Congenital Agammaglobulinemia Research Articles

Who's your data? Primary immune deficiency differential diagnosis prediction via machine learning and data mining of the USIDNET registry

PurposeThere are currently more than 480 primary immune deficiency (PID) diseases and about 7000 rare diseases that together afflict around 1 in every 17 humans. Computational aids based on data mining and machine learning might facilitate the diagnostic task by extracting rules from large datasets and making predictions when faced with new problem cases. In a proof-of-concept data mining study, we aimed to predict PID diagnoses using a supervised machine learning algorithm based on classification tree boosting. MethodsThrough a data query at the USIDNET registry we obtained a database of 2396 patients with common diagnoses of PID, including their clinical and laboratory features. We kept 286 features and all 12 diagnoses to include in the model. We used the XGBoost package with parallel tree boosting for the supervised classification model, and SHAP for variable importance interpretation, on Python v3.7. The patient database was split into training and testing subsets, and after boosting through gradient descent, the predictive model provides measures of diagnostic prediction accuracy and individual feature importance. After a baseline performance test, we used the Class Weighting Hyperparameter, or scale_pos_weight to correct for imbalanced classification. ResultsThe twelve PID diagnoses were CVID (1098 patients), DiGeorge syndrome, Chronic granulomatous disease, Congenital agammaglobulinemia, PID not otherwise classified, Specific antibody deficiency, Complement deficiency, Hyper-IgM, Leukocyte adhesion deficiency, ectodermal dysplasia with immune deficiency, Severe combined immune deficiency, and Wiskott-Aldrich syndrome. For CVID, the model found an accuracy on the train sample of 0.80, with an area under the ROC curve (AUC) of 0.80, and a Gini coefficient of 0.60. In the test subset, accuracy was 0.76, AUC 0.75, and Gini 0.51. The positive feature value to predict CVID was highest for upper respiratory infections, asthma, autoimmunity and hypogammaglobulinemia. Features with the highest negative predictive value were high IgE, growth delay, abscess, lymphopenia, and congenital heart disease. For the rest of the diagnoses, accuracy stayed between 0.75 and 0.99, AUC 0.46–0.87, Gini 0.07–0.75, and LogLoss 0.09–8.55. DiscussionClinicians should remember to consider the negative predictive features together with the positives. We are calling this a proof-of-concept study to continue with our explorations. A good performance is encouraging, and feature importance might aid feature selection for future endeavors. In the meantime, we can learn from the rules derived by the model and build a user-friendly decision tree to generate differential diagnoses.

Comparison of Demographic and Clinical Characteristics Among X-Linked and Autosomal Recessive Agammaglobulinemia

Background: Congenital agammaglobulinemia is an inborn error of immunity, resulting in the impairment of effective antibody production. Agammaglobulinemia may be due to X-linked or autosomal genetic abnormalities. The primary defect in X-Linked agammaglobulinemia (XLA) and autosomal recessive agammaglobulinemia (ARAG) is the B cell precursors’ failure to mature B-lymphocytes and, ultimately, plasma cells. This study aims to evaluate the differences in clinical and paraclinical characteristics of XLA and ARAG patients. Method: A total of 58 patients were enrolled in this retrospective study. The data were extracted from the Iranian primary immunodeficiency registry (IPIDR). Forty-eight of the patients were diagnosed with XLA, while the other ten were diagnosed with ARAG. Measures including demographic data, clinical manifestations, and laboratory data of the patients were compared between the groups. Results: Patients with ARAG, presented manifestations at an earlier age and had a lower diagnosis delay compared to XLA patients. However, the mortality rate was not significantly affected. The pattern of organ involvement also differed between the two groups, as patients with ARAG showed manifestations that are more chronic in nature (e.g., autoimmunity, lymphoproliferation, and allergy). In contrast, XLA patients were more prone to infections and other associated complications (e.g., meningitis, sinusitis, diarrhea, and bronchiectasis). Meningitis was exclusively observed in the XLA group. The number of CD19+ B cells was significantly higher in the ARAG group (P=0.002), While the level of IgM was significantly higher in the XLA group (P=0.045). Conclusion: Identifying the clinical presentations of XLA and ARAG, may assist clinicians in early diagnosis in the setting of limited available genetic studies.

