Research

Disease burden for patients with primary immunodeficiency diseases identified at reference hospitals in Guanajuato, Mexico.

PLoS One. 2017;12(4):e0175867

Authors: Guaní-Guerra E, Jiménez-Romero AI, García-Ramírez UN, Velázquez-Ávalos JM, Martínez-Guzmán E, Sandoval-Ramírez E, Camacho-Meza I

Abstract
BACKGROUND: In addition to the deleterious effect on health, there is considerable economic and psychosocial morbidity associated with primary immunodeficiency diseases (PID). Also, the cost of a late diagnosis frequently results in a heavy disease burden on the patient. The objective of this study was to collect and analyze data on patients with PID in the state of Guanajuato in Mexico, to indirectly estimate the burden of the disease.
METHODS: An observational, longitudinal, and comparative study was conducted. A total of 44 patients were included and grouped according to the updated classification of PID.
RESULTS: The median time elapsed from the onset of symptoms to the reference and diagnosis by a tertiary hospital was of 2.17 (IQR = 6.44) years. Before diagnosis, the number of hospitalizations/year per patient was 0.86 (IQR = 2.28), the number of visit to emergency room/year per patient was 0.92 (IQR = 1.77), the number of doctor’s visits/year per patient was 15 (IQR = 11.25), whereas the school/work absence days per patient were reported in 52.72 (IQR = 56.35) days per year. After diagnosis, 20 patients (45.45%) received IVIG replacement therapy, and all of them presented a significant improvement (p <0.05) in all the mentioned variables. Characteristically, even when patients with PID received IVIG, there was still an important disease burden when comparing them against healthy controls. Complications secondary to PID were detected in 19 patients (43.18%). The reported overall mortality rate was 6.82% (n = 3).
CONCLUSIONS: We were able to indirectly estimate an important disease burden in patients with PID; which is considered to be preventable, at least in part, with effective interventions like health planning, research, collaboration with primary care providers, and generation of policies and practices, in order to improve the quality of life and care of families with PID.

PMID: 28448570 [PubMed – in process]

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Infectious and Non-Infectious Pulmonary Complications in Primary Immunodeficiencies.

J Investig Allergol Clin Immunol. 2017 Apr 27;:0

Authors: Yazdani R, Abolhassani H, Asgardoon M, Shaghaghi M, Modaresi M, Azizi G, Aghamohammadi A

Abstract
Primary immunodeficiency disorders (PIDs) have been described as diseases caused by one or more defects of the immune system. These patients are more likely to experience recurrent and/or severe infections and have a tendency to develop a wide range of complications. Respiratory diseases are the main and initial manifestation for the majority of PID patients and most common complication in this group of patients. Pulmonary complications present a significant cause of morbidity and also mortality among patients suffering from different forms of PIDs. Early diagnosis and appropriate treatment can prevent or at least slow down the development of respiratory complications of PIDs. Since the spectrum of pulmonary complications in PIDs is broad, we divided pulmonary complications into upper respiratory (e.g., sinusitis, otitis media and laryngeal angioedema) and lower respiratory (e.g., pneumonia, bronchitis, bronchiectasis, interstitial lung diseases, organizing pneumonia, pulmonary adenopathies and malignancies, hyperreactive airway diseases, pulmonary dysgenesis and treatment side effects) complications. This review covers the most important respiratory manifestations observed in patients with PIDs.

PMID: 28446389 [PubMed – as supplied by publisher]

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Cooperation of neurotrophin receptor TrkB and Her2 in breast cancer cells facilitates brain metastases.

Breast Cancer Res. 2017 Apr 26;19(1):51

Authors: Choy C, Ansari KI, Neman J, Hsu S, Duenas MJ, Li H, Vaidehi N, Jandial R

