Worldwide, most patient registries for IEI are national, with limited geographical/temporal scope. This 30-year ESID registry analysis of 30,628 patients’ longitudinal datasets enables robust epidemiological studies on natural courses, including diagnosis, treatment, and survival, supporting expanded newborn screening and future AI applications in IEI research.

The European Society for Immunodeficiencies patient registry (ESID-R), established in 1994, is one of the world's largest databases on inborn errors of immunity (IEI). IEI are genetic disorders predisposing patients to infections, autoimmunity, inflammation, allergies and malignancies. Treatments include antimicrobial therapy, immunoglobulin replacement, immune modulation, stem cell transplantation and gene therapy. Data from 194 centers in 33 countries capture clinical manifestations and treatments from birth onward, with annually expected updates. This report reviews the ESID-R's structure, data content, and impact. The registry includes 30,628 patient datasets (aged 0-97.9 years; median follow-up: 7.2 years; total 825,568.2 patient-years), with 13,550 cases in 15 sub-studies. It has produced 84 peer-reviewed publications (mean citation rate: 95). Findings include real-world observations of IEI diagnoses, genetic causes, clinical manifestations, treatments, and survival trends. The ESID-R fosters global collaboration, advancing IEI research and patient care. This report highlights the key role of the multi-national ESID-R, led by an independent medical society, in evidence-based discovery.

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.

Patient registries are instrumental for clinical research in rare diseases. They help to achieve a sufficient sample size for epidemiological and clinical research and to assess the feasibility of clinical trials. The European Society for Immunodeficiencies (ESID) registry currently comprises information on more than 25,000 patients with inborn errors of immunity (IEI). The prerequisite of a patient to be included into the ESID registry is an IEI either defined by a defect in a gene included in the disease classification of the international union of immunological societies, or verified by applying clinical criteria. Because a relevant number of patients, including those with common variable immunodeficiency (CVID), representing the largest group of patients in the registry, remain without a genetic diagnosis, consensus on classification of these patients is mandatory. Here, we present clinical criteria for a large number of IEI that were designed in expert panels with an external review. They were implemented for novel entries and verification of existing data sets from 2014, yielding a substantial refinement. For instance, 8% of adults and 27% of children with CVID (176 of 1704 patients) were reclassified to 22 different immunodeficiencies, illustrating progress in genetics, but also the previous lack of standardized disease definitions. Importantly, apart from registry purposes, the clinical criteria are also helpful to support treatment decisions in the absence of a genetic diagnosis or in patients with variants of unknown significance.

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 105 of the CVID cohort (the individual disease burden), and of the general population (the societal disease burden).

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.

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.

Complement immunodeficiencies (excluding hereditary angioedema and mannose binding lectin deficiency) are rare. Published literature consists largely of case reports and small series. We collated data from 18 cities across Europe to provide an overview of primarily homozygous, rather than partial genotypes and their impact and management.

Purpose of review We provide an overview on the latest developments in primary immunodeficiency registries worldwide, on the basis of the recent literature amended by some older references to achieve completeness. Recent findings New primary immunodeficiency registries are emerging worldwide, although existing databases continue to thrive and provide valuable insights for clinicians and researchers. Summary In the area of rare disease research, data on a meaningful number of patients can only be achieved via collaboration. Registries for primary immunodeficiency are organized on different geographic levels and appear in various technical forms. Some registries are operated within single departments or hospitals, whereas others collect data from a country in the form of a national registry. With modern information technology and networks, it has become feasible to easily extend documentation to the transnational level. Most patient registries cover similar but not identical sets of data, whereas some have a special focus on, for example, genetics or incorporate only data from patients who have undergone a specific form of treatment. This review shows the usefulness and power of international immunodeficiency registries, as well as possible hurdles and limitations.

