Predominantly Antibody Deficiencies Research Articles

Heterozygous SERPINA1 Defects and Their Impact on Clinical Manifestations of Patients with Predominantly Antibody Deficiencies.

Patients with predominantly antibody deficiencies (PADs) display hypogammaglobulinemia with a high prevalence of infections, along with autoimmune manifestations, benign and malignant lymphoproliferation and granulomatous disease. It is noteworthy that PAD patients, even those with defects in the same causative genes, display a variable clinical phenotype, suggesting that additional genetic polymorphisms, located in either immune-related or non-immune-related genes, may affect their clinical and laboratory phenotype. In this context, we analyzed 80 PAD patients, including 70 with common variable immunodeficiency (CVID) for SERPINA1 defects, in order to investigate the possible contribution to PAD clinical phenotype. Ten CVID patients carried heterozygous pathogenic SERPINA1 defects with normal alpha-1 antitrypsin levels. Interestingly, the presence of the Z allele (rs28929474), which was found in three patients, was significantly associated with liver disease; hepatic complications were also observed in patients carrying the p.Leu23Gln (rs1379209512) and the p.Phe76del (rs775982338) alleles. Conversely, no correlation of SERPINA1 defective variants with respiratory complications was observed, although patients with pathogenic variants exhibit a reduced probability of developing autoimmune diseases. Therefore, we recommend SERPINA1 genetic analysis in PAD in order to identify patients with a higher risk for liver disease.

A Nationwide Study of the Delayed Diagnosis and the Clinical Manifestations of Predominantly Antibody Deficiencies and CTLA4-Mediated Immune Dysregulation Syndrome in Greece.

Background and Objectives: Predominantly antibody deficiencies (PAD) represent the most common type of primary immunodeficiencies in humans, characterized by a wide variation in disease onset, clinical manifestations, and outcome. Considering that the prevalence of PAD in Greece is unknown, and there is limited knowledge on the clinical and laboratory characteristics of affected patients, we conducted a nationwide study. Materials and Methods: 153 patients (male/female: 66/87; median age: 43.0 years; range: 7.0-77.0) diagnosed, and followed-up between August 1979 to September 2023. Furthermore, we classified our cohort into five groups according to their medical history, immunoglobulin levels, and CTLA4-mutational status: 123 had common variable immunodeficiency (CVID), 12 patients with "secondary" hypogammaglobulinemia due to a previous B-cell depletion immunotherapy for autoimmune or malignant disease several years ago (median: 9 years, range 6-14) displaying a typical CVID phenotype, 7 with combined IgA and IgG subclass deficiencies, 5 patients with CVID-like disease due to CTLA4-mediated immune dysregulation syndrome, and 6 patients with unclassified hypogammaglobulinemia. Results: We demonstrated a remarkable delay in PAD diagnosis, several years after the onset of related symptoms (median: 9.0 years, range: 0-43.0). A family history of PAD was only present in 11.8%, with the majority of patients considered sporadic cases. Most patients were diagnosed in the context of a diagnostic work-up for recurrent infections, or recurrent/resistant autoimmune cytopenias. Interestingly, 10 patients (5.6%) had no history of infection, diagnosed due to either recurrent/resistant autoimmunity, or during a work-up of their medical/family history. Remarkable findings included an increased prevalence of lymphoproliferation (60.1%), while 39 patients (25.5%) developed bronchiectasis, and 16 (10.5%) granulomatous disease. Cancer was a common complication in our cohort (25 patients, 16.3%), with B-cell malignancies representing the most common neoplasms (56.7%). Conclusion: Our findings indicate the necessity of awareness about PAD and their complications, aiming for early diagnosis and the appropriate management of affected patients.

Cytokine Response Following SARS-CoV-2 Antigen Stimulation in Patients with Predominantly Antibody Deficiencies.

