Manish Butte

The German National Registry of Primary Immunodeficiencies (2012-2017).

Front Immunol. 2019;10:1272

Authors: El-Helou SM, Biegner AK, Bode S, Ehl SR, Heeg M, Maccari ME, Ritterbusch H, Speckmann C, Rusch S, Scheible R, Warnatz K, Atschekzei F, Beider R, Ernst D, Gerschmann S, Jablonka A, Mielke G, Schmidt RE, Schürmann G, Sogkas G, Baumann UH, Klemann C, Viemann D, von Bernuth H, Krüger R, Hanitsch LG, Scheibenbogen CM, Wittke K, Albert MH, Eichinger A, Hauck F, Klein C, Rack-Hoch A, Sollinger FM, Avila A, Borte M, Borte S, Fasshauer M, Hauenherm A, Kellner N, Müller AH, Ülzen A, Bader P, Bakhtiar S, Lee JY, Heß U, Schubert R, Wölke S, Zielen S, Ghosh S, Laws HJ, Neubert J, Oommen PT, Hönig M, Schulz A, Steinmann S, Schwarz K, Dückers G, Lamers B, Langemeyer V, Niehues T, Shai S, Graf D, Müglich C, Schmalzing MT, Schwaneck EC, Tony HP, Dirks J, Haase G, Liese JG, Morbach H, Foell D, Hellige A, Wittkowski H, Masjosthusmann K, Mohr M, Geberzahn L, Hedrich CM, Müller C, Rösen-Wolff A, Roesler J, Zimmermann A, Behrends U, Rieber N, Schauer U, Handgretinger R, Holzer U, Henes J, Kanz L, Boesecke C, Rockstroh JK, Schwarze-Zander C, Wasmuth JC, Dilloo D, Hülsmann B, Schönberger S, Schreiber S, Zeuner R, Ankermann T, von Bismarck P, Huppertz HI, Kaiser-Labusch P, Greil J, Jakoby D, Kulozik AE, Metzler M, Naumann-Bartsch N, Sobik B, Graf N, Heine S, Kobbe R, Lehmberg K, Müller I, Herrmann F, Horneff G, Klein A, Peitz J, Schmidt N, Bielack S, Groß-Wieltsch U, Classen CF, Klasen J, Deutz P, Kamitz D, Lassay L, Tenbrock K, Wagner N, Bernbeck B, Brummel B, Lara-Villacanas E, Münstermann E, Schneider DT, Tietsch N, Westkemper M, Weiß M, Kramm C, Kühnle I, Kullmann S, Girschick H, Specker C, Vinnemeier-Laubenthal E, Haenicke H, Schulz C, Schweigerer L, Müller TG, Stiefel M, Belohradsky BH, Soetedjo V, Kindle G, Grimbacher B

Abstract
Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs. Methods: Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel. Results: The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1-25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36% of patients. Familial cases were observed in 21% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0-88 years). Presenting symptoms comprised infections (74%) and immune dysregulation (22%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE- syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49% of all patients received immunoglobulin G (IgG) substitution (70%-subcutaneous; 29%-intravenous; 1%-unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy. Conclusion: The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment.

PMID: 31379802 [PubMed – in process]

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Impaired polysaccharide responsiveness without agammaglobulinemia in three patients with hypomorphic mutations in Bruton Tyrosine Kinase – no detection by newborn screening for primary immunodeficiences.

Scand J Immunol. 2019 Aug 04;:e12811

Authors: Krüger R, Baumann U, Borte S, Kölsch U, Lorenz MR, Keller B, Harder I, Warnatz K, Ehl S, Schwarz K, Wahn V, von Bernuth H

Abstract
BACKGROUND: Hypomorphic mutations in the gene encoding Bruton Tyrosine Kinase (BTK) may result in milder phenotypes and delayed diagnosis of B-cell related immunodeficiencies due to residual BTK function. Newborn screening for kappa-deleting-recombination-excision circles (KRECs) reliably identifies classical X-linked agammaglobulinemia (XLA) patients with profound B-cell lymphopenia at birth but has not been evaluated in patients with residual BTK function.
OBJECTIVE: We aimed to evaluate clinical findings, BTK function and KREC copy numbers in three patients with BTK mutations presenting with impaired polysaccharide responsiveness without agammaglobulinemia.
PATIENTS CHARACTERISTICS AND METHODS: One patient had an invasive pneumococcal infection at the age of four years. All three patients (two brothers) had visible tonsils, normal to slightly decreased immunoglobulin G levels, undetectable pneumococcal antibodies despite pneumococcal conjugate vaccinations, no antibody response after a diagnostic polysaccharide vaccination as well as profound B-cell lymphopenia with residual B-cell differentiation. BTK mutations were identified by Sanger sequencing. BTK staining and phosphorylation assays were performed on peripheral B-cells. KREC copy numbers were determined from dried blood spots obtained within the first week of life as well as once at the age of eight, six and three years, respectively.
RESULTS: BTK staining showed residual protein expression. Also, residual BTK activity could be demonstrated. KREC copy numbers from dried blood spots were above the threshhold set for detection of patients with profound B-cell lymphopenia.
CONCLUSIONS: Male patients with impaired polysaccharide responsiveness should be evaluated for B-cell lymphopenia followed by BTK analyses irrespective of immunoglobulin levels or tonsil size. This article is protected by copyright. All rights reserved.

