Research

Health-Related Quality of Life and Emotional Health in X-Linked Carriers of Chronic Granulomatous Disease in the United Kingdom.

J Clin Immunol. 2019 Mar 13;:

Authors: Battersby AC, Braggins H, Pearce MS, McKendrick F, Campbell M, Burns S, Cale CM, Goldblatt D, Gennery AR

Abstract
X-linked chronic granulomatous disease (XL-CGD), a rare primary immunodeficiency due to a defect in the gp91phox NADPH oxidase subunit, results in recurrent, severe infection, inflammation, and autoimmunity. Patients have an absent, or significantly reduced, neutrophil oxidative burst. Due to lyonization, XL-CGD carriers have a dual population of functional and non-functional phagocytes and experience a range of symptoms including increased risk of autoimmunity, fatigue, and infection. Patients with CGD have poorer quality of life (QoL) than normal controls. We evaluated QoL and psychological health in UK XL-CGD carriers. Recruited participants completed the Medical Outcomes Study Short Form 36 version 2 (SF-36 V2), providing an overall score for mental and physical health. Psychological health was assessed using the Hospital Anxiety and Depression Scale (HADS) questionnaire. Seventy-five XL-CGD carriers were recruited from 62 families, median age 43 years (range 3-77). Fifty-six were mothers, 6 grandmothers, and 13 siblings. Sixty-two completed the SF36v2 and had reduced QoL scores compared with adult CGD patients and a UK age-matched female control cohort, indicating a reduced QoL. Sixty-one completed a HADS questionnaire. Over 40% experienced moderate or greater levels of anxiety with only one third being classified as normal. Higher anxiety scores significantly correlated with higher depression scores, lower self-esteem, presence of joint or bowel symptoms, and higher levels of fatigue (p < 0.05). This is the first study to evaluate QoL of XL-CGD carriers, and demonstrates high rates of anxiety and significantly reduced QoL scores. XL-CGD carriers should be considered as potential patients and pro-actively assessed and managed.

PMID: 30868346 [PubMed – as supplied by publisher]

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Cutaneous granulomas with primary immunodeficiency in children: a report of 17 new patients and a review of the literature.

J Eur Acad Dermatol Venereol. 2019 Mar 14;:

Authors: Leclerc-Mercier S, Moshous D, Neven B, Mahlaoui N, Martin L, Pellier I, Blanche S, Picard C, Fischer A, Perot P, Eloit M, Fraitag S, Bodemer C

Abstract
BACKGROUND: Pediatric cutaneous granulomas with primary immunodeficiency (PID) is a rare condition. The physiopathology is unclear, and treatment is challenging. We report on 17 pediatric cases and review the literature.
OBJECTIVES: To make dermatologists and dermatopathologists aware of the diagnostic value of skin granulomas in pediatric PID.
METHODS: We collected data on 17 patients with cutaneous granulomas and PID registered with us, and also reviewed 33 cases from the literature.
RESULTS: Cutaneous granuloma was the presenting feature of the PID in 15 of the 50 collated cases. The lesions presented as red-brownish nodules and infiltrated ulcerative plaques, predominantly on the face and limbs. Scleroderma-like infiltration on a single limb was observed in 10% of the cases. The associated PID was ataxia-telangiectasia (52%), combined immunodeficiency (24%), cartilage-hair hypoplasia (6%), and other subtypes (18%). The granulomas were mostly sarcoidal, tuberculoid, palisaded or undefined subtypes. In some patients, several different histopathologic granulomatous patterns were found in the same biopsy. Some granulomas were associated with the presence of a vaccine strain of rubella virus.
CONCLUSION: Cutaneous granulomas associated with a PID have a variable clinical presentation. A PID can be suspected when crusty, brownish lesions are found on the face or limbs. The concomitant presence of several histologic subtypes in a single patient is suggestive of a PID. This article is protected by copyright. All rights reserved.

PMID: 30869812 [PubMed – as supplied by publisher]

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How I manage patients with Wiskott Aldrich syndrome.

Br J Haematol. 2019 Mar 12;:

Authors: Rivers E, Worth A, Thrasher AJ, Burns SO

Abstract
Wiskott Aldrich syndrome (WAS) is a primary immunodeficiency disease resulting in recurrent infections, eczema and microthrombocytopaenia. In its classical form, significant combined immune deficiency, autoimmune complications and risk of haematological malignancy necessitate early correction with stem cell transplantation or gene therapy. A milder form, X-linked thrombocytopaenia (XLT), shares similar bleeding risk from thrombocytopaenia but is not associated with other significant clinical features and is generally managed conservatively. Here, we detail our approach to the diagnosis and treatment of classical WAS and XLT.

