Manish Butte

A Case With Wiskott-Aldrich Syndrome and Ascending Aorta Aneurysm.

J Pediatr Hematol Oncol. 2020 Sep 02;:

Authors: Barutcu A, Leblebisatan G, Leblebisatan S, Cil M, Sasmaz HI, Demir F

Abstract
Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency disorder that is characterized by a triad of microthrombocytopenia, severe immunodeficiency, and eczema. We report the case of a 7-year-old male patient with chronic thrombocytopenia that was diagnosed as WAS after dilatation of the ascending aorta was noticed. WAS is rare, and it is a disease that requires high suspicion for diagnosis. We recommend periodic echocardiography and magnetic resonance imaging examinations to evaluate aortic aneurysms in children with WAS and that surgical intervention should not be delayed when aneurysm is detected.

PMID: 32890078 [PubMed – as supplied by publisher]

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Efficacy and economics of targeted panel versus whole exome sequencing in 878 patients with suspected primary immunodeficiency.

J Allergy Clin Immunol. 2020 Sep 01;:

Authors: Platt CD, Zaman F, Bainter W, Stafstrom K, Almutairi A, Reigle M, Weeks S, Geha RS, Chou J, International Consortium for Immunodeficiencies

Abstract
BACKGROUND: NGS has become a first-line tool for diagnosis of PID. However, patient access remains limited due to restricted insurance coverage and a lack of guidelines addressing use of targeted panels vs WES.
OBJECTIVES: To compare targeted next generation sequencing (NGS) with whole exome sequencing (WES) in a global population of patients with primary immunodeficiency (PID).
METHODS: This is a longitudinal study of 878 patients with likely PID sequenced between 2010 and 2020. The majority of patients (n=780) were first sequenced using a 264 gene panel. This was followed by WES in selected cases if a candidate gene was not found. A subset of patients (n=98) were selected for a WES-only pipeline if the history was atypical for genes within the targeted panel.
RESULTS: Disease-causing variants were identified in 498 of the 878 probands (56%), encompassing 152 distinct monogenic disorders. Sixteen patients had disorders that were novel at the time of sequencing (1.8%). Diagnostic yield in patients sequenced by targeted panel was 56% (433 of 780 patients) with subsequent WES leading to an additional 18 diagnoses (overall diagnostic yield 58%, 451 of 780 patients). The WES-only approach had a diagnostic yield of 45% (45 of 98 patients), reflecting that these cases had less common clinical and laboratory phenotypes. Cost analysis, based on current commercial WES and targeted panel prices, demonstrated savings ranging from $300-$950 with a WES-only approach, depending on diagnostic yield.

PMID: 32888943 [PubMed – as supplied by publisher]

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Phase 2 multiple-dose study of an FcRn inhibitor, rozanolixizumab, in patients with primary immune thrombocytopenia.

Blood Adv. 2020 Sep 08;4(17):4136-4146

Authors: Robak T, Kaźmierczak M, Jarque I, Musteata V, Treliński J, Cooper N, Kiessling P, Massow U, Woltering F, Snipes R, Ke J, Langdon G, Bussel JB, Jolles S

