Diagnostic evaluation of paediatric autoimmune lymphoproliferative immunodeficiencies (ALPID): a prospective cohort study.

BACKGROUND: Lymphoproliferation and autoimmune cytopenias characterise autoimmune lymphoproliferative syndrome. Other conditions sharing these manifestations have been termed autoimmune lymphoproliferative syndrome-like diseases, although they are frequently more severe. The aim of this study was to define the genetic, clinical, and immunological features of these disorders to improve their diagnostic classification. METHODS: In this prospective cohort study, patients were referred to the Center for Chronic Immunodeficiency in Freiburg, Germany, between Jan 1, 2008 and March 5, 2022. We enrolled patients younger than 18 years with lymphoproliferation and autoimmune cytopenia, lymphoproliferation and at least one additional sign of an inborn error of immunity (SoIEI), bilineage autoimmune cytopenia, or autoimmune cytopenia and at least one additional SoIEI. Autoimmune lymphoproliferative syndrome biomarkers were determined in all patients. Sanger sequencing followed by in-depth genetic studies were recommended for patients with biomarkers indicative of autoimmune lymphoproliferative syndrome, while IEI panels, exome sequencing, or genome sequencing were recommended for patients without such biomarkers. Genetic analyses were done as decided by the treating physician. The study was registered on the German Clinical Trials Register, DRKS00011383, and is ongoing. FINDINGS: We recruited 431 children referred for autoimmune lymphoproliferative syndrome evaluation, of whom 236 (55%) were included on the basis of lymphoproliferation and autoimmune cytopenia, 148 (34%) on the basis of lymphoproliferation and another SoIEI, 33 (8%) on the basis of autoimmune bicytopenia, and 14 (3%) on the basis of autoimmune cytopenia and another SoIEI. Median age at diagnostic evaluation was 9·8 years (IQR 5·5-13·8), and the cohort comprised 279 (65%) boys and 152 (35%) girls. After biomarker and genetic assessments, autoimmune lymphoproliferative syndrome was diagnosed in 71 (16%) patients. Among the remaining 360 patients, 54 (15%) had mostly autosomal-dominant autoimmune lymphoproliferative immunodeficiencies (AD-ALPID), most commonly affecting JAK-STAT (26 patients), CTLA4-LRBA (14), PI3K (six), RAS (five), or NFκB (three) signalling. 19 (5%) patients had other IEIs, 17 (5%) had non-IEI diagnoses, 79 (22%) were unresolved despite extended genetics (ALPID-U), and 191 (53%) had insufficient genetic workup for diagnosis. 16 (10%) of 161 patients with a final diagnosis had somatic mutations. Alternative classification of patients fulfilling common variable immunodeficiency or Evans syndrome criteria did not increase the proportion of genetic diagnoses. INTERPRETATION: The ALPID phenotype defined in this study is enriched for patients with genetic diseases treatable with targeted therapies. The term ALPID might be useful to focus diagnostic and therapeutic efforts by triggering extended genetic analysis and consideration of targeted therapies, including in some children currently classified as having common variable immunodeficiency or Evans syndrome. FUNDING: Deutsche Forschungsgemeinschaft under Germany's Excellence Strategy. TRANSLATION: For the German translation of the abstract see Supplementary Materials section.

Professional Employment in Patients on Ventricular Assist Device Support-A National Multicenter Survey Study.

This study aimed to assess patients of working age returning to professional employment as a surrogate marker for functional recovery and psychosocial reintegration after ventricular assist device (VAD) implantation. A national, multicenter study considered professional employment and its relationship to sociodemographic, psychosocial, and clinical adverse outcomes in outpatients on VAD support. Patient-reported outcome measures were administered. The survey had a 72.7% response rate. Mean age of 375 subjects was 58 ± 11 years, 53 (14%) were female. Thirty-five patients (15.15%; 95% confidence interval [CI] = 10.9-20.6) were employed, and the majority of them (n = 29, 82.9%) were bridged to transplantation. A regression model after variable selection revealed younger age (odds ratio [OR] = 0.95; 95% CI = 0.91-0.98; p < 0.005), and higher education (OR = 3.05; 95% CI = 1.72-5.41; p < 0.001) associated with professional employment. Employed patients reported higher health-related quality of life (HRQoL) (Kansas City Cardiomyopathy Questionnaire [KCCQ] overall sum-score, OR = 1.04; 95% CI = 0.92-1.07; p < 0.007), the OR for those employed was 2.18 (95% CI = 0.89-5.41; p < 0.08) indicating no significant relation for employment and a history of adverse events. In this sample, professional employment was rather small; the likelihood of adverse events was not significantly different between groups. Those employed perceived better overall HRQoL, which may encourage clinicians to support professional employment for selected patients on VAD support.