PMID: 31378960 [PubMed – as supplied by publisher]

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Rituximab unveils hypogammaglobulinemia and immunodeficiency in children with autoimmune cytopenia.

J Allergy Clin Immunol Pract. 2019 Aug 01;:

Authors: Ottaviano G, Marinoni M, Graziani S, Sibson K, Barzaghi F, Bertolini P, Chini L, Corti P, Cancrini C, D’Alba I, Gabelli M, Gallo V, Giancotta C, Giordano P, Lassandro G, Martire B, Angarano R, Mastrodicasa E, Bava C, Miano M, Naviglio S, Verzegnassi F, Saracco P, Trizzino A, Biondi A, Pignata C, Moschese V

Abstract
BACKGROUND: Rituximab (RTX; anti-CD20 monoclonal antibody) is a treatment option in children with refractory immune thrombocytopenia (ITP), autoimmune haemolytic anaemia (AHA) and Evans syndrome (ES). Prevalence and clinical course of RTX-induced hypogammaglobulinemia in these patients are poorly known.
OBJECTIVE: To evaluate prevalence and risk factors for persistent hypogammaglobulinemia (PH) following RTX use.
METHODS: Clinical and immunological data from children treated with RTX for ITP, AHA and ES were collected from 16 Italian centers and one UK center at pre-RTX time-point (0), +6 months, and yearly, up to 4 years post-RTX. Patients with previously diagnosed malignancy or primary immune deficiency (PID) were excluded.
RESULTS: We analysed 53 children treated with RTX for ITP (n=36), AHA (n=13) and ES (n=4). Median follow-up was 30 months (range 12-48). Thirty-two percent of patients (17/53) experienced PH, defined as IgG <2SD for age at last follow-up (>12 months after RTX). Significantly delayed B cell recovery was observed in children experiencing PH (HR 0.55, p<.05), and 6/17 (35%) of patients had unresolved B cell lymphopenia at last follow-up. PH was associated with IgA and IgM deficiency, younger age at RTX use (51 vs. 116 months, p<.01), a diagnosis of AHA/ES, and better response to RTX. Nine patients with PH (9/17, 53%) were eventually diagnosed with a PID.
CONCLUSION: Post-RTX PH is a frequent condition in children with autoimmune cytopenia; a sizeable proportion of patients with post-RTX PH were eventually diagnosed with a PID. In depth investigation for PID is therefore recommended in these patients.

PMID: 31377437 [PubMed – as supplied by publisher]

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Chronic Granulomatous Disease-Associated IBD Resolves and Does Not Adversely Impact Survival Following Allogeneic HCT.

J Clin Immunol. 2019 Aug 02;:

Authors: Marsh RA, Leiding JW, Logan BR, Griffith LM, Arnold DE, Haddad E, Falcone EL, Yin Z, Patel K, Arbuckle E, Bleesing JJ, Sullivan KE, Heimall J, Burroughs LM, Skoda-Smith S, Chandrakasan S, Yu LC, Oshrine BR, Cuvelier GDE, Thakar MS, Chen K, Teira P, Shenoy S, Phelan R, Forbes LR, Chellapandian D, Dávila Saldaña BJ, Shah AJ, Weinacht KG, Joshi A, Boulad F, Quigg TC, Dvorak CC, Grossman D, Torgerson T, Graham P, Prasad V, Knutsen A, Chong H, Miller H, de la Morena MT, DeSantes K, Cowan MJ, Notarangelo LD, Kohn DB, Stenger E, Pai SY, Routes JM, Puck JM, Kapoor N, Pulsipher MA, Malech HL, Parikh S, Kang EM, submitted on behalf of the Primary Immune Deficiency Treatment Consortium