Cost Utility of Lifelong Immunoglobulin Replacement Therapy vs Hematopoietic Stem Cell Transplant to Treat Agammaglobulinemia

Lifelong immunoglobulin replacement therapy (IRT) is standard-of-care treatment for congenital agammaglobulinemia but accrues high annual costs ($30 000-$90 000 per year) and decrements to quality of life over patients' life spans. Hematopoietic stem cell transplant (HSCT) offers an alternative 1-time therapy, but has high morbidity and mortality. To evaluate the cost utility of IRT vs matched sibling donor (MSD) and matched unrelated donor (MUD) HSCT to treat patients with agammaglobulinemia in the US. This economic evaluation used Markov analysis to model the base-case scenario of a patient aged 12 months with congenital agammaglobulinemia receiving lifelong IRT vs MSD or MUD HSCT. Costs, probabilities, and quality-of-life measures were derived from the literature. Microsimulations estimated premature deaths for each strategy in a virtual cohort. One-way sensitivity and probabilistic sensitivity analyses evaluated uncertainty around parameter estimates performed from a societal perspective over a 100-year time horizon. The threshold for cost-effective care was set at $100 000 per quality-adjusted life-year (QALY). This study was conducted from 2020 across a 100-year time horizon. Immunoglobulin replacement therapy vs MSD or MUD HSCT for treatment of congenital agammaglobulinemia. The primary outcomes were incremental cost-effectiveness ratio (ICER) expressed in 2020 US dollars per QALY gained and premature deaths associated with each strategy. In this economic evaluation of patients with congenital agammaglobulinemia, lifelong IRT cost more than HSCT ($1 512 946 compared with $563 776 [MSD] and $637 036 [MUD]) and generated similar QALYs (20.61 vs 17.25 [MSD] and 17.18 [MUD]). Choosing IRT over MSD or MUD HSCT yielded ICERs of $282 166 per QALY gained over MSD and $255 633 per QALY gained over MUD HSCT, exceeding the US willingness-to-pay threshold of $100 000/QALY. However, IRT prevented at least 2488 premature deaths per 10 000 microsimulations compared with HSCT. When annual IRT price was reduced from $60 145 to below $29 469, IRT became the cost-effective strategy. Findings remained robust in sensitivity and probabilistic sensitivity analyses. In the US, IRT is more expensive than HSCT for agammaglobulinemia treatment. The findings of this study suggest that IRT prevents more premature deaths but does not substantially increase quality of life relative to HSCT. Reducing US IRT cost by 51% to a value similar to IRT prices in countries implementing value-based pricing may render it the more cost-effective strategy.

Agammaglobulinemia: from X-linked to Autosomal Forms of Disease.

Interruptions or alterations in the B cell development pathway can lead to primary B cell immunodeficiency with resultant absence or diminished immunoglobulin production. While the most common cause of congenital agammaglobulinemia is X-linked agammaglobulinemia (XLA), accounting for approximately 85% of cases, other genetic forms of agammaglobulinemia have been identified. Early recognition and diagnosis of these conditions are pivotal for improved outcomes and prevention of sequelae and complications. The diagnosis of XLA is often delayed, and can be missed if patient has a mild phenotype. The lack of correlation between phenotype and genotype in this condition makes management and predicting outcomes quite difficult. In contrast, while less common, autosomal recessive forms of agammaglobulinemia present at younger ages and with typically more severe clinical features resulting in an earlier diagnosis. Some diagnostic innovations, such as KREC level measurements and serum BCMA measurements, may aid in facilitating an earlier identification of agammaglobulinemia leading to prompt treatment. Earlier diagnosis may improve the overall health of patients with XLA.

