Manish Butte

Late-onset and long-lasting autoimmune neutropenia: an analysis from the Italian Neutropenia Registry.

Blood Adv. 2020 Nov 24;4(22):5644-5649

Authors: Fioredda F, Rotulo GA, Farruggia P, Dagliano F, Pillon M, Trizzino A, Notarangelo L, Luti L, Lanza T, Terranova P, Lanciotti M, Ceccherini I, Grossi A, Porretti L, Verzegnassi F, Mastrodicasa E, Barone A, Russo G, Bonanomi S, Boscarol G, Finocchi A, Veltroni M, Ramenghi U, Onofrillo D, Martire B, Ghilardi R, Giordano P, Ladogana S, Marra N, Zanardi S, Beier F, Miano M, Dufour C

Abstract
Primary autoimmune neutropenia (pAN) is typified by onset in early infancy and a mild/moderate phenotype that resolves within 3 years of diagnosis. In contrast, secondary AN is classically an adult disease associated with malignancy, autoimmunity, immunodeficiency, viral infection, or drugs. This study describes a cohort of 79 children from the Italian Registry who, although resembling pAN, did not fully match the criteria for pAN because neutropenia either appeared after age 5 years (LO-Np) or lasted longer than 3 years (LL-Np). These 2 categories compared with classical pAN showed a far inferior rate of resolution (P < .001), lower severity of neutropenia (P = .03), leukopenia (P < .001), lymphopenia (P < .001) with low B+ (P = .001), increased need of granulocyte colony-stimulating factor (P = .04), and increased frequency of autoimmunity over the disease course (P < .001). A paired comparison between LO-Np and LL-Np suggested that LO-Np had a lower rate of resolution (P < .001) and lower white blood cell (P < .001) and lymphocyte (P < .001) values, higher occurrence of apthae (P = .008), and a stronger association with autoimmune diseases/markers (P = .001) than LL-Np, thus suggesting a more pronounced autoimmune signature for LO-Np. A next-generation sequencing panel applied in a small subgroup of LO-Np and LL-Np patients identified variants related to immune dysregulations. Overall, these findings indicate that there are important differences among pAN LL-Np and LO-Np. Forms rising after 3 years of age, with low tendency to resolution, require tight monitoring and extensive immune investigations aimed to early identify underlying immunologic disease.

PMID: 33206964 [PubMed – in process]

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Immunoglobulin Replacement Therapy Versus Antibiotic Prophylaxis as Treatment for Incomplete Primary Antibody Deficiency.

J Clin Immunol. 2020 Nov 18;:

Authors: Smits BM, Kleine Budde I, de Vries E, Ten Berge IJM, Bredius RGM, van Deuren M, van Dissel JT, Ellerbroek PM, van der Flier M, van Hagen PM, Nieuwhof C, Rutgers B, Sanders LEAM, Simon A, Kuijpers TW, van Montfrans JM

Abstract
BACKGROUND: Patients with an IgG subclass deficiency (IgSD) ± specific polysaccharide antibody deficiency (SPAD) often present with recurrent infections. Previous retrospective studies have shown that prophylactic antibiotics (PA) and immunoglobulin replacement therapy (IRT) can both be effective in preventing these infections; however, this has not been confirmed in a prospective study.
OBJECTIVE: To compare the efficacy of PA and IRT in a randomized crossover trial.
METHODS: A total of 64 patients (55 adults and 9 children) were randomized (2:2) between two treatment arms. Treatment arm A began with 12 months of PA, and treatment arm B began with 12 months of IRT. After a 3-month bridging period with cotrimoxazole, the treatment was switched to 12 months of IRT and PA, respectively. The efficacy (measured by the incidence of infections) and proportion of related adverse events in the two arms were compared.
RESULTS: The overall efficacy of the two regimens did not differ (p = 0.58, two-sided Wilcoxon signed-rank test). A smaller proportion of patients suffered a related adverse event while using PA (26.8% vs. 60.3%, p < 0.0003, chi-squared test). Patients with persistent infections while using PA suffered fewer infections per year after switching to IRT (2.63 vs. 0.64, p < 0.01).
CONCLUSION: We found comparable efficacy of IRT and PA in patients with IgSD ± SPAD. Patients with persistent infections during treatment with PA had less infections after switching to IRT.
CLINICAL IMPLICATION: Given the costs and associated side-effects of IRT, it should be reserved for patients with persistent infections despite treatment with PA.

