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Background Common variable immunodeficiency disorders (CVID) are a group of rare innate disorders characterized by specific antibody deficiency and increased rates of infections, comorbidities and mortality. The burden of CVID in Europe has not been previously estimated. We performed a retrospective analysis of the European Society for Immunodeficiencies (ESID) registry data on the subset of patients classified by their immunologist as CVID and treated between 2004 and 2014. The registered deaths and comorbidities were used to calculate the annual average age-standardized rates of Years of Life Lost to premature death (YLL), Years Lost to Disability (YLD) and Disability Adjusted Life Years (DALY=YLL + YLD). These outcomes were expressed as a rate per 10 5 of the CVID cohort (the individual disease burden), and of the general population (the societal disease burden). Results Data of 2700 patients from 23 countries were analysed. Annual comorbidity rates: bronchiectasis, 21.9%; autoimmunity, 23.2%; digestive disorders, 15.6%; solid cancers, 5.5%; lymphoma, 3.8%, exceeded the prevalence in the general population by a factor of 34.0, 7.6, 8.1, 2.4 and 32.6, respectively. The comorbidities of CVID caused 8722 (6069; 12,363) YLD/10 5 in this cohort, whereas 44% of disability burden was attributable to infections and bronchiectasis. The total individual burden of CVID was 36,785 (33,078, 41,380) DALY/10 5 . With estimated CVID prevalence of ~ 1/ 25,000, the societal burden of CVID ensued 1.5 (1.3, 1.7) DALY/10 5 of the general population. In exploratory analysis, increased mortality was associated with solid tumor, HR (95% CI): 2.69 (1.10; 6.57) p  = 0.030, lymphoma: 5.48 (2.36; 12.71) p  < .0001 and granulomatous-lymphocytic interstitial lung disease: 4.85 (1.63; 14.39) p  = 0.005. Diagnostic delay (median: 4 years) was associated with a higher risk of death: 1.04 (1.02; 1.06) p  = .0003, bronchiectasis: 1.03 (1.01; 1.04) p  = .0001, solid tumor: 1.08 (1.04; 1.11) p < .0001 and enteropathy: 1.02 (1.00; 1.05) p  = .0447 and stayed unchanged over four decades ( p  = .228). Conclusions While the societal burden of CVID may seem moderate, it is severe to the individual patient . Delay in CVID diagnosis may constitute a modifiable risk factor of serious comorbidities and death but showed no improvement. Tools supporting timely CVID diagnosis should be developed with high priority.

Mutations in DOCK8 result in autosomal recessive Hyper-IgE syndrome with combined immunodeficiency (CID). However, the natural course of disease, long-term prognosis, and optimal therapeutic management have not yet been clearly defined. In an international retrospective survey of patients with DOCK8 mutations, focused on clinical presentation and therapeutic measures, a total of 136 patients with a median follow-up of 11.3 years (1.3–47.7) spanning 1693 patient years, were enrolled. Eczema, recurrent respiratory tract infections, allergies, abscesses, viral infections and mucocutaneous candidiasis were the most frequent clinical manifestations. Overall survival probability in this cohort [censored for hematopoietic stem cell transplantation (HSCT)] was 87 % at 10, 47 % at 20, and 33 % at 30 years of age, respectively. Event free survival was 44, 18 and 4 % at the same time points if events were defined as death, life-threatening infections, malignancy or cerebral complications such as CNS vasculitis or stroke. Malignancy was diagnosed in 23/136 (17 %) patients (11 hematological and 9 epithelial cancers, 5 other malignancies) at a median age of 12 years. Eight of these patients died from cancer. Severe, life-threatening infections were observed in 79/136 (58 %); severe non-infectious cerebral events occurred in 14/136 (10 %). Therapeutic measures included antiviral and antibacterial prophylaxis, immunoglobulin replacement and HSCT. This study provides a comprehensive evaluation of the clinical phenotype of DOCK8 deficiency in the largest cohort reported so far and demonstrates the severity of the disease with relatively poor prognosis. Early HSCT should be strongly considered as a potential curative measure.