Intravenous immunoglobulin replacement therapy in 114 cases of congenital agammaglobulinemia

Objective: To analyze the clinical characteristics of congenital agammaglobulinemia and the efficacy of intravenous immunoglobulin (IVIG) replacement therapy for this disease. Methods: The basic characteristics, clinical manifestations, laboratory examinations, and outcomes of 114 patients with congenital agammaglobulinemia diagnosed in Children's Hospital of Chongqing Medical University from January 1988 to April 2020 were retrospectively analyzed. The efficacy of IVIG in improving the clinical symptoms between regular and irregular treatment groups were compared by χ2 test. To explore the clinical characteristics associated with delayed diagnosis and treatment, the patients were also stratified into following subgroups: non-cough, short-term cough and long-term cough groups, chronic lung disease and non-chronic lung disease groups, and arthritis and non-arthritis groups. The age at onset, age at diagnosis, time consumed for diagnosis, initial time of immunoglobulin replacement, dose of IVIG, IgG trough level between the above groups were compared by t test, F test or non-parametric test. Results: All the 114 patients were male, with the onset age of (22±18) months. The age at diagnosis was (89±54) months, time consumed in diagnosis was (63±46) months, and the initial time of immunoglobulin replacement was (75±45) months. A total of 66 patients had been followed up to April 2020, with a follow-up period of (54±41) months. Among these children, 42 (63.6%) received regular infusion, whose monthly IVIG dose was (538±105) mg/kg and IgG trough level was (5.8±1.5) g/L, whereas 24 patients (36.4%) were treated irregularly. There was no significant difference in the improvement rate of fever, cough, sinusitis, diarrhea, otitis media and arthritis between regular and irregular IVIG replacement groups (all P>0.05). Sixty-one out of the 66 patients (92.4%) had fever before IVIG treatment, whose fever episodes were significantly decreased after IVIG treatment (5 (2,12) vs. 0 (0, 1) per year, Z =-6.436, P<0.01). Sixty patients (90.9%) suffered from wet cough before treatment and 36 (54.5%) after treatment. Initial time of immunoglobulin replacement was significantly delayed in the long-term cough (27 cases) and short-term cough groups (9 cases) compared with non-cough group (18 cases) ((97±51) vs. (64±41) vs. (63±42) months, F=3.554, P=0.035). Twenty-nine patients (43.9%) were diagnosed with chronic lung disease, whose initial time of immunoglobulin replacement (103 (75,144) vs. 46 (26,64) months, Z=-4.330, P<0.01), age at diagnosis (103 (75,142) vs. 47 (31,68) months, Z=-3.486, P<0.01), and time consumed in diagnosis (91 (55,129) vs. 29 (10,41) months, Z =-4.386, P<0.01) were significantly later and longer than those in children without chronic lung disease (37 cases). In addition, thirty-two patients(48.5%) were diagnosed with arthritis, whose initial time of immunoglobulin replacement ((98±51) vs. (58±39) months,t=3.420, P=0.001) and time consumed in diagnosis ((74±49) vs. (44±40) months, t=2.600, P=0.010) were also significantly later and longer than those in children without arthritis (34 cases). Conclusions: After immunoglobulin replacement therapy, the clinical symptoms such as fever, sinusitis, diarrhea, and otitis media can be improved more or less. However, long-term wet cough, chronic lung disease, and arthritis are still prominent clinical problems, which could be controlled by standard immunoglobulin replacement therapy in some patients.

Seroconversion after coronavirus disease 2019 vaccination in patients with immune deficiency

Safety and efficacy are 2 major drivers for any vaccination strategy and have come to the forefront in the setting of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. Patients with underlying primary or secondary immunodeficiencies have variable response to vaccination, but inactivated or nonviable vaccines are generally considered safe in patients with immune deficiency.1 The efficacy of inactivated vaccines is variable in patients with humoral immune deficiencies, in which many can mount a protective T-cell–dependent antibody response to protein-conjugated vaccines, except for patients with congenital agammaglobulinemia, such as X-linked agammaglobulinemia (XLA), who may lack the ability to mount any antibody response.