Predominantly antibody deficiencies (PADs) are inborn disorders characterized by immune dysregulation and increased susceptibility to infections. Response to vaccination, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), may be impaired in these patients, and studies on responsiveness correlates, including cytokine signatures to antigen stimulation, are sparse. In this study, we aimed to describe the spike-specific cytokine response following whole-blood stimulation with SARS-CoV-2 spike peptides in patients with PAD (n = 16 with common variable immunodeficiency and n = 15 with selective IgA deficiency) and its relationship with the occurrence of coronavirus disease 2019 (COVID-19) during up to 10-month follow-up period. Spike-induced antibody and cytokine production was measured using ELISA (anti-spike IgG, IFN-γ) and xMAP technology (interleukin-1β (IL-1β), IL-4, IL-6, IL-10, IL-15, IL-17A, IL-21, TNF-α, TGF-β1). No difference was found in the production of cytokines between patients with PAD and controls. Anti-spike IgG and cytokine levels did not predict contraction of COVID-19. The only cytokine that distinguished between vaccinated and naturally infected unvaccinated PAD patients was IFN-γ (median 0.64 (IQR = 1.08) in vaccinated vs. 0.10 (IQR = 0.28) in unvaccinated). This study describes the spike-specific cytokine response to SARS-CoV-2 antigens, which is not predictive of contracting COVID-19 during the follow-up.

Kinetics of immune responses elicited after three mRNA COVID-19 vaccine doses in predominantly antibody-deficient individuals

Mass vaccination campaigns reduced COVID-19 incidence and severity. Here, we evaluated the immune responses developed in SARS-CoV-2-uninfected patients with predominantly antibody-deficiencies (PAD) after three mRNA-1273 vaccine doses. PAD patients were classified based on their immunodeficiency: unclassified primary antibody-deficiency (unPAD, n=9), common variable immunodeficiency (CVID, n=12), combined immunodeficiency (CID, n=1), and thymoma with immunodeficiency (TID, n=1). unPAD patients and healthy controls (HCs, n=10) developed similar vaccine-induced humoral responses after two doses. However, CVID patients showed reduced binding and neutralizing titers compared to HCs. Interestingly, these PAD groups showed lower levels of Spike-specific IFN-γ-producing cells. CVID individuals also presented diminished CD8+ T cells. CID and TID patients developed cellular but not humoral responses. While the third vaccine dose boosted humoral responses in most PAD patients, it had limited effect on expanding cellular immunity. Vaccine-induced immune responses in PAD individuals are heterogeneous, and should be immunomonitored to define a personalized therapeutic strategies.

Comparison of pulmonary lesions using lung ultrasound and high-resolution computed tomography in adult patients with primary humoral immunodeficiencies.

Pulmonary involvement is the most common complication in patients with predominantly antibody deficiencies (PADs). Therefore, patients require repeated imaging tests. Unlike high-resolution computed tomography (HRCT), lung ultrasonography (LUS) does not expose patients to X-rays or contrast agents, and can be performed even at the bedside. This study aimed to evaluate lung lesions using simultaneous LUS and HRCT in a group of patients with PADs. Twenty-nine adult patients (13 women and 16 men) diagnosed with PADs according to the ESID criteria (23 Common variable immunodeficiency, 2 X-linked agammaglobulinemia, 2 IgG subclass deficiencies, and 2 Unspecified hypogammaglobulinemia) were included in the study. The mean age was 39.0 ± 11.9 years. The mean time elapsed between the first symptoms of PADs and the examination was 15.4 ± 10.1 years. Lung ultrasonography and high-resolution computed tomography were performed simultaneously according to a defined protocol during the clinic visits. In both examinations, lesions were compared in the same 12 regions: for each lung in the upper, middle, and lower parts, separately, front and back. A total of 435 lesions were described on LUS, whereas 209 lesions were described on HRCT. The frequencies of lesions in the lung regions were similar between LUS and HRCT. In both examinations, lesions in the lower parts of the lungs were most often reported (LUS 60.9% vs. HRCT 55.5%) and least often in the upper parts of the lungs (LUS 12.7% vs. HRCT 12.0%). The most frequently described lesions were LUS consolidations (99; 22.8%) and HRCT fibrosis (74; 16.5%). A statistically significant relationship was found in the detection of fibrosis in 11 of the 12 regions (phi = 0.4-1.0). Maximum values of the phi coefficient for the upper part of the left lung were recorded. Compared with HRCT, LUS is an effective alternative for evaluating and monitoring pulmonary lesions in adult patients with PADs, especially for pulmonary fibrosis.

B Cell Subsets in Colombian Adults with Predominantly Antibody Deficiencies, Bronchiectasis or Recurrent Pneumonia.