Purpose Nijmegen Breakage Syndrome (NBS) is a rare inherited condition, characterized by microcephaly, chromosomal instability, immunodeficiency, and predisposition to malignancy. This retrospective study, characterizing the clinical and immunological status of patients with NBS at time of diagnosis, was designed to assess whether any parameters were useful in disease prognosis, and could help determine patients qualified for hematopoietic stem cell transplantation. Methods The clinical and immunological characteristics of 149 NBS patients registered in the online database of the European Society for Immune Deficiencies were analyzed. Results Of the 149 NBS patients, 91 (61 %), of median age 14.3 years, remained alive at the time of analysis. These patients were clinically heterogeneous, with variable immune defects, ranging from negligible to severe dysfunction. Humoral deficiencies predisposed NBS patients to recurrent/chronic respiratory tract infections and worsened long-term clinical prognosis. Eighty malignancies, most of lymphoid origin (especially non-Hodgkin’s lymphomas), were diagnosed in 42 % of patients, with malignancy being the leading cause of death in this cohort. Survival probabilities at 5, 10, 20 and 30 years of age were 95, 85, 50 and 35 %, respectively, and were significantly lower in patients with than without malignancies. Conclusions The extremely high incidence of malignancies, mostly non-Hodgkin’s lymphomas, was the main risk factor affecting survival probability in NBS patients. Because treatment of NBS is very difficult and frequently unsuccessful, the search for an alternative medical intervention such as hematopoietic stem cell transplantation is of great clinical importance.

Purpose Estimating the underlying demand for immunoglobulin (Ig) is important to ensure that adequate provision is made for patients with primary immune deficiency (PID) in the context of the competing demands for Ig and to ensure optimal therapeutic regimens. The concept of latent therapeutic demand (LTD) was used to estimate evidence-based requirements and compared to the actual Ig consumption in different countries. The estimates were performed for common variable immunodeficiency (CVID) and X-linked Agammaglobulinaemia (XLA), the two most commonly studied PIDs using Ig. Methods The LTD model for CVID and XLA was derived using decision analysis methodology. Data for the epidemiology and treatment variables were obtained from peer-reviewed publications, clinical registries and publicly-available patient surveys. Incomplete data records from registries were excluded from analysis. The variables impacting LTD were ranked in order of sensitivity through a tornado diagram. The uncertainty surrounding the variables was modeled using probabilistic distributions and evaluated using Monte Carlo simulation. Results Treatment dosage and prevalence were determined to be the most sensitive variables driving demand. The average potential usage of Ig for the treatment of CVID and XLA was estimated at 72 g per 1,000 population, which is higher than the estimated Ig usage in CVID and XLA of 27–41 g per 1,000 population in the US. Conclusion The potential demand for treating CVID and XLA exceeds the currently observed usage of Ig in these disorders. Variable usage in different countries is due to varying prevalence and dosage practices. Under-reporting in patient registries represents a major obstacle to calculating the true prevalence of CVID and XLA. Modeling demand relies heavily upon accurate prevalence and practice estimates which reemphasize the importance of accurate registries and improved registry methods. As better data becomes available, revision of model variables provides opportunities to anticipate and prepare for evolving patient needs.

Primary immunodeficiency disease (PID) has traditionally been viewed as a group of illnesses seen in the paediatric age group. New advances in diagnosis and treatment have led to an increase in the number of elderly PID patients. However, there is lack of research evidence on which to base clinical management in this group of patients. Management decisions often have to be based therefore on extrapolations from other patient cohorts or from younger patients. Data from the European Society for Immunodeficiencies demonstrates that the vast majority of elderly patients suffer from predominantly antibody deficiency syndromes. We review the management of PID disease in the elderly, with a focus on antibody deficiency disease.

Studies of chest computed tomography (CT) in patients with primary antibody deficiency syndromes (ADS) suggest a broad range of bronchial pathology. However, there are as yet no multicentre studies to assess the variety of bronchial pathology in this patient group. One of the underlying reasons is the lack of a consensus methodology, a prerequisite to jointly document chest CT findings. We aimed to establish an international platform for the evaluation of bronchial pathology as assessed by chest CT and to describe the range of bronchial pathologies in patients with antibody deficiency. Ffteen immunodeficiency centres from 9 countries evaluated chest CT scans of patients with ADS using a predefined list of potential findings including an extent score for bronchiectasis. Data of 282 patients with ADS were collected. Patients with common variable immunodeficiency disorders (CVID) comprised the largest subgroup (232 patients, 82.3%). Eighty percent of CVID patients had radiological evidence of bronchial pathology including bronchiectasis in 61%, bronchial wall thickening in 44% and mucus plugging in 29%. Bronchiectasis was detected in 44% of CVID patients aged less than 20 years. Cough was a better predictor for bronchiectasis than spirometry values. Delay of diagnosis as well as duration of disease correlated positively with presence of bronchiectasis. The use of consensus diagnostic criteria and a pre-defined list of bronchial pathologies allows for comparison of chest CT data in multicentre studies. Our data suggest a high prevalence of bronchial pathology in CVID due to late diagnosis or duration of disease.

