Manish Butte

[Severe combined immunodeficiency: The time for newborn screening has come].

Rev Chil Pediatr. 2019 Dec;90(6):581-588

Authors: Hoyos Bachiloglu R, Sotomayor F C, Poli H C

Abstract
Primary immunodeficiencies (PIDs) are a set of about 350 genetic disorders that affect the normal function of the immune system. Advances in genetic diagnosis have allowed the description of new defects in the immune system, broadening the clinical spectrum of PIDs’ manifestations beyond susceptibility to infection. Although most PIDs present with recurrent or opportunistic infections, a subgroup of them may be recognized by the early development of auto-inflammatory events, tumors and, paradoxically, the coexistence of autoimmunity and immunodeficiency in the same patient. As their clinical manifestations, the severity of PIDs is highly variable. Severe combined immunodefi ciency (SCID), a PID that affects cellular and humoral immunity, is one of the most severe forms of PIDs and the only available curative treatment in Latin America is hematopoietic stem cells trans plantation. All patients affected by SCID die during the first two years of life if they are not diagnosed and treated opportunely. In contrast, early transplantation of patients with SCID can lead to excellent survival outcomes. Despite recent advances in the diagnosis of PIDs in Chile, diagnostic resources are not available throughout the country, making the early diagnosis of SCID and other forms of PID difficult in big areas of Chile. The objective of this article is to review general concepts on the patho physiology, diagnosis, and initial management of SCID and raise the need for the implementation of neonatal screening for SCID in Chile.

PMID: 32186580 [PubMed – as supplied by publisher]

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Whole-exome sequencing for the identification of rare variants in primary immunodeficiency genes in children with sepsis – a prospective population-based cohort study.

Clin Infect Dis. 2020 Mar 18;:

Authors: Borghesi A, Trück J, Asgari S, Sancho-Shimizu V, Agyeman PKA, Bellos E, Giannoni E, Stocker M, Posfay-Barbe KM, Heininger U, Bernhard-Stirnemann S, Niederer-Loher A, Kahlert CR, Natalucci G, Relly C, Riedel T, Kuehni CE, Thorball CW, Chaturvedi N, Martinon-Torres F, Kuijpers TW, Coin L, Wright V, Herberg J, Levin M, Aebi C, Berger C, Fellay J, Schlapbach LJ, EUCLIDS consortium and the Swiss Paediatric Sepsis Study

Abstract
BACKGROUND: The role of primary immunodeficiencies (PID) in susceptibility to sepsis remains unknown. It is unclear whether children with sepsis benefit from genetic investigations. We hypothesized that sepsis may represent the first manifestation of underlying PID. We applied whole-exome sequencing (WES) to a national cohort of children with sepsis to identify rare, predicted pathogenic variants in PID genes.
METHODS: Multicenter population-based prospective study including previously healthy children ≥28 days and <17 years admitted with blood culture-proven sepsis. Using a stringent variant filtering procedure, analysis of WES data was restricted to rare, predicted pathogenic variants in 240 PID genes for which increased susceptibility to bacterial infection has been reported.
RESULTS: 176 children presenting with 185 sepsis episodes underwent WES (median age 52 months, IQR 15.4-126.4). 41 unique predicted pathogenic PID variants (1 homozygous, 5 hemizygous, and 35 heterozygous) were found in 35/176 (20%) patients, including 3/176 (2%) patients carrying variants which were previously reported to lead to PID. The variants occurred in PID genes across all 8 PID categories as defined by the International Union of Immunological Societies. We did not observe a significant correlation between clinical or laboratory characteristics of patients and the presence or absence of PID variants.
CONCLUSIONS: Applying WES to a population-based cohort of previously healthy children with bacterial sepsis detected Variants of Uncertain Significance in PID genes in one out of five children. Future studies need to investigate the functional relevance of these variants to determine whether variants in PID genes contribute to pediatric sepsis susceptibility.

