Manish Butte

Treatment with emapalumab in an ADA-SCID patient with refractory hemophagocytic lymphohistiocytosis-related graft failure and disseminated BCGitis.

Haematologica. 2020 Aug 13;:

Authors: Tucci F, Gallo V, Barzaghi F, Ferrua F, Migliavacca M, Calbi V, Doglio M, Fratini ES, Karakas Z, Guner S, Zambelli M, Parisi C, Milani R, Gattillo S, Mazzi B, Oltolini C, Barbera M, Baldoli C, Cirillo DM, Asnaghi V, De Min C, Cicalese MP, Ciceri F, Aiuti A, Bernardo ME

Abstract
Emapalumab, a fully human anti-IFNγ monoclonal antibody, has been approved in the US as second-line treatment of primary hemophagocytic lymphohistiocytosis (HLH) patients and has shown promise in patients with graft failure (GF) requiring a second allogeneic hematopoietic stem cell transplantation (HSCT). The blockade of IFNγ activity may increase the risk of severe infections, including fatal mycobacteriosis. We report a case of secondary HLH-related GF in the context of HLA-haploidentical HSCT successfully treated with emapalumab in the presence of concomitant life-threatening infections, including disseminated tuberculosis (TB). A 4 years old girl with Adenosine Deaminase-Severe Combined Immunodeficiency complicated by disseminated TB came to our attention for ex-vivo hematopoietic stem cell-gene therapy. After engraftment failure of gene corrected cells, she received two HLA-haploidentical T-cell depleted HSCT from the father, both failed due to GF related to concomitant multiple infections and secondary HLH. Emapalumab administration allowed to control HLH, as well as to prevent GF after a third haplo-HSCT from the mother. Remarkably, all infections improved with antimicrobial medications and disseminated TB did not show any reactivation. This seminal case supports emapalumab use for treatment of secondary HLH and prevention of GF in patients undergoing haplo-HSCT even in the presence of multiple infections, including TB.

PMID: 32817285 [PubMed – as supplied by publisher]

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Decreased frequency of allergy in juvenile idiopathic arthritis: results of a case-control study.

Mod Rheumatol. 2020 Aug 20;:1-19

Authors: Avar-Aydin PO, Nepesov S, Barut K, Sahin S, Adrovic A, Cokugras HC, Kasapcopur O

Abstract
Objectives: To determine the frequency of Th2-mediated allergic diseases (AD) in mainly Th1-driven juvenile idiopathic arthritis (JIA) subtypes.Methods: Ninty-nine JIA patients and 128 control subjects were enrolled in a prospective case-control study. All subjects were assessed with standard allergy questionnaire, complete blood cell count, and total serum immunoglobulin (sIg) E. sIgs G, A, M, Juvenile Arthritis Disease Activity Score-27 (JADAS27), and serum acute phase reactants (sAPR) were obtained in JIA. In the presence of allergic symptoms, skin prick (SPT) and pulmonary function tests (PFT) were performed.Results: Despite similar allergy risk factors, the frequencies of asthma and allergic rhinitis were lower in JIA group (all p ≤ 0.02). Allergic patients with JIA performed lower FEV1/FVC ratio, PEF, and FEF25-75 compared to control group (all p ≤ 0.04). JADAS27 and sAPR were similar among JIA patients with and without AD. Two JIA patients were found to have hypogammaglobulinemia.Conclusions: The frequencies of AD, asthma, and allergic rhinitis may decrease in Th1-mediated JIA subtypes although the coexistence does not appear to affect the severity of arthritis whereas allergic symptoms may resolve after immunosuppressive treatment. PFTs should be obtained periodically in JIA. JIA patients may have an underlying primary immunodeficiency (ID) or immunosuppressive drugs may cause secondary ID. Key PointsCompared to the population, the frequency of Th2-mediated allergic diseases is lower in oligoarthritis and RF-negative polyarthritis that are primarily driven by a Th1 activity.The coexistence of allergic diseases in juvenile idiopathic arthritis does not affect the severity of arthritis.Pulmonary function tests can be thought to be obtained periodically in juvenile idiopathic arthritis.Immunological workup should be considered in atypically or severely presented patients with juvenile idiopathic arthritis before the initiation of immunosuppressive therapy to differentiate primary and secondary immunodeficiency.

