European Society For Immunodeficiencies Research Articles

Clinical efficacy of SARS-CoV-2 Omicron-neutralizing antibodies in immunoglobulin preparations for the treatment of agammaglobulinemia in patients with primary antibody deficiency.

Immunocompromised individuals are at significantly elevated risk for severe courses of coronavirus disease 2019 (COVID-19). In addition to vaccination,severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing antibodies (nAbs) have been applied throughout the pandemic, with time of treatment onset and potency against the currently prevailing virus variant identified as relevant factors for medical benefit. Using data from the European Society for Immunodeficiencies (ESID) registry, the present study evaluated COVID-19 cases in three groups of patients with inborn errors of immunity (IEI; 981 agammaglobulinemia patients on immunoglobulin replacement therapy (IGRT); 8960 non-agammaglobulinemia patients on IGRT; 14 428 patients without IGRT), and the neutralizing capacity of 1100 immunoglobulin lots against SARS-CoV-2 ("Wuhan" and Omicron strains), throughout 3 years. From the first (2020/2021) to the second (2021/2022) cold season, i.e., during the virus drift to the more contagious Omicron variants, an increase in case numbers was recorded that was comparable (~2- to 3-fold) for all three study groups. During the same period, immunoglobulin lots showed a profound nAb increase against the archetypal SARS-CoV-2 strain, yet only low levels of Omicron nAbs. Notably, shortly before the third (2022/2023) cold season, Omicron-neutralizing capacity of released immunoglobulin lots had plateaued at high levels. From the second to the third cold season, COVID-19 cases dropped markedly. While a ~6-fold case reduction was recorded for the groups of non-agammaglobulinemia patients on IGRT and IEI patients not receiving IGRT, the decline was ~30-fold for the group of agammaglobulinemia patients on IGRT. These findings suggest a substantial COVID-19-protective effect of IGRT, at least for distinct groups of antibody-deficient patients.

Immunological Evaluation of Pediatric Patients with Polyautoimmunity.

Autoimmunity can be the first or predominant manifestation in patients with primary immunodeficiency disorder, also referred to as inborn errors of immunity (IEI). This study aims to evaluate the immune status of pediatric patients with polyautoimmunity to identify those with underlying immune defects. In this cross-sectional study, pediatric patients with polyautoimmunity including at least one confirmed autoimmune endocrine disease were enrolled. Demographic and clinical data were collected using a questionnaire based on medical records and direct family interviews. For each patient, a basic immunologic evaluation was performed. The clinical diagnosis was established according to the criteria of the European Society for Immunodeficiencies (ESID). Based on the presence or absence of a history of severe and/or recurrent infections, patients were divided into two groups for comparison. Thirty-nine patients, 18 males (46.2%) and 21 females (53.8%), were included. Fourteen patients (35.9%) had consanguineous parents. Fifteen patients (38.5%) had a history of severe and/or recurrent infections. The median (interquartile range: IQR) age of our patients at the time of evaluation was 11.1 (9-16) years. The median (IQR) age at the onset of infections and autoimmunities were 3 (1-10.8) and 5 (2.6-8) years, respectively. The most common infectious complications reported were pneumonia and candidiasis, each in 12.8% of the patients. The most prevalent autoimmune disorders were type 1 diabetes (74.3%) and autoimmune thyroiditis (58.9%). IEI was diagnosed in six patients (15.38%), five of which were from the group with severe or recurrent infections: three with selective IgA deficiency, two with common variable immunodeficiency (CVID), and one with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX), but without a history of infections. The occurrence of early onset polyautoimmunity in association with severe and/or recurrent infections or in patients with a positive family history should be a warning sign for physicians to initiate an evaluation for possible immunodeficiency disorders to prevent complications through early treatment.

