Hypogammaglobulinemic Patients Research Articles

Multicenter, Prospective Study to Investigate the Efficacy and Safety of Intravenous-Immunoglobulin Therapy in Elderly Patients with Diffuse Large B Cell Lymphoma Treated with R-Mini-CHOP

Background The median age at initial diagnosis of DLBCL is estimated to be between the ages of 60 and 70. The number of elderly patients with DLBCL is gradually increasing. But, treatment outcomes of elderly patients were not significantly improved compared to younger patients. Infection is an independent predictor of treatment outcome in patients with DLBCL, and the risk of infection increases with age. The incidence of hypogammaglobulinemia in patients with malignant lymphoma increased from 15% to 39% after rituximab therapy. There was a significant decrease in the occurrence of major infections after intravenous immunoglobulins (IVIG) prophylaxis in hypogammaglobulinemia patients with lymphoproliferative. disorders. In this multicenter prospective study, infection prevention effect and treatment outcomes were identified using IVIG in elderly DLBCL patients with hypogammaglobulinemia who received rituximab combination chemotherapy. Methods In the current study, newly diagnosed DLBCL patients aged 70 years or older who were planning to receive R-mini-CHOP therapy were included. Patients with hypogammaglobulinemia at diagnosis were assigned to the IVIG group. Patients received R-mini-CHOP (rituximab: 375mg/m 2 D1; cyclophosphamide: 400mg/m 2 D1; doxorubicin: 25mg/m 2 D1; vincristine: 1.0mg D1, and prednisolone 40mg/m 2 from D1 to D5), and pegylated G-CSF. After the first cycle of R-mini-CHOP, 400mg/kg of IVIG was administered on D3 and D11. After the second cycle to sixth cycle of chemotherapy, patients received 400mg/kg of IVIG on D11. The primary objective was to evaluate the efficacy of IVIG in reducing severe infections. Grade 3 or 4 infections were defined as severe infections. Results A total of 118 elderly patients were newly diagnosed with DLBCL and were scheduled to receive R-mini-CHOP therapy. Hypogammaglobulinemia was identified in 85 (72.0%) patients. Decreased immunoglobulin D (n=42) and immunoglobulin M (n=39) level were most common, and 18 patients had two or more types of hypogammaglobulinemia at the same time. Fifty-six patients were assigned to the group receiving IVIG. Median age was 77 years (range, 70-90), and 31 (55.4%) were male. In patients who completed R-mini-CHOP and IVIG treatment, complete remission rate was 79.4%. Severe infections of grade 3 or 4 occurred in 3 of 56 (5.4%) patients, and only five (8.9%) patients had COVID-19 infection during the study period. Adverse effects associated with IVIG include fever/chilling, nausea/vomiting which were generally manageable. Only one patient discontinued the study because of chest pain that occurred during IVIG administration. In patients with hypogammaglobulinemia who did not receive IVIG, severe infections occurred in 8 of 29 (27.6%) patients, and COVID-19 infection was developed in 7 of 29 (24.1%). In patients without hypogammaglobulinemia, severe infection occurred in 5 of 33 (15.2%), and COVID-19 infection was developed in 8 of 33 (24.2%) patients. Patients receiving IVIG had a significantly reduced incidence of severe infection compared to patients not receiving IVIG (p=0.028). Furthermore, COVID-19 infection rate during R-mini-CHOP therapy was lower in IVIG receiving patients (p=0.050). Long-term outcomes with relapse rate and survival will be followed up and updated. Conclusion In elderly patients with DLBCL, the combination of R-mini-CHOP and IVIG was safe and effective in preventing infection. In the COVID-19 era, the combination of chemotherapy and IVIG should be considered in elderly DLBCL patients to reduce infection rate and improve treatment outcomes.

Identifying Causes of Unscheduled Healthcare Interactions and Changes to Patient Disposition in Individuals Receiving Outpatient Commercial Bispecific Antibody Therapy in Relapsed/Refractory Multiple Myeloma (RRMM)