PMID: 33206257 [PubMed – as supplied by publisher]

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Infection Phenotypes Among Patients with Primary Antibody Deficiency Mined from a US Patient Registry.

J Clin Immunol. 2020 Nov 17;:

Authors: Pickett G, Motazedi T, Kutac C, Cahill G, Cunnigham-Rundles C, Fuleihan RL, Sullivan KE, Rider NL

Abstract
PURPOSE: Primary immunodeficiency disorders (PIDs) affect immune system development and/or function, increase infection susceptibility, and cause dysregulation or both. Recognition of PID requires assessment about the normal state of infection frequency and microbiology. To help clarify infection characteristics, we use data mined from the US Immunodeficiency Network (USIDNET) registry among primary antibody deficiency (PAD) patients before diagnosis.
METHODS: We analyzed PAD patient data from the USIDNET registry prior to ultimate diagnosis. Our analysis included basic descriptive statistics for 8 major infection subtypes and significance testing for comparing infection rate by specific organisms across 7 distinct PAD subtypes.
RESULTS: Of 2038 patients reviewed, 1259 (61.8%) had infections reported prior to diagnosis. Most (77.4%) had four or less reported infections prior to diagnosis; however, some suffered up to 16 infections. Infection patterns differed across the PAD subtypes. Patients with agammaglobulinemia differed significantly from patients with all other forms of PAD studied in at least one infection category, whereas patients with CVID differed from 3 other PAD categories in at least one infection category. Patterns of infections in patients with hypogammaglobulinemia, specific antibody deficiency, and transient hypogammaglobulinemia were less unique. For each of the infection types, bacteria were the most prevalent cause of disease.
CONCLUSIONS: Our data shows that distinct subtypes of PAD display unique infection patterns. We also show that patients with agammaglobulinemia suffer more invasive infections and differ most significantly from all other forms of PAD studied. Our analysis has broad implications about infection surveillance, progression, and vulnerability by PAD subtype.

PMID: 33205244 [PubMed – as supplied by publisher]

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Autoimmunity in Common Variable Immunodeficiency: A Systematic Review and Meta-Analysis.

Expert Rev Clin Immunol. 2020 Nov 18;:

Authors: Rizvi FS, Zainaldain H, Rafiemanesh H, Jamee M, Hossein-Khannazer N, Hamedifar H, Sabzevari A, Yazdani R, Abolhassani H, Aghamohammadi A, Azizi G

Abstract
OBJECTIVES: Common variable immunodeficiency (CVID) is the most common symptomatic inborn error of immunity characterized by variable clinical manifestations including infections, autoimmunity, chronic lung disease, polyclonal lymphocytic infiltration, enteropathy, and malignancy. This study aimed to evaluate the prevalence of autoimmunity in CVID patients. In this study, the authors aimed to assess the prevalence of various types of autoimmune manifestations in CVID patients and evaluate the probable associations between autoimmunity and other clinical and immunological features in these patients.
METHODS: Web of Science, Scopus, and PubMed databases were searched systemically to find eligible studies from the earliest available date to February 2020 with standard keywords. Pooled estimates of the autoimmunity prevalence and the corresponding 95% confidence intervals (CI) were calculated using random-effects models.
RESULTS: The overall prevalence of autoimmunity was 29.8% (95% CI: 26.4-33.3; I2=82.8%). The prevalences of hematologic autoimmune diseases, autoimmune gastrointestinal disorders, autoimmune rheumatologic disorders, autoimmune skin disorders and autoimmune endocrinopathy in CVID patients were 18.9% (95% CI: 15.4-22.5; I2=87.0%), 11.5% (95% CI: 8.7-14.4; I2=84.1%), 6.4% (95% CI: 3.8-9.0; I2=88.3%), 5.9% (95% CI: 3.9-7.8; I2=86.5%) and 2.5% (95% CI: 1.7-3.3; I2=38.9%), respectively. There were significantly higher lymphocyte, CD3+ T cell, and CD4+ T cell count among CVID patients without autoimmunity (p<0.05). Furthermore, failure to thrive, organomegaly, enteropathy, and meningitis was significantly higher in CVID patients with autoimmunity compared to patients without autoimmunity (p<0.05).
CONCLUSIONS: Many CVID patients could present with autoimmunity as part of the disease or even as the first or only clinical manifestation of the disease. Care providers may need to pay particular attention to the possible association of these two disorders since the co-occurrence of CVID and autoimmunity could be a misleading clue.