The prevalence of immunodeficiency in a special population: intern doctors

Background: This study analyzes the immune system parameters of intern doctors working actively during the COVID-19 pandemic. When an intern doctor failed to respond to the treatment during a severe COVID-19 condition, the immune system panel was examined and as a result, it revealed an underlying immunodeficiency. The death of the intern doctor caused several concerns among other intern doctors, and for this reason, their immune systems were also considered to be examined. This study aims to demonstrate that immunodeficiencies might be more common than is known among the general population. Methods: In this single-center study, the demographic characteristics and European Society for Immunodeficiencies (ESID) diagnostic criteria of 92 intern doctors have been examined retrospectively. For the study, immune system parameters (complete blood count, serum immunoglobulins and subgroup levels, specific vaccine responses, isohemagglutinin titers, lymphocyte subgroups, and class-switched memory B cell (cSMB) levels have been evaluated. Results: When the demographic characteristics have been analyzed it is seen that the median age is 23.6 (21-28) years, and 64 (70%) of the intern doctors are female. In immune system parameters, one or more are found to be low in 51.08% of the doctors. Among the immunoglobulin subgroups, low IgG4 has been the most common. Selective IgA deficiency has been detected in 2.17% and selective IgM deficiency has been detected in also 2.17% of them. Low B cells (CD19+) are detected in 10.9% and low levels of class-switched memory B cells are found in 35.7% of them. Conclusion: This study reveals that deficient immunological parameters, especially selective Ig A, selective IgM deficiency, and low IgG4, might be more frequent than known. Depending on the data, it can be concluded that immunodeficiency might be more common than it is known among the general population; however, low immunological parameters alone do not lead to immunodeficiency.

Evaluation of the Effectiveness of the 6 Warning Signs of the European Society for Immunodeficiencies for Primary Immunodeficiencies in Older Adults

Introduction: Diagnostic delay in cases of primary immunodeficiency (PID) is a significant problem for clinicians, and most do not have sufficient awareness of this uncommon disorder. The European Society for Immunodeficiencies (ESID) has developed 6 warning signs to increase awareness of adult PIDs. The aim of this study was to determine the prevalence of PID in older adults regardless of the reason for presentation and to evaluate the effectiveness of the 6 warning signs of ESID in the diagnosis of PIDs. Methods: The study included 1,331 patients aged ≥65 years who presented at our clinic for any reason and were questioned about the ESID 6 warning signs for PIDs. After the exclusion of reasons for secondary immunodeficiency (SID), all the patients underwent immunological evaluation for the diagnosis of potential underlying PIDs. Results: After excluding 6 patients diagnosed with SID, PID was diagnosed in 16 (1.2%) of 1,325 older adults using ESID warning signs. The most common reasons for presentation were infection (69%) in the PID group and urticaria and/or angioedema (41.5%) in the non-PID group. The most common PID subgroup was common variable immunodeficiency (50%). In 12 of the patients diagnosed with PID, there was at least 1 positive ESID warning sign. In 4 patients, PID was determined despite negative ESID warning signs. The patients diagnosed with PID showed a significant, minimal level of agreement with questions 1 and 4 of the ESID warning signs (p < 0.001, ĸ = 0.204, p = 0.005, ĸ = 0.208, respectively). Conclusion: The ESID warning signs do not encompass all the symptoms and findings of PIDs. There is a need for more infection-centered questions to determine PIDs in older adults. Therefore, the ESID warning signs should be further developed.

Activated phosphoinositide 3-kinase δ syndrome: Update from the ESID Registry and comparison with other autoimmune-lymphoproliferative inborn errors of immunity

Activated phosphoinositide-3-kinase δ syndrome (APDS) is an inborn error of immunity (IEI) with infection susceptibility and immune dysregulation, clinically overlapping with other conditions. Management depends on disease evolution, but predictors of severe disease are lacking. This study sought to report the extended spectrum of disease manifestations in APDS1 versus APDS2; compare these to CTLA4 deficiency, NFKB1 deficiency, and STAT3 gain-of-function (GOF) disease; and identify predictors of severity in APDS. Data was collected from the ESID (European Society for Immunodeficiencies)-APDS registry and was compared with published cohorts of the other IEIs. The analysis of 170 patients with APDS outlines high penetrance and early onset of APDS compared to the other IEIs. The large clinical heterogeneity even in individuals with the same PIK3CD variant E1021K illustrates how poorly the genotype predicts the disease phenotype and course. The high clinical overlap between APDS and the other investigated IEIs suggests relevant pathophysiological convergence of the affected pathways. Preferentially affected organ systems indicate specific pathophysiology: bronchiectasis is typical of APDS1; interstitial lung disease and enteropathy are more common in STAT3 GOF and CTLA4 deficiency. Endocrinopathies are most frequent in STAT3 GOF, but growth impairment is also common, particularly in APDS2. Early clinical presentation is a risk factor for severe disease in APDS. APDS illustrates how a single genetic variant can result in a diverse autoimmune-lymphoproliferative phenotype. Overlap with other IEIs is substantial. Some specific features distinguish APDS1 from APDS2. Early onset is a risk factor for severe disease course calling for specific treatment studies in younger patients.