In the original version of this article unfortunately two authors were missing: Dr. Jürgen Weidemann and Dr. Daniel Berthold. The correct list of authors is presented above.

Anxiety disorders (AD) are associated with altered connectivity in large-scale intrinsic brain networks. It remains uncertain how much these signatures overlap across different phenotypes due to a lack of well-powered cross-disorder comparisons. We used resting-state functional magnetic resonance imaging (rsfMRI) to investigate differences in functional connectivity (FC) in a cross-disorder sample of AD patients and healthy controls (HC). Before treatment, 439 patients from two German multicenter clinical trials at eight different sites fulfilling a primary diagnosis of panic disorder and/or agoraphobia (PD/AG, N = 154), social anxiety disorder (SAD, N = 95), or specific phobia (SP, N = 190) and 105 HC underwent an 8 min rsfMRI assessment. We performed categorical and dimensional regions of interest (ROI)-to-ROI analyses focusing on connectivity between regions of the defensive system and prefrontal regulation areas. AD patients showed increased connectivity between the insula and the thalamus compared to controls. This was mainly driven by PD/AG patients who showed increased (insula/hippocampus/amygdala—thalamus) and decreased (dorsomedial prefrontal cortex/periaqueductal gray—anterior cingulate cortex) positive connectivity between subcortical and cortical areas. In contrast, SAD patients showed decreased negative connectivity exclusively in cortical areas (insula—orbitofrontal cortex), whereas no differences were found in SP patients. State anxiety associated with the scanner environment did not explain the FC between these regions. Only PD/AG patients showed pronounced connectivity changes along a widespread subcortical-cortical network, including the midbrain. Dimensional analyses yielded no significant results. The results highlighting categorical differences between ADs at a systems neuroscience level are discussed within the context of personalized neuroscience-informed treatments. PROTECT-AD’s registration at NIMH Protocol Registration System: 01EE1402A and German Register of Clinical Studies: DRKS00008743. SpiderVR’s registration at ClinicalTrials.gov: NCT03208400.

The extent of charge transfer between adsorbed reactants and a catalyst surface plays a key role in determining binding energy and catalytic activity. Here, we describe the technique of ‘isopotential titration’ (IPT) to quantify the magnitude and direction of charge transfer between adsorbates and catalytic surfaces. The method used a ‘catalytic condenser’ device (Pt/C/70 nm HfO2/p++-Si) to evaluate the adsorption of hydrogen on a platinum-on-carbon conductive surface on a HfO2 (70 nm) film on a silicon wafer, with a potentiostat applying fixed (zero) voltage between the conductive Pt/C and silicon wafer layers. Dissociative adsorption of hydrogen on Pt resulted in electron flow through the external circuit from the Pt electrode toward the Si substrate, indicating that adsorbed hydrogen atoms donated electron density to the Pt surface, which then equilibrated with electrons flowing through the potentiostat to the silicon substrate. Desorption of hydrogen from the Pt surface exhibited equal and opposite current flow. The magnitude of the measured charge transfer upon hydrogen adsorption increased with increasing temperature from 100 to 200 °C, consistent with a larger change in H surface coverage at higher temperatures for cycling gaseous H2 partial pressures between 0.5% and 99.999%. Charge transferred from H atoms to the Pt was estimated as 0.17% of an electron donated per adsorbed H atom. The extent of charge transfer was comparable with a computed Bader charge analysis, which calculated an average of 0.4% of an electron transferred from adsorbing H to Pt at high surface coverage. With hydrogen adsorption being an example, isopotential titrations provide a new tool to quantify charge transfer events in heterogeneous catalytic systems.