PMID: 33203275 [PubMed – as supplied by publisher]

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Expanding Phenotype of Schimke Immuno-Osseous Dysplasia: Congenital Anomalies of the Kidneys and of the Urinary Tract and Alteration of NK Cells.

Int J Mol Sci. 2020 Nov 15;21(22):

Authors: Bertulli C, Marzollo A, Doria M, Di Cesare S, La Scola C, Mencarelli F, Pasini A, Affinita MC, Vidal E, Magini P, Dimartino P, Masetti R, Greco L, Palomba P, Conti F, Pession A

Abstract
Schimke immuno-osseous dysplasia (SIOD) is a rare multisystemic disorder with a variable clinical expressivity caused by biallelic variants in SMARCAL1. A phenotype-genotype correlation has been attempted and variable expressivity of biallelic SMARCAL1 variants may be associated with environmental and genetic disturbances of gene expression. We describe two siblings born from consanguineous parents with a diagnosis of SIOD revealed by whole exome sequencing (WES). Results: A homozygous missense variant in the SMARCAL1 gene (c.1682G>A; p.Arg561His) was identified in both patients. Despite carrying the same variant, the two patients showed substantial renal and immunological phenotypic differences. We describe features not previously associated with SIOD-both patients had congenital anomalies of the kidneys and of the urinary tract and one of them succumbed to a classical type congenital mesoblastic nephroma. We performed an extensive characterization of the immunophenotype showing combined immunodeficiency characterized by a profound lymphopenia, lack of thymic output, defective IL-7Rα expression, and disturbed B plasma cells differentiation and immunoglobulin production in addition to an altered NK-cell phenotype and function. Conclusions: Overall, our results contribute to extending the phenotypic spectrum of features associated with SMARCAL1 mutations and to better characterizing the underlying immunologic disorder with critical implications for therapeutic and management strategies.

PMID: 33203071 [PubMed – in process]

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Multiplexed Functional Assessment of Genetic Variants in CARD11.

Am J Hum Genet. 2020 Nov 12;:

Authors: Meitlis I, Allenspach EJ, Bauman BM, Phan IQ, Dabbah G, Schmitt EG, Camp ND, Torgerson TR, Nickerson DA, Bamshad MJ, Hagin D, Luthers CR, Stinson JR, Gray J, Lundgren I, Church JA, Butte MJ, Jordan MB, Aceves SS, Schwartz DM, Milner JD, Schuval S, Skoda-Smith S, Cooper MA, Starita LM, Rawlings DJ, Snow AL, James RG

Abstract
Genetic testing has increased the number of variants identified in disease genes, but the diagnostic utility is limited by lack of understanding variant function. CARD11 encodes an adaptor protein that expresses dominant-negative and gain-of-function variants associated with distinct immunodeficiencies. Here, we used a “cloning-free” saturation genome editing approach in a diploid cell line to simultaneously score 2,542 variants for decreased or increased function in the region of CARD11 associated with immunodeficiency. We also described an exon-skipping mechanism for CARD11 dominant-negative activity. The classification of reported clinical variants was sensitive (94.6%) and specific (88.9%), which rendered the data immediately useful for interpretation of seven coding and splicing variants implicated in immunodeficiency found in our clinic. This approach is generalizable for variant interpretation in many other clinically actionable genes, in any relevant cell type.

PMID: 33202260 [PubMed – as supplied by publisher]

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[Analysis of clinical features and genetic variants in an infant with Bloom syndrome].

Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2020 Jul 10;37(7):764-766

Authors: Shan Y, Yang Z, Yang X, Lei K, Fu P, Yi M, Ma L, Ran N

Abstract
OBJECTIVE: To analyze the clinical features and genetic variants in a 13-month-old child with Bloom syndrome.
METHODS: Clinical data of the child was collected. Genetic variants were detected by high-throughput sequencing and Sanger sequencing.
RESULTS: The child was born at full term but was small for gestational age. His clinical features included loss of appetite, severe growth retardation, microcephaly, and small mandible. Genetic testing found that he had carried compound heterozygous c.1068+3A>C and c.1069-1G>C variants of the BLM gene, both of which were unreported previously.
CONCLUSION: Bloom syndrome is mainly characterized by severe growth retardation in infancy. The novel variants have expanded the variant spectrum of the BLM gene.

PMID: 32619260 [PubMed – indexed for MEDLINE]

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