Complete Hematological Remission after Decitabine Treatment in a Patient with Congenital Agammaglobulinemia, FLT3- and TP53-Mutated Acute Myeloid Leukemia

Older and unfit patients with Acute Myeloid Leukemia (AML), which are uneligible for standard induction therapy, have limited treatment options. The therapeutic approach in these cases is based on the use of hypomethylating agents, either decitabine or azacitidine, or Low-Dose Cytarabine (LDAC). However, despite the extensive use of these agents, there is no consensus regarding the extent of their efficacy, and clinical benefit deriving from their use is very modest. We present a case of FLT3- and TP53-mutated AML in an unfit patient with congenital agammaglobulinemia, responsive to single agent decitabine, with a response duration of over 20 months.

Agammaglobulinemia: Epidemiology, Pathogenesis, Clinical Phenotype, Diagnosis, Prognosis and Management.

Agammaglobulinemia is a type of primary antibody deficiencies, characterized by severe reduction in serum level of all types of immunoglobulins level and absence of B cells in the peripheral blood. X-linked and various autosomal recessive/dominant mutations have been identified underlying the pathogenesis of this disorder. Affected patients present a broad range of clinical manifestations, including respiratory infections, gastrointestinal complications, Enterovirus infections, autoimmunity, and malignancies. This disease can be controlled by different therapeutic strategies. In this review, we describe different aspects of agammaglobulinemia such as epidemiology, pathogenesis, clinical phenotype, diagnosis, management, and prognosis of congenital agammaglobulinemia.

Distinct Clinical Features and Novel Mutations in Taiwanese Patients With X-Linked Agammaglobulinemia.

Background: X-linked agammaglobulinemia (XLA) is caused by a mutation of the Bruton's tyrosine kinase (BTK) gene and is the most common genetic mutation in patients with congenital agammaglobulinemia. The aim of this study was to analyze the clinical features, genetic defects, and/or BTK expression in patients suspected of having XLA who were referred from the Taiwan Foundation of Rare Disorders (TFRD).Methods: Patients with recurrent bacterial infections in the first 2 years of life, serum IgG/A/M below 2 standard deviations of the normal range, and ≦2% CD19+B cells were enrolled during the period of 2004–2019. The frequency of infections, pathogens, B-lymphocyte subsets, and family pedigree were recorded. Peripheral blood samples were sent to our institute for BTK expression and genetic analysis.Results: Nineteen (from 16 families) out of 29 patients had BTK mutations, including 7 missense mutations, 7 splicing mutations, 1 nonsense mutation, 2 huge deletions, and 2 nucleotide deletions. Six novel mutations were detected: c.504G>T [p.K168N], c.895-2A>G [p.Del K290 fs 23*], c.910T>G [p.F304V], c.1132T>C [p.T334H], c.1562A>T [p.D521V], and c.1957delG [Del p.D653 fs plus 45 a.a.]. All patients with BTK mutations had obviously decreased BTK expressions. Pseudomonas sepsis developed in 14 patients and led to both Shanghai fever and recurrent hemophagocytic lymphohistiocytosis (HLH). Recurrent sinopulmonary infections and bronchiectasis occurred in 11 patients. One patient died of pseudomonas sepsis and another died of hepatocellular carcinoma before receiving optimal treatment. Two patients with contiguous gene deletion syndrome (CGS) encompassing the TIMM8A/DDP1 gene presented with early-onset progressive post-lingual sensorineural Deafness, gradual Dystonia, and Optic Neuronopathy syndrome (DDON) or Mohr-Tranebjaerg syndrome (MTS).Conclusion: Pseudomonas sepsis was more common (74%) than recurrent sinopulmonary infections in Taiwanese XLA patients, and related to Shanghai fever and recurrent HLH, both of which were prevented by regular immunoglobulin infusions. Approximately 10% of patients belonged to CGS involving the TIMM8A/DDP1 gene and presented with the DDON/MTS phenotype in need of aggressive psychomotor therapy.