A report on the clinical efficacy of rituximab administration in patients with inborn errors of immunity and autoimmune manifestations

BackgroundRituximab (RTX), an anti-CD20 monoclonal antibody, is considered a novel therapeutic agent in a variable spectrum of immune disorders. Herein, we investigated the clinical efficacy of RTX in inborn errors of immunity (IEIs) with autoimmune manifestations. MethodsPatients with IEIs diagnosed clinically based on European Society for Immunodeficiencies (ESID) diagnostic criteria with at least one autoimmune manifestation referred to Mofid Children's Hospital, Tehran, Iran, between 2010 and 2021 were investigated. Medical records of patients were retrospectively investigated. All patients had received RTX as a course of at least four 375 mg/m2 infusions in weekly intervals. Complete and partial responses were defined as normalization or improvement of biological markers of hemolysis and the requirement for maintenance treatment. ResultsTwenty-three patients (65.2% females and 34.8% males) with common variable immunodeficiency (CVID) (5, 21.7%), unspecified primary immune regulatory disorder (PIRD) (5, 21.7%), LRBA deficiency (4, 17.4%), non-syndromic combined immunodeficiency (CID) (2, 8.7%), STAT3-GOF mutation (2, 8.7%), ataxia-telangiectasia (2, 8.7%), Epstein-Barr virus (EBV)-susceptible PIRD (1, 4.3%), Nijmegen breakage syndrome (1, 4.3%), and familial hemophagocytic lymphohistiocytosis (fHLH) (1, 4.3%) were enrolled.The median (IQR) age at the time of the study, the onset of symptoms, and diagnosis were 12 (6–14), 3 (1–5), and 5 (3–9) years, respectively. Fourteen (60.8%) patients had consanguineous parents. Autoimmune manifestations included cytopenia (17, 73.9%), Kawasaki disease (1, 4.3%), thyroiditis (1, 4.3%), juvenile idiopathic arthritis (JIA) (1, 4.3%), enteropathy (4, 17.4%), mixed connective tissue disease (MCTD) (2, 8.7%), systemic lupus erythematosus (SLE) (2, 8.7%), and Behcet's syndrome (1, 4.3%). The cumulative response rate was 86.8% (complete response: 14, 60.8%, partial response: 6, 26%). At the end of the survey, 8 (34.7%) patients were deceased. ConclusionsRituximab is a promising therapeutic option for autoimmune disorders in the context of IEI. Regular follow-up after the initial rituximab infusion is essential in IEI children.

Molecular profile of patients with inborn errors of immunity from Nepal

Background and AimsInborn errors of immunity (IEIs) are increasingly being diagnosed in various regions of the world. There are significant challenges in the diagnosis and treatment of IEIs in resource-limited countries. With the availability of one immunologist and increasing awareness, IEIs are diagnosed with increasing frequency and accuracy in Nepal. IEIs are also being evaluated in children presenting with autoimmune manifestations. We describe the profile of patients diagnosed with IEIs in Nepal during 2020–2022. MethodsRecords of all patients with IEIs who were diagnosed and treated at our tertiary care center in Nepal from August 2020 to April 2022 were analysed. Lead author (DB) has examined and diagnosed all cases. IEIs were diagnosed based on the European Society for Immunodeficiencies (ESID) diagnostic criteria and genetic analysis. ResultsThirty-two patients with IEI (19 boys; 13 girls) and 801 children with autoimmune disorders were diagnosed during the study period. Genetic analysis was done on 18 patients. The diagnostic profile of the patients includes patients with chronic granulomatous disease, X-linked agammaglobulinemia, severe combined immunodeficiency, Job syndrome, selective IgA deficiency, specific antibody deficiency, Wiskott-Aldrich Syndrome, CTLA4 deficiency, IPEX syndrome, IFN-IL12 axis defect, hereditary angioedema, MonoMac syndrome, ARPC1B deficiency, leukocyte adhesion defect, PAPA syndrome, autoimmune lymphoproliferative syndrome, ADA2 deficiency, early-complement deficiency lupus, familial cold auto-inflammatory syndrome, A20 haploinsufficiency, and Blau syndrome. Some patients succumbed before the scope of diagnosis. HSCT is planned for 3 patients. ConclusionsOur is the first report of genetically proven IEIs in Nepal. Logistic constraints coupled with a lack of awareness of IEIs among laity and pediatrician accounted for a missed diagnosis, late diagnosis, and poor outcomes in resource-limited settings. Antimicrobial prophylaxis reduced the incidence of breakthrough infections. The lack of HSCT facilities precludes definitive treatment of many IEIs.

COVID-19 vaccination in patients with primary immunodeficiencies: an international survey on patient vaccine hesitancy and self-reported adverse events.

