Hypogammaglobulinemia Research Articles

Clearance of Immunodeficiency-associated Vaccine-derived Poliovirus Infection With Pocapavir

Pocapavir exhibits antiviral activity against both polio and nonpolio enteroviruses. There is limited experience of the use of this investigational drug in young children with enteroviral infection. We describe the successful clearance of prolonged immunodeficiency-associated vaccine-derived type 3 poliovirus infection by pocapavir in an infant with underlying X-linked agammaglobulinemia.

Chronic high-level multidrug-resistant Campylobacter coli enterocolitis in an agammaglobulinemia patient: Oral gentamicin efficacy

BackgroundCampylobacter is the most common cause of infectious diarrhea in agammaglobulinemia patients. These infections can be severe, prolonged, and recurrent in such patients. Patient and methodsWe report a 29-year-old male patient with X-linked agammaglobulinemia with Campylobacter coli enterocolitis that persisted for nine months despite multiple 10- to 14-day courses of oral ciprofloxacin and azithromycin. ResultsThe isolate was highly resistant to ciprofloxacin, erythromycin, tetracycline, and fosfomycin. The patient failed to respond to intravenous ertapenem, 1.0g/day for two weeks, to which the pathogen was susceptible. He was finally cured with oral gentamicin, 80mg four times daily, and stool cultures remained negative during the seven-month follow-up. ConclusionOral aminoglycoside might be the most appropriate choice for eradication of persistent Campylobacter in the intestinal tract for macrolide- and fluoroquinolone-resistant isolate in agammaglobulinemia patients with chronic diarrhea or relapsing systemic infections.

A possible role for B cells in COVID-19? Lesson from patients with agammaglobulinemia

Summary COVID-19 had a mild clinical course in patients with Agammaglobulinemia lacking B lymphocytes, whereas it developed aggressively in Common Variable Immune Deficiency. Our data offer mechanisms for possible therapeutic targets.

Multiplexed Proteomic Analysis for Diagnosis and Screening of Five Primary Immunodeficiency Disorders From Dried Blood Spots.

Early detection of Primary Immunodeficiencies Disorders (PIDDs) is of paramount importance for effective treatment and disease management. Many PIDDs would be strong candidates for newborn screening (NBS) if robust screening methods could identify patients from dried blood spots (DBS) during the neonatal period. As majority of congenital PIDDs result in the reduction or absence of specific proteins, direct quantification of these target proteins represents an attractive potential screening tool. Unfortunately, detection is often limited by the extremely low protein concentrations in blood cells and limited blood volume present in DBS. We have recently developed a robust novel method for quantification of low abundance proteins in DBS for PIDDs using peptide immunoaffinity enrichment coupled to selected reaction monitoring (immuno-SRM). Here, we further generated a multiplexed Immuno-SRM panel for simultaneous screening of eight signature peptides representing five PIDD-specific and two cell-type specific proteins from DBS. In samples from 28 PIDD patients including two carriers, representing X-Linked Agammaglobulinemia (XLA), Wiskott-Aldrich Syndrome (WAS), X-Linked Chronic Granulomatous Disease (XL-CGD), DOCK8 Deficiency and ADA deficiency, peptides representing each disease are significantly reduced relative to normal controls and patient identification had excellent agreement with clinical and molecular diagnosis. Also included in the multiplex panel are cell specific markers for platelets (CD42) and Natural Killer Cells (CD56). In patients with WAS, CD42 levels were found to be significantly reduced consistent with characteristic thrombocytopenia. A patient with WAS analyzed before and after bone marrow transplant showed normalized WAS protein and platelet CD42 after treatment highlighting the ability of immuno-SRM to monitor the effects of PIDD treatment. The assay was readily reproduced in two separate laboratories with similar analytical performance and complete agreement in patient diagnosis demonstrating the effective standardized methods. A high-throughput Immuno-SRM method screens PIDD-specific peptides in a 2.5-min runtime meeting high volume NBS workflow requirements was also demonstrated in this report. This high-throughput method returned identical results to the standard Immuno-SRM PIDD panel. Immuno-SRM peptide analysis represents a robust potential clinical diagnostic for identifying and studying PIDD patients from easily collected and shipped DBS and supports a significant potential for early PIDD diagnosis through newborn screening.