Evaluation of respiratory complications in patients with X‐linked and autosomal recessive agammaglobulinemia

Congenital agammaglobulinemia is the first primary immunodeficiency disorder characterized by a defect in B lymphocyte development and subsequently decreased immunoglobulin levels. These patients are prone to suffer from recurrent infections mostly involving the respiratory tract. In this study, we aimed to describe in detail respiratory tract complications as the most prominent clinical feature among agammaglobulinemic patients. A total number of 115 patients were included. Demographic, clinical, and genetic data were collected from the patients' medical records. Among the available patients, pulmonary function tests (PFTs) and/or high-resolution computed tomography (HRCT) were performed. Respiratory tract complications (85.2%) especially pneumonia (62.6%) were the most prominent clinical features in our cohort. Among patients with abnormal PFT results (N=19), a mixed respiratory pattern was observed in 36.8%. HRCT was carried out in 29 patients; Bhalla scoring-based evaluation of these patients indicated excellent (44.8%), followed by good (34.5%) and mild (20.7%) results. Bronchiectasis was found in 13 patients undergoing HRCT (44.8%). We found significant inverse correlations between the Bhalla score and incidence rate of pneumonia, as well as the presence of bronchiectasis. Patients with abnormal PFT results had statistically significant higher bronchiectasis frequency and lower Bhalla scores compared to those with normal results. Forty-one patients were deceased, and here, respiratory failure was the most common cause of death (45.5%). High prevalence of respiratory tract infections among agammaglobulinemic patients and subsequent progression to permanent lung damage highlights the importance of implementing respiratory evaluation as part of routine follow-up program of agammaglobulinemic patients. Physicians should be aware of this and regularly monitor the respiratory function of these patients to allow for timely diagnosis and treatment initiation aiming to improve patients' prognosis and quality of life.

Epidemiological and clinical features of patients with primary antibody deficiency disorders in the east of Turkey

Aim: To describe the demographic and clinical features of patients diagnosed with primary antibody deficiency Material and Methods: The medical records of pediatric patients who were diagnosed with primary antibody deficiency were reviewed. Patients were diagnosed with primary antibody deficiency based on the European Society for Immunodeficiencies diagnostic criteria. Result: A total of 60 patients with primary antibody deficiency were identified; 39 patients (65%) were male and median age was 5 (1-18) years of age, while median diagnosis age was 3 (6 mo-14 yr) years. Twenty-one patients (35%) were diagnosed with transient hypogammaglobulinemia of infancy, thirteen (21.7%) with selective Ig A deficiency, five (8.3%) with congenital agammaglobulinemia, five (8.3%) with selective Ig M deficiency, five (8.3%) with unclassified hypogammaglobulinemia, four (6.7%) with Ig G subclass deficiency, two (3.3%) with severe combined immune deficiency, two (3.3%) with common variable immunodeficiency, two (3.3%) with hyper Ig M syndrome, and one patient was diagnosed with pneumococcal vaccine responsiveness, respectively. Eleven patients (18.3%) had consanguinity and six patients (10%) had family history. The most common complaint was frequent respiratory tract infections. Four patients had dermatitis in addition to infection. Three patients had hematopoietic stem cell transplantation and 23 patients (38.3%) received intravenous immunoglobulin treatment. Two patients died during the follow up. Conclusion: Our results indicated that diagnosis is delayed and the patients who are diagnosed with primary antibody deficiency frequently have respiratory tract infections.

Humoral immunodeficiencies: conferred risk of infections and benefits of immunoglobulin replacement therapy.

Primary immunodeficiency (PID) diseases result from genetic defects of the immune system that increase a patient's susceptibility to infections. The types of infections that occur in patients with PID diseases are dictated largely by the nature of the immunodeficiency, which can be defined by dysfunction of cellular or humoral defenses. An increasing number of PID diseases, including those with both cellular and humoral defects, have antibody deficiency as a major feature, and as a result can benefit from immunoglobulin replacement therapy. In fact, the most common PID diseases worldwide are antibody deficiencies and include common variable immunodeficiency, congenital agammaglobulinemia, hyper‐IgM syndrome, specific antibody deficiency, and Good syndrome. Although immunoglobulin replacement therapy is the cornerstone of treatment for the majority of these conditions, a thorough understanding of the specific infections for which these patients are at increased risk can hasten diagnosis and guide additional therapies. Moreover, the infection trends in some patients with PID disease who have profound defects of cellular immunity, such as autosomal‐dominant hyper‐IgE syndrome (Job/Buckley syndrome) or dedicator of cytokinesis 8 (DOCK8) deficiency, suggest that select patients might benefit from immunoglobulin replacement therapy even if their immunodeficiency is not limited to antibody defects. In this review, we provide an overview of the predisposition to infections seen in PID disease that may benefit from immunoglobulin replacement therapy.

