Manish Butte

Bacille Calmette-Guerin Complications in Newly Described Primary Immunodeficiency Diseases: 2010-2017.

Front Immunol. 2018;9:1423

Authors: Nunes-Santos CJ, Rosenzweig SD

Abstract
Bacille Calmette-Guerin (BCG) vaccine is widely used as a prevention strategy against tuberculosis. BCG is a live vaccine, usually given early in life in most countries. While safe to most recipients, it poses a risk to immunocompromised patients. Several primary immunodeficiency diseases (PIDD) have been classically associated with complications related to BCG vaccine. However, a number of new inborn errors of immunity have been described lately in which little is known about adverse reactions following BCG vaccination. The aim of this review is to summarize the existing data on BCG-related complications in patients diagnosed with PIDD described since 2010. When BCG vaccination status or complications were not specifically addressed in those manuscripts, we directly contacted the corresponding authors for further clarification. We also analyzed data on other mycobacterial infections in these patients. Based on our analysis, around 8% of patients with gain-of-function mutations in STAT1 had mycobacterial infections, including localized complications in 3 and disseminated disease in 4 out of 19 BCG-vaccinated patients. Localized BCG reactions were also frequent in activated PI3Kδ syndrome type 1 (3/10) and type 2 (2/18) vaccinated children. Also, of note, no BCG-related complications have been described in either CTLA4 or LRBA protein-deficient patients; and not enough information on BCG-vaccinated NFKB1 or NFKB2-deficient patients was available to drive any conclusions about these diseases. Despite the high prevalence of environmental mycobacterial infections in GATA2-deficient patients, only one case of BCG reaction has been reported in a patient who developed disseminated disease. In conclusion, BCG complications could be expected in some particular, recently described PIDD and it remains a preventable risk factor for pediatric PIDD patients.

PMID: 29988375 [PubMed]

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Primary Immunodeficiencies Unravel the Role of IL-2/CD25/STAT5b in Human Natural Killer Cell Maturation.

Front Immunol. 2018;9:1429

Authors: Caldirola MS, Rodríguez Broggi MG, Gaillard MI, Bezrodnik L, Zwirner NW

Abstract
Natural killer (NK) cells play a pivotal role during immunity against viruses and circumstantial evidence also indicates that they can protect the host against developing tumors. Peripheral blood NK cells comprise CD56brightCD16lo/- cells that constitutively express CD25 (IL-2Rα) and CD56dimCD16hi cells that express CD25 upon activation. Using NK cells from two patients, one with a primary immunodeficiency characterized by a homozygous mutation in CD25 (born in year 2007 and studied since she was 3 years old) and one with a homozygous mutation in STAT5b (born in year 1992 and studied since she was 10 years old), we observed that the absence of IL-2 signaling through CD25 promotes the accumulation of CD56brightCD16high NK cells, and that CD56brightCD16lo, CD56brightCD16high, and CD56dimCD16high NK cells of this patient exhibited higher content of perforin and granzyme B, and proliferation capacity, compared to healthy donors. Also, CD56bright and CD56dim NK cells of this patient exhibited a reduced IFN-γ production in response to cytokine stimulation and increased degranulation against K562 cells. Also, the CD25-deficient patient presented a lower frequency of terminally differentiated NK cells in the CD56dimCD16hi NK subpopulation compared to the HD (assessed by CD57 and CD94 expression). Remarkably, CD56dimCD16high NK cells from both patients exhibited notoriously higher expression of CD62L compared to HD, suggesting that in the absence of IL-2 signaling through CD25 and STAT5b, NK cells fail to properly downregulate CD62L during their transition from CD56brightCD16lo/- to CD56dimCD16hi cells. Thus, we provide the first demonstration about the in vivo requirement of the integrity of the IL-2/CD25/STAT5b axis for proper human NK cell maturation.

PMID: 29988287 [PubMed]

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Familial inheritance and screening of first-degree relatives in common variable immunodeficiency and immunoglobulin A deficiency patients.

Int J Immunopathol Pharmacol. 2018 Jan-Dec;32:2058738418779458

Authors: Karaca NE, Severcan EU, Bilgin BG, Azarsiz E, Akarcan S, Gunaydın NC, Gulez N, Genel F, Aksu G, Kutukculer N