Abstract
INTRODUCTION: Inflammatory bowel disease (IBD) affects approximately 1/3 of patients with chronic granulomatous disease (CGD). Comprehensive investigation of the effect of allogeneic hematopoietic cell transplantation (HCT) on CGD IBD and the impact of IBD on transplant outcomes is lacking.
METHODS: We collected data retrospectively from 145 patients with CGD who had received allogeneic HCT at 26 Primary Immune Deficiency Treatment Consortium (PIDTC) centers between January 1, 2005 and June 30, 2016.
RESULTS: Forty-nine CGD patients with IBD and 96 patients without IBD underwent allogeneic HCT. Eighty-nine percent of patients with IBD and 93% of patients without IBD engrafted (p = 0.476). Upper gastrointestinal acute GVHD occurred in 8.5% of patients with IBD and 3.5% of patients without IBD (p = 0.246). Lower gastrointestinal acute GVHD occurred in 10.6% of patients with IBD and 11.8% of patients without IBD (p = 0.845). The cumulative incidence of acute GVHD grades II-IV was 30% (CI 17-43%) in patients with IBD and 20% (CI 12-29%) in patients without IBD (p = 0.09). Five-year overall survival was equivalent for patients with and without IBD: 80% [CI 66-89%] and 83% [CI 72-90%], respectively (p = 0.689). All 33 surviving evaluable patients with a history of IBD experienced resolution of IBD by 2 years following allogeneic HCT.
CONCLUSIONS: In this cohort, allogeneic HCT was curative for CGD-associated IBD. IBD should not contraindicate HCT, as it does not lead to an increased risk of mortality. This study is registered at clinicaltrials.gov NCT02082353.

PMID: 31376032 [PubMed – as supplied by publisher]

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A novel mutation of the ITGB2 gene in a Chinese Zhuang minority patient with leukocyte adhesion deficiency type 1 and glucose-6-phosphate dehydrogenase deficiency.

Gene. 2019 Jul 30;:144027

Authors: Zhang Y, Yang X, He X, Liu H, Guo P, Liu X, Xiao Y, Feng X, Wang Y, Li L

Abstract
OBJECTIVES: To explore the clinical and molecular characteristics of a Chinese Zhuang minority patient with leukocyte adhesion deficiency type-1 (LAD-1) and glucose-6-phosphate dehydrogenase deficiency (G6PDD).
METHODS: Routine clinical and physical examinations were performed, and patient data was collected and analyzed. Protein expression levels of Itgb2 and glucose-6-phosphate dehydrogenase (G6pd) proteins were assessed by flow cytometry and the glucose-6-phosphate (G6P) substrate method, respectively. Whole exome sequencing was performed to investigate genetic variations of the patient and his parents.
RESULTS: The patient had fester disease and delayed separation of the umbilical cord at birth. Staphylococcus was detected in the fluid secretion of the auditory meatus of the patient. He exhibited a recurrent cheek scab, swollen hand, and swollen gum. Hematological examination indicated dramatic elevation of leukocytes including lymphocytes, monocytes, neutrophils and eosinophils. A novel homozygous mutation was detected in the ITGB2 gene of the patient, which was determined to be a two nucleotide deletion at the site of c.1537-1538 (c.1537-1538delGT), causing a frameshift of 24 amino acids from p.513 and inducing a stop codon (p.V513Lfs*24). A base substitution mutation was identified at c.1466 (c.1466G>T) of G6PD on chromosome X of the patient, which resulted in an amino acid change from arginine to leucine at p.489 (p.R489L). The patient also showed deficient lymphocyte expression of CD18 (2.99%) and significant downregulation of the G6pd protein.
CONCLUSIONS: The patient was diagnosed with G6PDD and moderate LAD-1. The combination of LAD-1 and G6PDD in this case may have been due to the high incidence of genetic disease in this minority ethnic population. Analyzing existing LAD-1 and G6PDD cases from different populations can facilitate disease diagnosis and treatment. Particularly, reporting pathogenic mutations of LAD-1 and G6PDD will be crucial for genetic testing and prenatal diagnosis in an effort to decrease the incidence of these diseases.

PMID: 31374327 [PubMed – as supplied by publisher]

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How to Identify Common Variable Immunodeficiency Patients Earlier: General Practice Patterns.

J Clin Immunol. 2019 Aug 01;:

Authors: Ilkjær FV, Rasmussen LD, Martin-Iguacel R, Westh L, Katzenstein TL, Hansen AE, Nielsen TL, Larsen CS, Johansen IS