To evaluate and describe lymphocyte populations' and B cell subsets' frequencies in patients presenting with Predominantly antibody deficiencies (PAD) and diagnosed with bronchiectasis or recurrent pneumonia seen in Cali (Colombian Southwest region). 16 subjects with PAD, 20 subjects with pulmonary complications (bronchiectasis or recurrent pneumonia) and 20 healthy donors (HD). Controls and probands between 14 and 64 years old, regardless of gender were included. Lymphocyte populations (T, B and NK cells) and B cell subsets were evaluated in peripheral blood mononuclear cells using flow cytometry, T/B/NK reagent and the pre-germinal center antibody panel proposed by the EUROflow consortium were used. EUROclass and the classification proposed by Driessen et al. were implemented. CVID patients exhibited increase absolute numbers of CD8+ T cells and reduce NK cells as compare with HD, other PAD cases or pulmonary complications. PAD B cell subsets were disturbed when compared to the age range-matched healthy donors. Among B cell subsets, the memory B cell compartment was the most affected, especially switched memory B cells. Four participants were classified as B- and two CVID as smB-Trnorm and smB-21low groups according to EUROclass classification. The most frequent patterns proposed by Driessen et al. were B cell production and germinal center defect. B cell subsets, especially memory B cells, are disturbed in PAD patients from Southwestern Colombia. To the best of our knowledge this is the most comprehensive study of B cell subsets in Colombian adults.

Pulmonary manifestations in a cohort of patients with inborn errors of immunity: an 8-year follow-up study.

Inborn errors of immunity (IEIs) are a group of congenital diseases caused by genetic defects in the development and function of the immune system. The involvement of the respiratory tract is one of the most common presentations in IEIs. Overall, 117 patients with diagnosed IEIs were followed-up within 8 years at the National Research Institute of Tuberculosis and Lung Diseases (NRITLD). Demographic, clinical, and laboratory data were collected in a questionnaire. Pulmonary function test (PFT), chest X-ray (CXR), and high-resolution computed tomography (HRCT) scans were obtained where applicable. Our study population consisted of 48 (41%) patients with predominantly antibody deficiencies (PADs), 39 (32%) patients with congenital defects of phagocytes, 14 (11.9%) patients with combined immunodeficiency (CID), and 16 (14%) patients with Mendelian susceptibility to mycobacterial diseases (MSMD). . Recurrent pneumonia was the most common manifestation, while productive cough appeared to be the most common symptom in almost all diseases. PFT showed an obstructive pattern in patients with PAD, a restrictive pattern in patients with CID, and a mixed pattern in patients with CGD. HRCT findings were consistent with bronchiectasis in most PAD patients, whereas consolidation and mediastinal lesions were more common in the other groups. Pulmonary manifestations vary among different groups of IEIs. The screening for lung complications should be performed regularly to reveal respiratory pathologies in early stages and follow-up on already existing abnormalities.

Establishing the Molecular Diagnoses in a Cohort of 291 Patients With Predominantly Antibody Deficiency by Targeted Next-Generation Sequencing: Experience From a Monocentric Study.

Predominantly antibody deficiencies (PAD) are a heterogeneous group of disorders characterized by dysfunctional antibody production, low immunoglobulin levels in serum and impaired vaccine responses. The clinical picture is variable, ranging from mild symptoms to severe complications, which may include autoimmunity, gastrointestinal disease, allergy, and malignancies. If left untreated, PAD patients are at risk of enduring disease progression, irreversible organ damage, and reduced life expectancy. A timely diagnosis has been shown to significantly improve disease prognosis. Here, we report on our experience using targeted gene panel sequencing by employing Agilent’s HaloPlex or SureSelect and Illumina’s MiSeq technologies in a cohort of 291 individuals who presented with low or absent immunoglobulin levels in combination with or without other clinical features. In total, we have detected over 57 novel or previously reported relevant mutations in ADA, ADA2, BTK, CTLA4, LRBA, NFKB1, NFKB2, PIK3CD, STAT3, and TNFRSF13B. Overall, a genetic diagnosis could be made in 24.7% of the investigated patients. The percentage of coverage for the targeted regions ranged from 90% to 98% in this study. Moreover, functional assays were performed on a defined group of the patients carrying candidate variants in CTLA4, LRBA, NFKB1 and BTK, which confirmed their deleterious effect on protein expression and/or function. This study reiterates that the immunological heterogeneity of predominantly antibody deficiencies may have a diverse genetic origin, although certain clinical features may hint towards a specific group of defects. Employing targeted sequencing panels proves to be a very time- and cost-efficient, yet reliable, method for the establishment of a genetic diagnosis in individuals with PAD. However, in case of negative panel results, or if functional testing reveals inconspicuous observations in patients with a clear indication for genetic testing, further work-up including whole exome or whole genome sequencing should be considered.