Hypogammaglobulinemia Following Heart Transplantation - Prevalence and Clinical Importance

Hypogammaglobulinemia (HGG) can be identified in patients following solid organ transplantation and is thought to be predominantly due to immunosuppression. There is limited data describing the extent, degree and clinical outcomes associated with HGG following heart transplantation. The aim of this study is to investigate the prevalence and clinical significance of HGG in heart transplant recipients. We retrospectively reviewed data of patients who had underwent heart transplantation at our institution between 4/2014 and 12/2018. We excluded patients with multi-organ transplantation. We defined serum IgG <700 mg/dl as mild and <450 mg/dl as severe HGG. We classified patients into normal, mild HGG and severe HGG groups based on the lowest IgG level during follow-up. We compared clinical outcomes between the groups from the date of the lowest IgG level. We enrolled 132 patients who had at least one serum IgG value following heart transplantation during the study period. Mean age was 53±14 years old and 94 (71%) patients were male. During 761 (463, 1266) days of follow-up, patients had a median of 4 (3, 6) IgG measurements. Prevalence of severe HGG was highest (27%) 3-6 months post-heart transplant and then decreased to 5% at 1-2 years (Figure A). Survival freedom of infection was 51%, 35% and 17% at 2 years in the normal, mild HGG and severe HGG groups, respectively (P=0.03, Figure B). Overall survival and rejection-free survival were comparable between the groups. There is a high prevalence of HGG in the early post-heart transplant period that decreases over time. HGG is significantly associated with infectious complications. Further studies are needed to investigate the prophylactic treatment of HGG with IVIG in heart transplant recipients.

THE RELATIONSHIP BETWEEN THE EFFECT OF IMMUNOGLOBULIN THERAPY AND THE FUNCTIONAL POTENCIES OF THE CELLULAR LINK OF THE IMMUNE SYSTEM IN X-LINKED AGAMMAGLOBULINEMIA

Objective:to evaluate the effectiveness of intravenous immunoglobulins in X-linked agammaglobulinemia, to identify changes in the cellular link of the innate and adaptive immune response associated with an insufficient effect of replacement therapy.Materials and methods:12 patients with X-AGH were under dynamic observation. BTK genetic defect confirmed using next generation sequencing technology. After verification of the diagnosis, patients received IVIG replacement therapy at a saturation dose and then at a maintenance dose. The data of prospective observation for a full year of regular IVIG therapy with an assessment of the severity of the disease, monthly monitoring of the pre-transfusion IgG level and determination of the quantitative and functional parameters of the components of the adaptive and innate immune response every three months are presented.Results:regular replacement therapy contributed to a decrease in the frequency of exacerbations of foci of chronic infection, a decrease in the frequency and duration of antibiotic therapy, however, in 30 % of cases, the frequency of exacerbations remained high, and antibiotic courses were doubled than the standard ones. A comparative analysis of the parameters of the immune system showed that with a smaller effect of IVIG, the functional potentials of T-effectors are less significant than in the comparison group and the properties of neutrophils and natural killers are more inhibited.Summary:the relationship between the severity of the clinical manifestation of XLA on the background of replacement therapy and the preservation of the functional potencies of the cellular components of the immune system provides the basis for a possible combination of IVIG therapy with drugs that affect the properties of cellular elements of the immune system.

Chronic Rhinosinusitis in Pediatric Immunodeficiency

Chronic rhinosinusitis and other sinopulmonary infections can be a hallmark of impaired immunity in children. Rhinosinusitis in the setting of immunodeficiency can often be chronic and refractory, and involve opportunistic pathogens. We review the evaluation and management of pediatric chronic rhinosinusitis in the context of primary immunodeficiency diseases. Immunodeficiencies found to be associated with chronic rhinosinusitis include common variable immune deficiency, X-linked agammaglobulinemia, antibody deficiencies, hyper-IgM syndrome, hyper-IgE syndrome, Wiskott–Aldrich syndrome, activated PI3K disease, DiGeorge syndrome, and chronic granulomatous disease. Chronic rhinosinusitis in children may be a clinical manifestation of immunodeficiency. The evaluation and diagnosis of immunodeficiencies are essential for initiating appropriate therapeutic strategies, including antibiotics, prophylaxis, topical therapy, surgery, and immunoglobulin replacement.