Clinical characteristics and genetic profiles of 174 patients with X-linked agammaglobulinemia: Report from Shanghai, China (2000-2015).

X-linked agammaglobulinemia (XLA) is a humoral primary immunodeficiency. XLA patients typically present with very low numbers of peripheral B cells and a profound deficiency of all immunoglobulin isotypes. Most XLA patients carry mutations in Bruton tyrosine kinase (BTK) gene.The genetic background and clinical features of 174 Chinese patients with XLA were investigated. The relationship between specific BTK gene mutations and severity of clinical manifestations was also examined. Mutations were graded from mild to severe based on structural and functional prediction through bioinformatics analysis.One hundred twenty-seven mutations were identified in 142 patients from 124 families, including 45 novel mutations and 82 recurrent mutations that were distributed over the entire BTK gene sequence. Variation in phenotypes was observed, and there was a tendency of association between genotype and age of disease onset.This report constitutes the largest group of patients with BTK mutations in China. A genotype–phenotype correlation was observed in this study. Early diagnosis of congenital agammaglobulinemia should be based on clinical symptoms, family history, and molecular analysis of the BTK gene.

Abstract 228: HYQVIA in Postural Orthostatic Tachycardia Syndrome(POTS)

Postural Orthostatic Tachycardia Syndrome (POTS) is a form of dysautonomia associated with variety of symptoms like Headache, Abdominal discomfort, Dizziness/presyncope, Nausea, Fatigue, Lightheadedness, Sweating Sleep disorder, Tremor, Anxiety, Palpitations, Exercise intolerance which is believed to be caused by an underlying infectious and/or autoimmune trigger. HYQVIA is an immune globulin with a recombinant human hyaluronidase indicated for the treatment of Primary Immunodeficiency (PI) in adults. This includes, but is not limited to, common variable immunodeficiency (CVID), X-linked agammaglobulinemia, congenital agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies. HYQVIA is a gammaglobulin and is a slow metabolizer given subcutaneously once a month.There is data that Intravenous immunoglobulin(IVIg) helps POTS patients. We present a case of 57 year old female diagnosed with autonomic failure,orthostatic intolerance and primary immune deficiency. She was given IVIg for primary immune deficiency. She was previously reported for severe autonomic failure. From then, she was doing extremely well, had more energy and she thinks more clearly. She also had much better attitude. She was getting albumin every 2 weeks or so for volume expansion. She felt IVIg had helped her. Her immunoglobulin was switched from Gammagard to HYQVIA 35 grams. After she did, her blood pressure had gone up. She took it with albumin and she felt palpitations and chest pain.She was stopped on albumin, as albumin and HYQVIA combined could cause more volume expansion and push her into fluid overload or even congestive heart failure. After she stopped albumin without HYQVIA, she did well. Similarly, she cut back on midodrine which is an α1 adrenergic agonist, and works by stimulating receptors that noradrenaline normally works on. After swallowing, midodrine is rapidly converted into another, more active drug that binds to noradrenaline receptors causing blood vessels to narrow, thereby increasing blood pressure andreduction in heart rate in POTS patients. She was only HYQVIA and had been feeling extremely well.

Respiratory Health and Related Quality of Life in Patients with Congenital Agammaglobulinemia in the Northern Region of the UK.