The Sars-CoV-2 pandemic caused great concern for this novel virus among patients with primary immunodeficiency (PID) or inborn errors of immunity (IEI) and their families. When COVID-19 vaccination program started, no data existed on adverse events (AEs) in this particular patient population, nor if patients felt hesitancy being vaccinated. To explore i) reasons for COVID-19 vaccination hesitancy, ii) the number and symptoms of AEs and their severity, durability and management. The organisations International Patient Organisation for Primary Immunodeficiencies (IPOPI), European Society for Immunodeficiencies (ESID) and International Nursing Group for Immunodeficiencies (INGID) distributed a global self-administered online survey. The survey was completed by 1317 patients (mean 47, range 12-100, years) from 40 countries. 41.7% of the patients denoted some hesitancy to COVID-19 vaccination, mainly having doubts about postvaccination protection related to their underlying PID and concerns about negative long-term effects. More women (22.6%) reported "very" or "pretty much" hesitancy compared to men (16.4%) (P<0.05). The most common systemic AEs were fatigue, muscle/body pain and headache, usually the same day or the day after the vaccination and lasting for 1-2 days. 27.8% of the respondents reported severe systemic AEs after any dose of COVID-19 vaccine. Only a minority (7.8%) of these patients visited a health-care professional and 20 patients (1.5%) were hospitalized or seen at emergency room without specifying subsequent admission at the hospital. Significantly more local and systemic AEs were reported after the second dose. No differences regarding AEs were observed across different PID subgroups or vaccine types. At the time of the survey, almost half of the patients reported having felt hesitancy to COVID-19 vaccination highlighting the importance and need of developing joint international guidelines and education programs about COVID-19 vaccination. The types of AEs were comparable to healthy controls, but more frequent AEs were reported. Clinical studies and prospective, detailed registration of AEs related to COVID-19 vaccines in this patient population is of great importance. It is crucial to elucidate whether there is a coincidental or causal association between COVID-19 vaccine and some severe systemic AEs. Our data do not contradict that patients with PID can be advised to be vaccinated against COVID-19, in accordance with applicable national guidelines.

The spectrum of inborn errors of immunity: a single tertiary center retrospective study in Alborz, Iran.

Background. Inborn errors of immunity (IEIs) are a group of heterogeneous disorders with inherited faults in the immune system that increase susceptibility to infections, malignancies, lymphoproliferation, and autoimmune/autoinflammatory disorders. Methods. We retrospectively studied the demographic characteristics, clinical features, and immunological profiles of the 90 IEIs patients, who were diagnosed and classified according to the European Society for Immunodeficiencies (ESID) and International Union of Immunological Societies (IUIS) criteria from July 2010 to June 2021. The study was carried out in the Non-communicable Diseases Research Center, Imam Ali Hospital, Alborz, Iran. Results. Within a period of 11 years, 53 (58.9%) males and 37 (41.1%) females were diagnosed and followed up for 20 IEI disorders. The median (IQR) age of onset, age of clinical diagnosis and diagnostic delay was 0.7 (0.08-2.0), 3.18 (1.0-8.0) and 1.5 (0.17-5.0) years, respectively. Twelve patients (36.4%) had a positive family history of IEI, and the majority of patients (84.5%) had recurrent infections. Pneumonia (51.7%) was the most common clinical manifestation among IEI patients, followed by skin complications (46.2%). The most frequently diagnosed IEI was immunoglobulin A deficiency (IgAD) (14.4%) and severe combined immunodeficiency (SCID) (11.1%). Predominantly antibody deficiencies group (36.7%) was the most common category, followed by combined immunodeficiencies with associated or syndromic features group (27.8%). Conclusions. IEIs have different patterns within populations with high consanguinity. There is a need to search for underlying genetic and epigenetic factors in most common IEIs in Alborz.

Killer cell cluster immunity state in adult patients with common variable immunodeficiency

