Research

Increased Incidence of Fatigue in Patients with Primary Immunodeficiency Disorders: Prevalence and Associations Within the US Immunodeficiency Network Registry.

J Clin Immunol. 2017 Jan 26;:

Authors: Hajjar J, Guffey D, Minard CG, Orange JS

Abstract
INTRODUCTION: Patients with primary immunodeficiency (PID) often report fatigue, yet this symptom has not been studied in PID. Fatigue affects 6-7.5% of healthy adults. The goal of this study is to estimate the prevalence of fatigue in patients with PID and investigate its associated factors.
METHODS: We analyzed 2537 PID patients registered in USIDNET to determine responses to the field “fatigue” in the core registry form. Demographics, immune phenotypes, and comorbid conditions were compared between fatigued and non-fatigued patients to identify relevant associations and potential drivers. A focused analysis was performed for patients with predominantly antibody deficiency disorders (PADs).
RESULTS: Fatigue was reported in 25.9% (95% CI 23.7-28.3) of PAD patients, compared to 6.4% (95% CI 4.9-8.2) of non-PAD. Patients with common variable immunodeficiency (CVID) had the highest prevalence of fatigue (p < 0.001) among all PID diagnoses. Other factors that were associated with a higher rate of fatigue among PAD patients included female sex, higher BMI, depression, bronchiectasis, and autoimmunity. Additionally, fatigued PAD patients had lower absolute lymphocyte, CD3, CD4, and CD8 counts compared to non-fatigued patients.
CONCLUSION: Our findings suggest that fatigue is overrepresented in PAD patients. Prospective studies to estimate prevalence, risk factors, and fatigue etiology in PID are warranted, so therapeutic interventions can be considered.

PMID: 28124237 [PubMed – as supplied by publisher]

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The plethora, clinical manifestations and treatment options of autoimmunity in patients with primary immunodeficiency.

Turk Pediatri Ars. 2016 Dec;51(4):186-192

Authors: Barış HE, Kıykım A, Nain E, Özen AO, Karakoç-Aydıner E, Barış S

Abstract
AIM: Although the association between primary immunodeficiency and autoimmunity is already well-known, it has once again become a topic of debate with the discovery of newly-defined immunodeficiencies. Thus, investigation of the mechanisms of development of autoimmunity in primary immunodefficiency and new target-specific therapeutic options has come to the fore. In this study, we aimed to examine the clinical findings of autoimmunity, autoimmunity varieties, and treatment responses in patients who were genetically diagnosed as having primary immunodeficiency.
MATERIAL AND METHODS: The files of patients with primary immunodeficiency who had clinical findings of autoimmunity, who were diagnosed genetically, and followed up in our clinic were investigated. The demographic and clinical features of the patients and their medical treatments were evaluated.
RESULTS: Findings of autoimmunity were found in 30 patients whose genetic mutations were identified. The mean age at the time of the first symptoms was 8.96±14.64 months, and the mean age of receiving a genetic diagnosis was 82.55±84.71 months. The most common diseases showing findings of autoimmunity included immune dysregulation, polyendocrinopathy, enteropathy X-linked syndrome (16.7%); autoimmune lymphoproliferative syndrome (10%); lipopolysaccharide-responsive beige-like anchor protein deficiency (10%); and DiGeorge syndrome (10%). Twelve (40%) patients showed findings of autoimmunity at the time of first presentation. The most common findings of autoimmunity included inflammatory bowel disease, inflammatory bowel disease-like findings (n=14, 46.7%), immune thrombocytopenic purpura (n=11, 36.7%), and autoimmune hemolytic anemia (n=9, 30.0%). A response to immunosupressive agents was observed in 15 (50%) patients. Ten patients underwent hematopoietic stem cell transplantation. Six patients were lost to follow-up due to a variety of complications.
CONCLUSION: Autoimmunity is frequently observed in patients with primary immunodeficiency. The possibility of primary immunodeficiency should be considered in patients with early-onset manifestations of autoimmunity, and these patients should be carefully monitored in terms of immunodeficiency development. Early diagnosis of primary immunodeficiency may provide favorable outcomes in terms of survival.

PMID: 28123330 [PubMed – in process]

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Immediate adverse reactions to intravenous immunoglobulin in children: a single center experience.

