Blog

Primary immunodeficiency with chronic enteropathy and developmental delay in a boy arising from a novel homozygous RIPK1 variant.

June 20, 2019 By Manish Butte

Primary immunodeficiency with chronic enteropathy and developmental delay in a boy arising from a novel homozygous RIPK1 variant.

J Hum Genet. 2019 Jun 18;:

Authors: Uchiyama Y, Kim CA, Pastorino AC, Ceroni J, Lima PP, de Barros Dorna M, Honjo RS, Bertola D, Hamanaka K, Fujita A, Mitsuhashi S, Miyatake S, Takata A, Miyake N, Mizuguchi T, Matsumoto N

Abstract
Identification of genetic causes of primary monogenic immunodeficiencies would strengthen the current understanding of their immunopathology. Pathogenic variants in genes in association with tumor necrosis factor α (TNFα) signaling, including OTULIN, TNFAIP3, RBCK1, and RNF31 cause human congenital autoinflammatory diseases with/without immunodeficiency. RIPK1, encoding a receptor interacting serine/threonine kinase 1, is present in protein complexes mediating signal transduction including TNF receptor 1. Biallelic loss-of-function variants in RIPK1 were recently reported in individuals with primary immunodeficiency with intestinal bowel disease and arthritis. Here, we report a novel homozygous RIPK1 variant in a boy with immunodeficiency and chronic enteropathy. Our patient exhibited severe motor delay and mild intellectual disability, which were previously unknown. The present results are expected to deepen the current understanding of clinical features based on RIPK1 abnormalities.

PMID: 31213653 [PubMed – as supplied by publisher]

Systemic lupus erythematosus and immunodeficiency.

June 18, 2019 By Manish Butte

Systemic lupus erythematosus and immunodeficiency.

Immunol Med. 2019 Jun 17;:1-9

Authors: Sawada T, Fujimori D, Yamamoto Y

Abstract
Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease that develops in genetically susceptible individuals in response to environmental factors. SLE and primary immunodeficiency disease (PID) share some clinical manifestations in that certain PIDs present with autoimmune phenomena. Patients with SLE become susceptible to infection via three pathways. First, SLE and PID share some genetic factors, such as complement and mannose-binding lectin genes, which predispose patients to infection. Second, patients with SLE have an inherently high risk of infection because of their intrinsic immunological abnormalities induced by SLE. Third, patients with SLE receiving immunosuppressive treatment are at high risk of infection. Further studies delineating the abnormalities related to both autoimmunity and immunodeficiency would be warranted to identify a new potential drug target for SLE.

PMID: 31204893 [PubMed – as supplied by publisher]

Bacille Calmette-Guerin (BCG) complications in children with severe combined immunodeficiency (SCID).

June 18, 2019 By Manish Butte

Bacille Calmette-Guerin (BCG) complications in children with severe combined immunodeficiency (SCID).

Infect Dis (Lond). 2019 Jun 17;:1-8

Authors: Barkai G, Somech R, Stauber T, Barziali A, Greenberger S

Abstract
Background: Bacille Calmette-Guerin (BCG) is included in the routine vaccination program in Gaza and the West Bank. Although safe, complications can occur and include local, extra-regional and disseminated BCG infection. Therefore it is contraindicated in immunodeficiencies. However, most infants are immunized prior to diagnosis of immunodeficiency. We report clinical and immunological characteristics of patients referred with severe combined immunodeficiency (SCID) who suffered from BCG complications. Methods: Files of patients referred for evaluation of immunodeficiency from January 2008 to February 2016 were retrieved. All patients have received BCG. Cell surface markers of peripheral blood mononuclear cells (PBMCs) were measured by immunofluorescent staining and flow cytometry. Serum concentrations of immunoglobulins were measured using nephelometry. Genetic diagnosis of SCID was made by direct Sanger sequencing of candidate genes. BCG complications were classified as: a) local; b) regional; c) distant; and d) disseminated disease. Results: Twenty-one children were diagnosed with SCID. BCG complications were diagnosed in 12 (57.1%). Eight patients developed local and regional disease (67%) and 4 (33%) had disseminated infection. Patients received at least three drugs: isoniazid, ethambutol and rifampicin. Outcome was relatively favorable with eight patients surviving (66.6%). No death related to BCG infection was observed. Disseminated disease was associated with reduced numbers of total lymphocytes, CD3 and CD8 levels (p < .05). Conclusions: Although high rates of BCG complications were observed, mortality was not increased and outcomes were good. Increased awareness in countries where BCG vaccine is not routinely administered and newborn screening programs for SCID could reduce complication rates.

