Manish Butte

Recent advances in primary immunodeficiency: from molecular diagnosis to treatment.

F1000Res. 2020;9:

Authors: Bucciol G, Meyts I

Abstract
The technological advances in diagnostics and therapy of primary immunodeficiency are progressing at a fast pace. This review examines recent developments in the field of inborn errors of immunity, from their definition to their treatment. We will summarize the challenges posed by the growth of next-generation sequencing in the clinical setting, touch briefly on the expansion of the concept of inborn errors of immunity beyond the classic immune system realm, and finally review current developments in targeted therapies, stem cell transplantation, and gene therapy.

PMID: 32226610 [PubMed – in process]

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Identification of human peripheral blood monocyte gene markers for early screening of solid tumors.

PLoS One. 2020;15(3):e0230905

Authors: Chen S, Liu M, Liang B, Ge S, Peng J, Huang H, Xu Y, Tang X, Deng L

Abstract
As cancer mortality is high in most regions of the world, early screening of cancer has become increasingly important. Minimally invasive screening programs that use peripheral blood mononuclear cells (PBMCs) are a new and reliable strategy that can achieve early detection of tumors by identifying marker genes. From 797 datasets, four (GSE12771, GSE24536, GSE27562, and GSE42834) including 428 samples, 236 solid tumor cases, and 192 healthy controls were chosen according to the inclusion criteria. A total of 285 genes from among 440 reported genes were selected by meta-analysis. Among them, 4 of the top significantly differentially expressed genes (ANXA1, IFI44, IFI44L, and OAS1) were identified as marker genes of PBMCs. Pathway enrichment analysis identified, two significant pathways, the ‘primary immunodeficiency’ pathway and the ‘cytokine-cytokine receptor interaction’ pathway. Protein- protein interaction (PPI) network analysis revealed the top 27 hubs with a degree centrality greater than 23 to be hub genes. We also identified 3 modules in Molecular Complex Detection (MCODE) analysis: Cluster 1 (related to ANXA1), Cluster 2 (related to IFI44 and IFI44L) and Cluster 3 (related to OAS1). Among the 4 marker genes, IFI44, IFI44L, and OAS1 are potential diagnostic biomarkers, even though their results were not as remarkable as those for ANXA1 in our study. ANXA1 is involved in the immunosuppressive mechanism in tumor-bearing hosts and may be used in a new strategy involving the use of the host’s own immunity to achieve tumor suppression.

PMID: 32226026 [PubMed – in process]

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COVID-19: Pandemic Contingency Planning for the Allergy and Immunology Clinic.

J Allergy Clin Immunol Pract. 2020 Mar 26;:

Authors: Shaker MS, Oppenheimer J, Grayson M, Stukus D, Hartog N, Hsieh EWY, Rider N, Dutmer CM, Vander Leek TK, Kim H, Chan ES, Mack D, Ellis AK, Lang D, Lieberman J, Fleischer D, Golden DBK, Wallace D, Portnoy J, Mosnaim G, Greenhawt M

Abstract
In the event of a global infectious pandemic, drastic measures may be needed that limit or require adjustment of ambulatory allergy services. However, no rationale for how to prioritize service shut down and patient care exists. A consensus-based ad-hoc expert panel of allergy/immunology specialists from the United States and Canada developed a service and patient prioritization schematic to temporarily triage allergy/immunology services. Recommendations and feedback were developed iteratively, using an adapted modified Delphi methodology to achieve consensus. During the ongoing pandemic while social distancing is being encouraged, most allergy/immunology care could be postponed/delayed or handled through virtual care. With the exception of many patients with primary immunodeficiency, patients on venom immunotherapy, and patients with asthma of a certain severity, there is limited need for face-to-face visits under such conditions. These suggestions are intended to help provide a logical approach to quickly adjust service to mitigate risk to both medical staff and patients. Importantly, individual community circumstances may be unique and require contextual consideration. The decision to enact any of these measures rests with the judgment of each clinician and individual health care system. Pandemics are unanticipated, and enforced social distancing/quarantining is highly unusual. This expert panel consensus document offers a prioritization rational to help guide decision making when such situations arise and an allergist/immunologist is forced to reduce services or makes the decision on his or her own to do so.

PMID: 32224232 [PubMed – as supplied by publisher]

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Immunoglobulin G (IgG) and IgG Subclass Concentrations Differ According to Sex and Race.