Long-term follow-up of 168 patients with X-linked agammaglobulinemia reveals increased morbidity and mortality

X-linked agammaglobulinemia (XLA) is the prototype of primary humoral immunodeficiencies. Long-term follow-up studies regarding disease-related complications and outcome are scarce. Our aim was to describe the natural history of XLA. A nationwide multicenter study based on the Italian Primary Immunodeficiency Network registry was established in 2000 in Italy. Affected patients were enrolled by documenting centers, and the patients' laboratory, clinical, and imaging data were recorded on an annual base. Data on the patients (N= 168) were derived from a cumulative follow-up of 1370 patient-years, with a mean follow-up of 8.35 years per patient. The mean age at diagnosis decreased after establishment of the Italian Primary Immunodeficiency Network registry (84 months before vs 23 months after). Respiratory, skin, and gastrointestinal manifestations were the most frequent clinical symptoms at diagnosis and during long-term follow-up. Regular immunoglobulin replacement treatment reduced the incidence of invasive infections. Affected patients developed chronic lung disease over time (47% after 40 years of follow-up) in the presence of chronic sinusitis (84%). Malignancies were documented in a minority of cases (3.7%). Overall survival for affected patients was significantly reduced when compared with that for the healthy male Italian population, and it further deteriorated in the presence of chronic lung disease. This is the first detailed long-term follow-up study for patients with XLA, revealing that although immunoglobulin replacement treatment reduces the incidence of invasive infections, it does not appear to influence the development of chronic lung disease. The overall survival of affected patients is reduced. Further studies are warranted to improve patients' clinical management and increase awareness among physicians.

Bruton tyrosine kinase deficiency augments NLRP3 inflammasome activation and causes IL-1β-mediated colitis.

Bruton tyrosine kinase (BTK) is present in a wide variety of cells and may thus have important non-B cell functions. Here, we explored the function of this kinase in macrophages with studies of its regulation of the NLR family, pyrin domain-containing 3 (NLRP3) inflammasome. We found that bone marrow-derived macrophages (BMDMs) from BTK-deficient mice or monocytes from patients with X-linked agammaglobulinemia (XLA) exhibited increased NLRP3 inflammasome activity; this was also the case for BMDMs exposed to low doses of BTK inhibitors such as ibrutinib and for monocytes from patients with chronic lymphocytic leukemia being treated with ibrutinib. In mechanistic studies, we found that BTK bound to NLRP3 during the priming phase of inflammasome activation and, in doing so, inhibited LPS- and nigericin-induced assembly of the NLRP3 inflammasome during the activation phase of inflammasome activation. This inhibitory effect was caused by BTK inhibition of protein phosphatase 2A-mediated (PP2A-mediated) dephosphorylation of Ser5 in the pyrin domain of NLRP3. Finally, we show that BTK-deficient mice were subject to severe experimental colitis and that such colitis was normalized by administration of anti-IL-β or anakinra, an inhibitor of IL-1β signaling. Together, these studies strongly suggest that BTK functions as a physiologic inhibitor of NLRP3 inflammasome activation and explain why patients with XLA are prone to develop Crohn's disease.

Recurrent Campylobacter Enteritis in Patients with Hypogammaglobulinemia: Review of the Literature.

Recurrent Campylobacter enteritis is a well-recorded complication of primary hypogammaglobulinemia but has only rarely been reported with other types of immunodeficiency, and no cases have been reported after rituximab-associated secondary hypogammaglobulinemia. We therefore reviewed our local microbiology laboratory databases and conducted a literature search, to provide a detailed characterization of the immunodeficiency states associated with recurrent Campylobacter enteritis. Published cases had primary hypogammaglobulinemia, most frequently in the setting of common variable immunodeficiency, x-linked agammaglobulinemia, and Good syndrome. No cases were identified in the literature after rituximab or secondary hypogammaglobulinemia. We report a 73-year-old patient with recurrent Campylobacter enteritis and hypogammaglobulinemia in the setting of non-Hodgkin lymphoma, chemotherapy, and maintenance rituximab. Physicians should be aware of the association of recurrent Campylobacter enteritis and immunodeficiency, most commonly in primary hypogammaglobulinemia. Rituximab alone may not be sufficiently immunosuppressive for recurrent campylobacteriosis to occur; additional factors, including hematological malignancy and its treatment, appear necessary. Patients with recurrent Campylobacter enteritis and those starting rituximab should be investigated for hypogammaglobulinemia and B-lymphopenia.

