The Development of a New Questionnaire to Measure the Burden of Immunoglobulin Treatment in Patients with Primary Immunodeficiencies: The IgBoT-35.

Purpose: To describe the development and psychometric testing of a new questionnaire to measure the burden of immunoglobulin treatment (Ig) from the perspective of patients with primary immunodeficiencies (PID). Patients and Methods: An online, cross-sectional survey was administered to PID patients across 10 countries (nine European and Canada) who were receiving either intravenous (IVIg) or subcutaneous (SCIg) immunoglobulin therapy. The range and distribution of the responses (ie, levels of missing data, floor and ceiling effects), exploratory factor analysis (using factor loadings of 0.4 or greater) and measures of internal consistency reliability (ie, Cronbach's alpha coefficient, inter-item and item-total correlations) were used to identify the domain and item pool. Results: In total, 472 patients completed the questionnaire, of which 395 were included in the analysis (32% underwent IVIg and 67% underwent SCIg). The final instrument contained 34 items across eight domains of treatment burden (time, organisation and planning, leisure and social, interpersonal relationships, employment and education, travel, consequences of treatment and emotional) and an additional Ig treatment burden global question at the end of the measure. All the scales achieved good internal reliability (Cronbach's alpha coefficient ranged from 0.70 to 0.85) and, with the exception of one item exceeded the minimum threshold of 0.35 for item-total correlations. Treatment burden was lower than anticipated across the different treatment routes and countries, although overall was more burdensome for patients undergoing IVIg compared to SCIg treatment. Conclusion: The IgBoT-35 appears to be a reliable, patient-generated questionnaire and may help to identify more individualised and preferred therapies for the PID patient when used in clinical practice. A new survey with a sample of US patients is currently being undertaken to further establish its validity and conceptual model. The overall Ig burden of treatment scores appeared to be low. PID patient preferences are important to guide treatment decisions and ensuring patients receive the right treatment at the right time

Initial presenting manifestations in 16,486 patients with inborn errors of immunity include infections and noninfectious manifestations

Background: Inborn errors of immunity (IEI) are rare diseases, which makes diagnosis a challenge. A better description of the initial presenting manifestations should improve awareness and avoid diagnostic delay. Whilst increased infection susceptibility is a well-known initial IEI manifestation, less is known about the frequency of other presenting manifestations. / Objective: To analyze age-related initial presenting manifestations of IEI including different IEI disease cohorts. Methods: We analyzed data on 16,486 patients of the European Society for Immunodeficiencies (ESID) registry. Patients with autoinflammatory diseases were excluded due to the limited number registered. / Results: Overall, 68% of patients initially presented with infections only, 9% with immune dysregulation only and 9% with a combination of both. Syndromic features were the presenting feature in 12%, 4% had laboratory abnormalities only, 1.5% were diagnosed due to family history only and 0.8% presented with malignancy. Two thirds of IEI patients presented before the age of 6 years, but a quarter of patients only developed initial symptoms as adults. Immune dysregulation was most frequently recognized as an initial IEI manifestation between 6 and 25 years of age with male predominance until age 10, shifting to female predominance after age 40. Infections were most prevalent as a first manifestation in patients presenting after age 30. / Conclusion: An exclusive focus on infection-centered warning signs would have missed around 25% of IEI patients that initially present with other manifestations. / Clinical implications: We provide a data-based rationale to add immune dysregulation and syndromic features to the IEI warning signs, which may significantly improve early IEI diagnosis

Absence of the spleen(s) in conjoined twins: a diagnostic clue of laterality defects? Radiological study of historical specimens

Laterality defects are quite common in thoracoileopagus and parapagus dicephalus but rare in other types of conjoined twins. To present the presumed laterality defects in cephalothoracoileopagus and prosopothoracoileopagus conjoined twins, based on the unilateral or bilateral absence or duplication of the spleen. Three human anatomical specimens of craniothoracoileopagus (CTIP) twins and one of prosopothoracoileopagus (PTIP) twins were investigated. The specimens were part of the Museum Vrolik collection of the Department of Anatomy and Embryology of the Academic Medical Centre, University of Amsterdam, The Netherlands. The specimens were taken out of their jars and scanned with multidetector CT and volumetric T2-weighted MRI at 1.5 T. The internal anatomy of the specimens was largely in accordance with previous reports. However, there was no recognisable spleen in the right twin in one CTIP specimen, in the left twin in one other CTIP specimen, and in both twins in the third CTIP specimen and in the PTIP specimen. Asplenia and polysplenia are considered reliable indicators of right and left isomerism, respectively. However, three of our four specimens had laterality patterns that did not correspond with those previously reported. Since no other parameters of laterality defects could be verified in these specimens, we concluded that asplenia was unlikely to be caused by laterality defect

Pediatric-onset Evans syndrome: Heterogeneous presentation and high frequency of monogenic disorders including LRBA and CTLA4 mutations