Eur Ann Allergy Clin Immunol. 2017 Jan;49(1):11-14

Authors: Kaba S, Keskindemirci G, Aydogmus C, Siraneci R, Erol Cipe F

Abstract
Intravenous immunoglobulin (IVIG) is commonly used in primary and secondary immunodeficiency diseases as well as autoimmune conditions as immunomodulatator treatment. Immediate adverse events which are generally mild and occur during infusion are seen in 6 hours. Reported immediate adverse events are in a wide range from 1%-40% in pediatric patients. 115 patients who received IVIG (except newborns) were included into this crosssectional study. IVIG was given to patients for primary immunodeficiencies (n=8), ITP (n=65), Kawasaki disease (n=11), secondary immunosupression (n=28), and passive immunization (n=3). 5%, 10% IVIG preparations and pentaglobin were used. Headache, fever, chills, nausea, rash, arthralgia, myalgia and back pain were accepted as mild immediate events. There were 62 (54%) boys and 53 (46%) girls aged 1 month-18 years. Mean age of the group was 7.4±4.6 years. Immediate adverse events due to IVIG infusions were seen in 29 (25.2%) of all patients. Gender and types of the disease were not different in significance regarding the presence of adverse events. The rate of adverse events did not change with receiving pre-medication. The most common reaction was fever/chills. Immediate reactions were seen in first 6 hours in 7 patients and during infusion in the remaining. They were treated with slowing of the infusion rate and infusion was stopped in 3 patients because of moderate events. Because of the increasingly use of IVIG therapy, it is important to know the side effects. High doses, high infusion rates, accompanying infection may worsen the adverse effects especially in primary immunodeficiency diseases.

PMID: 28120600 [PubMed – in process]

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Childhood recurrent pneumonia caused by endobronchial sutures: A case report.

Medicine (Baltimore). 2017 Jan;96(4):e5992

Authors: Zan Y, Liu H, Zhong L, Qiu L, Tao Q, Chen L

Abstract
BACKGROUND: Recurrent pneumonia is defined as more than two episodes of pneumonia in one year or three or more episodes anytime in life. Common clinical scenarios leading to recurrent pneumonia include anatomical abnormalities of respiratory tract, immunodeficiency, congenital heart diseases, primary ciliary dyskinesia, etc.
CASE REPORT: A school-aged girl suffered from 1-2 episodes of pneumonia each year after trachea connection and lung repair operation resulted from an accident of car crash. Bronchoscopy revealed the sutures twisted with granulation in the left main bronchus and the patient’s symptoms relieved after removal of the sutures. Here we report for the first time that surgical suture was the cause of recurrent pneumonia.
CONCLUSIONS: This case indicates that children with late and recurrent onset of pneumonia should undergo detailed evaluation including bronchoscopy.

PMID: 28121955 [PubMed – in process]

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Adoptive T Cell Immunotherapy for Patients with Primary Immunodeficiency Disorders.

Curr Allergy Asthma Rep. 2017 Jan;17(1):3

Authors: McLaughlin LP, Bollard CM, Keller M

Abstract
Primary immunodeficiency disorders (PID) are a group of inborn errors of immunity with a broad range of clinical severity but often associated with recurrent and serious infections. While hematopoietic stem cell transplantation (HSCT) can be curative for some forms of PID, chronic and/or refractory viral infections remain a cause of morbidity and mortality both before and after HSCT. Although antiviral pharmacologic agents exist for many viral pathogens, these are associated with significant costs and toxicities and may not be effective for increasingly drug-resistant pathogens. Thus, the emergence of adoptive immunotherapy with virus-specific T lymphocytes (VSTs) is an attractive option for addressing the underlying impaired T cell immunity in many PID patients. VSTs have been utilized for PID patients following HSCT in many prior phase I trials, and may potentially be beneficial before HSCT in patients with chronic viral infections. We review the various methods of generating VSTs, clinical experience using VSTs for PID patients, and current limitations as well as potential ways to broaden the clinical applicability of adoptive immunotherapy for PID patients.

PMID: 28116637 [PubMed – in process]

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A human immunodeficiency syndrome caused by mutations in CARMIL2.

Nat Commun. 2017 Jan 23;8:14209

Authors: Schober T, Magg T, Laschinger M, Rohlfs M, Linhares ND, Puchalka J, Weisser T, Fehlner K, Mautner J, Walz C, Hussein K, Jaeger G, Kammer B, Schmid I, Bahia M, Pena SD, Behrends U, Belohradsky BH, Klein C, Hauck F

Abstract
Human T-cell function is dependent on T-cell antigen receptor (TCR) and co-signalling as evidenced by immunodeficiencies affecting TCR-dependent signalling pathways. Here, we show four human patients with EBV(+) disseminated smooth muscle tumours that carry two homozygous loss-of-function mutations in the CARMIL2 (RLTPR) gene encoding the capping protein regulator and myosin 1 linker 2. These patients lack regulatory T cells without evidence of organ-specific autoimmunity, and have defective CD28 co-signalling associated with impaired T-cell activation, differentiation and function, as well as perturbed cytoskeletal organization associated with T-cell polarity and migration disorders. Human CARMIL2-deficiency is therefore an autosomal recessive primary immunodeficiency disorder associated with defective CD28-mediated TCR co-signalling and impaired cytoskeletal dynamics.

PMID: 28112205 [PubMed – in process]

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Investigation of genetic defects in severe combined immunodeficiency patients from Turkey by targeted sequencing.