BACKGROUND:Common variable immunodeficiency (CVID) is an antibody deficiency with an equal sex distribution and a high variability in clinical presentation. The main features include respiratory tract infections and their associated complications, enteropathy, autoimmunity, and lymphoproliferative disorders.OBJECTIVE:This study analyzes the clinical presentation, association between clinical features, and differences and effects of immunoglobulin treatment in Europe.METHODS:Data on 2212 patients with CVID from 28 medical centers contributing to the European Society for Immunodeficiencies Database were analyzed retrospectively.RESULTS:Early disease onset (<10 years) was very frequent in our cohort (33.7%), especially in male subjects (39.8%). Male subjects with early-onset CVID were more prone to pneumonia and less prone to other complications suggesting a distinct disease entity. The diagnostic delay of CVID ranges between 4 and 5 years in many countries and is particularly high in subjects with early-onset CVID. Enteropathy, autoimmunity, granulomas, and splenomegaly formed a set of interrelated features, whereas bronchiectasis was not associated with any other clinical feature. Patient survival in this cohort was associated with age at onset and age at diagnosis only. There were different treatment strategies in Europe, with considerable differences in immunoglobulin dosing, ranging from 130 up to 750 mg/kg/mo. Patients with very low trough levels of less than 4 g/L had poor clinical outcomes, whereas higher trough levels were associated with a reduced frequency of serious bacterial infections.CONCLUSION:Patients with CVID are being managed differently throughout Europe, affecting various outcome measures. Clinically, CVID is a truly variable antibody deficiency syndrome.

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 XLAwas 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.

Summary Hypogammaglobulinaemias are the most common primary immunodeficiency diseases. This group of diseases is very heterogeneous, and little is known about these diseases in children. In the Pediatric Predominantly Antibody Deficiencies (PedPAD) study, we analysed data from the European Society for Immunodeficiencies (ESID) online database to gain more insight into the characteristics of children with hypogammaglobulinaemia; 46 centres in 18 different countries agreed to participate. Data from 2076 of the 3191 children who were registered at the time of data extraction with a diagnosis of hypogammaglobulinaemia (this excludes agammaglobulinaemia and defects in class-switch recombination) were available for analysis. The data set showed several limitations. Because of country-related differences in diagnostic criteria used for the classification of different types of primary hypogammaglobulinaemia, further analysis of the data was performed in the combined data set. The most striking observation is the strong majority of male patients in the group of children with primary hypogammaglobulinaemia (n = 1292, 63%). This male predominance was observed in each of the 18 countries involved. The boys were younger at diagnosis (mean age males 5·3 years; mean age females 5·8 years). Moreover, one or more complications were more frequently reported in boys (12%) compared to girls (5%). The male predominance suggests that patients with an undetected or unknown X-linked genetic cause are included in this group of children registered as primary hypogammaglobulinaemia.

In 2009, a federally funded clinical and research consortium (PID-NET, http://www.pid-net.org) established the first national registry for primary immunodeficiencies (PID) in Germany. The registry contains clinical and genetic information on PID patients and is set up within the framework of the existing European Database for Primary Immunodeficiencies, run by the European Society for Primary Immunodeficiencies. Following the example of other national registries, a central data entry clerk has been employed to support data entry at the participating centres. Regulations for ethics approvals have presented a major challenge for participation of individual centres and have led to a delay in data entry in some cases. Data on 630 patients, entered into the European registry between 2004 and 2009, were incorporated into the national registry. From April 2009 to March 2012, the number of contributing centres increased from seven to 21 and 738 additional patients were reported, leading to a total number of 1368 patients, of whom 1232 were alive. The age distribution of living patients differs significantly by gender, with twice as many males than females among children, but 15% more women than men in the age group 30 years and older. The diagnostic delay between onset of symptoms and diagnosis has decreased for some PID over the past 20 years, but remains particularly high at a median of 4 years in common variable immunodeficiency (CVID), the most prevalent PID.

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.