Abstract
Common variable immunodeficiency (CVID) and immunoglobulin A deficiency (IgAD) are the most prevalent primary immunodeficiency disorders. High rates of familial inheritance have been described in CVID and IgAD, but it is unknown in different ethnic populations. We aimed to determine the prevalence of familial cases and whether they showed more severe clinical characteristics than sporadic ones in Turkish patients. A total of 40 CVID and 70 IgAD patients and their 251 first-degree relatives (FDRs) were evaluated. Demographic, clinical, and laboratory data were reviewed. A familial case was defined as a patient with at least one affected FDR (A-FDR). The rate of parental consanguinity was 19.1%. There were 37 familial cases (37/110) (33.6%) with at least one A-FDR. There were 48 A-FDRs who had immunoglobulins lower than age-related normals (48/251) (19.1%). Pulmonary infections were significantly higher in familial cases. To our knowledge, this study includes the highest number of CVID/IgAD patients and their FDRs in literature. Familial cases are at least 30% of the IgAD and CVID patients, and they have more frequent lower respiratory tract infections than sporadic ones, so these patients have to be evaluated depending on their being familial or sporadic for better management. The risk of carrying any immunologic alterations in relatives of patients with IgAD and CVID is approximately 20%. Although most A-FDRs are asymptomatic, considering the risk of progression to CVID by age, we highly recommend routine screening for FDRs.

PMID: 29978731 [PubMed – in process]

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Validation of a high performance functional assay for individual radiosensitivity in pediatric oncology: a prospective cohort study (ARPEGE).

BMC Cancer. 2018 Jul 06;18(1):719

Authors: Bernier-Chastagner V, Hettal L, Gillon V, Fernandes L, Huin-Schohn C, Vazel M, Tosti P, Salleron J, François A, Cérimèle E, Perreira S, Peiffert D, Chastagner P, Vogin G

Abstract
BACKGROUND: Approximately 900 children/adolescents are treated with radiotherapy (RT) every year in France. However, among the 80% of survivors, the cumulative incidence of long-term morbidity – including second malignancies – reach 73.4% thirty years after the cancer diagnosis. Identifying a priori the subjects at risk for RT sequelae is a major challenge of paediatric oncology. Individual radiosensitivity (IRS) of children/adolescents is unknown at this time, probably with large variability depending on the age when considering the changes in metabolic functions throughout growth. We previously retrospectively showed that unrepaired DNA double strand breaks (DSB) as well a delay in the nucleoshuttling of the pATM protein were common features to patients with RT toxicity. We aim to validate a high performance functional assay for IRS prospectively.
METHODS/DESIGN: ARPEGE is a prospective open-label, non-randomized multicentre cohort study. We will prospectively recruit 222 children/adolescents who require RT as part of their routine care and follow them during 15 years. Prior RT we will collect blood and skin samples to raise a primary dermal fibroblast line to carry out in blind the IRS assay. As a primary objective, we will determine its discriminating ability to predict the occurrence of unusual early skin, mucous or hematological toxicity. The primary endpoint is the measurement of residual double-strand breaks 24 h after ex vivo radiation assessed with indirect immunofluorescence (γH2AX marker). Secondary endpoints include the determination of pATM foci at 10 min and 1 h (pATM marker) and micronuclei at 24 h. In parallel toxicity including second malignancies will be reported according to NCI-CTCAE v4.0 reference scale three months of the completion of RT then periodically during 15 years. Confusion factors such as irradiated volume, skin phototype, previous chemotherapy regimen, smoking, comorbities (diabetes, immunodeficiency, chronic inflammatory disease…) will be reported.
DISCUSSION: ARPEGE would be the first study to document the distribution of IRS in the pediatric subpopulation. Screening hypersensitive patients would be a major step forward in the management of cancers, opening a way to personalized pediatric oncology.
TRIAL REGISTRATION: ID-RCB number: 2015-A00975-44, ClinicalTrials.gov Identifier: NCT02827552 Registered 7/6/2016.

PMID: 29976172 [PubMed – in process]

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Endovascular Management of a Rare Case of Pediatric Vertebral Artery Mycotic Aneurysm: A Case Report.

Pediatr Neurosurg. 2018 Jul 04;:1-5

Authors: Nadarajah J, Sebastian LJD, Jain N, Gaikwad SB, Jauhari P, Saini A

Abstract
Pediatric posterior-circulation aneurysms are uncommon, difficult-to-treat lesions associated with significant morbidity and mortality. Infections and trauma are important risk factors in children. Here, we present a 10-year-old boy with a lower respiratory tract infection, rapidly progressive right-neck swelling, and weakness of the right upper limb. Imaging revealed a partially thrombosed right vertebral-artery pseudoaneurysm with multiple cavitory lung lesions. Subsequent laboratory work-up showed underlying primary immunodeficiency disorder (chronic granulomatous disease). The aneurysm was successfully managed by parent-artery occlusion. The child made a complete recovery without neurological sequelae.

PMID: 29975956 [PubMed – as supplied by publisher]

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Efficacy-safety of Facilitated Subcutaneous Immunoglobulin in Immunodeficiency Due to Hematological Malignancies. A Single-Center Retrospective Analysis.