The subpopulation spectrum of killer cluster lymphocytes in peripheral blood was assessed by flow cytometry in combination, along with analysis of clinical manifestations in 30 adult patients (12 males and 18 females, mean age 37.512.3 years) diagnosed with common variable immunodeficiency (CVID). All the patients were observed at the Department of Immunopathology and Allergology at the State Institution Republican Scientific and Practical Center of Radiation Medicine and Human Ecology (Gomel, Republic of Belarus). The diagnosis was based on clinical and laboratory criteria developed by the European Society for Immunodeficiencies, using Common Variable Immunodeficiency Diagnostic Criteria, 2020. The patients were examined in the apparent absence of infectious inflammatory disease, prior to monthly immunoglobulin injections. The control group consisted of 30 healthy subjects, comparable in age and sex with the patients cohort, free of clinical and laboratory signs of immunological insufficiency. The patients with CVID had a reduced content of NK cells (CD3-CD16+CD56+) and CD3-CD8+ lymphocytes in peripheral blood (p% = 0.009, rabs = 0.03 and p%, abs 0.001 respectively), along with increase of T cytotoxic cells and NKT lymphocytes (CD3+CD8+; p% = 0.02, rabs = 0.009 and CD3+CD16+CD56+; p%, 0.001, rabs = 0.004, respectively). Severe NK cell lymphopenia showed inverse correlation with the numbers of T cyclers (rs% = -0.545, p = 0.03), activated T cytotoxic lymphocytes (CD3+CD8+CD38+; rs% = -0.38, p = 0.04), and directly correlated with CD3-CD8+ cell counts (rs% = 0.481, p = 0.008). We also revealed a correlation between the parameters of killer lymphocyte cluster (CD3-CD16+CD56+, CD3-CD8+, CD3+CD16+CD56+) and severity of clinical manifestations in CVID patients. The most pronounced changes in the killer cell subpopulations were observed in patients with a combined clinical phenotype infection syndrome + autoimmune syndrome and infection syndrome + autoimmune syndrome + enteropathy. Thus, the marked changes of killer cell subpopulations manifesting as decreased counts of NK cells and CD3-CD8+ lymphocytes, along with increased NKT lymphocytes and T killer numbers are associated with more severe clinical phenotypes of CVID and, above all, with development of autoimmune disorders.

Application of the diagnostic criteria for Common Variable Immunodeficiency in resource-limited settings.

Common variable immunodeficiency (CVID) is the most prevalent symptomatic humoral deficiency; however, its heterogeneous presentation makes the diagnosis difficult. The present study is aimed to verify the CVID diagnostic criteria as established by the European Society for Immunodeficiencies in 42 CVID patients from our outpatient clinic. Information was collected from their medical records and when needed, lymphocyte subpopulations in peripheral blood (PB) were performed by flow cytometry. All the patients fulfilled the clinical working definition for CVID and showed decreased serum IgG and IgA at diagnosis. Over two-thirds of the patients had decreased memory B cell percentages. However, the remaining patients exhibited other quantitative B cell defects in PB. Evaluation of vaccination responses was only found in 13 records and 69% were not responsive. None of the patients were subjected to vaccination studies to both, T-cell dependent and independent antigens. The two required tests to evaluate T cell responses were performed in 84.2% of the patients and reported normal. Without the support of third-party payers, only 34.2% of our patients would have completed the required evaluations. Further efforts are needed to speed up CVID diagnosis in low-resourced settings, increasing the availability of the required resources and optimizing the healthcare supply chain.

Inborn Errors of Immunity on the Island of Ireland — a Cross-Jurisdictional UKPID/ESID Registry Report

The epidemiology of inborn errors of immunity (IEI) in the Republic of Ireland was first published in 2005 but has not been updated since. IEI prevalence data from Northern Ireland was last published in 2018. Using data from the United Kingdom Primary Immune Deficiency (UKPID) and European Society for Immunodeficiencies (ESID) registries, we reviewed all registered cases of IEI affecting adult patients ≥ 18 years of age from the two largest immunology specialist centres in Northern Ireland and the Republic of Ireland, respectively and calculated the combined minimum adult prevalence of IEI on the island of Ireland for the first time. We also recorded data pertaining to presenting symptoms of IEI, diagnostic delay, immunoglobulin data, and genetic testing, as well as briefly reporting data pertaining to secondary immunodeficiency in both countries. As of 1 May 2020, we identified a minimum adult IEI prevalence in Ireland of 8.85/100,000 population.

Professor Asghar Aghamohammadi (1951-2020)