PMID: 31204539 [PubMed – as supplied by publisher]

Exome sequencing in routine diagnostics: a generic test for 254 patients with primary immunodeficiencies.

June 18, 2019 By Manish Butte

Exome sequencing in routine diagnostics: a generic test for 254 patients with primary immunodeficiencies.

Genome Med. 2019 Jun 17;11(1):38

Authors: Arts P, Simons A, AlZahrani MS, Yilmaz E, AlIdrissi E, van Aerde KJ, Alenezi N, AlGhamdi HA, AlJubab HA, Al-Hussaini AA, AlManjomi F, Alsaad AB, Alsaleem B, Andijani AA, Asery A, Ballourah W, Bleeker-Rovers CP, van Deuren M, van der Flier M, Gerkes EH, Gilissen C, Habazi MK, Hehir-Kwa JY, Henriet SS, Hoppenreijs EP, Hortillosa S, Kerkhofs CH, Keski-Filppula R, Lelieveld SH, Lone K, MacKenzie MA, Mensenkamp AR, Moilanen J, Nelen M, Ten Oever J, Potjewijd J, van Paassen P, Schuurs-Hoeijmakers JHM, Simon A, Stokowy T, van de Vorst M, Vreeburg M, Wagner A, van Well GTJ, Zafeiropoulou D, Zonneveld-Huijssoon E, Veltman JA, van Zelst-Stams WAG, Faqeih EA, van de Veerdonk FL, Netea MG, Hoischen A

Abstract
BACKGROUND: Diagnosis of primary immunodeficiencies (PIDs) is complex and cumbersome yet important for the clinical management of the disease. Exome sequencing may provide a genetic diagnosis in a significant number of patients in a single genetic test.
METHODS: In May 2013, we implemented exome sequencing in routine diagnostics for patients suffering from PIDs. This study reports the clinical utility and diagnostic yield for a heterogeneous group of 254 consecutively referred PID patients from 249 families. For the majority of patients, the clinical diagnosis was based on clinical criteria including rare and/or unusual severe bacterial, viral, or fungal infections, sometimes accompanied by autoimmune manifestations. Functional immune defects were interpreted in the context of aberrant immune cell populations, aberrant antibody levels, or combinations of these factors.
RESULTS: For 62 patients (24%), exome sequencing identified pathogenic variants in well-established PID genes. An exome-wide analysis diagnosed 10 additional patients (4%), providing diagnoses for 72 patients (28%) from 68 families altogether. The genetic diagnosis directly indicated novel treatment options for 25 patients that received a diagnosis (34%).
CONCLUSION: Exome sequencing as a first-tier test for PIDs granted a diagnosis for 28% of patients. Importantly, molecularly defined diagnoses indicated altered therapeutic options in 34% of cases. In addition, exome sequencing harbors advantages over gene panels as a truly generic test for all genetic diseases, including in silico extension of existing gene lists and re-analysis of existing data.

PMID: 31203817 [PubMed – in process]

Gain-of-function CEBPE mutation causes non-canonical autoinflammatory inflammasomopathy.

June 16, 2019 By Manish Butte

Gain-of-function CEBPE mutation causes non-canonical autoinflammatory inflammasomopathy.

J Allergy Clin Immunol. 2019 Jun 12;:

Authors: Göös H, Fogarty CL, Sahu B, Plagnol V, Rajamäki K, Nurmi K, Liu X, Einarsdottir E, Jouppila A, Pettersson T, Vihinen H, Krjutskov K, Saavalainen P, Järvinen A, Muurinen M, Greco D, Scala G, Curtis J, Nordström D, Flaumenhaft R, Vaarala O, Kovanen PE, Keskitalo S, Ranki A, Kere J, Lehto M, Notarangelo LD, Nejentsev S, Eklund KK, Varjosalo M, Taipale J, Seppänen MR

