Manish Butte

A hereditary angioedema screening on an index case: Turkey.

Asian Pac J Allergy Immunol. 2019 Sep;37(3):154-161

Authors: Ozkars MY, Keskin O, Bayram N, Keskin M, Bayram H, Sahin Y, Kucukosmanoglu E, Attila N, Kirik SK

Abstract
BACKGROUND: Hereditary angioedema (HAE) is characterised by recurrent episodes of angioedema and can be fatal.
OBJECTIVE: The present study aimed to screen HAE.
METHODS: A total of 60 individuals were screened. The frequency and severity of symptoms were scored from 0 to 8. Measurements were taken of C4 and C1 esterase inhibitor protein (C1-INH) levels. Mutation in the C1 inhibitor gene was examined in 9 patients with HAE.
RESULTS: A positive correlation between the C1 esterase inhibitor protein levels and C4 level was detected in the group as a whole (p < 0.001, r = 0.725, n = 60). Anegative correlation between the C1 esterase inhibitor protein level and severity score was observed in the whole group (p < 0.001, r = -0.486, n = 60). A negative correlation was also detected in the entire group between the C4 level and severity score (p = 0.002, r = -0.389, n = 60). In the patients with HAE, a positive correlation between the C1 esterase inhibitor protein level and C4 levels was detected (p = 0.034, r = 0.705, n = 9). A heterozygous c. 601A > T nonsense variant was identified at the C1 esterase inhibitor gene-SERPING1-in patients with Type 1 HAE.
CONCLUSION: It is well known that there is a prolonged delay in the diagnosis of HAE. The present study demonstrates that it is very important and even life-saving to screen for HAE on the basis of an index case.

PMID: 30118244 [PubMed – indexed for MEDLINE]

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Genetic, Immunological, and Clinical Features of the First Mexican Cohort of Patients with Chronic Granulomatous Disease.

J Clin Immunol. 2020 Feb 10;:

Authors: Blancas-Galicia L, Santos-Chávez E, Deswarte C, Mignac Q, Medina-Vera I, León-Lara X, Roynard M, Scheffler-Mendoza SC, Rioja-Valencia R, Alvirde-Ayala A, Lugo Reyes SO, Staines-Boone T, García-Campos J, Saucedo-Ramírez OJ, Del-Río Navarro BE, Zamora-Chávez A, López-Larios A, García-Pavón-Osorio S, Melgoza-Arcos E, Canseco-Raymundo MR, Mogica-Martínez D, Venancio-Hernández M, Pacheco-Rosas D, Pedraza-Sánchez S, Guevara-Cruz M, Saracho-Weber F, Gámez-González B, Wakida-Kuzunoki G, Morán-Mendoza AR, Macías-Robles AP, Ramírez-Rivera R, Vargas-Camaño E, Zarate-Hernández C, Gómez-Tello H, Ramírez-Sánchez E, Ruíz-Hernández F, Ramos-López D, Acuña-Martínez H, García-Cruz ML, Román-Jiménez MG, González-Villarreal MG, Álvarez-Cardona A, Llamas-Guillén BA, Cuellar-Rodríguez J, Olaya-Vargas A, Ramírez-Uribe N, Boisson-Dupuis S, Casanova JL, Espinosa-Rosales FJ, Serafín-López J, Yamazaki-Nakashimada M, Espinosa-Padilla S, Bustamante J