Abstract
Primary immune thrombocytopenia (ITP) is a predominantly immunoglobulin G (IgG)-autoantibody-mediated disease characterized by isolated thrombocytopenia. Rozanolixizumab, a subcutaneously infused humanized monoclonal anti-neonatal Fc receptor (FcRn) antibody, reduced serum IgG in healthy volunteers. In this phase 2, multicenter, open-label study, patients with persistent/chronic primary ITP received 1 to 5 once-weekly subcutaneous infusions of rozanolixizumab (cumulative doses, 15-21 mg/kg). Primary objectives were safety and tolerability, and secondary objectives were clinical efficacy (change in platelet count) and pharmacodynamic effect (change in IgG). In all, 51 (77.3%) of 66 patients reported 1 or more adverse events (AEs), all mild-to-moderate, most commonly headaches (26 [39.4%] of 66), of which 15 were treatment related. Four patients had serious AEs, but none were treatment related. No AEs resulted in discontinuation of the study drug. No serious infections occurred. Platelet counts of ≥50 × 109/L were achieved at least once at any time after multiple infusions (5 × 4, 3 × 7, or 2 × 10 mg/kg: 35.7%, 35.7%, and 45.5% of patients, respectively) or single infusions (15 or 20 mg/kg: 66.7% and 54.5% patients, respectively). Minimum mean IgG levels and maximum mean platelet counts both occurred by day 8 in the higher (15 and 20 mg/kg) single-dose cohorts and maximum platelet count occurred by day 11 onward in the multiple-dose cohorts. No clinically meaningful changes occurred in IgA, IgM, IgE, or albumin levels. In patients with persistent/chronic primary ITP, rozanolixizumab demonstrated a favorable safety profile and rapid, substantial platelet increases concordant with substantial IgG reductions, especially with single doses. By day 8, in the 15 and 20 mg/kg single-dose cohorts, >50% patients achieved clinically relevant platelet responses (≥50 × 109/L), coinciding with the lowest mean IgG levels. These data support phase 3 development of rozanolixizumab in persistent/chronic primary ITP. This trial was registered at www.clinicaltrials.gov as #NCT02718716.

PMID: 32886753 [PubMed – as supplied by publisher]

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Low Plasma Gelsolin Concentrations in Chronic Granulomatous Disease.

Inflammation. 2020 Sep 04;:

Authors: Audley J, Gliniewicz EF, Zarember KA, Hong HS, Wald G, Kuhns DB, Kang E, Malech HL, Suffredini AF, Noveck RJ, Dinubile MJ, Levinson SL, Stossel TP, Gallin JI

Abstract
Plasma gelsolin (pGSN) is the secreted isoform of an intracellular actin remodeling protein found in high concentrations in human plasma. Clinical studies demonstrate reduced pGSN concentrations in several disease states, including severe trauma, burns, and sepsis. Markedly decreased pGSN concentrations in these conditions precede and predict adverse clinical outcomes. In this study, we measured pGSN in patients with chronic granulomatous disease (CGD), a primary immunodeficiency characterized by recurrent infections and dysregulated inflammation. pGSN was quantified using a sandwich ELISA in plasma from healthy volunteers, clinically stable CGD patients, and X-linked CGD carriers and in sera from 12 CGD patients undergoing bone marrow transplantation. pGSN was also quantified in healthy volunteers challenged with intravenous endotoxin. pGSN concentrations were lower in CGD patients without active infection or systemic inflammation compared with healthy control subjects. In CGD patients undergoing bone marrow transplantation, pGSN concentrations increased significantly following successful transplant. X-linked carriers of CGD had normal pGSN. Despite reduction of pGSN in CGD patients, we did not detect significant changes in pGSN over 24 h following challenge of healthy volunteers with intravenous endotoxin (4 ng/kg) that elicited a febrile response. We describe, for the first time, significantly lower pGSN in clinically stable patients with CGD compared with age- and sex-matched healthy volunteers. Low pGSN levels in CGD patients significantly increased following bone marrow transplantation. X-linked carriers of CGD had normal pGSN. In healthy volunteers challenged with intravenous endotoxin, pGSN is not an acute phase reactant.

PMID: 32886268 [PubMed – as supplied by publisher]

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CD8-positive Cutaneous Lymphoproliferation Associated with Large Granular Lymphocyte Leukemia in a Patient with X-linked Agammaglobulinemia.

J Cutan Pathol. 2020 Sep 03;:

Authors: Daou H, Hatch LA, Weinkle A, Morey GE, Messina J, Zhang X, Sokol L, Seminario-Vidal L