Anxiety and Depression Among Patients with Predominantly Antibody Deficiencies and the Importance of Early Diagnosis

ABSTRACT Objective: Diagnostic delay is one of the major problems for patients with predominantly antibody deficiencies (PAD) that can lead to anxiety and depression disorders, like in other chronic diseases. We aimed to detect the frequencies of anxiety and depression in PAD patients. The second aim was to determine the influence of diagnosis delay on the patients’ anxiety and depression. Materials and Methods: In this prospective study, 40 patients and 50 healthy controls answered the Hospital Anxiety and Depression Scale (HADS). We compared the anxiety, depression, and the total scores of the patients and the healthy controls. We divided the patients into two groups as delayed and early diagnosed patients according to median diagnostic delay year and compared the HADS scores of the two groups. Results: The anxiety, depression and the total scores of PAD patients were significantly higher compared to the healthy controls; (p=0.001, p=0.001, p=0.001), respectively. The HADS scores were significantly higher in the delayed diagnosis patient group than the early diagnosed patient group (p=0.001, p=0.003, p=0.001), respectively. We also confirmed this positive relationship between delayed diagnosis and the HADS scores with Spearman’s correlation analysis. Conclusion: We demonstrated that psychiatric disorders such as anxiety and depression are common in PAD patients, and delayed diagnosis strongly affects their anxiety and depression. Collaboration with psychologists and psychiatrists during the management of these patients may improve the quality of their life. Keywords: Predominantly antibody deficiencies, early diagnosis, anxiety, depression

Known and potential molecules associated with altered B cell development leading to predominantly antibody deficiencies.

Predominantly antibody deficiencies (PADs) encompass a heterogeneous group of disorders characterized by low immunoglobulin serum levels in the presence or absence of peripheral B cells. Clinical presentation of affected patients may include recurrent respiratory and gastrointestinal infections, invasive infections, autoimmune manifestations, allergic reactions, lymphoproliferation, and increased susceptibility to malignant transformation. In the last decades, several genetic alterations affecting B-cell development/maturation have been identified as causative of several forms of PADs, adding important information on the genetic background of PADs, which in turn should lead to a better understanding of these disorders and precise clinical management of affected patients. This review aimed to present a comprehensive overview of the known and potentially involved molecules in the etiology of PADs to elucidate the pathogenesis of these disorders and eventually offer a better prognosis for affected patients.

B Cell Subgroups as Potential Biomarkers in Predominantly Antibody Deficiencies with Complications.

Predominantly antibody deficiencies (PADs) are the most prevalent primary immunodeficiencies that are caused by genetic disorders and result in impairment of the immune system. Therefore, PAD diagnosis has been extensively studied, yet their B-cell defects and underlying genetic alterations remain largely unknown. The aim of this study is to determine the immunological differences in PAD patients categorized by patients showing different complications such as splenomegaly, bronchiectasis, and chronic diarrhea. A total of 45 participants, consisting of 27 patients diagnosed with PAD and 18 healthy control individuals were included in this study. The relationship between B cell subgroups in PAD patients and control groups are investigated. Additionally, the association between B cell subgroups and complications such as splenomegaly, bronchiectasis, and chronic diarrhea in PAD patients are studied. In this study, we found an association between splenomegaly and various B cell subgroups such as naive B cells, CD21low B cells, and SW memory B cells. In the correlation analysis, we found a negative correlation between naive B cells and splenomegaly. Additionally, to the best of our knowledge, this study is the first to show a statistically significant association between memory B cells and chronic diarrhea as well as between transitional B cells and bronchiectasis. This study provides biomarkers to predict PAD patients' clinical progression or disease complications.

Application of Flow Cytometry in Predominantly Antibody Deficiencies.