Clinical and genetic heterogeneity renders confirmation or exclusion of autoimmune lymphoproliferative syndrome difficult. To re-evaluate and improve the currently suggested diagnostic approach to patients with suspected FAS mutation, the most frequent cause of autoimmune lymphoproliferative syndrome, we prospectively determined 11 biomarkers in 163 patients with splenomegaly or lymphadenopathy and presumed or proven autoimmune cytopenia(s). Among 98 patients sequenced for FAS mutations in CD3+TCRα/β+CD4−CD8− “double negative” T cells, 32 had germline and six had somatic FAS mutations. The best a priori predictor of FAS mutations was the combination of vitamin B12 and soluble FAS ligand (cut-offs 1255 pg/mL and 559 pg/mL, respectively), which had a positive predictive value of 92% and a negative predictive value of 97%. We used these data to develop a web-based probability calculator for FAS mutations using the three most discriminatory biomarkers (vitamin B12, soluble FAS ligand, interleukin-10) of the 11 tested. Since more than 60% of patients with lymphoproliferation and autoimmune cytopenia(s) in our cohort did not harbor FAS mutations, 15% had somatic FAS mutations, and the predictive value of double-negative T-cell values was rather low (positive and negative predictive values of 61% and 77%, respectively), we argue that the previously suggested diagnostic algorithm based on determination of double-negative T cells and germline FAS sequencing, followed by biomarker analysis, is not efficient. We propose vitamin B12 and soluble FAS ligand assessment as the initial diagnostic step with subsequent decision on FAS sequencing supported by a probability-calculating tool.

Introduction:The category 'hypogammaglobulinemia' in the ESID Online Database (divided in 15 subcategories) contains all antibody deficient patients who are not categorised as agammaglobulinemia or hyper-IgM-hypogammaglobulinemia; it is by far the largest group of antibody deficient patients in the database. The pediatric data have not yet been analysed separately before.Objective:To describe the clinical and laboratory characteristics of children with hypogammaglobulinemia in the ESID Online Database.Methods:After consenting to participate, data from 46 participating centres in 18 countries were analysed.Results:The ESID database contains data on 3191 children with hypogammaglobulinemia of which 1980 (1244 boys) were available for analysis, almost half of them (48%) from Turkey. The most prevalent reported diagnoses are IgA-deficiency (490; 25%), transient hypogammaglobulinemia (476; 24%) and CVID (448; 23%). The mean age at onset of symptoms is 2.7 years and at diagnosis 5.6 years. A huge variation is noted in the registration, and many data items are missing or incomplete. More importantly, potentially incorrect diagnoses have been registered, e. g. 137 children with CVID were <2 years-of-age at presentation, in 81/189 'CVID' patients normal or high IgG-levels were reported at presentation, the same was true for IgA-levels in 186/434 'IgA-deficient' patients.Discussion and conclusion:The category of hypogammaglobulinemia is very heterogeneous, solid criteria for the differential diagnosis are lacking. A more precise characterization needs to be made. Furthermore, our data suggest that for an optimal registration, an electronic controller, built into the database system, ruling out obvious mistakes as described, should be considered.

Summary Primary immunodeficiency diseases (PIDs) comprise a heterogeneous group of rare disorders. This study was devised in order to compare management of these diseases in the northern hemisphere, given the variability of practice among clinicians in North America. The members of two international societies for clinical immunologists were asked about their management protocols in relation to their PID practice. An anonymous internet questionnaire, used previously for a survey of the American Academy of Allergy, Asthma and Immunology (AAAAI), was offered to all full members of the European Society for Immunodeficiency (ESID). The replies were analysed in three groups, according to the proportion of PID patients in the practice of each respondent; this resulted in two groups from North America and one from Europe. The 123 responses from ESID members (23·7%) were, in the majority, very similar to those of AAAAI respondents, with > 10% of their practice devoted to primary immunodeficiency. There were major differences between the responses of these two groups and those of the general AAAAI respondents whose clinical practice was composed of < 10% of PID patients. These differences included the routine use of intravenous immunoglobulin therapy (IVIg) for particular types of PIDs, initial levels of IVIg doses, dosing intervals, routine use of prophylactic antibiotics, perceptions of the usefulness of subcutaneous immunoglobulin therapy (SCIg) and of the risk to patients' health of policies adopted by health-care funders. Differences in practice were identified and are discussed in terms of methods of health-care provision, which suggest future studies for ensuring continuation of appropriate levels of immunoglobulin replacement therapies.