Abstract
BACKGROUND: Patients with primary breast cancer that is positive for human epidermal growth factor receptor 2 (Her2+) have a high risk of developing metastases in the brain. Despite gains with systemic control of Her2+ disease using molecular therapies, brain metastases remain recalcitrant to therapeutic discovery. The clinical predilection of Her2+ breast cancer cells to colonize the brain likely relies on paracrine mechanisms. The neural niche poses unique selection pressures, and neoplastic cells that utilize the brain microenvironment may have a survival advantage.
METHODS: Tropomyosin-related kinase B (TrkB), Her2, and downstream targets were analyzed in primary breast cancer, breast-to-brain metastasis (BBM) tissues, and tumor-derived cell lines using quantitative real-time PCR, western blot, and immunohistochemical assessment. TrkB function on BBM was confirmed with intracranial, intracardiac, or mammary fat pad xenografts in non-obese diabetic/severe combined immunodeficiency mice. The function of brain-derived neurotrophic factor (BDNF) on cell proliferation and TrkB/Her2 signaling and interactions were confirmed using selective shRNA knockdown and selective inhibitors. The physical interaction of Her2-TrkB was analyzed using electron microscopy, co-immunoprecipitation, and in silico analysis. Dual targeting of Her2 and TrkB was analyzed using clinically utilized treatments.
RESULTS: We observed that patient tissues and cell lines derived from Her2+ human BBM displayed increased activation of TrkB, a neurotrophin receptor. BDNF, an extracellular neurotrophin, with roles in neuronal maturation and homeostasis, specifically binds to TrkB. TrkB knockdown in breast cancer cells led to decreased frequency and growth of brain metastasis in animal models, suggesting that circulating breast cancer cells entering the brain may take advantage of paracrine BDNF-TrkB signaling for colonization. In addition, we investigated a possible interaction between TrkB and Her2 receptors on brain metastatic breast cancer cells, and found that BDNF phosphorylated both its cognate TrkB receptor and the Her2 receptor in brain metastatic breast cancer cells.
CONCLUSION: Collectively, our findings suggest that heterodimerization of Her2 and TrkB receptors gives breast cancer cells a survival advantage in the brain and that dual inhibition of these receptors may hold therapeutic potential.

PMID: 28446206 [PubMed – in process]

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II Brazilian Consensus on the use of human immunoglobulin in patients with primary immunodeficiencies.

Einstein (Sao Paulo). 2017;15(1):1-3

Authors: Goudouris ES, Silva AMDR, Ouricuri AL, Grumach AS, Condino-Neto A, Costa-Carvalho BT, Prando CCM, Kokron CM, Vasconcelos DM, Tavares FS, Segundo GRS, Barreto ICDP, Dorna MB, Barros MAMT, Forte WCN

Abstract
In the last few years, new primary immunodeficiencies and genetic defects have been described. Recently, immunoglobulin products with improved compositions and for subcutaneous use have become available in Brazil. In order to guide physicians on the use of human immunoglobulin to treat primary immunodeficiencies, based on a narrative literature review and their professional experience, the members of the Primary Immunodeficiency Group of the Brazilian Society of Allergy and Immunology prepared an updated document of the 1st Brazilian Consensus, published in 2010. The document presents new knowledge about the indications and efficacy of immunoglobulin therapy in primary immunodeficiencies, relevant production-related aspects, mode of use (routes of administration, pharmacokinetics, doses and intervals), adverse events (major, prevention, treatment and reporting), patient monitoring, presentations available and how to have access to this therapeutic resource in Brazil. RESUMO Nos últimos anos, novas imunodeficiências primárias e defeitos genéticos têm sido descritos. Recentemente, produtos de imunoglobulina, com aprimoramento em sua composição e para uso por via subcutânea, tornaram-se disponíveis em nosso meio. Com o objetivo de orientar o médico no uso da imunoglobulina humana para o tratamento das imunodeficiências primárias, os membros do Grupo de Assessoria em Imunodeficiências da Associação Brasileira de Alergia e Imunologia produziram um documento que teve por base uma revisão narrativa da literatura e sua experiência profissional, atualizando o I Consenso Brasileiro publicado em 2010. Apresentam-se novos conhecimentos sobre indicações e eficácia do tratamento com imunoglobulina nas imunodeficiências primárias, aspectos relevantes sobre a produção, forma de utilização (vias de administração, farmacocinética, doses e intervalos), efeitos adversos (principais efeitos, prevenção, tratamento e notificação), monitorização do paciente, apresentações disponíveis e forma de obtenção deste recurso terapêutico em nosso meio.

PMID: 28444082 [PubMed – in process]

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Augmented expression of RUNX1 deregulates the global gene expression of U87 glioblastoma multiforme cells and inhibits tumor growth in mice.