PMID: 32185379 [PubMed – as supplied by publisher]

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Heterogeneity of Liver Disease in Common Variable Immunodeficiency Disorders.

Front Immunol. 2020;11:338

Authors: Pecoraro A, Crescenzi L, Varricchi G, Marone G, Spadaro G

Abstract
Common variable immunodeficiency (CVID) is the most frequent primary immunodeficiency (PID) in adulthood and is characterized by severe reduction of immunoglobulin serum levels and impaired antibody production in response to vaccines and pathogens. Beyond the susceptibility to infections, CVID encompasses a wide spectrum of clinical manifestations related to a complex immune dysregulation that also affects liver. Although about 50% CVID patients present persistently deranged liver function, burden, and nature of liver involvement have not been systematically investigated in most cohort studies published in the last decades. Therefore, the prevalence of liver disease in CVID widely varies depending on the study design and the sampling criteria. This review seeks to summarize the evidence about the most relevant causes of liver involvement in CVID, including nodular regenerative hyperplasia (NRH), infections and malignancies. We also describe the clinical features of liver disease in some monogenic forms of PID included in the clinical spectrum of CVID as ICOS, NFKB1, NFKB2, CTLA-4, PI3Kδ pathway, ADA2, and IL21-R genetic defects. Finally, we discuss the clinical applications of the various diagnostic tools and the possible therapeutic approaches for the management of liver involvement in the context of CVID.

PMID: 32184784 [PubMed – in process]

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Leukocyte adhesion defect: Where do we stand circa 2019?

Genes Dis. 2020 Mar;7(1):107-114

Authors: Das J, Sharma A, Jindal A, Aggarwal V, Rawat A

Abstract
Migration of polymorphonuclear leukocytes from bloodstream to the site of inflammation is an important event required for surveillance of foreign antigens. This trafficking of leukocytes from bloodstream to the tissue occurs in several distinct steps and involves several adhesion molecules. Defect in adhesion of leukocytes to vascular endothelium affecting their subsequent migration to extravascular space gives rise to a group of rare primary immunodeficiency diseases (PIDs) known as Leukocyte Adhesion Defects (LAD). Till date, four classes of LAD are discovered with LAD I being the most common form. LAD I is caused by loss of function of common chain, cluster of differentiation (CD)18 of β2 integrin family. These patients suffer from life-threatening bacterial infections and in its severe form death usually occurs in childhood without bone marrow transplantation. LAD II results from a general defect in fucose metabolism. These patients suffer from less severe bacterial infections and have growth and mental retardation. Bombay blood group phenotype is also observed in these patients. LAD III is caused by abnormal integrin activation. LAD III patients suffer from severe bacterial and fungal infections. Patients frequently show delayed detachment of umbilical cord, impaired wound healing and increased tendency to bleed. LAD IV is the most recently described class. It is caused by defects in β2 and α4β1 integrins which impairs lymphocyte adhesion. LAD IV patients have monogenic defect in cystic-fibrosis-transmembrane-conductance-regulator (CFTR) gene, resulting in cystic fibrosis. Pathophysiology and genetic etiology of all LAD syndromes are discussed in detail in this paper.

PMID: 32181281 [PubMed]

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An updated review on activated PI3 kinase delta syndrome (APDS).

Genes Dis. 2020 Mar;7(1):67-74

Authors: Singh A, Joshi V, Jindal AK, Mathew B, Rawat A

Abstract
Activated Phosphoinositide 3-kinase δ syndrome (APDS) is a newly recognised primary immunodeficiency disease. It has currently been a hot topic of clinical research and new data are emerging regarding its pathogenesis, clinical manifestations and treatment. Patients with APDS syndrome have significant autoimmune manifestations and lymphoproliferation. It is important to differentiate APDS from the usual polygenic CVID in view of the availability of targeted therapy like mTOR inhibitors such as Rapamycin and selective PI3Kδ inhibitors. We provide a comprehensive review on this interesting disorder focusing light on its etiology, genetic research and emerging therapy.