Síndrome de Good: associação entre timoma, hipogamaglobulinemia, aplasia pura da série vermelha e parvovírus B19 – um estudo de caso

Objetivo: Relatar o caso de um paciente acometido por Síndrome de Good, detalhando o quadro clínico inicial, evolução da doença, tratamento realizado, bem como os exames laboratoriais e de imagens responsáveis pelo seu diagnóstico. Relato do Caso: Paciente do sexo feminino, 52 anos, com timoma diagnosticado por exame de imagem após quadros infecciosos recorrentes e sucessivas transfusões de concentrados de hemácias por repetidas anemias. Tratada cirurgicamente com timectomia, apresentou ao exame histopatológico um timoma medular. Obteve resolução temporária do quadro anêmico por cerca de um ano. Desenvolveu novamente quadros de anemia e infecção, sendo aventada alguma causa de imunodeficiência subjacente, com investigação e diagnóstico laboratorial de hipogamaglobulinemia e infecção oportunista por parvovírus B19. Tratada com sucesso por meio de infusões de imunoglobulina humana. Considerações Finais: Poucos estudos debatem acerca da Síndrome de Good, dificultando a criação de medidas terapêuticas e embasamento teórico acerca do assunto.

Primary Immunodeficiency Diagnoses seen in Patients with Chronic Lung Disease: Findings from the USIDNET Registry

In patients with chronic lung disease (CLD), a diagnosis of underlying primary immunodeficiency (PID) can have unique implications on evaluation and management. It is important to recognize the full spectrum of PID diagnoses that can present with CLD. The USIDNET Registry was queried for patients with chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD). Demographics, diagnoses, diagnosis dates, infections, immunology tests, and treatments were extracted. There were 116 patients (median age 22 years, range 0-81) with reported ILD (90.5%, 105/116) and COPD (20.7%, 24/116). Both ILD and COPD were reported in 11.2% (13/116). PIDs most commonly reported with ILD were common variable immunodeficiency (CVID) (56.2%, 59/105), severe combined immunodeficiency (11.4%, 12/105), and chronic granulomatous disease (CGD) (7.6%, 8/105). Chronic mucocutaneous candidiasis (CMC), Hyper-IgE Syndrome (HIES), and PIK3CD disorder were reported in 2.9% (3/105); autoimmune lymphoproliferative syndrome, GATA2 deficiency, hypogammaglobulinemia, IL-10 mutation, X-linked agammaglobulinemia in 1.9% (2/105); and ataxia-telangiectasia, CTLA4 deficiency, DiGeorge Syndrome, Hyper-IgM syndrome in 1.0% (1/105). ILD diagnosis preceded or coincided with PID diagnosis in 29.5% (31/105). PIDs commonly reported with COPD were CVID (37.5%, 9/24), HIES (16.7%, 4/24), and PIK3CD disorder (8.3%, 2/24). CGD, CMC, combined immunodeficiency, GATA2 deficiency, and hypogammaglobulinemia were reported in 4.2% (1/24). COPD diagnosis preceded or coincided with PID diagnosis in 25.0% (6/24). CLD was associated with a range of PID diagnoses. Importantly, PID was diagnosed after or at time of CLD diagnosis in 29.3% (34/116) of patients, providing support that immune evaluation may be prudent in CLD patients with frequent infections.

Low-dose Btk inhibitors selectively block platelet activation by CLEC-2.

Inhibitors of Bruton tyrosine kinase (Btk) have been proposed as novel antiplatelet agents. In this study we show that low concentrations of the Btk inhibitor ibrutinib block CLEC-2-mediated activation and tyrosine phosphorylation including Syk and PLCγ2 in human platelets. Activation is also blocked in patients with X-linked agammaglobulinemia (XLA) caused by a deficiency or absence of Btk. In contrast, the response to GPVI is delayed in the presence of low concentrations of ibrutinib or in patients with XLA, and tyrosine phosphorylation of Syk is preserved. A similar set of results is seen with the second-generation inhibitor, acalabrutinib. The differential effect of Btk inhibition in CLEC- 2 relative to GPVI signaling is explained by the positive feedback role involving Btk itself, as well as ADP- and thromboxane A2-mediated activation of P2Y12 and TP receptors, respectively. This feedback role is not seen in mouse platelets and, consistent with this, CLEC-2-mediated activation is blocked by high but not by low concentrations of ibrutinib. Nevertheless, thrombosis was absent in eight out of 13 mice treated with ibrutinib. These results show that Btk inhibitors selectively block activation of human platelets by CLEC-2 relative to GPVI suggesting that they can be used at low doses in patients to target CLEC-2 in thrombo-inflammatory disease.