PMID: 32815440 [PubMed – as supplied by publisher]

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Hereditary Angioedema: An Updated Experience with Patients with Angioedema in Puerto Rico.

P R Health Sci J. 2019 12;38(4):248-254

Authors: Rosado-Quiñones AM, Zaragoza-Urdaz R

Abstract
OBJECTIVE: This was a study of patients with hereditary angioedema (HAE) and their responses to new therapies, measured in terms of HAE attack rates, the number of hospitalizations and emergency room (ER) visits, and the impact of HAE on their quality of life (QOL).
METHODS: Patients that came at a private practice with recurrent angioedema without urticaria from 2013 through 2016. All HAE (types I & II) patients received rescue treatment and prophylaxis for those who had 2 or more attacks per month.
RESULTS: Of 48 patients, 22 (45.8%) patients with HAE (I or II) were identified. 45.5% of those HAE patients were on prophylaxis and 77.3% were on rescue therapy. Treatment effects were reported as percentages of the HAE patients in each attack/month category: Before treatment, 41.2% of the patients had 0 to 1 attack; after treatment, 84.2%. Similarly, 23.5% had 2 to 3 attacks before treatment, fell to 17.6%, after treatment. Finally, 35.3% experienced more than 3 attacks prior to treatment; and none after treatment. The number of ER visits in 6 months decreased from 64 (3.8 per patient) to 7 (0.4 per patient), and hospitalizations in 6 months decreased from 35 (2.1 per patient) to 7 (0.4 per patient) after treatment. The diagnosis delay averaged 4.3 years; patients diagnosed on or before 2012 averaged 8.6 years; patients diagnosed after 2012 averaged 0.4 years.
CONCLUSION: HAE patients showed improved treatment responses as documented by decreased diagnostic delay, attack rates, ER visits and hospitalizations and improved QOL in treated patients.

PMID: 31935311 [PubMed – indexed for MEDLINE]

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Wiskott-Aldrich syndrome in four male siblings from a consanguineous family from Lebanon.

Clin Immunol. 2020 Aug 16;:108573

Authors: Mansour R, El-Orfali Y, Saber A, Noun D, Youssef N, Youssef Y, Hanna-Wakim R, Dbaibo G, Abboud M, Massaad MJ

Abstract
BACKGROUND: Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency disorder (PID) characterized by microthrombocytopenia, bloody diarrhea, eczema, recurrent infections, and a high incidence of autoimmunity and malignancy.
OBJECTIVE: To investigate the mechanism of thrombocytopenia and infections in four boys of consanguineous parents from Lebanon.
METHODS: Patient gDNA was studied using Next Generation Sequencing and Sanger Sequencing. Protein expression was determined by immunoblotting, and mRNA expression by semi-quantitative RT-PCR. F-actin polymerization and cellular proliferation were assayed by flow cytometry.
RESULTS: We identified a threonine to a methionine change at position 45 (T45M) of the WAS protein (WASp) that abolished protein expression and disturbed F-actin polymerization and T cell proliferation, but not B cell proliferation. In addition, the levels of the WAS-interacting protein (WIP) were significantly decreased in the patients.
CONCLUSION: The mutation identified severely destabilizes WASp and affects the downstream signaling events important for T cell function, but not B cell function. It was previously known that the stability of WASp depends on WIP. In this manuscript, we report that the stability of WIP also depends on WASp. Finally, it is important to suspect X-linked PIDs even in consanguineous families.
CLINICAL IMPLICATIONS: The patients are above the optimal age for transplant in WAS, and it is difficult to identify one or more donors for four patients, therefore, they represent ideal candidates for gene therapy or interleukin-2 therapy.

PMID: 32814211 [PubMed – as supplied by publisher]

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A Nonsense N -Terminus NFKB2 Mutation Leading to Haploinsufficiency in a Patient with a Predominantly Antibody Deficiency.