Tumour Biol. 2017 Apr;39(4):1010428317698357

Authors: Bogoch Y, Friedlander-Malik G, Lupu L, Bondar E, Zohar N, Langier S, Ram Z, Nachmany I, Klausner JM, Pencovich N

Abstract
Glioblastoma multiforme is the most common and aggressive primary brain tumor in adults. A mesenchymal phenotype was associated with tumor aggressiveness and poor prognosis in glioblastoma multiforme patients. Recently, the transcription factor RUNX1 was suggested as a driver of the glioblastoma multiforme mesenchymal gene expression signature; however, its independent role in this process is yet to be described. Here, we assessed the role of RUNX1 in U87 glioblastoma multiforme cells in correspondence to its mediated transcriptome and genome-wide occupancy pattern. Overexpression of RUNX1 led to diminished tumor growth in nude and severe combined immunodeficiency mouse xenograft tumor model. At the molecular level, RUNX1 occupied thousands of genomic regions and regulated the expression of hundreds of target genes, both directly and indirectly. RUNX1 occupied genomic regions that corresponded to genes that were shown to play a role in brain tumor progression and angiogenesis and upon overexpression led to a substantial down-regulation of their expression level. When overexpressed in U87 glioblastoma multiforme cells, RUNX1 down-regulated key pathways in glioblastoma multiforme progression including epithelial to mesenchymal transition, MTORC1 signaling, hypoxia-induced signaling, and TNFa signaling via NFkB. Moreover, master regulators of the glioblastoma multiforme mesenchymal phenotype including CEBPb, ZNF238, and FOSL2 were directly regulated by RUNX1. The data suggest a central role for RUNX1 as master regulator of gene expression in the U87 glioblastoma multiforme cell line and mark RUNX1 as a potential target for novel future therapies for glioblastoma multiforme.

PMID: 28443460 [PubMed – in process]

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[Consensus on antimicrobial management and infection prevention in primary immunodeficiency diseases].

Zhonghua Er Ke Za Zhi. 2017 Apr 02;55(4):248-255

Authors: Subspecialty Group of Immunology,the Society of Pedeatrics,Chinese Medical Association, Editorial Board of Chinese Joural of Pediatrics

PMID: 28441819 [PubMed – in process]

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Costs of Hospital Admission on Primary Immunodeficiency Diseases.

Iran J Public Health. 2017 Mar;46(3):342-350

Authors: Gholami K, Laali E, Abolhassani H, Ahmadvand A, Mohebbi N, Javadi MR, Aghamohammadi A, Rezaei N

Abstract
BACKGROUND: Primary immunodeficiency diseases (PID) are heterogeneous group of inherited disorders mainly characterized by recurrent infections leading to several times hospital admissions. The economic impact of PID is a challenging issue; therefore, this study was designed to determine the medical costs of hospitalizations in this group of patients as an indicator of the direct cost of these diseases.
METHODS: One hundred and ten children with PID hospitalized in the Children’s Medical Center Hospital, Tehran, Iran were included in this study during Jan 2011 and Jan 2012. All direct costs during the admission period were calculated, using the hospital information system.
RESULTS: Medical cost was 7.090$ per patient per admission. Among them, about 1.580$ belong to drug consuming during hospitalization. Anti-infective drugs for systemic use were the most cost-consuming group of drugs, followed by alimentary tract and metabolism and blood and blood forming organs agents. Investigation of anti-infective group internally showed that immune sera and immunoglobulin and antiviral agents for systemic use consisting the most important medication for PID patients during hospital admission.
CONCLUSION: Although the results of economic evaluations in a region cannot necessarily be applied to other regions, having an overall estimation of hospital admission costs and types of drugs used during admission could be helpful in health policy system.

PMID: 28435820 [PubMed – in process]

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Persistent lymphopenia is an independent predictor of mortality in critically ill emergency general surgical patients.