Scand J Immunol. 2017 Jan 21;:

Authors: Erman B, Bilic I, Hirschmugl T, Salzer E, Boztug H, Sanal Ö, Çağdaş Ayvaz D, Tezcan I, Boztug K

Abstract
Primary immunodeficiencies (PIDs) represent a large group of disorders with an increased susceptibility to infections. Severe combined immunodeficiency (SCID) is the most severe form of primary immunodeficiencies (PIDs) with marked T-cell lymphopenia. Investigation of the genetic etiology using classical Sanger sequencing is associated with considerable diagnostic delay. We here established a custom-designed, next generation sequencing-based panel to efficiently identify disease-causing genetic defects in PID patients and applied this method in SCID patients of Turkish origin with previously undefined genetic etiology. We used HaloPlex enrichment technology, a targeted, next generation sequencing (NGS)-based method which was designed to diagnose patients with SCID and other PIDs. Our HaloPlex panel included a total of 356 PID-related genes and we searched disease-causing mutations in 19 Turkish SCID patients without a genetic diagnosis. The coverage of targeted regions ranged from 97.47% to 99.62% with an average of 98.31% for all patients. All SCID genes were covered with the percentage of at least 97.3%. We made a genetic diagnosis in 6 out of 19 (33%) patients, including four novel disease-causing mutations identified in RAG1, JAK3 and IL2RG, respectively. We showed that this NGS-based method can provide rapid genetic diagnosis for patients suffering from SCID, potentially facilitating clinical treatment decisions. In addition, this method can be useful for screening of PID patients. This article is protected by copyright. All rights reserved.

PMID: 28109013 [PubMed – as supplied by publisher]

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Leukocyte Adhesion Deficiency Type I: A Rare Primary Immunodeficiency Disorder.

Pediatr Allergy Immunol. 2017 Jan 20;:

Authors: Tipu HN

Abstract
Leukocyte adhesion deficiency type I (LAD-I) is a rare autosomal recessive primary immunodeficiency disorder that is caused by mutations in ITGB2 gene encoding β2 subunit (CD18) of integrins(1) . Integrins are required for neutrophils adhesion to endothelium during their emigration to inflammatory site. Hence, integrin deficiency leads to poor neutrophils extravasation, neutrophilia, lack of pus formation and recurrent bacterial infections(2) . Clinical suspicion is confirmed with integrins detection on neutrophils surface by flow cytometry. Worldwide, only about 300 cases have been reported so far and incidence is one in one million(1) . However, due to high rate of consanguineous marriages in Pakistan, this incidence is expected to be higher. Previously we had reported a case of LAD-I in 2008(3) , however, since then no new case of the disease has been reported in Pakistan. Here, we present two cases of LAD-I diagnosed in our institute within four months of each other. This article is protected by copyright. All rights reserved.

PMID: 28107557 [PubMed – as supplied by publisher]

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Screening and analysis of breast cancer genes regulated by the human mammary microenvironment in a humanized mouse model.

Oncol Lett. 2016 Dec;12(6):5261-5268

Authors: Zheng M, Wang J, Ling L, Xue D, Wang S, Zhao Y

Abstract
Tumor microenvironments play critical regulatory roles in tumor growth. Although mouse cancer models have contributed to the understanding of human tumor biology, the effectiveness of mouse cancer models is limited by the inability of the models to accurately present humanized tumor microenvironments. Previously, a humanized breast cancer model in severe combined immunodeficiency mice was established, in which human breast cancer tissue was implanted subcutaneously, followed by injection of human breast cancer cells. It was demonstrated that breast cancer cells showed improved growth in the human mammary microenvironment compared with a conventional subcutaneous mouse model. In the present study, the novel mouse model and microarray technology was used to analyze changes in the expression of genes in breast cancer cells that are regulated by the human mammary microenvironment. Humanized breast and conventional subcutaneous mouse models were established, and orthotopic tumor cells were obtained from orthotopic tumor masses by primary culture. An expression microarray using Illumina HumanHT-12 v4 Expression BeadChip and database analyses were performed to investigate changes in gene expression between tumors from each microenvironment. A total of 94 genes were differentially expressed between the primary cells cultured from the humanized and conventional mouse models. Significant upregulation of genes that promote cell proliferation and metastasis or inhibit apoptosis, such as SH3-domain binding protein 5 (BTK-associated), sodium/chloride cotransporter 3 and periostin, osteoblast specific factor, and genes that promote angiogenesis, such as KIAA1618, was also noted. Other genes that restrain cell proliferation and accelerate cell apoptosis, including tripartite motif containing TRIM36 and NES1, were downregulated. The present results revealed differences in various aspects of tumor growth and metabolism between the two model groups and indicated the functional changes specific to the human mammary microenvironment.

PMID: 28101242 [PubMed – in process]

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