Professor Asghar Aghamohammadi, the founder of the Immunology and Genetics Journal, passed away on November 14th, 2020, at the age of 69. We were terribly shocked by his death due to the Coronavirus Disease 2019 (COVID-19), while he had been working continuously and actively until late October, before his admission to the hospital because of an infection by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Professor Aghamohammadi was born in 1951 in Khouzestan Province, Iran. After completing his primary education in Ahvaz, he studied medicine in Mashad University of Medical Sciences and Jundishapur University of Medical Sciences. After graduating in 1978, he joined the Red Crescent Organization in Iran. Afterwards, he continued his education in pediatrics in 1984, followed by a fellowship in clinical immunology and allergy in 1988. Consequently, he became the faculty member in the Department of Pediatrics, Children’s Medical Center, Tehran University of Medical Sciences, where he dedicated all his life researching on the Primary Immunodeficiency Diseases (PIDs), by making the infrastructure for increasing the general awareness about PIDs, conducting fundamental research on PIDs, and facilitating the diagnosis and treatment of patients with PIDs. Professor Aghamohammadi established the “Iranian Association for PID Patients Support”, the “Iranian Primary Immunodeficiency Diseases Registry (IPIDR)”, “Research Center for Immunodeficiencies”, “Iranian PID Network”, and the “Immunology and Genetics Journal”. His international collaborations and hard works, along with his honesty, are some of his landmarks, which made him one of the world’s scientists top 1%. This is what the young generation should learn from him. The international PIDs communities, including the European Society for Immunodeficiencies (ESID), the Clinical Immunology Society (CIS), the International Patient Organization for Primary Immunodeficiencies (IPOPI), the Jeffrey Modell Foundation (JMF), and the J Project respect him a lot and cannot forget his amazing efforts in the field of PIDs for all these years. We all at the Research Center for Immunodeficiencies (RCID) and the Immunology and Genetics Journal (IGJ), are still in shock and cannot imagine continuing without him. We will not forget that the father of the PIDs in Iran was a remarkable scientist. He will remain in the minds and hearts of all those who were close to him. May his name be always remembered with respect and love.

Simple Measurement of IgA Predicts Immunity and Mortality in Ataxia-Telangiectasia

Patients with ataxia-telangiectasia (A-T) suffer from progressive cerebellar ataxia, immunodeficiency, respiratory failure, and cancer susceptibility. From a clinical point of view, A-T patients with IgA deficiency show more symptoms and may have a poorer prognosis. In this study, we analyzed mortality and immunity data of 659 A-T patients with regard to IgA deficiency collected from the European Society for Immunodeficiencies (ESID) registry and from 66 patients with classical A-T who attended at the Frankfurt Goethe-University between 2012 and 2018. We studied peripheral B- and T-cell subsets and T-cell repertoire of the Frankfurt cohort and survival rates of all A-T patients in the ESID registry. Patients with A-T have significant alterations in their lymphocyte phenotypes. All subsets (CD3, CD4, CD8, CD19, CD4/CD45RA, and CD8/CD45RA) were significantly diminished compared to standard values. Patients with IgA deficiency (n = 35) had significantly lower lymphocyte counts compared to A-T patients without IgA deficiency (n = 31) due to a further decrease of naïve CD4 T-cells, central memory CD4 cells, and regulatory T-cells. Although both patient groups showed affected TCR-ß repertoires compared to controls, no differences could be detected between patients with and without IgA deficiency. Overall survival of patients with IgA deficiency was significantly diminished. For the first time, our data show that patients with IgA deficiency have significantly lower lymphocyte counts and subsets, which are accompanied with reduced survival, compared to A-T patients without IgA deficiency. IgA, a simple surrogate marker, is indicating the poorest prognosis for classical A-T patients. Both non-interventional clinical trials were registered at clinicaltrials.gov 2012 (Susceptibility to infections in ataxia-telangiectasia; NCT02345135) and 2017 (Susceptibility to Infections, tumor risk and liver disease in patients with ataxia-telangiectasia; NCT03357978)

The 10th anniversary of the world primary immunodeficiency week: A J Project celebration

The 10^th anniversary of the world primary immunodeficiency week: A J Project celebration

Le déficit sélectif en IgA

Selective IgA deficiency (SIgAD) is defined by the European Society for Immunodeficiencies (ESID) as a serum IgA of less than 0.07g/L in patients greater than 4 years old with normal levels of IgG and IgM, normal vaccine responses, and with the exclusion of secondary causes of hypogammaglobulinemia. When serum IgA level is higher than 0.07g/L but two standard deviations below normal for age, the condition may be referred to as partial IgA deficiency, which is quite common. SIgAD is the most common primary immunodeficiency in Europe (1/600 in France) and most patients with SIgAD are asymptomatic (75–90%). The clinical complications associated with SIgAD include recurrent respiratory infections (in particular involving Haemophilus influenza and Streptococcus pneumoniae) and gastrointestinal (mainly due to Giardialamblia), autoimmune and allergic manifestations (anaphylaxis if blood products with IgA are administrated), inflammatory gastrointestinal disease. There is no specific treatment for SIgAD and each patient must be managed individually. While asymptomatic subjects do not need any treatment, it is still necessary for them to be up-to-date with vaccinations. If the patient experiences recurrent infections, prophylactic antibiotics may be beneficial. Immunoglobulin replacement therapy should be considered in patients with SIgAD and concomitant IgG subclass deficiency. Treatment for autoimmune and allergic manifestations is based on current standards of care for specific disease entities. To improve quality of life and reduce morbidity, an interdisciplinary team approach is essential.