Predominantly antibody deficiencies (PADs) are a heterogeneous group of primary immunodeficiency disorders (PIDs), consisting of recurrent infections, autoimmunity, inflammation, and other immune complications. In the recent years, several immunological and genetic defects have been recognized in PADs. Currently, 45 distinct PAD disorders with 40 different genetic defects have been identified based on the 2019 IUIS classification. Genetic analysis is helpful for diagnosing PIDs; however, genetic studies are expensive, time-consuming, and unavailable everywhere. Flow cytometry is a highly sensitive tool for evaluating the immune system and diagnosing PADs. In addition to cell populations and subpopulations assay, flow cytometry can measure cell surface, intracellular and intranuclear proteins, biological changes associated with specific immune defects, and certain functional immune abnormalities. These capabilities help in rapid diagnostic and prognostic assessment as well as in evaluating the pathogenesis of PADs. For the first time, this review particularly provides an overview of the application of flow cytometry for diagnosis, immunophenotyping, and determining the pathogenesis of PADs.

Screening for Primary immunodeficiency in Egyptian children with repeated infections

Abstract Introduction Despite efforts, primary immunodeficiency disorders (PIDs) are still under estimated. Predominantly antibody deficiencies (PADs) account for approximately two-thirds of all PIDs. We sought to screen for immunoglobulin deficiency among Egyptian infants and children presenting with unusually recurrent, severe and/ or persistent infections. Methods We conducted a cross sectional study that included 75 children presenting with clinical history and/or features suggestive of immunodeficiency. They were enrolled from Children’s Hospitals of Ain Shams and Mansoura Universities. They were subjected to clinical evaluation and measurement of serum immunoglobulin (Ig) levels: IgA, IgG and IgM (by nephelometry) and IgE (by ELISA). Results Patients’ ages ranged between 0.5-14 years (median (IQR): 2(0.83-3) with male to female ratio 2:1. Pneumonia was the most common infection (84%) followed by gastroenteritis (64%). Eleven patients (14.7%) had allergic manifestations and three (4%) had suppurative lung disease. Duration of infections per year ranged 3-150 days (median (IQR): 65(60-90), with average of 5 times hospitalization per year. Eighteen (24%) patients had failure to thrive and 21 patients (28%) had absent BCG scar. According to immunological evaluation, 7 patients (9.3%) had combined immunodeficiency, 4 (5%) had agammaglobulinemia, 2 (2.5%) had hypogammaglobulinemia, 2 (2.5%) had Hyper-immunoglobulin E syndrome and one had HIV infection. Patients without B cell defects had significantly higher frequency infection and hospitalization per year compared to those with B cell defects (p = 0.017 and 0.019 respectively). Conclusion: Primary immunodeficiency disorders are not rare. The awareness of families and primary health care physicians is crucial in the establishment of early diagnosis and initiation of appropriate therapy.

Defects in memory B-cell and plasma cell subsets expressing different immunoglobulin-subclasses in patients with CVID and immunoglobulin subclass deficiencies

Predominantly antibody deficiencies (PADs) are the most prevalent primary immunodeficiencies, but their B-cell defects and underlying genetic alterations remain largely unknown. We investigated patients with PADs for the distribution of 41 blood B-cell and plasma cell (PC) subsets, including subsets defined by expression of distinct immunoglobulin heavy chain subclasses. Blood samples from 139 patients with PADs, 61 patients with common variable immunodeficiency (CVID), 68 patients with selective IgA deficiency (IgAdef), 10 patients with IgG subclass deficiency with IgA deficiency, and 223 age-matched control subjects were studied by using flow cytometry with EuroFlow immunoglobulin isotype staining. Patients were classified according to their B-cell and PC immune profile, and the obtained patient clusters were correlated with clinical manifestations of PADs. Decreased counts of blood PCs, memory B cells (MBCs), or both expressing distinct IgA and IgG subclasses were identified in all patients with PADs. In patients with IgAdef, B-cell defects were mainly restricted to surface membrane (sm)IgA+ PCs and MBCs, with 2 clear subgroups showing strongly decreased numbers of smIgA+ PCs with mild versus severe smIgA+ MBC defects and higher frequencies of nonrespiratory tract infections, autoimmunity, and affected family members. Patients with IgG subclass deficiency with IgA deficiency and those with CVID showed defects in both smIgA+ and smIgG+ MBCs and PCs. Reduced numbers of switched PCs were systematically found in patients with CVID (absent in 98%), with 6 different defective MBC (and clinical) profiles: (1) profound decrease in MBC numbers; (2) defective CD27+ MBCs with almost normal IgG3+ MBCs; (3) absence of switched MBCs; and (4) presence of both unswitched and switched MBCs without and; (5) with IgG2+ MBCs; and (6) with IgA1+ MBCs. Distinct PAD defective B-cell patterns were identified that are associated with unique clinical profiles.

