direct comparison of 5% IVIG and 10% IVIG products in PID subjects, the pharmacokinetic analysis demonstrated bioequivalence of Gammaplex 10% and Gammaplex 5% at the 28-day dosing interval. The Gammaplex 10% formulation was safe and well tolerated in pediatric and adult PID subjects. Based on the results from this bridging study in PID subjects, Gammaplex 10% could be expected to have a therapeutic effect similar to the licensed Gammaplex 5%, which has demonstrated efficacy and tolerability in patients with PID and idiopathic thrombocytopenic purpura.

PMID: 28316003 [PubMed – as supplied by publisher]

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Mutations in PIK3R1 can lead to APDS2, SHORT syndrome or a combination of the two.

Clin Immunol. 2017 Mar 13;:

Authors: Bravo García-Morato M, García-Miñaúr S, Molina Garicano J, Santos Simarro F, López-Grandos E, Ferreira Cerdán A, Rodríguez Pena R

Abstract
Mutations in PIK3R1 gene have been associated to two different conditions: a primary immunodeficiency, called APDS2, of recent description and SHORT syndrome. 47 patients with APDS2 have been reported to date, only one of them sharing both PIK3R1-related phenotypes. Here we describe two more patients affected by APDS2 and SHORT syndrome, which highlights that this association may not be so infrequent. We recommend that patients with mutations in PIK3R1 gene should be assessed by both clinical immunologists and clinical geneticists.

PMID: 28302518 [PubMed – as supplied by publisher]

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