J Clin Immunol. 2020 Aug 19;:

Authors: Kuehn HS, Bernasconi A, Niemela JE, Almejun MB, Gallego WAF, Goel S, Stoddard JL, Sánchez RGP, Franco CAA, Oleastro M, Grunebaum E, Ballas Z, Cunningham-Rundles C, Fleisher TA, Franco JL, Danielian S, Rosenzweig SD

Abstract
The noncanonical NF-κB pathway is implicated in diverse biological and immunological processes. Monoallelic C-terminus loss-of-function and gain-of-function mutations of NFKB2 have been recently identified as a cause of immunodeficiency manifesting with common variable immunodeficiency (CVID) or combined immunodeficiency (CID) phenotypes. Herein we report a family carrying a heterozygous nonsense mutation in NFKB2 (c.809G > A, p.W270*). This variant is associated with increased mRNA decay and no mutant NFKB2 protein expression, leading to NFKB2 haploinsufficiency. Our findings demonstrate that bona fide NFKB2 haploinsufficiency, likely caused by mutant mRNA decay and protein instability leading to the transcription and expression of only the wild-type allele, is associated with clinical immunodeficiency, although with incomplete clinical penetrance. Abnormal B cell development, hypogammaglobulinemia, poor antibody response, and abnormal noncanonical (but normal canonical) NF-κB pathway signaling are the immunologic hallmarks of this disease. This adds a third allelic variant to the pathophysiology of NFKB2-mediated immunodeficiency disorders.

PMID: 32813180 [PubMed – as supplied by publisher]

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Rapid identification and characterization of infected cells in blood during chronic active Epstein-Barr virus infection.

J Exp Med. 2020 Nov 02;217(11):

Authors: Fournier B, Boutboul D, Bruneau J, Miot C, Boulanger C, Malphettes M, Pellier I, Dunogué B, Terrier B, Suarez F, Blanche S, Castelle M, Winter S, Delecluse HJ, Molina T, Picard C, Ehl S, Moshous D, Galicier L, Barlogis V, Fischer A, Neven B, Latour S

Abstract
Epstein-Barr virus (EBV) preferentially infects epithelial cells and B lymphocytes and sometimes T and NK lymphocytes. Persistence of EBV-infected cells results in severe lymphoproliferative disorders (LPDs). Diagnosis of EBV-driven T or NK cell LPD and chronic active EBV diseases (CAEBV) is difficult, often requiring biopsies. Herein, we report a flow-FISH cytometry assay that detects cells expressing EBV-encoded small RNAs (EBERs), allowing rapid identification of EBV-infected cells among PBMCs. EBV-infected B, T, and/or NK cells were detectable in various LPD conditions. Diagnosis of CAEBV in 22 patients of Caucasian and African origins was established. All exhibited circulating EBV-infected T and/or NK cells, highlighting that CAEBV is not restricted to native American and Asian populations. Proportions of EBV-infected cells correlated with blood EBV loads. We showed that EBV-infected T cells had an effector memory activated phenotype, whereas EBV-infected B cells expressed plasma cell differentiation markers. Thus, this method achieves accurate and unambiguous diagnoses of different forms of EBV-driven LPD and represents a powerful tool to study their pathophysiological mechanisms.

PMID: 32812031 [PubMed – in process]

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Quantification of 1,3-β-D-Glucan by Wako β-Glucan Assay for rapid exclusion of invasive fungal infections in critical patients: a diagnostic test accuracy study.