Eur J Trauma Emerg Surg. 2016 Dec;42(6):755-760

Authors: Vulliamy PE, Perkins ZB, Brohi K, Manson J

Abstract
INTRODUCTION: Lymphopenia has been associated with poor outcome following sepsis, burns and trauma. This study was designed to establish whether lymphocyte count was associated with mortality in emergency general surgery (EGS) patients, and whether persistent lymphopenia was an independent predictor of mortality.
METHODS: A retrospective review of a prospectively compiled database of adult patients requiring ICU admission between 2002 and 2013 was performed. EGS patients with acute intra-abdominal pathology and organ dysfunction were included. Lymphocyte counts obtained from the day of ICU admission through to day 7 were examined. Multivariate logistic regression models were used to determine the relationship between persistent lymphopenia and outcome. The primary outcome measure was in-hospital mortality.
RESULTS: The study included 173 patients, of whom 135 (78 %) had a low lymphocyte count at admission to ICU and 91 % (158/173) developed lymphopenia on at least one occasion. Lymphocyte counts were lower among non-survivors compared with survivors on each day from day 2 (0.62 vs 0.81, p = 0.03) through to day 7 (0.87 vs 1.15, p < 0.01). Patients with a persistently low lymphocyte count during the study period had significantly higher mortality when compared to patients with other lymphocyte patterns (64 vs 29 %, p < 0.01). On multivariate regression analysis, persistent lymphopenia was independently associated with increased in-hospital mortality [odds ratio 3.5 (95 % CI 1.7-7.3), p < 0.01].
CONCLUSION: Lymphopenia is commonly observed in critically ill EGS patients. Patients with persistent lymphopenia are 3.5 times more likely to die and lymphopenia is an independent predictor of increased mortality in this patient group.

PMID: 26501197 [PubMed – indexed for MEDLINE]

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Humoral primary immunodeficiency diseases: clinical overview and chest high-resolution computed tomography (HRCT) features in the adult population.

Clin Radiol. 2017 Apr 19;:

Authors: Cereser L, Girometti R, d’Angelo P, De Carli M, De Pellegrin A, Zuiani C

Abstract
Humoral primary immunodeficiency diseases (hPIDs) are a heterogeneous group of hereditary disorders resulting in abnormal susceptibility to infections of the sinopulmonary tract. Some of these conditions (e.g., common variable immunodeficiency disorders [CVID]) imply a number of non-infectious thoracic complications such as non-infectious airway disorders, diffuse lung parenchymal diseases, and neoplasms. Chest high-resolution computed tomography (HRCT) is a key imaging tool to characterise and quantify the extent of underlying thoracic involvement, as well as to direct and monitor treatment. The aims of this review are to provide a brief clinical overview of hPIDs and describe the related chest HRCT imaging features in the adult population, with a special focus on CVID and its complications.

PMID: 28433201 [PubMed – as supplied by publisher]

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Resolution of Primary Immune Defect in 22q11.2 Deletion Syndrome.

J Clin Immunol. 2017 Apr 20;:

Authors: Suksawat Y, Sathienkijkanchai A, Veskitkul J, Jirapongsananuruk O, Visitsunthorn N, Vichyanond P, Pacharn P

Abstract
PURPOSE: Patients with 22q11.2 deletion syndrome have a variable decrease in immunological parameters, especially regarding T cell counts. The aim of this study was to investigate immunological change over time and factors associated with immunological recovery among patients with 22q11.2 deletion syndrome.
METHODS: Patients with 22q11.2 deletion syndrome diagnosed by fluorescence in situ hybridization (FISH) were studied. Immunological parameters were evaluated every 6 months until patients returned to normal. Infection and vaccination histories were recorded and analyzed, and Kaplan-Meier survival curves were plotted to describe resolution of immunodeficiency.
RESULTS: Forty-nine patients with an age range of 4 to 222 months were included. Twenty-five (51%) patients were female. In hypocalcemia, the odds ratio for CD4 lymphopenia was 17.03 (95%CI 1.82-159.23; p value = 0.01). Thirty patients (61.2%) exhibited decreased CD4+ T cell numbers, which returned to normal level in 18 (60%) patients. Median age of CD4+ T cell resolution was 2.5 years. T cell functions were abnormal in three patients. T cell functions returned to normal in all patients at a median age of 1.1 years. Six patients (13.5%) had abnormal serum immunoglobulin levels, with levels improving in four patients at 1.4 years of age. The most common infection was pneumonia (69.4%). BCG vaccination was administered in 47 of 49 patients at birth. Among 32 patients who had T cell defect, one patient developed BCGitis and one developed disseminated BCG.
CONCLUSION: Immunodeficiencies identified among patients with 22q11.2 deletion syndrome were T cell defect (65.3%) and decreased immunoglobulin levels (12.2%). Median age of CD4 resolution was 2.5 years.

PMID: 28429103 [PubMed – as supplied by publisher]

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