Anticancer Res. 2018 Jul;38(7):4187-4191

Authors: Dimou M, Iliakis T, Maltezas D, Bitsani A, Kalyva S, Koudouna A, Kotsanti S, Petsa P, Papaioannou P, Kyrtsonis MC, Panayiotidis P

Abstract
BACKGROUND/AIM: Hematological malignancies are frequently complicated by secondary immunodeficiency (SID). Immunoglobulin replacement with intravenous gamma globulins (IVIg) reduces infection incidence, antibiotics’ need and hospitalization days in these patients. Facilitated subcutaneous immunoglobulin replacement (fSCIg) has been studied in primary immunodeficiency patients and is equally efficacious with several advantages (self-administration, same bioavailability, long infusion intervals, fewer adverse drug reactions). fSCIg has been less extensively studied in SID. We present our retrospective single-center data of fSCIg administration to hematological patients with SID, focusing on efficacy and safety issues.
PATIENTS AND METHODS: Overall, 33 hematological patients with hypogammaglobulinemia were treated with fSCIg according to ESMO 2015 guidelines, between mid-October 2015 and mid-January 2018 in our Department.
RESULTS: The infection rate was very low (18.1%). Shorter infusion intervals further reduced it. ADRs were rare (9%) and mild (grade 1). fSCIg managed to reduce the everyday nursery/hospital burden of our tertiary hospital.
CONCLUSION: fSCIg compares favorably to IVIg replacement in SID patients.

PMID: 29970548 [PubMed – in process]

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Disentangling the link between supplemental feeding, population density, and the prevalence of pathogens in urban stray cats.

PeerJ. 2018;6:e4988

Authors: Hwang J, Gottdenker NL, Oh DH, Nam HW, Lee H, Chun MS

Abstract
Background: Supplemental feeding of free-roaming animals, including wildlife and feral or stray animals, is well known to have a substantial impact on various aspects of animal ecology including habitat use, activity patterns, and host-pathogen interactions. Among them, an increased population density (PD) of animals receiving supplemental food raises concerns regarding the transmission of pathogens in these host populations. The primary aim of this study was to investigate how supplemental feeding is associated with host PD and prevalence of pathogens with different transmission modes in urban stray cats. We hypothesized that supplemental feeding would be positively associated with host PD and the prevalence of pathogens with density-dependent transmission modes compared with pathogens with transmission modes that are considered relatively density-independent.
Methods: This study was conducted in six districts in Seoul, Republic of Korea which were selected based on different degrees of supplemental feeding and cat caretaker activity (CCA). The PD of stray cats was estimated by mark-recapture surveys. Stray cat blood samples (N = 302) were collected from stray cats by local animal hospitals from each district performing the trap-neuter-release which tested for eight pathogens with different transmission modes (feline immunodeficiency virus, feline leukemia virus (FeLV), feline panleukopenia virus, feline calicivirus, feline herpesvirus-1, Bartonella henselae, hemoplasma, and Toxoplasma gondii) with molecular or serological assays. Associations between the prevalence of each pathogen and PD, CCA, and sex of cats were statistically analyzed.
Results: In contrast to initial predictions, the cat PD was generally higher in low CCA districts. The prevalence of (FeLV), which is transmitted through direct contact, was significantly higher in areas with a high CCA, conforming to our hypothesis. On the other hand, the prevalence of feline parvovirus, which can be spread by environmental transmission, was higher in low CCA districts. The remaining six pathogens did not show any association with the CCA; however, they had a unique association with the PD or the sex of the stray cats.
Discussion: Our findings suggest that in addition to influencing the PD, supplemental feeding may affect the prevalence of pathogens in urban animals by mechanisms such as increased aggregation and/or altered foraging strategies, with different consequences depending on the transmission mode of each pathogen.

PMID: 29967720 [PubMed]

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Hematological Malignancies Associated With Primary Immunodeficiency Disorders.

Clin Immunol. 2018 Jun 29;:

Authors: Lucy D, Eyal G

Abstract
Primary Immunodeficiency disorders (PID) have been increasingly recognized in association with hematologic malignancies. To better appreciate this association, a systemic search of the Ovid MEDLINE database was performed with terms related of hematologic malignancies and all PID described in the 2017 International Union of Immunological Societies Expert Committee for Primary Immunodeficiency. More than 60 PID distinct PID, caused by cell-intrinsic and extrinsic mechanisms were associated with diverse hematologic malignancies. These occurred among all subgroups of PID, including syndromic and non-syndromic combined PID affecting cellular and humoral immunity, predominantly antibody deficiencies and defects of immune regulation. In addition, defects in phagocyte numbers or functions, or in innate immunity were associated with hematologic malignancies. Increased awareness and vigilance for the possibility of malignancy is required when caring for patients with PID.

PMID: 29966714 [PubMed – as supplied by publisher]

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