PMID: 30864154 [PubMed – as supplied by publisher]

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Novel Diagnostic Tool for p47 phox -Deficient Chronic Granulomatous Disease Patient and Carrier Detection.

Mol Ther Methods Clin Dev. 2019 Jun 14;13:274-278

Authors: Wrona D, Siler U, Reichenbach J

Abstract
Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by mutations of the phagocytic nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Autosomal recessive p47 phox -deficient CGD (p47 phox CGD) is the second most frequent form of the disease in western countries, and more than 94% of patients have a disease-causing dinucleotide deletion (ΔGT) in the neutrophil cytosolic factor 1 (NCF1) gene. The ΔGT mutation is most likely transferred onto the NCF1 from one of its two pseudogenes co-localized on the same chromosome. The presence of NCF1 pseudogenes in healthy individuals makes the genetic diagnostics of ΔGT p47 phox CGD challenging, as it requires the distinction between ΔGT in NCF1 and in the two pseudogenes. We have developed a diagnostic tool for the identification of p47 phox CGD based on PCR co-amplification of NCF1 and its pseudogenes, followed by band intensity quantification of restriction fragment length polymorphism products. The single-day, reliable p47 phox CGD diagnostics allow for robust discrimination of homozygous ΔGT p47phox CGD patients from heterozygous carriers and healthy individuals, as well as for monitoring gene therapy efficacy.

PMID: 30859112 [PubMed]

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Rethinking newborn screening for severe combined immunodeficiency: Lessons from an international partnership for patients with primary immunodeficiencies in Pakistan.

Clin Immunol. 2019 Mar 08;:

Authors: Wallace JG, Tipu HN, Stafstrom K, Alosaimi MF, Massaad MJ, Bainter W, Geha RS, Chou J

PMID: 30858051 [PubMed – as supplied by publisher]

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Rationale and design of a prospective, multicentre, randomised, conventional treatment-controlled, parallel-group trial to evaluate the efficacy and safety of ulinastatin in preventing acute respiratory distress syndrome in high-risk patients.

BMJ Open. 2019 Mar 07;9(3):e025523

Authors: Wang Z, Tao L, Yan Y, Zhu X

Abstract
INTRODUCTION: Acute respiratory distress syndrome (ARDS) is challenging in the intensive care unit (ICU). Although pharmacotherapy for ARDS has gained increasing attention, most trials have yielded negative results. Patients with ARDS have usually been recruited as subjects; the inflammatory reaction has already expanded into a cascade at this point, and its severity is sufficient to damage the lung parenchyma. This raises the question of whether early treatment can prevent ARDS and the associated lung injury. We hypothesise that ARDS is preventable in high-risk patients by administration of ulinastatin as an anti-inflammatory drug before ARDS onset, and we are performing a study to test ulinastatin, a protease inhibitor, versus treatment-as-usual in a group of patients at increased risk for ARDS.
METHODS AND ANALYSIS: This report presents the protocol for a multicentre, randomised, conventional treatment-controlled, parallel group study to prevent the development of ARDS using ulinastatin in high-risk patients. The study population will comprise patients at risk of ARDS in the ICU (≥18 years of age and Lung Injury Prediction Score of >4); patients with confirmed ARDS and some other conditions (immunodeficiency, use of some drugs, etc.) will be excluded. The enrolled patients will be randomly allocated to an ulinastatin group (ulinastatin will be intravenously administered every 8 hours for a total of 600 000 U/day for five consecutive days) or control group. The efficacy of ulinastatin in preventing ARDS development will be evaluated by the incidence rate of ARDS as the primary outcome; the secondary outcomes include the severity of ARDS, clinical outcome, extrapulmonary organ function and adverse events incurred by ulinastatin. Based on the results of preliminary studies and presuming the incidence of ARDS will decrease by 9% in high-risk patients, 880 patients are needed to obtain statistical power of 80%.
ETHICS AND DISSEMINATION: This study has been approved by the Peking University Third Hospital Medical Science Research Ethics Committee. The findings will be published in peer-reviewed journals and presented at national and international conferences.
TRIAL REGISTRATION NUMBER: NCT03089957; Pre-results.

PMID: 30850411 [PubMed – in process]

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A synonymous splice site mutation in IL2RG gene causes late-onset combined immunodeficiency.