Abstract
PURPOSE: Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by an inability of phagocytes to produce reactive oxygen species, impairing their killing of various bacteria and fungi. We summarize here the 93 cases of CGD diagnosed in Mexico from 2011 to 2019.
METHODS: Thirteen Mexican hospitals participated in this study. We describe the genetic, immunological, and clinical features of the 93 CGD patients from 78 unrelated kindreds.
RESULTS: Eighty-two of the patients (88%) were male. All patients developed bacterial infections and 30% suffered from some kind of fungal infection. Fifty-four BCG-vaccinated patients (58%) presented infectious complications of BCG vaccine. Tuberculosis occurred in 29%. Granulomas were found in 56% of the patients. Autoimmune and inflammatory diseases were present in 15% of patients. A biological diagnosis of CGD was made in 89/93 patients, on the basis of NBT assay (n = 6), DHR (n = 27), and NBT plus DHR (n = 56). The deficiency was complete in all patients. The median age of biological diagnosis was 17 months (range, 0-186 months). A genetic diagnosis was made in 83/93 patients (when material was available), corresponding to CYBB (n = 64), NCF1 (n = 7), NCF2 (n = 7), and CYBA (n = 5) mutations.
CONCLUSIONS: The clinical manifestations in these Mexican CGD patients were similar to those in patients elsewhere. This cohort is the largest in Latin America. Mycobacterial infections are an important cause of morbidity in Mexico, as in other countries in which tuberculosis is endemic and infants are vaccinated with BCG. X-linked CGD accounted for most of the cases in Mexico, as in other Latin American countries. However, a significant number of CYBA and NCF2 mutations were identified, expanding the spectrum of known causal mutations.

PMID: 32040803 [PubMed – as supplied by publisher]

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Histocompatibility Complex Status and Mendelian Randomization Analysis in Unsolved Antibody Deficiency.

Front Immunol. 2020;11:14

Authors: Abolhassani H, Lim CK, Aghamohammadi A, Hammarström L

Abstract
The pathogenesis in the majority of patients with common variable immunodeficiency (CVID), the most common symptomatic primary immunodeficiency, remains unknown. We aimed to compare the minor and major histocompatibility complex (MHC) markers as well as polygenic scores of common genetic variants between patients with monogenic CVID and without known genetic mutation detected. Monogenic patients were identified in a CVID cohort using whole exome sequencing. Computational full-resolution MHC typing and confirmatory PCR amplicon-based high-resolution typing were performed. Exome-wide polygenic scores were developed using significantly different variants and multi-variant Mendelian randomization (MR) analyses were used to test the causality of significant genetic variants on antibody levels and susceptibility to infectious diseases. Among 83 CVID patients (44.5% females), monogenic defects were found in 40 individuals. Evaluation of the remaining CVID patients without known genetic mutation detected showed 13 and 27 significantly associated MHC-class I and II alleles, respectively. The most significant partial haplotype linked with the unsolved CVID was W*01:01:01-DMA*01:01:01-DMB*01:03:01:02-TAP1*01:01:01 (P < 0.001), where carriers had a late onset of the disease, only infection clinical phenotype, a non-familial form of CVID, post-germinal center defects and a non-progressive form of their disease. Exclusion of monogenic diseases allowed MR analyses to identify significant genetic variants associated with bacterial infections and improved discrepancies observed in MR analyses of previous GWAS studies with low pleiotropy mainly for a lower respiratory infection, bacterial infection and Streptococcal infection. This is the first study on the full-resolution of minor and major MHC typing and polygenic scores on CVID patients and showed that exclusion of monogenic forms of the disease unraveled an independent role of MHC genes and common genetic variants in the pathogenesis of CVID.

PMID: 32038658 [PubMed – in process]

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Cost and impact of early diagnosis in primary immunodeficiency disease: A literature review.

Clin Immunol. 2020 Feb 05;:108359

Authors: Elsink K, van Montfrans JM, van Gijn ME, Blom M, van Hagen PM, Kuijpers TW, Frederix GWJ