Abstract 2255: The impact of primary immunodeficiency informed molecular landscape on the biology and prognosis of refractory malignancies

Abstract Introduction: Cancer is one of the most common causes of death in patients with primary immunodeficiencies (PIDs). The immune surveillance concept postulates that PIDs are an important contributor to cancer growth and outcomes. Although several immunodeficiency syndromes are known to be associated with malignancies in children and adults, currently, the molecular mechanisms that link immune functions to cancers are poorly understood. Here we describe distinct molecular characteristics in adult cancers with respect to PID-associated genes that impact survival outcomes in affected patients. Methods: In this study, we integrated transcriptome data of 28 adult cancers from the public database The Cancer Genome Atlas (TCGA) with respective healthy tissues as control from the Genotype-Tissue Expression (GTEx) project. Unified datasets integrating GTEx healthy samples and TCGA cancer data were provided by the Recount2 protocol and differential expression analyses (DEA) were carried out using the integrated limma-voom and edgeR pipelines in the TCGAbiolinks R package. Gene ontology (GO) enrichment analyses were performed using the pathfindR R package. Mutational and clinical data of adult cancer patient samples in TCGA and the AACR Project GENIE were consolidated using cBioPortal and the maftools R package. PID-associated genes were curated from the latest registry by the European Society for Immunodeficiencies (ESID). Results: Of 307 PID-associated genes, 151 (32.0%) up-regulated and 88 (18.6%) down-regulated genes were identified across the 28 unified TCGA-GTEx datasets. From the identified differentially expressed gene sets, GO analysis revealed enrichment in immunological pathways related to complement and coagulation cascades (27/28 datasets), systemic lupus erythematosus (25/28), in addition to Fanconi anemia (22/28). The greatest frequency of mutations in PID-associated genes from the consolidated TCGA and GENIE datasets were KRAS (14.83%), KMT2D (10.03%), TERT (8.99%), PRKDC (7.59%) and PTEN (6.18%) across all cancer types, with a total of 259 affected PID-associated genes. Survival analyses using Cox proportional-hazards and Kaplan-Meier models will assess the clinical implications of the identified molecular alterations in affected patients. Conclusion: Our integrative approach aids in the elucidation of molecular mechanisms that bridge PIDs to tumour biology. These data may help identify important biomarkers and potential future targeted therapeutics. Citation Format: Son Tran, Luis Murguia-Favela, Aru Narendran. The impact of primary immunodeficiency informed molecular landscape on the biology and prognosis of refractory malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2255.

Effectiveness of low-dose intravenous immunoglobulin therapy in minor primary antibody deficiencies: A 2-year real-life experience.

Primary antibody deficiencies (PAD) are the most prevalent group of primary immunodeficiencies (PID) in adults and immunoglobulin replacement therapy (IRT) is the mainstay therapy to improve clinical outcomes. IRT is, however, expensive and, in minor PAD, clear recommendations concerning IRT are lacking. We conducted a retrospective real-life study to assess the effectiveness of low-dose IRT in minor PAD on 143 patients fulfilling European Society for Immunodeficiencies (ESID) diagnostic criteria for immunoglobulin (Ig)G subclass deficiency (IgGSD) or unclassified antibody deficiency (UAD). All patients were treated with intravenous low-dose IRT (0.14±0.06 g/kg/month). Immunoglobulin (Ig) classes and IgG subclasses were measured at baseline and after 1year of IRT. The annual rate of total infections, upper respiratory tract infections (URTI), lower respiratory tract infections (LRTI) and hospitalizations was measured at baseline and after 1 and 2 years of IRT. After 1 year of IRT significant improvement was demonstrated in: (a) serum IgG (787.9±229.3 versus 929.1±206.7mg/dl; p<0.0001); (b) serum IgG subclasses (IgG1=351.4±109.9 versus 464.3±124.1, p<0.0001; IgG2=259.1±140 versus 330.6±124.9, p<0.0001; IgG3=50.2±26.7 versus 55.6±28.9mg/dl, p<0.002); (c) annual rate of total infections (5.75±3.87 versus 2.13±1.74, p<0.0001), URTI (1.48±3.15 versus 0.69±1.27; p<0.005), LRTI (3.89±3.52 versus 1.29±1.37; p<0.0001) and hospitalizations (0.37±0.77 versus 0.15±0.5; p<0.0002). The improvement persisted after 2 years of IRT. No significant improvement in URTI annual rate was noted in UAD and in patients with bronchiectasis. In conclusion, low-dose IRT can improve clinical outcomes in UAD and IgGSD patients, providing a potential economical advantage over the standard IRT dose.