IntroductionPatients with congenital agammaglobulinemia, characterized by a defect in B lymphocyte differentiation causing B alymphocytosis, require life-long IgG replacement. There is scant literature regarding the effectiveness of IgG treatment at preventing mucosal (particularly sinopulmonary tract) infection and whether current management adequately restores “normal” health and quality of life (QoL). We aimed to document infective episodes pre- and post-commencing IgG replacement, determine any change in lung function and structure and assess respiratory status and QoL in a cohort of patients treated in Newcastle.MethodsClinical data were extracted from medical records of 15 patients identified from the immunology database, focusing on infective episodes, serial chest CT and spirometry results. Thirteen patients completed a selection of standardized and validated questionnaires assessing physical health, respiratory health and QoL.ResultsPediatric patients on IgG therapy suffered fewer infections per patient year (0.74) than adults (2.13). 6/14 patients showed deteriorating respiratory status despite adequate therapy. Health questionnaires revealed a significant burden of respiratory disease on a patient’s life.ConclusionClinical data showed patients with congenital agammaglobulinemia receiving immunoglobulin therapy retained a higher than average infection rate, most of which affected mucosal barriers. Most patients self-reported worse respiratory symptoms, a lower respiratory-related QoL and a lower general health QoL relative to a healthy population. Most participants had progressive structural lung damage and decreased lung function. These results suggest that current management is not entirely effective at preventing deterioration of respiratory health or restoring QoL.

Cohort of Iranian Patients with Congenital Agammaglobulinemia: Mutation Analysis and Novel Gene Defects

ABSTRACTObjectives: Impairment in early B-cell development can cause a predominantly antibody deficiency with severe depletion of peripheral B-cells. Mutations in the gene encoding for Bruton’s-tyrosine-kinase (BTK) and the components of the pre-B-cell receptor complex or downstream signaling molecules have been related to this defect in patients with agammaglobulinemia.Methods: Iranian patients with congenital agammaglobulinemia were included and the correlation between disease-causing mutations and parameters such as clinical and immunologic phenotypes were evaluated in available patients.Results: Out of 87 patients, a molecular investigation was performed on 51 patients leading to identification of 39 cases with BTK (1 novel mutation), 5 cases of µ-heavy chain (3 novel mutations) and 1 case of Igα-deficiencies.Conclusion: Although there is no comprehensive correlation between type of responsible BTK mutation and severity of clinical phenotype, our data suggest that BTK-deficient and autosomal recessive agammaglobulinemia patients differ significantly regarding clinical/immunologic characteristics.

Primary antibody deficiencies at Queen Rania Children Hospital in Jordan: single center experience.

Primary antibody deficiency, the most common primary immunodeficiency disorder, represents a heterogeneous spectrum of conditions caused by a defect in any critical stage of B cell development and is characterized by impaired production of normal amounts of antigen-specific antibodies. This retrospective study aimed at description and analysis of demographic, clinical, immunological features and complications of subjects diagnosed with primary antibody deficiency at a referral center in Jordan. The medical records of pediatric patients who were diagnosed as primary antibody deficiency (PAD) during the period from January 2006 to June 2013 were reviewed. Patients were diagnosed as PADs based on the Pan-American Group for Immunodeficiency (PAGID) and the European Society for Immunodeficiency (ESID) diagnostic criteria. A total number of 53 patients with PAD were identified; 37(70%) males and 16(30%) females, 16(30%) patients with congenital agammaglobulinemia, 16(30%) patients with common variable immunodeficiency, 4(7.5%) patients with IgG subclass deficiency, 10(19%) cases with transient hypogammaglobulinemia of infancy and 7(13.5%) patients as undefined PAD. The most common infection among patients was pneumonia (62%); followed by suppurative otitis media in 49% of patients. Cytopenia was the most noted autoimmune association and was found at prevalence of 22 %, other autoimmune associations (17%) including inflammatory arthritis, discoid lupus, inflammatory bowel disease, vasculitis and celiac disease. The prevalence of long-term complications was 58%, the most frequent ones were; stunted growth in 13%, bronchiectasis and lymphoproliferation in 11% for each. Our results indicated that congenital agammaglobulinemia and common variable immunodeficiency are the most frequent primary antibody deficiency in our patients. The awareness of families, general population as well as primary health physicians is crucial in the establishment of early diagnosis and prompt commencement of appropriate therapy for PADs.