Comparison of Common Monogenic Defects in a Large Predominantly Antibody Deficiency Cohort

Predominantly antibody deficiencies (PADs) are the most common primary immunodeficiencies, characterized by hypogammaglobulinemia and inability to generate effective antibody responses. We intended to report most common monogenic PADs and to investigate how patients with PAD who were primarily diagnosed as suffering from agammaglobulinemia, hyper-IgM (HIgM) syndrome, and common variable immunodeficiency (CVID) have different clinical and immunological findings. Stepwise next-generation sequencing and Sanger sequencing were performed for confirmation of the mutations in the patients clinically diagnosed as suffering from agammaglobulinemia, HIgM syndrome, and CVID. Among 550 registered patients, the predominant genetic defects associated with agammaglobulinemia (48 Bruton's tyrosine kinase [BTK] and 6 μ heavy chain deficiencies), HIgM syndrome (21 CD40 ligand and 7 activation-induced cytidine deaminase deficiencies), and CVID (17 lipopolysaccharides-responsive beige-like anchor deficiency and 12 atypical Immunodeficiency, Centromeric instability, and Facial dysmorphism syndromes) were identified. Clinical disease severity was significantly higher in patients with μ heavy chain and CD40 ligand mutations compared with patients with BTK (P= .003) and activation-induced cytidine deaminase (P=.009) mutations. Paralysis following live polio vaccination was considerably higher in patients with μ heavy chain deficiency compared with BTK deficiency (P < .001). We found a genotype-phenotype correlation among patients with BTK mutations regarding clinical manifestation of meningitis and chronic diarrhea. Surprisingly, we noticed that first presentations in most patients with Immunodeficiency, Centromeric instability, and Facial dysmorphism were respiratory complications (P= .008), whereas first presentations in patients with lipopolysaccharides-responsive beige-like anchor deficiency were nonrespiratory complications (P=.008). This study highlights similarities and differences in the clinical and genetic spectrum of the most common PAD-associated gene defects. This comprehensive comparison will facilitate clinical decision making, and improve prognosis and targeted treatment.

Delayed Diagnosis and Complications of Predominantly Antibody Deficiencies in a Cohort of Australian Adults.

Predominantly antibody deficiencies (PADs) are the most common type of primary immunodeficiency in adults. PADs frequently pass undetected leading to delayed diagnosis, delayed treatment, and the potential for end-organ damage including bronchiectasis. In addition, PADs are frequently accompanied by comorbid autoimmune disease, and an increased risk of malignancy. To characterize the diagnostic and clinical features of adult PAD patients in Victoria, Australia. We identified adult patients receiving, or having previously received immunoglobulin replacement therapy for a PAD at four hospitals in metropolitan Melbourne, and retrospectively characterized their clinical and diagnostic features. 179 patients from The Royal Melbourne, Alfred and Austin Hospitals, and Monash Medical Centre were included in the study with a median age of 49.7 years (range: 16-87 years), of whom 98 (54.7%) were female. The majority of patients (116; 64.8%) met diagnostic criteria for common variable immunodeficiency (CVID), and 21 (11.7%) were diagnosed with X-linked agammaglobulinemia (XLA). Unclassified hypogammaglobulinemia (HGG) was described in 22 patients (12.3%), IgG subclass deficiency (IGSCD) in 12 (6.7%), and specific antibody deficiency (SpAD) in 4 individuals (2.2%). The remaining four patients had a diagnosis of Good syndrome (thymoma with immunodeficiency). There was no significant difference between the age at diagnosis of the disorders, with the exception of XLA, with a median age at diagnosis of less than 1 year. The median age of reported symptom onset was 20 years for those with a diagnosis of CVID, with a median age at diagnosis of 35 years. CVID patients experienced significantly more non-infectious complications, such as autoimmune cytopenias and lymphoproliferative disease, than the other antibody deficiency disorders. The presence of non-infectious complications was associated with significantly reduced survival in the cohort. Our data are largely consistent with the experience of other centers internationally, with clear areas for improvement, including reducing diagnostic delay for patients with PADs. It is likely that these challenges will be in part overcome by continued advances in implementation of genomic sequencing for diagnosis of PADs, and with that opportunities for targeted treatment of non-infectious complications.

The PedPAD study: boys predominate in the hypogammaglobulinaemia registry of the ESID online database

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.