Evans syndrome (ES) is defined by the combination of autoimmune hemolytic anemia and immune thrombocytopenia. Clinical presentation includes manifestations of immune dysregulation, found in primary immune deficiencies, autoimmune lymphoproliferative syndrome with FAS (ALPS-FAS), Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) and Lipopolysaccharide-Responsive vesicle trafficking Beige-like and Anchor protein (LRBA) defects. We report the clinical history and genetic results of 18 children with ES after excluding ALPS-FAS. Thirteen had organomegaly, five lymphocytic infiltration of non-lymphoid organs, nine hypogammaglobulinemia and fifteen anomalies in lymphocyte phenotyping. Seven patients had genetic defects: three CTLA4 mutations (c.151C>T; c.109+1092_568-512del; c.110-2A>G) identified by Sanger sequencing and four revealed by Next Generation Sequencing: LRBA (c.2450+1C>T), STAT3 gain-of-function (c.2147C>T; c.2144C>T) and KRAS (c.37G>T). No feature emerged to distinguish patients with or without genetic diagnosis. Our data on pediatric-onset ES should prompt physicians to perform extensive screening for mutations in the growing pool of genes involved in primary immune deficiencies with autoimmunity

It’s long-term, well it’s for life basically: Understanding and exploring the burden of immunoglobulin treatment in patients with primary immunodeficiency disorders

This paper describes the burden of receiving immunoglobulin (Ig) treatment from the perspective of patients diagnosed with a Primary Immunodeficiency (PID). Thirty semi-structured interviews with patients receiving intravenous (n=21) and subcutaneous immunoglobulin (n=9) therapy, either at home or in hospital were undertaken. Underpinned by a phenomenological theoretical framework, and using a qualitative, inductive thematic approach to prioritise patients’ concerns, we identified that Ig treatment requires considerable effort by the patient, particularly in relation to the amount of time, organization and planning that is needed. They also face numerous physical, social, relationship, emotional, role functioning, travelling, and financial challenges in their effort to undergo and maintain their infusions and care for their health. Some qualitative differences in treatment burden were noted between home and hospital settings which contributed to non-adherence to those regimes. Immunoglobulin treatment burden is complex and influenced by therapeutic mode and setting and the personal circumstances of the patient. As choice over treatment method appears to be mainly informed by lifestyle needs, PID patients may benefit from more information about these potential Ig lifestyle influences when selecting which form of treatment to take together with their health professional

The European internet-based patient and research database for primary immunodeficiencies: results 2006-2008

Primary immunodeficiencies (PID) are rare diseases; therefore transnational studies are essential to maximize the scientific outcome and to improve diagnosis and therapy. In order to estimate the prevalence of PID in Europe as well as to establish and evaluate harmonized guidelines for the diagnosis and treatment of PID, the European Society for Immunodeficiencies (ESID) has developed an internet-based database for clinical and research data on patients with PID. This database is a platform for epidemiological analyses as well as the development of new diagnostic and therapeutic strategies and the identification of novel disease-associated genes. Within 4 years, 7430 patients from 39 countries have been documented in the ESID database. Common variable immunodeficiency (CVID) represents the most common entity, with 1540 patients or 20.7% of all entries, followed by isolated immunoglobulin (Ig)G subclass deficiency (546 patients, 7.4%). Evaluations show that the average life expectancy for PID patients varies from 1 to 49 years (median), depending on the type of PID. The prevalence and incidence of PID remains a key question to be answered. As the registration progress is far from finished we can only calculate minimum values for PID, with e.g. France currently showing a minimum prevalence of 3.72 patients per 100,000 inhabitants. The most frequently documented permanent treatment is immunoglobulin replacement; 2819 patients (42% of all patients alive) currently receive this form of treatment

Current Transition Practice for Primary Immunodeficiencies and Autoinflammatory Diseases in Europe: a RITA-ERN Survey

background due to the absence of curative treatments for inborn errors of immunity (IEI), children born with IEI require long-term follow-up for disease manifestations and related complications that occur over the lifespan. effective transition from pediatric to adult services is known to significantly improve adherence to treatment and long-term outcomes. It is currently not known what transition services are available for young people with IEI in europe. objective to understand the prevalence and practice of transition services in europe for young people with IEI, encompassing both primary immunodeficiencies (PID) and systemic autoinflammatory disorders (AID). methods a survey was generated by the european reference network on immunodeficiency, autoinflammatory, and autoimmune diseases transition working group and electronically circulated, through professional networks, to pediatric centers across europe looking after children with IEI. results seventy-six responses were received from 52 centers, in 45 cities across 17 different countries. all services transitioned patients to adult services, mainly to specialist PID or AID centers, typically transferring up to ten patients to adult care each year. the transition process started at a median age of 16-18 years with transfer to the adult center occurring at a median age of 18-20 years. 75% of PID and 68% of AID centers held at least one joint appointment with pediatric and adult services prior to the transfer of care. approximately 75% of PID and AID services reported having a defined transition process, but few centers reported national disease-specific transition guidelines to refer to. conclusions transition services for children with IEI in europe are available in many countries but lack standardized guidelines to promote best practice