PMID: 32181277 [PubMed]

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Gene therapy and genome editing for primary immunodeficiency diseases.

Genes Dis. 2020 Mar;7(1):38-51

Authors: Zhang ZY, Thrasher AJ, Zhang F

Abstract
In past two decades the gene therapy using genetic modified autologous hematopoietic stem cells (HSCs) transduced with the viral vector has become a promising alternative option for treating primary immunodeficiency diseases (PIDs). Despite of some pitfalls at early stage clinical trials, the field of gene therapy has advanced significantly in the last decade with improvements in viral vector safety, preparatory regime for manufacturing high quality virus, automated CD34 cell purification. Hence, the overall outcome from the clinical trials for the different PIDs has been very encouraging. In addition to the viral vector based gene therapy, the recent fast moving forward developments in genome editing using engineered nucleases in HSCs has provided a new promising platform for the treatment of PIDs. This review provides an overall outcome and progress in gene therapy clinical trials for SCID-X, ADA-SCID, WAS, X- CGD, and the recent developments in genome editing technology applied in HSCs for developing potential therapy, particular in the key studies for PIDs.

PMID: 32181274 [PubMed]

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Recent advances in elucidating the genetics of common variable immunodeficiency.

Genes Dis. 2020 Mar;7(1):26-37

Authors: Aggarwal V, Banday AZ, Jindal AK, Das J, Rawat A

Abstract
Common variable immunodeficiency disorders (CVID), a heterogeneous group of inborn errors of immunity, is the most common symptomatic primary immunodeficiency disorder. Patients with CVID have highly variable clinical presentation. With the advent of whole genome sequencing and genome wide association studies (GWAS), there has been a remarkable improvement in understanding the genetics of CVID. This has also helped in understanding the pathogenesis of CVID and has drastically improved the management of these patients. A multi-omics approach integrating the DNA sequencing along with RNA sequencing, proteomics, epigenetic and metabolomics profile is the need of the hour to unravel specific CVID associated disease pathways and novel therapeutic targets. In this review, we elaborate various techniques that have helped in understanding the genetics of CVID.

PMID: 32181273 [PubMed]

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An updated review on phenocopies of primary immunodeficiency diseases.

Genes Dis. 2020 Mar;7(1):12-25

Authors: Singh A, Jindal AK, Joshi V, Anjani G, Rawat A

Abstract
Primary immunodeficiency diseases (PIDs) refer to a heterogenous group of disorders characterized clinically by increased susceptibility to infections, autoimmunity and increased risk of malignancies. These group of disorders present with clinical manifestations similar to PIDs with known genetic defects but have either no genetic defect or have a somatic mutation and thus have been labelled as “Phenocopies of PIDs”. These diseases have been further subdivided into those associated with somatic mutations and those associated with presence of auto-antibodies against various cytokines. In this review, we provide an update on clinical manifestations, diagnosis and management of these diseases.

PMID: 32181272 [PubMed]

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Current status and prospects of primary immunodeficiency diseases in Asia.

Genes Dis. 2020 Mar;7(1):3-11

Authors: Pilania RK, Chaudhary H, Jindal AK, Rawat A, Singh S

Abstract
Primary Immunodeficiency Diseases (PIDs) are increasingly being reported across the World. Several advances have been made in the diagnostic and therapeutic research related to PIDs. With increasing awareness, the field of PIDs has rapidly evolved in Asia as well. In this review, we summarize the progress that has been made in the field of PIDs in Asian countries; major limitations and challenges faced by the clinicians working in this field in Asia; difference in spectrum of PIDs in Asia from rest of the World; current state of diagnostic and treatment facilities available in various countries in Asia and the future prospects of these diseases in the continent.

PMID: 32181271 [PubMed]

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