Abstract
Patients with primary immunodeficiency are at increased risk for malignancy, especially hematologic neoplasms. This paper reports a unique case of a 47-year-old man with X-linked agammaglobulinemia who presented with progressive asymptomatic violaceous papules and plaques on his face, hands and trunk for one year. Skin biopsies revealed deep, nodular infiltrates of histiocytes and CD8-positive lymphocytes with a CD4:CD8 ratio of 1:10. Laboratory studies demonstrated cytopenias. Flow cytometry in the skin, blood, and bone marrow (BM) showed a CD3+/CD8+/CD57+ large granular lymphocyte population. BM biopsy showed 30% involvement with these atypical T-cells. T-cell gene rearrangement studies of skin, blood and BM revealed identical T-cell clones. He was diagnosed with T-large granular lymphocyte leukemia (T-LGLL) with an associated CD8+ cutaneous lymphoproliferation. Skin involvement was suspected to represent infiltration by T-LGLL. However, co-existence of two lymphoproliferative disorders, T-LGLL and CD8+ granulomatous lymphoproliferative disorder, remains a possibility. In general, cutaneous infiltrates associated with LGLL are rare and poorly understood. It has been suggested that they are markers of poor prognosis. Our case report describes skin, blood, and bone marrow findings in an immunosuppressed patient with T-LGLL in detail. These findings have not yet been reported and their significance requires further investigation. This article is protected by copyright. All rights reserved.

PMID: 32885480 [PubMed – as supplied by publisher]

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Hematopoietic Stem Cell Transplantation in Children with Inborn Errors of Immunity: a Multi-center Experience in Colombia.

J Clin Immunol. 2020 Sep 02;:

Authors: Olaya M, Franco A, Chaparro M, Estupiñan M, Aristizabal D, Builes-Restrepo N, Franco JL, Zea-Vera AF, Estacio M, Manzi E, Beltran E, Perez P, Patiño J, Pachajoa H, Medina-Valencia D

Abstract
PURPOSE: To characterize the pediatric population with inborn errors of immunity (IEI) that was treated with hematopoietic stem cell transplantation (HSCT) in three reference centers in Colombia. What have been the characteristics and outcomes of hematopoietic stem cell transplantation in pediatric patients with inborn errors of immunity in three reference care centers in Colombia between 2007 and 2018?
METHODS: We conducted an observational, retrospective cohort study in children with a diagnosis of IEI who underwent HSCT between 2007 and 2018.
RESULTS: Forty-seven patients were identified, and 5 were re-transplanted. Sixty-eight percent were male. The median age at diagnosis was 0.6 years, and for HSCT was 1.4 years. The most common diseases were chronic granulomatous disease (38%) followed by severe combined immune deficiencies (19%) and hemophagocytic lymphohistiocytosis (15%). Cord blood donors were the most used source of HSCT (44%). T cell-replete grafts from haploidentical donors using post-transplantation cyclophosphamide represent 37% of the cohort. All patients received conditioning, 62% with a non-myeloablative regimen. Calcineurin inhibitors were the main graft-versus-host disease prophylaxis (63.8%). Acute graft-versus-host disease developed in 35% of the total patients. The most frequent post-transplant infections were viral and fungal infections. The 1-year overall survival rates for the patients who received HSCT from identical, haploidentical, and cord sources were 80%, 72%, and 63%, respectively. The 5-year overall survival was 63%.
CONCLUSIONS: HSCT is a curative treatment option for some IEI and can be performed with any donor type. Early and timely treatment in referral centers can improve survival.

PMID: 32880086 [PubMed – as supplied by publisher]

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HLA DR covers Bare Lymphocyte Syndrome.

Scand J Immunol. 2020 Sep 01;:e12968

Authors: Yadav RM, Madkaikar M, Bargir UA, Ganapule A, Dalvi A, Gupta M

Abstract
Major Histocompatibility Complex (MHC) Class II deficiency also called Bare Lymphocyte Syndrome (BLS) is a combined primary immunodeficiency causing an impairment of both the cellular and humoral immune responses1 . This autosomal recessive disorder is characterized by absent Human Leukocyte Antigen – DR (HLA-DR) expression on immune cells resulting from a defect in genes encoding one or more of the 4 distinct regulatory proteins required for MHC Class II genes expression namely class II trans activator (CIITA) under group A , RFX containing ankyrin repeats (RFXANK) under group B , the fifth member of the RFX (RFX5) under group C , and RFX-associated protein (RFXAP) under group D. Patients may have varied clinical presentation, however, severe infections of the respiratory and gastrointestinal tracts in the first year of life itself are common.

PMID: 32875602 [PubMed – as supplied by publisher]

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