OP0004 AUTOIMMUNE AND INFLAMMATORY MANIFESTATIONS IN COMMON VARIABLE IMMUNODEFICIENCY DISORDERS

Background:Common variable immunodeficiency (CVID) disorders are the second most frequent immunodeficiency worldwide and autoimmune diseases (AD) are present in 20% of such patients, cytopenia being the most frequent manifestation [1]. Defects in central and peripheral tolerance, activation/proliferation of B cells, and hypogammaglobulinemia are key features of the disease, along with a reduction in CD4+T cells, abnormalities in Treg and defective secretion of regulatory cytokines, that could perpetuate autoimmune - autoinflammatory phenomena.Objectives:To describe immune and inflammatory disorders in our CVID cohort.Methods:Retrospective analysis of 33 patients who fulfill the European Society for Immunodeficiencies (ESID) Registry – Work criteria for CVID diagnosis [2] treated in the immunodeficiency unit of our tertiary university hospital. After getting an informed consent form, medical records were revised to obtain clinical, analytical and immunological data.Results:Of the 33 CVID patients analysed, 11 had some autoimmune/inflammatory manifestation. Seven patients presented autoimmune thrombocytopenia (AIT), and one of them also had non-severe neutropenia. Two patients also had seronegative spondyloarthropathy, one patient had cutaneous psoriasis, and two patients had alopecia. There were no cases of type 1 diabetes, vitiligo or thyroid disorders. Interestingly, four patients had lung involvement, two of them with granulomatous-lymphocytic interstitial lung disease (GLILD), one with organising pneumonia and one with usual interstitial pneumonia. Five of the eleven patients required immunosuppressive treatment, mostly with steroids. One case of AIT required concomitant treatment with azathioprine and the patient with psoriasis was treated with methotrexate. In six patients, autoimmune disorder was the first manifestation.Conclusion:33% of the CVID patients had autoimmune or inflammatory manifestations in our cohort; six patients had one immune/inflammatory phenomena, four had two different disorders and one patient presented with three different ones. The most frequent manifestation was AIT, as seen in previous reports. In six cases, the autoimmune-inflammatory manifestation was the first symptom attributable to CVID. In conclusion, AD are common in CVID patients, so clinicians must be aware of possible immunodeficiencies in this type of patients.

Clinical and Genetic Profile of X-Linked Agammaglobulinemia: A Multicenter Experience From India.

BackgroundThere is paucity of literature on XLA from developing countries. Herein we report the clinical and molecular profile and outcome in a multicenter cohort of patients with XLA from India.MethodsData on XLA from all regional centers supported by the Foundation for Primary Immunodeficiency Diseases (FPID), USA and other institutions providing care to patients with PIDs were collated. Diagnosis of XLA was based on European Society for Immunodeficiencies (ESID) criteria.ResultsWe received clinical details of 195 patients with a provisional diagnosis of XLA from 12 centers. At final analysis, 145 patients were included (137 ‘definite XLA’ and eight ‘probable/possible XLA’). Median age at onset of symptoms was 12.0 (6.0, 36.0) months and median age at diagnosis was 60.0 (31.5, 108) months. Pneumonia was the commonest clinical manifestation (82.6%) followed by otitis media (50%) and diarrhea (42%). Arthritis was seen in 26% patients while 23% patients developed meningitis. Bronchiectasis was seen in 10% and encephalitis (likely viral) in 4.8% patients. Pseudomonas aeruginosa was the commonest bacterial pathogen identified followed by Streptococcus pneumoniae, Staphylococcus aureus and Klebsiella pneumoniae. Molecular analysis revealed 86 variants in 105 unrelated cases. Missense variants in BTK gene were the most common (36%) followed by frameshift (22%) and nonsense variants (21%). Most pathogenic gene variants (53%) were clustered in the distal part of gene encompassing exons 14–19 encoding for the tyrosine kinase domain. Follow-up details were available for 108 patients. Of these, 12% had died till the time of this analysis. The 5-year and 10-year survival was 89.9% and 86.9% respectively. Median duration of follow-up was 61 months and total duration of follow-up was 6083.2 patient-months. All patients received intravenous immunoglobulin (IVIg) replacement therapy. However, in many patients IVIg could not be given at recommended doses or intervals due to difficulties in accessing this therapy because of financial reasons and lack of universal health insurance in India. Hematopoietic stem cell transplant was carried out in four (2.8%) patients.ConclusionThere was a significant delay in the diagnosis and facilities for molecular diagnosis were not available at many centers. Optimal immunoglobulin replacement is still a challenge