Abstract
BACKGROUND: C/EBPε is a transcription factor involved in late myeloid lineage differentiation and cellular function. The only previously known disorder linked to C/EBPε is the autosomal recessive neutrophil-specific granule deficiency leading to severely impaired neutrophil function and early mortality.
OBJECTIVE: The aim was to molecularly characterize the effects of C/EBPε transcription factor’s Arg219His mutation, identified in Finnish family with previously genetically uncharacterized autoinflammatory and immunodeficiency syndrome.
METHODS: Genetic analysis, proteomics, genome-wide transcriptional profiling by RNA-sequencing, ChIP-sequencing and assessment of the inflammasome function of primary macrophages were performed.
RESULTS: Studies revealed a novel mechanism of genome-wide gain-of-function that dysregulated transcription of 464 genes. Mechanisms involved dysregulated non-canonical inflammasome activation due to decreased association with transcriptional repressors leading to increased chromatin occupancy and considerable changes in transcriptional activity including increased expression of NLRP3 and constitutively expressed caspase-5 in macrophages.
CONCLUSION: We describe a novel autoinflammatory disease with defective neutrophil function caused by homozygous Arg219His mutation in transcription factor C/EBPε. Mutated C/EBPε acts as a regulator of both the inflammasome and interferome, and the Arg219His mutation causes the first human monogenic neomorphic and non-canonical inflammasomopathy/immunodeficiency. The mechanism, including widely dysregulated transcription, is likely not unique for C/EBPε. Similar multiomics approaches should as well be utilized in studying other transcription factor-associated diseases.

PMID: 31201888 [PubMed – as supplied by publisher]

[Chronic granulomatous disease. Update and review].

June 15, 2019 By Manish Butte

[Chronic granulomatous disease. Update and review].

Rev Alerg Mex. 2019 Apr-Jun;66(2):232-245

Authors: López-Hernández I, Suárez-Gutiérrez M, Santos-Chávez EE, Espinosa S, Blancas-Galicia L

Abstract
Chronic granulomatous disease (CGD) is a primary immunodeficiency syndrome which is characterized by increased susceptibility to severe fungal and bacterial infections. CGD is the result of the lack of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme in the patient’s phagocytes to produce superoxide. It is characterized by recurrent infections with a narrow spectrum of bacteria and fungi, as well as a common set of inflammatory complications, including inflammatory bowel disease. The most frequently found pathogens are Staphylococcus aureus, species of Aspergillus, species of Klebsiella, Burkholderia cepacia, Serratia marcescens and species of Salmonella. Long term antibiotic prophylaxis has helped fight infections associated with chronic granulomatous disease, while the steady progress in bone marrow transplants and the possibility of gene therapy are defined as permanent treatment options.

PMID: 31200421 [PubMed – in process]

Safety and efficacy of ex vivo expanded CD34+ stem cells in murine and primate models.

June 15, 2019 By Manish Butte

Safety and efficacy of ex vivo expanded CD34+ stem cells in murine and primate models.

Stem Cell Res Ther. 2019 Jun 13;10(1):173

Authors: Zhang Y, Shen B, Guan X, Qin M, Ren Z, Ma Y, Dai W, Ding X, Jiang Y

Abstract
BACKGROUND: Hematopoietic stem cell (HSC) transplantation has been widely applied to the treatment of malignant blood diseases. However, limited number of functional HSCs hinders successful transplantation. The purpose of our current study is to develop a new and cost-efficient medium formulation that could greatly enhance the expansion of HSCs while retaining their long-term repopulation and hematopoietic properties for effective clinical transplantation.
METHODS: Enriched human CD34+ cells and mobilized nonhuman primate peripheral blood CD34+ cells were expanded with a new, cost-efficient expansion medium formulation, named hematopoietic expansion medium (HEM), consisting of various cytokines and nutritional supplements. The long-term repopulation potential and hematologic-lineage differentiation ability of expanded human cells were studied in the non-obese diabetic/severe combined immunodeficiency mouse model. Furthermore, the efficacy and safety studies were performed by autologous transplantation of expanded primate cells in the nonhuman primate model.
RESULTS: HEM could effectively expand human CD34+ cells by up to 129 fold within 9 days. Expanded HSCs retained long-term repopulation potential and hematologic-lineage differentiation ability, as indicated by (1) maintenance (over unexpanded HSCs) of immunophenotypes of CD38-CD90+CD45RA-CD49f+ in CD34+ cells after expansion; (2) significant presence of multiple human hematopoietic lineages in mouse peripheral blood and bone marrow following primary transplantation; (3) enrichment (over unexpanded HSCs) in SCID-repopulating cell frequency measured by limiting dilution analysis; and (4) preservation of both myeloid and lymphoid potential among human leukocytes from mouse bone marrow in week 24 after primary transplantation or secondary transplantation. Moreover, the results of autologous transplantation in nonhuman primates demonstrated that HEM-expanded CD34+ cells could enhance hematological recovery after myelo-suppression. All primates transplanted with the expanded autologous CD34+ cells survived for over 18 months without any noticeable abnormalities.
CONCLUSIONS: Together, these findings demonstrate promising potential for the utility of HEM to improve expansion of HSCs for clinical application.