Abstract
BACKGROUND: New, innovative, costly diagnostic methods for patients with primary immunodeficiencies (PID) demand upfront insight into their potential cost savings and added value for individual patients. As such, high quality, comparable economic evaluations are of utmost importance to enable informed decisions. The objective of this review was therefore to create an extensive overview of current costing studies and potential cost savings of early diagnosis in primary immunodeficiency disease.
METHODS: A literature search in PubMed was conducted and studies involving any form of costing study in the field of PIDs were included. Of the included studies, study characteristics, cost parameters and benefits of early diagnosis were extracted and outlined in separate tables.
RESULTS: Twenty two studies met the inclusion criteria and were included in the review. The papers were categorized according to their subject: neonatal screening for severe combined immunodeficiency (SCID), Ig replacement therapies and studies reporting on costs of general or specific PIDs. Within and between these groups variability in reported costing characteristics was observed. In studies that reported cost savings pre- and post-diagnosis, cost savings ranged from 6500 to 108,463 USD of total costs per patient.
CONCLUSION: This literature review shows that, regardless of what aspect of PIDs has been studied, in nearly all cases early diagnosis reduces health care consumption and leads to better health outcomes for patients with PIDs. We found considerable variability in costing characteristics of economic evaluations of PID patients, which hampers the comparability of outcomes. More effort is needed to create uniformity and define cost parameters in economic evaluations in the field of PIDs, facilitating further prospective research to extensively assess the benefits of early diagnosis.

PMID: 32035178 [PubMed – as supplied by publisher]

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Establishment and Characterisation by Expression Microarray of Patient-Derived Xenograft Panel of Human Pancreatic Adenocarcinoma Patients.

Int J Mol Sci. 2020 Jan 31;21(3):

Authors: Roche S, O’Neill F, Murphy J, Swan N, Meiller J, Conlon NT, Geoghegan J, Conlon K, McDermott R, Rahman R, Toomey S, Straubinger NL, Straubinger RM, O’Connor R, McVey G, Moriarty M, Clynes M

Abstract
Pancreatic cancer remains among the most lethal cancers worldwide, with poor early detection rates and poor survival rates. Patient-derived xenograft (PDX) models have increasingly been used in preclinical and clinical research of solid cancers to fulfil unmet need. Fresh tumour samples from human pancreatic adenocarcinoma patients were implanted in severe combined immunodeficiency (SCID) mice. Samples from 78% of treatment-naïve pancreatic ductal adenocarcinoma patients grew as PDX tumours and were confirmed by histopathology. Frozen samples from F1 PDX tumours could be later successfully passaged in SCID mice to F2 PDX tumours. The human origin of the PDX was confirmed using human-specific antibodies; however, the stromal component was replaced by murine cells. Cell lines were successfully developed from three PDX tumours. RNA was extracted from eight PDX tumours and where possible, corresponding primary tumour (T) and adjacent normal tissues (N). mRNA profiles of tumour vs. F1 PDX and normal vs. tumour were compared by Affymetrix microarray analysis. Differential gene expression showed over 5000 genes changed across the N vs. T and T vs. PDX samples. Gene ontology analysis of a subset of genes demonstrated genes upregulated in normal vs. tumour vs. PDX were linked with cell cycle, cycles cell process and mitotic cell cycle. Amongst the mRNA candidates elevated in the PDX and tumour vs. normal were SERPINB5, FERMT1, AGR2, SLC6A14 and TOP2A. These genes have been associated with growth, proliferation, invasion and metastasis in pancreatic cancer previously. Cumulatively, this demonstrates the applicability of PDX models and transcriptomic array to identify genes associated with growth and proliferation of pancreatic cancer.

PMID: 32024004 [PubMed – in process]

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Pegylated recombinant human granulocyte colony-stimulating factor regulates the immune status of patients with small cell lung cancer.

Thorac Cancer. 2020 Feb 05;:

Authors: Sun J, Bai H, Wang Z, Duan J, Li J, Guo R, Wang J

Abstract
BACKGROUND: Small cell lung cancer (SCLC) is an aggressive disease involving immunodeficiency for which chemotherapy is the standard treatment. Pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) is widely used for primary or secondary prophylaxis of febrile neutropenia (FN) in chemotherapy. However, whether PEG-rhG-CSF influences immune cells, such as lymphocytes, remains unclear.
METHODS: A total of 17 treatment-naïve SCLC patients were prospectively enrolled and divided into the PEG-rhG-CSF and control groups according to their FN risk. Longitudinal sampling of peripheral blood was performed before, after and 4-6 days after the first cycle of chemotherapy. Flow cytometry was used to assess lymphocyte subsets, including CD3+ T, CD4+ T, CD8+ T, NK, and B cells. The diversity and clonality of the T-cell receptor (TCR) repertoire was analyzed by next-generation sequencing.
RESULTS: In the PEG-rhG-CSF group, the proportions of CD3+ T and CD4+ T cells had increased significantly (P = 0.002, P = 0.020, respectively), whereas there was no increase in CD8+ T cells. Further, TCR diversity increased (P = 0.009) and clonality decreased (P = 0.004) significantly after PEG-rhG-CSF treatment. However, these factors showed opposite trends before and after chemotherapy. Vβ and Jβ gene fragment types, which determine TCR diversity, were significantly amplified in the PEG-rhG-CSF group. The change in TCR diversity was significantly correlated with changes in the CD3+ T or CD4+ T cell proportions, but not the CD8+ T cell proportion.
CONCLUSIONS: PEG-rhG-CSF regulates the immune status of SCLC patients; CD4+ T cells may be the main effector cells involved in this process. These findings may optimize the treatment of SCLC.
KEY POINTS: PEG-rhG-CSF regulates SCLC immunity. PEG-rhG-CSF increased CD3+ T and CD4+ T cell proportions. PEG-rhG-CSF increased TCR diversity and decreased clonality in peripheral blood. Change in TCR diversity were correlated with CD3+ T or CD4+ T changes.

PMID: 32020764 [PubMed – as supplied by publisher]

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Correction to: Primary immunodeficiencies in Central and Eastern Europe-the power of networking Report on the activity of the Jeffrey Modell Foundation Centers Network in Central and Eastern Europe.

Immunol Res. 2020 Feb 04;:

Authors: Sediva A, Bataneant M, Belevtsev M, Blaziene A, Ciznar P, Förster-Waldl E, Kelecic J, Marodi J, Naumova E, Nasrullayeva G, Ress K, Serban M, Sitkauskiene B, Toth B, Modell V, Modell F, Tenembaum V, Marković M, Avcin T

Abstract
Due to authors’ internal mistake they have misspelled the name of one of the co-authors in this article.

PMID: 32020506 [PubMed – as supplied by publisher]

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Invasive Saprochaete capitata Infection in a Patient with Autosomal Recessive CARD9 Deficiency and a Review of the Literature.

J Clin Immunol. 2020 Feb 04;:

Authors: Erman B, Fırtına S, Aksoy BA, Aydogdu S, Genç GE, Doğan Ö, Bozkurt C, Fışgın T, Çipe FE

Abstract
PURPOSE: Autosomal recessive (AR) CARD9 deficiency is an inherited immune disorder which results in impaired innate immunity against various fungi. Superficial and invasive fungal infections, mainly caused by Candida or Trichophyton species, are the hallmark of CARD9 deficiency. Together with the increasing number of CARD9-deficient patients reported, different pathogenic fungal species have been described such as Phialophora, Exophiala, Corynespora, Aureobasidium, and Ochroconis. Saprochaete capitata is an opportunistic infectious agent in immunocompromised patients and is a common cause of invasive fungal disease in patients with hematological malignancies. In this study, we investigated the causative genetic defect in a patient with S. capitata fungal infection which disseminated to lymph nodes and common bile duct.
METHODS: The identification of the isolated yeast strain was made by direct microscopic examination and confirmed by internal transcribed spacer (ITS) sequencing. We applied whole exome sequencing to search for the disease-causing mutation. Sanger sequencing was used to validate the mutation in the patient and his parents.
RESULTS: S. capitata was isolated from the biopsy specimen as the causative microorganism responsible for the invasive fungal disease in the patient. Whole exome sequencing revealed a homozygous c.883C > T, (p.Q295*) mutation in CARD9, confirmed by Sanger sequencing.
CONCLUSIONS: This is the first report of invasive Saprochaete infection associated with autosomal recessive (AR) CARD9 deficiency in the literature and thereby further extends the spectrum of fungal diseases seen in these patients.

PMID: 32020378 [PubMed – as supplied by publisher]

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