Ann Allergy Asthma Immunol. 2020 Mar 26;:

Authors: Harkness T, Fu X, Zhang Y, Choi HK, Stone JH, Blumenthal KG, Wallace ZS

Abstract
BACKGROUND: Serum immunoglobulin G (IgG) concentrations are integral to the workup of immune deficiencies and IgG4-related disease (IgG4-RD). Demographic differences in IgG concentrations are poorly described but could influence test interpretation, contribute to racial disparities in primary immunodeficiency diagnosis, and explain demographic differences in IgG concentrations in IgG4-RD.
OBJECTIVE: To assess differences in IgG and IgG subclass concentrations according to sex and race.
METHODS: We identified patients with IgG and IgG subclass concentrations measured in a large healthcare system. Multivariate-adjusted differences in IgG and IgG subclass concentrations and the proportion of subjects with results outside of reference ranges according to sex and race were estimated.
RESULTS: Of the 12,851 patients, the mean age was 54.7 years and 7,917 (62%) were female. 11,673 (91%), 611 (5%), and 302 (2%) were White, Black, and Asian, respectively. Compared to White patients, Asian and Black patients had higher mean concentrations of IgG (1340.0 and 1504.4 vs. 988.1 mg/dL; p<0.001), IgG1 (782.0 and 938.4 vs. 592.4 mg/dL, p<0.001), IgG2 (493.5 and 384.2 vs. 305 mg/dL; p<0.001), IgG3 (76.6 and 91.9 vs. 55.9 mg/dL; p<0.001), and IgG4 (140.4 and 53.6 vs. 41.6 mg/dL; p<0.001). IgG4 concentrations were higher in males than females (56.3 vs. 37.4 mg/dL; p < 0.001). Similar observations were made when comparing the proportions of patients with results outside of reference ranges and after stratifying by diagnosis.
CONCLUSION: IgG and IgG subclass concentrations differ according to sex and race. These findings may have implications for the interpretation of these test results but require confirmation in diverse, healthy populations.

PMID: 32224206 [PubMed – as supplied by publisher]

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Current and emerging biologics for the treatment of hereditary angioedema.

Expert Opin Biol Ther. 2019 06;19(6):517-526

Authors: Perego F, Wu MA, Valerieva A, Caccia S, Suffritti C, Zanichelli A, Bergamaschini L, Cicardi M

Abstract
INTRODUCTION: Hereditary angioedema due to C1-INH deficiency (C1-INH-HAE) is a rare disease with unpredictable, self-limiting and localized swelling episodes involving the cutaneous and subcutaneous tissues. In the last decade, the spectrum of the possibilities to control the disease has considerably changed with the development of biologic therapies making necessary a careful evaluation of the differences among current and emerging treatments to properly optimize the management of patients.
AREAS COVERED: This review serves to summarize the literature regarding the use of biologics for the treatment of C1-INH-HAE. Medications already available on the market and new drugs in different phases of development are addressed.
EXPERT OPINION: The advent of biologic therapies dramatically improved the lives of patients with C1-INH-HAE although further improvement is still needed. Whether this is cost/effective will be answered in the next years when we will see if these major advances will benefit the majority of the patients.

PMID: 30912460 [PubMed – indexed for MEDLINE]

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Genetic diagnosis of autoinflammatory disease patients using clinical exome sequencing.

Eur J Med Genet. 2020 Mar 25;:103920

Authors: Batlle-Masó L, Mensa-Vilaró A, Solís-Moruno M, Marquès-Bonet T, Arostegui JI, Casals F

Abstract
Autoinflammatory diseases comprise a wide range of syndromes caused by dysregulation of the innate immune response. They are difficult to diagnose due to their phenotypic heterogeneity and variable expressivity. Thus, the genetic origin of the disease remains undetermined for an important proportion of patients. We aim to identify causal genetic variants in patients with suspected autoinflammatory disease and to test the advantages and limitations of the clinical exome gene panels for molecular diagnosis. Twenty-two unrelated patients with clinical features of autoinflammatory diseases were analyzed using clinical exome sequencing (∼4800 genes), followed by bioinformatic analyses to detect likely pathogenic variants. By integrating genetic and clinical information, we found a likely causative heterozygous genetic variant in NFKBIA (p.D31N) in a North-African patient with a clinical picture resembling the deficiency of interleukin-1 receptor antagonist, and a heterozygous variant in DNASE2 (p.G322D) in a Spanish patient with a suspected lupus-like monogenic disorder. We also found variants likely to increase the susceptibility to autoinflammatory diseases in three additional Spanish patients: one with an initial diagnosis of juvenile idiopathic arthritis who carries two heterozygous UNC13D variants (p.R727Q and p.A59T), and two with early-onset inflammatory bowel disease harbouring NOD2 variants (p.L221R and p.A728V respectively). Our results show a similar proportion of molecular diagnosis to other studies using whole-exome or targeted resequencing in primary immunodeficiencies. Thus, despite its main limitation of not including all candidate genes, clinical exome targeted sequencing can be an appropriate approach to detect likely causative variants in autoinflammatory diseases.

PMID: 32222431 [PubMed – as supplied by publisher]

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