High level of psychosocial adjustment in patients on ongoing ventricular assist device support in the years one to three after VAD implantation-A national multi-center Study.

BACKGROUND: Advanced heart failure therapies such as durable ventricular assist device (VAD) support require psychosocial adjustment for those affected. Since VAD implantation has become an established treatment strategy, a focus on psychosocial factors is needed. OBJECTIVES: To investigate the construct of psychosocial adjustment and to further understand the role of social support. METHODS: In a nation-wide, multi-center, cross-sectional study, we recruited 393 participants with ongoing VAD support (3mts-3yrs on device; clinicaltrials.gov ID: NCT04234230). Patient demographics, psychosocial adjustment (perceived social support, anxiety, depression, and quality of life), and major adverse events (thromboembolic events, bleeding, driveline infections) were assessed. RESULTS: Overall, 85.8 % of the sample were male; mean age was 58.3 years (range 18-85). The majority of the sample (89.3 %) reported normal to high perceived social support. Participants expressed symptoms of anxiety within the normal range (M=6.0±3.9), mildly elevated depressive symptoms (HADS: M=7.6±2.9; PHQ-9: M=6.2±4.7), and good quality of life (KCCQ: M=65.3±17.9). Higher perceived social support was associated with lower levels of anxiety and depression, and higher levels of quality of life within our sample (all p<0.001). Driveline infection was the most prevalent adverse event (0.304 infections per person-years [32.6 % of patients]). Binary logistic regression models did not identify significant associations for the occurrence of adverse events and variables of psychosocial adjustment. CONCLUSION: Our sample perceived high levels of psychosocial adjustment. High perceived social support was associated with better outcomes in levels of anxiety, depression, and quality of life, demonstrating potential for the future development and evaluation of targeted multi-professional social support interventions including peer- and caregiver support.

Health-Related Quality of Life in Patients With Ventricular Assist Device: Psychometric Evaluation of the German Version of the Quality of Life With a Ventricular Assist Device Questionnaire.

BACKGROUND: Ventricular assist device (VAD) implantation has become an alternative treatment for patients with end-stage heart failure. In Germany, valid and reliable instruments to assess health-related quality of life in patients with VAD are lacking. OBJECTIVE: The aim of this study was to present the psychometric validation of the German version of the Quality of Life with a Ventricular Assist Device questionnaire. METHODS: In a multicenter, cross-sectional study, 393 participants (mean age, 58.3 years; 85.8% male, 60.3% bridge to transplant, and 72.8% living with VAD for ≤2 years) completed the German Quality of Life with a Ventricular Assist Device questionnaire of physical, emotional, social, cognitive, and meaning/spiritual domains. Item and confirmatory factor analyses were conducted to test item difficulty and discrimination and the underlying structure, respectively. To examine internal consistency, Cronbach α was assessed. Convergent construct validity was tested using the Kansas City Cardiomyopathy Questionnaire and the Patient Health Questionnaire-9. Readability was examined using Flesch Reading Ease index and Vienna Factual Text Formula. RESULTS: The Quality of Life with a Ventricular Assist Device showed reasonable item difficulty (Ptotal = .67) and mostly moderate to high discriminatory power (rit > 0.30). In confirmatory factor analysis, root-mean-square error of approximation (0.07) was acceptable for model fit, but no other indices. Acceptable internal consistency was found (α ≥ 0.79), with the exception of the cognitive domain (α = 0.58). The overall questionnaire and single domains demonstrated convergent validity (r ≥ 0.45, P < .001). The questionnaire showed adequate readability (Flesch Reading Ease, 64.11; Vienna Factual Text Formula, 6.91). CONCLUSION: Findings indicate a promising standardized clinical instrument to assess health-related quality of life in patients with VAD.

The GAIN Registry - a New Prospective Study for Patients with Multi-organ Autoimmunity and Autoinflammation.