Antibody-coated microbiota in nasopharynx of healthy individuals and IVIg-treated patients with hypogammaglobulinemia

We show that nasopharyngeal microbiota are coated by different immunoglobulin isotypes in healthy individuals and with IgG in X-linked agammaglobulinemia (XLA) patients treated with immunoglobulin replacement therapy.

Flow Cytometry for the Diagnosis of Primary Immunodeficiency Diseases: A Single Center Experience

PurposeWhile there is an urgent need for diagnosis and therapeutic intervention in patients with primary immunodeficiency diseases (PIDs), current genetic tests have drawbacks. We retrospectively reviewed the usefulness of flow cytometry (FCM) as a quick tool for immunophenotyping and functional assays in patients suspected to have PIDs at a single tertiary care institute.MethodsBetween January 2001 and June 2018, patients suspected of having PIDs were subjected to FCM tests, including lymphocyte subset analysis, detection of surface- or intracellular-target proteins, and functional analysis of immune cells, at Samsung Medical Center, Seoul, Korea. The genetic diagnosis was performed using Sanger or diagnostic exome sequencing.ResultsOf 60 patients diagnosed with definite or probable PID according to the European Society of Immune Deficiencies criteria, 24 patients were provided with useful information about immunological dysfunction after initial FCM testing. In 10 patients, the PID diagnosis was based on abnormal findings in FCM testing without genetic tests. The FCM findings provided strong evidence for the diagnosis of severe combined immunodeficiency (n = 6), X-linked chronic granulomatous diseases (CGD) (n = 6), leukocyte adhesion deficiency type 1 (n = 3), X-linked agammaglobulinemia (n = 11), autoimmune lymphoproliferative syndrome-FASLG (n = 1), and familial hemophagocytic lymphohistiocytosis type 2 (n = 1), and probable evidence for autosomal recessive-CGD (n = 2), autosomal dominant-hyper-immunoglobulin E (IgE)-syndrome (n = 1), and STAT1 gain-of-function mutation (n = 1). In PIDs derived from PIK3CD (n = 2), LRBA (n = 2), and CTLA4 mutations (n = 3), the FCM test provided useful evidence of immune abnormalities and a tool for treatment monitoring.ConclusionsThe initial application of FCM, particularly with known protein targets on immune cells, would facilitate the timely diagnosis of PIDs and thus would support clinical decisions and improve the clinical outcome.

Evaluation of pulmonary findings in patients with humoral immunodeficiency.

Aim:To determine the frequency of sinopulmonary infections, detect changes in the respiratory system, and measure functional capacity of the lungs in our patients with humoral immunodeficiency.Material and Methods:Fifty-six patients with humoral immunodeficiency were enrolled in this study. The clinical, laboratory, and radiologic data, and pulmonary function tests of the subjects were evaluated from their file records, retrospectively.Results:The distribution of our patients was as follows: 25 patients had common variable immune deficiency, three patients had X-linked agammaglobulinemia, five patients had hyper immunoglobulin M syndrome, 19 patients had deficiency of immunoglobulin G subset, and four patients had selective immunoglobulin A deficiency. The most common symptom of the patients was chronic cough (n=47, 83.9%). The most common pathologies on high-resolution computed tomography of the chest were atelectasis and bronchiectasis (27.7%). The most common pathology in pulmonary function tests was the presence of moderate obstructive patterns along with restrictive patterns (n=6,12.5%). The FEV 1, FVC, and FEF 25–75 values were significantly lower in patients with common variable immunodeficiency compared with the patients who had IgG subset deficiencies (p=0.001, p=0.01, p=0.01). Among the patients who were treated with intravenous immunoglobulin, the age at the diagnosis of immunodeficiency was higher in patients with bronchiectasis (14.2±8.4 years) compared with those without bronchiectasis (10.1±11.4 years) (p=0.04).Conclusion:Clinical findings are not sufficient to monitor the structural and functional changes in the respiratory system, and patients should be evaluated using high-resolution computed tomography of the chest and pulmonary function tests.