Int J Hematol. 2019 Mar 08;:

Authors: Yamashita M, Wakatsuki R, Kato T, Okano T, Yamanishi S, Mayumi N, Tanaka M, Ogura Y, Kanegane H, Nonoyama S, Imai K, Morio T

Abstract
X-Linked severe combined immunodeficiency (X-SCID) is a severe form of primary immunodeficiency characterized by absence of T cells and NK cells. X-SCID is caused by a loss-of-function mutation in the IL2RG gene that encodes common gamma chain (γc), which plays an essential role in lymphocyte development. We report the first case of hypomorphic X-SCID caused by a synonymous mutation in the IL2RG gene leading to a splice anomaly, in a family including two patients with diffuse cutaneous warts, recurrent molluscum contagiosum, and mild respiratory infections. The mutation caused aberrant splicing of IL2RG mRNA, subsequently resulted in reduced γc expression. The leaky production of normally spliced IL2RG mRNA produced undamaged protein; thus, T cells and NK cells were generated in the patients. Functional assays of the patients’ T cells and NK cells revealed diminished cytokine response in the T cells and absent cytokine response in the NK cells. In addition, the TCR repertoire in these patients was limited. These data suggest that a fine balance between aberrant splicing and leaky production of normally spliced IL2RG mRNA resulted in late-onset combined immunodeficiency in these patients.

PMID: 30850927 [PubMed – as supplied by publisher]

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Chronic Cholangiopathy Associated with Primary Immune Deficiencies Can Be Resolved by Effective Hematopoietic Stem Cell Transplantation.

J Pediatr. 2019 Mar 05;:

Authors: Hadžić N, Nademi Z, Deheragoda M, Zen Y, Elfeky R, Worth A, Veys P, Mieli-Vergani G, Davies EG

Abstract
OBJECTIVES: To investigate effects and outcome of hematopoietic stem cell transplantation (HSCT) on sclerosing cholangitis, in pediatric patients with different primary immunodeficiencies (PIDs).
STUDY DESIGN: From databases in 2 tertiary centers for immunodeficiencies and liver disease, we have identified children with PIDs and sclerosing cholangitis, who have paired clinical, radiologic, and histologic information before and after HSCT and studied their clinical progress and outcome.
RESULTS: Seven of 13 children (53.8%) died at a median interval of 4 months (range, 3 months-5 years) after HSCT. However, 6 surviving children (46.2%) with different PIDs and less severe cholangiopathies showed an improvement in markers of liver injury within months of successful unrelated reduced intensity conditioning HSCT. The repeated native liver biopsy, performed in 4 patients at a median of 96 (range, 4-144) months post-HSCT, showed a considerable improvement. Biochemical markers of liver function in the survivors completely normalized after a median of 13 months (range, 2-48). All patients continue to have a mildly dilated extrahepatic biliary system on ultrasonography with no intrahepatic ductal changes on magnetic resonance cholangiography after a follow-up of median 18 years (range, 2-20).
CONCLUSIONS: Effective HSCT has the potential to improve biochemical and histologic features of cholangiopathy in children with PIDs, presumably by clearance of chronic infection following establishment of immune competence. However, careful patient selection is critical as advanced liver injury is often associated with serious complications and mortality.

PMID: 30850087 [PubMed – as supplied by publisher]

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BAFF-driven B cell hyperplasia underlies lung disease in common variable immunodeficiency.

JCI Insight. 2019 Mar 07;4(5):

Authors: Maglione PJ, Gyimesi G, Cols M, Radigan L, Ko HM, Weinberger T, Lee BH, Grasset EK, Rahman AH, Cerutti A, Cunningham-Rundles C

Abstract
BACKGROUND: Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency and is frequently complicated by interstitial lung disease (ILD) for which etiology is unknown and therapy inadequate.
METHODS: Medical record review implicated B cell dysregulation in CVID ILD progression. This was further studied in blood and lung samples using culture, cytometry, ELISA, and histology. Eleven CVID ILD patients were treated with rituximab and followed for 18 months.
RESULTS: Serum IgM increased in conjunction with ILD progression, a finding that reflected the extent of IgM production within B cell follicles in lung parenchyma. Targeting these pulmonary B cell follicles with rituximab ameliorated CVID ILD, but disease recurred in association with IgM elevation. Searching for a stimulus of this pulmonary B cell hyperplasia, we found B cell-activating factor (BAFF) increased in blood and lungs of progressive and post-rituximab CVID ILD patients and detected elevation of BAFF-producing monocytes in progressive ILD. This elevated BAFF interacts with naive B cells, as they are the predominant subset in progressive CVID ILD, expressing BAFF receptor (BAFF-R) within pulmonary B cell follicles and blood to promote Bcl-2 expression. Antiapoptotic Bcl-2 was linked with exclusion of apoptosis from B cell follicles in CVID ILD and increased survival of naive CVID B cells cultured with BAFF.
CONCLUSION: CVID ILD is driven by pulmonary B cell hyperplasia that is reflected by serum IgM elevation, ameliorated by rituximab, and bolstered by elevated BAFF-mediated apoptosis resistance via BAFF-R.
FUNDING: NIH, Primary Immune Deficiency Treatment Consortium, and Rare Disease Foundation.

PMID: 30843876 [PubMed – in process]

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