Patient registries are a very important and essential tool for investigating rare diseases, as most physicians only see a limited number of cases during their career. Diseases of multi-organ autoimmunity and autoinflammation are especially challenging, as they are characterized by diverse clinical phenotypes and highly variable expressivity. The GAIN consortium (German multi-organ Auto Immunity Network) developed a dataset addressing these challenges. ICD-11, HPO, and ATC codes were incorporated to document various clinical manifestations and medications with a defined terminology. The GAIN dataset comprises detailed information on genetics, phenotypes, medication, and laboratory values. Between November 2019 and July 2022, twelve centers from Europe have registered 419 patients with multi-organ autoimmunity or autoinflammation. The median age at onset of symptoms was 13 years (IQR 3-28) and the median delay from onset to diagnosis was 5 years (IQR 1-14). Of 354 (84.5%) patients who were genetically tested, 248 (59.2%) had a defined monogenetic cause. For 87 (20.8%) patients, no mutation was found and for 19 (4.5%), the result was pending. The most common gene affected was NFkB1 (48, 11.5%), and the second common was CTLA4 (40, 9.5%), both genetic patient groups being fostered by specific research projects within GAIN. The GAIN registry may serve as a valuable resource for research in the inborn error of immunity community by providing a platform for etiological and diagnostic research projects, as well as observational trials on treatment options.

Excess length of stay and readmission following hospital-acquired bacteraemia: a population-based cohort study applying a multi-state model approach.

OBJECTIVES: Population-based estimates of excess length of stay after hospital-acquired bacteraemia (HAB) are few and prone to time-dependent bias. We investigated the excess length of stay and readmission after HAB. METHODS: This population-based cohort study included the North Denmark Region adult population hospitalized for ≥48 hours, from 2006 to 2018. Using a multi-state model with 45 days of follow-up, we estimated adjusted hazard ratios (aHRs) for end of stay and discharge alive. The excess length of stay was defined as the difference in residual length of stay between infected and uninfected patients, estimated using a non-parametric approach with HAB as time-dependent exposure. Confounder effects were estimated using pseudo-value regression. Readmission after HAB was investigated using the Cox regression. RESULTS: We identified 3457 episodes of HAB in 484 291 admissions in 205 962 unique patients. Following HAB, excess length of stay was 6.6 days (95% CI, 6.2-7.1 days) compared with patients at risk. HAB was associated with decreased probability of end of hospital stay (aHR, 0.60; 95% CI, 0.57-0.62) driven by the decreased hazard for discharge alive; the aHRs ranged from 0.30 (95% CI, 0.23-0.40) for bacteraemia stemming from 'heart and vascular' source to 0.72 (95% CI, 0.69-0.82) for the 'urinary tract'. Despite increased post-discharge mortality (aHR, 2.76; 95% CI, 2.38-3.21), HAB was associated with readmission (aHR, 1.42; 95% CI, 1.31-1.53). CONCLUSION: HAB was associated with considerably excess length of hospital stay compared with hospitalized patients without bacteraemia. Among patients discharged alive, HAB was associated with increased readmission rates.

Research on Rare Diseases in Germany - The GAIN Registry: a registry for individuals with congenital multi-organ autoimmune diseases.

Background: Patient registries are an important tool for networking medical caregivers and research, especially in the field of rare diseases. Individuals afflicted by multi-organ autoimmune diseases typically suffer from inflammation of multiple organs. Project: GAIN (German genetic multi-organ Auto-Immunity Network) is the German network for research and therapy optimisation for individuals with congenital multi-organ autoimmune diseases. As a sub-project of the network, the registry systematically collects data from this patient group and makes it available for research purposes. Results: A data set was developed and made available for the GAIN Registry that can map the complex clinical status of persons with multi-organ autoimmune diseases. Data from 486 individuals have been documented to date. Conclusions: The GAIN register allows for a very comprehensive documentation that clearly goes beyond previous approaches, e.g. by linking it to biosamples collected in the consortium. The planned inclusion of patients in the documentation, e.g. of data on quality of life, opens up a new field.

Inverse Probability Weighting Enhances Absolute Risk Estimation in Three Common Study Designs of Nosocomial Infections.

Purpose: When studying nosocomial infections, resource-efficient sampling designs such as nested case-control, case-cohort, and point prevalence studies are preferred. However, standard analyses of these study designs can introduce selection bias, especially when interested in absolute rates and risks. Moreover, nosocomial infection studies are often subject to competing risks. We aim to demonstrate in this tutorial how to address these challenges for all three study designs using simple weighting techniques. Patients and Methods: We discuss the study designs and explain how inverse probability weights (IPW) are applied to obtain unbiased hazard ratios (HR), odds ratios and cumulative incidences. We illustrate these methods in a multi-state framework using a dataset from a nosocomial infections study (n = 2286) in Moscow, Russia. Results: Including IPW in the analysis corrects the unweighted naïve analyses and enables the estimation of absolute risks. Resulting estimates are close to the full cohort estimates using substantially smaller numbers of patients. Conclusion: IPW is a powerful tool to account for the unequal selection of controls in case-cohort, nested case-control and point prevalence studies. Findings can be generalized to the full population and absolute risks can be estimated. When applied to a multi-state model, competing risks are also taken into account.