Clinical features and mutation analysis of X-linked agammaglobulinemia in 20 Chinese patients

X-linked agammagobulinemia (XLA) is a primary immunodeficiency caused by Bruton's tyrosine kinase (BTK) gene mutation. XLA patients have an extremely small amount of peripheral B cells and profound deficiency in all immunoglobulin isotypes. We analyzed the clinical, immunologic, and molecular characteristics of children with XLA in an attempt to improve the diagnosis and treatment of XLA in China. Twenty children with XLA-compatible phenotypes from 18 unrelated families were enrolled in this study. The BTK gene was amplified and sequenced, followed by mutation analysis in these children and their female relatives. Eighteen different mutations of the BTK gene were identified in the 20 patients. Eleven mutations had been reported previously including eight missense mutations (c.994C>T, c.1987C>A, c.1885G>T, c.502T>C, c.1085C>T, c.1816C>T, c.214C>T, c.1912G>A) and three nonsense mutations (c.1267T>A, c.1793C>G, c.1618C>T). Seven novel mutations of the BTK gene were also presented and included five missense mutations (c.134T>A, c.1646T>A, c.1829C>G, c.711G>T, c.1235G>A), one splice-site mutation (c.523+1G>A) and one insertion mutation (c.1024-1025in sTTGCTAAAGCAACTGCTAAAGCAAG). Eight out of 18 mutations of the BTK gene were located in the TK domain, 4 in the PH domain, 4 in the SH2 domain and 2 in the TH domain. Genetic study for carrier status was carried out in 18 families with definite BTK gene mutations. Nine carriers with BTK gene mutations were identified. Six families without carriers were detected, and 3 patients were not tested in this study. Our results support that molecular genetic testing represents an important tool for early confirmed diagnosis of congenital agammaglobulinemia and may allow accurate carrier detection and prenatal diagnosis.

Prevalence of Primary Immunodeficiency in Korea

This study represents the first epidemiological study based on the national registry of primary immunodeficiencies (PID) in Korea. Patient data were collected from 23 major hospitals. A total of 152 patients with PID (under 19 yr of age), who were observed from 2001 to 2005, have been entered in this registry. The period prevalence of PID in Korea in 2005 is 11.25 per million children. The following frequencies were found: antibody deficiencies, 53.3% (n = 81), phagocytic disorders, 28.9% (n = 44); combined immunodeficiencies, 13.2% (n = 20); and T cell deficiencies, 4.6% (n = 7). Congenital agammaglobulinemia (n = 21) and selective IgA deficiency (n = 21) were the most frequently reported antibody deficiency. Other reported deficiencies were common variable immunodeficiencies (n = 16), X-linked agammaglobulinemia (n = 15), IgG subclass deficiency (n = 4). Phagocytic disorder was mostly chronic granulomatous disease. A small number of patients with Wiskott-Aldrich syndrome, hyper-IgE syndrome, and severe combined immunodeficiency were also registered. Overall, the most common first manifestation was pneumonia. This study provides data that permit a more accurate estimation PID patients in Korea.

Primary B-Cell Deficiencies Reveal a Link between Human IL-17-Producing CD4 T-Cell Homeostasis and B-Cell Differentiation

IL-17 is a pro-inflammatory cytokine implicated in autoimmune and inflammatory conditions. The development/survival of IL-17-producing CD4 T cells (Th17) share critical cues with B-cell differentiation and the circulating follicular T helper subset was recently shown to be enriched in Th17 cells able to help B-cell differentiation. We investigated a putative link between Th17-cell homeostasis and B cells by studying the Th17-cell compartment in primary B-cell immunodeficiencies. Common Variable Immunodeficiency Disorders (CVID), defined by defects in B-cell differentiation into plasma and memory B cells, are frequently associated with autoimmune and inflammatory manifestations but we found no relationship between these and Th17-cell frequency. In fact, CVID patients showed a decrease in Th17-cell frequency in parallel with the expansion of activated non-differentiated B cells (CD21lowCD38low). Moreover, Congenital Agammaglobulinemia patients, lacking B cells due to impaired early B-cell development, had a severe reduction of circulating Th17 cells. Finally, we found a direct correlation in healthy individuals between circulating Th17-cell frequency and both switched-memory B cells and serum BAFF levels, a crucial cytokine for B-cell survival. Overall, our data support a relationship between Th17-cell homeostasis and B-cell maturation, with implications for the understanding of the pathogenesis of inflammatory/autoimmune diseases and the physiology of B-cell depleting therapies.