Abstract
PURPOSE: Diagnostic delay is a major problem concerning common variable immunodeficiency (CVID). We aimed to determine the pattern of general practitioner (GP) consultations in individuals diagnosed with CVID within 3 years before the diagnosis and whether the risk of diagnosis was associated with the frequency of consultations or character of examinations.
METHODS: We conducted a nested case-control study, identifying 132 adult CVID patients and 5940 age- and gender-matched controls from national registers during 1997-2013. We used conditional logistic regression to calculate the odds ratios (OR) and 95% confidence intervals (95%CI).
RESULTS: The median number of consultations among individuals with CVID was more than twice that of the controls in all 3 years (3rd, 10; 2nd, 11.5; and 1st, 15.4 vs. 4). We found a statistically significant association between the number of consultations and the risk of a subsequent CVID diagnosis, independent of age and gender, but strongest in the individuals < 40 years. In the 3rd year before diagnosis, having 9-15 consultations compared with 1-4 was associated with an OR (95%CI) of 5.0 (2.3-10.9), 2.4 (1.1-5.4), and 1.3 (0.3-5.3) for those aged 18-40, 41-60, and > 60, respectively. Several examinations (i.e., blood tests for inflammation/infection and pulmonary function test) were associated with increased odds of a subsequent CVID diagnosis.
CONCLUSION: The risk of a CVID diagnosis was highly related to both the number of consultations and the character of examinations performed by the GP. CVID should be a differential diagnosis among patients with multiple consultations, especially in patients < 40 years old.

PMID: 31372799 [PubMed – as supplied by publisher]

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Immunological features in pediatric patients with recurrent and severe infection: Identification of Primary Immunodeficiency Diseases in Merida, Venezuela.

Allergol Immunopathol (Madr). 2019 Jul 29;:

Authors: Linares NA, Bouchard M, Gutiérrez NS, Colmenares M, Cantor-Garcia A, Gabaldon-Figueira JC, Bellorin AV, Rujano B, Peterson DL, Salmen S

Abstract
INTRODUCTION AND OBJECTIVES: Primary immunodeficiency diseases (PIDs) are disorders associated mainly with recurrent and severe infection and an increase in susceptibility to autoimmune conditions and cancer. In Venezuela, PIDs are underdiagnosed and there is usually a delay in their diagnosis. Hence there are no data concerning the frequency and type of PIDs that occur. The aim of this study was to identify and quantify the types of PIDs that occur in Merida, a population within Venezuela.
PATIENTS OR MATERIALS AND METHODS: Following an informative program designed to alert local health professionals to the warning signs for PIDs, patients with a history of recurrent infections were referred to the Instituto de Inmunologia Clinica, Universidad de Los Andes.
RESULTS AND CONCLUSIONS: During the three-year period January 2014 to January 2017, thirty-two cases of PIDs were identified in pediatric patients, and 17 different types of PIDs, were identified. Predominantly antibody deficiencies were most frequent (40.6%), followed by immunodeficiencies affecting cellular and humoral immunity (21.8%), congenital defects of phagocyte (18.7%), CID with associated or syndromic features (9.3%), defects in intrinsic and innate immunity (6.4%) and diseases of immune dysregulation (3.2%). These results have important implications not only to the future approach for management of patients in our regions, but add important knowledge concerning PIDs in Latin America and worldwide.

PMID: 31371133 [PubMed – as supplied by publisher]

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Limited Tissue Biopsies and Hematolymphoid Neoplasms.

Am J Clin Pathol. 2019 Aug 01;:

Authors: Ingersoll KF, Zhao Y, Harrison GP, Li Y, Yang LH, Wang E

Abstract
OBJECTIVES: Use of fine-needle aspiration/needle core biopsy (FNA/CNB) in evaluating hematolymphoid processes has been debated. We investigate its applicability in various clinicopathologic settings.
METHODS: We retrospectively analyzed 152 cases of FNA/CNB.
RESULTS: Of 152 FNA/CNBs, 124 (81.6%) resulted in diagnoses without excisional biopsies, while 28 required subsequent excisional biopsies. Of these, 43 FNA/CNBs performed for suspected lymphoma relapse demonstrated 95.4% diagnostic rate (41/43), which was significantly better than those without history of lymphoma (77/109, 71%; odds ratio [OR], 8.5; confidence interval, 1.9-37.4). Patients with immunodeficiency also showed a high rate of diagnosis by FNA/CNB (100%). When stratified by types of disease, diffuse large B-cell lymphoma/high-grade B-cell lymphoma demonstrated a higher success rate (92.7%) than small B-cell lymphoma (79.2%), though the difference was not statistically significant (OR, 3.3; P value = .07). A subsequent excisional biopsy was required in 28 cases, 23 of which resulted in diagnoses concordant with the FNA/CNB. Five cases showed diagnostic discordance, reflecting pitfalls of FNA/CNB in unusual cases with complex pathology.
CONCLUSIONS: FNA/CNB is practical in evaluating most hematolymphoid lesions, with high efficacy in recurrent disease and some primary neoplasms with homogeneous/ aggressive histology, or characteristic immunophenotype.

PMID: 31365922 [PubMed – as supplied by publisher]

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