Mycoses. 2020 Aug 18;:

Authors: Cento V, Alteri C, Mancini V, Gatti M, Lepera V, Mazza E, Moioli MC, Merli M, Colombo J, Andrea Orcese C, Bielli A, Torri S, Gasparini LE, Vismara C, De Gasperi A, Brioschi P, Puoti M, Cairoli R, Lombardi G, Perno CF

Abstract
OBJECTIVES: Rapid and reliable exclusion of invasive fungal infections (IFI) by markers able to avoid unnecessary empirical antifungal-treatment is still a critical unmet clinical need. We investigated the diagnostic performance of a newly-available β-D-Glucan (BDG)-quantification assay, focusing on the optimization of the BDG cut-off values for IFI exclusion.
METHODS: BDG results by Wako β-Glucan Assay (lower-limit of detection [LLOD]=2.16 pg/mL, positivity≥11 pg/mL) on 2 consecutive serum samples were retrospectively analyzed in 170 patients, admitted to hematological wards (N=42), intensive care units (ICUs; N=80), or other wards (N=48), exhibiting clinical signs and/or symptoms suspected for IFI. Only patients with proven-IFI (EORTC/MSG criteria) were considered as true-positives in the assessment of BDG sensitivity, specificity, and predictive values.
RESULTS: Patients were diagnosed with no IFI (69.4%), proven IFI (25.3%) or probable IFI (5.3%). Two consecutive BDG-values CONCLUSIONS: The classification of Wako’s results as negative when 7.7 pg/mL, could be a promising diagnostic approach to confidently rule out an IFI in both ICU and non-ICU patients. The poor specificity in the ICU setting remains a concern, due to the difficulty to interpret positive results in this fragile population.

PMID: 32810888 [PubMed – as supplied by publisher]

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Primary Immunodeficiencies: Diseases of Children and Adults – A Review.

Adv Exp Med Biol. 2020 Aug 18;:

Authors: Lewandowicz-Uszyńska A, Pasternak G, Świerkot J, Bogunia-Kubik K

Abstract
Primary immunodeficiencies (PIDs) belong to a group of rare congenital diseases occurring all over the world that may be seen in both children and adults. In most cases, genetic predispositions are already known. As shown in this review, genetic abnormalities may be related to dysfunction of the immune system, which manifests itself as recurrent infections, increased risk of cancer, and autoimmune diseases. This article reviews the various forms of PIDs, including their characterization, management strategies, and complications. Novel aspects of the diagnostics and monitoring of PIDs are presented.

PMID: 32803731 [PubMed – as supplied by publisher]

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The Italian Registry for Primary Immunodeficiencies (Italian Primary Immunodeficiency Network; IPINet): Twenty Years of Experience (1999-2019).

J Clin Immunol. 2020 Aug 15;:

Authors: Lougaris V, Pession A, Baronio M, Soresina A, Rondelli R, Gazzurelli L, Benvenuto A, Martino S, Gattorno M, Biondi A, Zecca M, Marinoni M, Fabio G, Aiuti A, Marseglia G, Putti MC, Agostini C, Lunardi C, Tommasini A, Bertolini P, Gambineri E, Consolini R, Matucci A, Azzari C, Danieli MG, Paganelli R, Duse M, Cancrini C, Moschese V, Chessa L, Spadaro G, Civino A, Vacca A, Cardinale F, Martire B, Carpino L, Trizzino A, Russo G, Cossu F, Badolato R, Pietrogrande MC, Quinti I, Rossi P, Ugazio A, Pignata C, Plebani A

Abstract
Primary immunodeficiencies (PIDs) are heterogeneous disorders, characterized by variable clinical and immunological features. National PID registries offer useful insights on the epidemiology, diagnosis, and natural history of these disorders. In 1999, the Italian network for primary immunodeficiencies (IPINet) was established. We report on data collected from the IPINet registry after 20 years of activity. A total of 3352 pediatric and adult patients affected with PIDs are registered in the database. In Italy, a regional distribution trend of PID diagnosis was observed. Based on the updated IUIS classification of 2019, PID distribution in Italy showed that predominantly antibody deficiencies account for the majority of cases (63%), followed by combined immunodeficiencies with associated or syndromic features (22.5%). The overall age at diagnosis was younger for male patients. The minimal prevalence of PIDs in Italy resulted in 5.1 per 100.000 habitants. Mortality was similar to other European registries (4.2%). Immunoglobulin replacement treatment was prescribed to less than one third of the patient cohort. Collectively, this is the first comprehensive description of the PID epidemiology in Italy.

PMID: 32803625 [PubMed – as supplied by publisher]

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