Факторы, ассоциированные с вариативностью течения Х-сцепленной агаммаглобулинемии

Факторы, ассоциированные с вариативностью течения Х-сцепленной агаммаглобулинемии

SARS-CoV-2 infection in a patient with X-linked agammaglobulinemia treated with high doses of intravenous immunoglobulin and convalescent plasma

SARS-CoV-2 infection in a patient with X-linked agammaglobulinemia treated with high doses of intravenous immunoglobulin and convalescent plasma

Optimization of Therapy of Patient with Genetic Defect Antibody Production

Development of molecular genetics and immunological diagnostics, disclosure of pathogenesis of various forms of primary immunodeficiency (PID), improvement of therapeutic techniques contributed to the formation of a generation patients with PID older than 18 years. Experience shows that isolated replacement therapy, leading to a reduction in the frequency and severity of reactivation chronic foci of infection, is not able in some cases to fully stabilize the condition of patients, and the use of antibiotics remains inevitable. Interesting is the development and implementation of the concept of combined therapy of PID humoral therapy, the ideology of which is based on the combination of substitution therapy with exposure on the functional potential of the cellular link of the immune system. One of the perspective variants of influence on functions of cellular components of immune is the use of innate immunity receptor agonists. From the position of the specific clinical application deserves the attention medication Likopid (glucosaminilmuramyl dipeptide) - semi-synthetic analogue of muramyldipeptide, minimally biologically active substance peptidoglycan fragment of the cell wall of all known bacteria. Presented clinical case of X-linked agammaglobulinemia. The patient, despite regular replacement therapy with intravenous immunoglobulins with maintaining a pretransfusion IgG level of at least 8 g/l, continued to register episodes of exacerbation of chronic conjunctivitis up to 10 times a year. Application of licopid in addition to IVIG therapy contributed to the improvement quality of life, reducing the frequency of exacerbations, conjunctivitis and duration of use antibiotics. This example illustrates the role of cellular components innate immune response in clinical manifestation of insufficiency humoral link adaptive immunity, and confirms the possibility of additional correction of these parameters to improve the efficiency of the standard substitution therapy.

Subcutaneous Immunoglobulin for Antibody Deficiency in Antineutrophil Cytoplasmic Antibody (ANCA)-associated Vasculitis.

ObjectivesIntravenous immunoglobulin G (IVIG) is used to treat antineutrophil cytoplasmic antibody (ANCA) patients with recurrent infections as a result of hypogammaglobulinemia (HG) induced by treatment regimens. We sought to characterize clinical features, treatment, and outcomes for patients treated with the novel subcutaneous IgG (SCIG) for the aforementioned purpose. MethodsWe conducted a retrospective study of 136 patients in our ANCA database to identify patients with recurrent infections and HG subsequently treated with SCIG. Patient demographics, serologies, treatment, and immunological parameters were assessed. ResultsOf 136 patients, four were treated with SCIG. All were Caucasian, proteinase-3 (PR3)-positive, and the majority (n = 3) were females. All patients had pulmonary involvement, and regimens of cyclophosphamide (CYC) and/or rituximab (RTX) were employed for induction and remission. Three patients each experienced recurrent bouts of respiratory tract infections and shingles. Ig levels (G, M, and A) were reduced in all patients, except for one patient who had normal IgA levels. CD19/20 cells were depleted and CD3/4/8/NK cells were preserved in all patients. Three patients had no discernible antibody response to the pneumococcal vaccine (specific pneumococcal serotypes measured pre- and post-vaccine). The mean duration elapsed between the first rituximab administration and commencement of SCIG was 7.2 years. The IgG level normalized and none of the patients had a recurrence of infection since the initiation of SCIG. ConclusionThis data, albeit preliminary, is the first series that demonstrates SCIG can be a reliable alternative to IVIG in ANCA patients with recurrent infections secondary to HG. Early identification of this subset of patients is likely to mitigate infectious risks, associated morbidity, and hospitalization.