PMID: 31196160 [PubMed – in process]

Primary cutaneous CD8+ CD30+ lymphoproliferative disorder in a patient with acquired CD4 immunodeficiency.

June 15, 2019 By Manish Butte

Primary cutaneous CD8+ CD30+ lymphoproliferative disorder in a patient with acquired CD4 immunodeficiency.

G Ital Dermatol Venereol. 2019 Jun 12;:

Authors: Pileri A, Gunnella S, Grandi V, Maio V, Santucci M, Pimpinelli N, Lymphoma Italian Foundation (Fondazione Italiana Linfomi, FIL) – Cutaneous Lymphoma Task Force (Commissione Linfomi Cutanei)

PMID: 31195783 [PubMed – as supplied by publisher]

Pediatric Toxic Shock Syndrome After a 7% Burn: A Case Study and Systematic Literature Review.

June 14, 2019 By Manish Butte

Pediatric Toxic Shock Syndrome After a 7% Burn: A Case Study and Systematic Literature Review.

Ann Plast Surg. 2019 Jun 11;:

Authors: Khajuria A, Nadama HH, Gallagher M, Jones I, Atkins J

Abstract
INTRODUCTION: Toxic shock syndrome (TSS) is a life-threatening condition, which occurs in children after sustaining a burn. Often diagnosed retrospectively, many patients may not receive optimal treatment.The primary objective of this study was to evaluate a severe and complex case of TSS at our unit and subsequently conduct a Preferred Reporting for Systematic Reviews and Meta-Analyses-compliant systematic literature review, to identify cases of postthermal injury TSS and evaluate their presentation and management.
CASE REPORT: A 9-year-old boy with Down syndrome presented with a 7% total body surface area scald to his back and posterior head. Four days after discharge, he developed a fever. The following day, he deteriorated, becoming stridulous and unresponsive. A working diagnosis of TSS was made. The patient’s intensive care stay was arduous with multiple complications, including 2 cardiac arrests.
METHODS: A Preferred Reporting for Systematic Reviews and Meta-Analyses-compliant systematic literature review was conducted. MEDLINE, PubMed, and Web of Science were searched using key terms “burns, thermal injury, scalds, paediatric, child, infant, neonate, toxic shock syndrome” to identify cases. Two authors independently checked each study against inclusion criteria.
RESULTS: The systematic literature search yielded 9 articles, identifying 40 cases. Ages ranged between 9 months and 8 years. The mean number of days’ postburn patients presented with symptoms of TSS was 2.5 days (1-7 days). The most common presenting symptoms were fever (75%), rash (70%), and diarrhea, and/or vomiting (52.5%). Intravenous immunoglobulins were administered in 11 (27.5%) cases.
DISCUSSION: We have highlighted a case where a possible delayed diagnosis along with the immunodeficiency seen in Down syndrome may have impacted the severity of TSS. The literature review highlighted that a significant proportion of patients do not meet diagnostic criteria.
CONCLUSIONS: It is fundamental that appropriate diagnostic and management guidelines are developed. Furthermore, this case highlights the importance of educating patient’s carers and health professionals of key symptoms to be wary of postburn.

PMID: 31192868 [PubMed – as supplied by publisher]

Peripheral Neuropathy Due to Common Variable Immunodeficiency: Case Report and Narrative Review.

June 14, 2019 By Manish Butte

Peripheral Neuropathy Due to Common Variable Immunodeficiency: Case Report and Narrative Review.

Gerontol Geriatr Med. 2019 Jan-Dec;5:2333721419850644

Authors: Long CP, Suzuki H, Vitale K

Abstract
A 63-year-old woman with common variable immunodeficiency (CVID) presented with 1 year of insidious onset lower extremity pain and weakness. She underwent a circuitous workup, failed to improve despite treatment for various presumed diagnoses. She presented to a University physical medicine and rehabilitation clinic with continued symptoms. Electrophysiologic testing was recommended revealing a lower extremity motor greater than sensory axonal neuropathy. While CVID has known central nervous system complications, to our knowledge, this represents the second known reported case of peripheral neuropathy. We review the literature on CVID and summarize neurological disease mechanisms and manifestations. Although peripheral neuropathy is a rarely documented complication of CVID, providers need to be aware of potential peripheral nervous system complications of primary immune deficiencies such as CVID due to its significant impact on physical performance, balance, and fall risks.

PMID: 31192279 [PubMed]