Introduction: Teclistamab is a BCMA targeting bispecific antibody that was FDA approved for treating relapsed/refractory multiple myeloma (RRMM) based off the results of the MajesTEC-1 trial (Usmani S, et al. Lancet 2021, Moreau P, et al. N Engl J Med 2022), and is the first bispecific antibody approved for myeloma treatment. While patients included in the MajesTEC-1 study were monitored closely per trial protocols, little is known about what patient-reported care concerns and education gaps may exist outside of a trial setting with standard of care teclistamab and whether these gaps lead to a high number of unscheduled healthcare interactions. Methods: We retrospectively analyzed patient reported symptom concerns for commercial teclistamab patients at Memorial Sloan Kettering Cancer Center (MSKCC) via review of the electronic health record for a 4-month observation period following treatment initiation. Patients were included in the study if they had a response to teclistamab (per IMWG criteria), remained on treatment for at least 4 months as of our data cut-off (07/20/2023), and did not have evidence of disease progression during the observation period. Collected data included all unscheduled healthcare visits, including urgent care visits, emergency room visits, and hospital admissions. We also evaluated all outpatient communications, including telephone calls to physicians' offices and messages sent to physicians' offices through MSKCC's online patient portal. The total observation period included the first 4 months of therapy, during which patients were scheduled to receive treatment weekly and be seen by their physicians at regular 4-week intervals. Results: We identified 52 patients treated with teclistamab at our center as of the data cut-off, 19 of which met our inclusion criteria. Of note, this population had poorer performance status (89% vs 67% ECOG ≥1) and had more heavily pretreated disease (6 vs 5 median prior lines of therapy) when compared to the MajesTEC-1 population, with the majority not being eligible for MajesTEC-1 per its criteria. Within this population, 79% of patients communicated with their physicians' offices outside of their scheduled monthly appointments, with an average of 2.3 (0-8) communications sent per patient during the 4-month observation period. The most common reason for communication was upper respiratory tract infection (URI) symptoms, accounting for 24% of all communications. Other notable reasons included gastrointestinal (GI) symptoms (20%), disease related pain (13%), injection site reactions (9%) and symptoms of volume overload (9%). Unscheduled visits included 8 urgent care (UC) visits, and 20 emergency department (ED) visits involving 11/19 patients. The 20 ED visits led to 16 inpatient admissions, not including planned admissions for step-up dosing (data summarized in Figure 1), with a median length of stay of 4 days (2-24 days). URI symptoms triggered 50% of UC visits and 40% of the ED visits not leading to inpatient admission, but only accounted for 6% of hospital admissions. The most common cause of hospital admission was a non-URI acute infection (29%). Conclusions: Our data suggest that RRMM patients being treated with outpatient teclistamab have frequent unscheduled healthcare interactions. The high prevalence of URIs in our population indicates that infection rates in this frequently hypogammaglobulinemic patient population may be underreported. However, these do not frequently lead to inpatient admissions or to significant morbidity/mortality. Overall, teclistamab patients would likely benefit from improved patient education with regards to expected side effects of therapy, with pre-existing management plans in place for URIs, GI symptoms, and injection site reactions. Applying these principles may limit excessive healthcare visits for patients, particularly in those with heavily relapsed/refractory myeloma with poor disease prognosis. Data from additional patients, including patients receiving step-up dosing as outpatients as part of a pilot study, will be presented at the meeting.

Chronic or recurrent Campylobacter enteritis in primary immunodeficiency: a UK national case-series and review of the literature.

Chronic or recurrent Campylobacter enteritis in primary immunodeficiency: a UK national case-series and review of the literature.

Sequencing the B cell receptor repertoires of antibody-deficient individuals with and without infection susceptibility

PurposeMost individuals with antibody deficiency (hypogammaglobulinemia) need immunoglobulin replacement therapy (IgG-RT) from healthy plasma donors to stay clear of infections. However, a small subset of hypogammaglobulinemic patients do not require this substitution therapy. We set out to investigate this clinical conundrum by asking whether the peripheral B cell receptor repertoires differ between antibody-deficient patients who do and do not need IgG-RT. MethodsWe sequenced and analyzed IgG and IgM heavy chain B cell receptor repertoires from peripheral blood mononuclear cells (PBMCs) isolated from patients with low serum IgG concentrations who did or did not require IgG-RT. ResultsCompared to the patients who did not need IgG-RT, those who needed IgG-RT had higher numbers of IgG antibody clones, higher IgM diversity, and less oligoclonal IgG and IgM repertoires. The patient cohorts had different heavy chain variable gene usage, and the patients who needed IgG-RT had elevated frequencies of IgG clones with higher germline identity (i.e., fewer somatic hypermutations). ConclusionAntibody-deficient patients with infection susceptibility who needed IgG-RT had more diverse peripheral antibody repertoires that were less diverged from germline and thus may not be as optimal for targeting pathogens, possibly contributing to infection susceptibility.

Sequencing the B Cell Receptor Repertoires of Antibody-Deficient Individuals With and Without Infection Susceptibility

PurposeMost individuals with antibody deficiency (hypogammaglobulinemia) need immunoglobulin replacement therapy (IgG-RT) from healthy plasma donors to stay clear of infections. However, a small subset of hypogammaglobulinemic patients do not require this substitution therapy. We set out to investigate this clinical conundrum by asking whether the peripheral B cell receptor repertoires differ between antibody-deficient patients who do and do not need IgG-RT.MethodsWe sequenced and analyzed IgG and IgM heavy chain B cell receptor repertoires from peripheral blood mononuclear cells (PBMCs) isolated from patients with low serum IgG concentrations who did or did not require IgG-RT.ResultsCompared to the patients who did not need IgG-RT, those who needed IgG-RT had higher numbers of IgG antibody clones, higher IgM diversity, and less oligoclonal IgG and IgM repertoires. The patient cohorts had different heavy chain variable gene usage, and the patients who needed IgG-RT had elevated frequencies of IgG clones with higher germline identity (i.e., fewer somatic hypermutations).ConclusionAntibody-deficient patients with infection susceptibility who needed IgG-RT had more diverse peripheral antibody repertoires that were less diverged from germline and thus may not be as optimal for targeting pathogens, possibly contributing to infection susceptibility.

Immunogenicity of a third COVID-19 messenger RNA vaccine dose in primary immunodeficiency disorder patients with functional B-cell defects

Immunogenicity of a third COVID-19 messenger RNA vaccine dose in primary immunodeficiency disorder patients with functional B-cell defects

Intravenous immunoglobulin therapy for COVID-19 ARDS

Intravenous immunoglobulin therapy for COVID-19 ARDS

Variable clinical characteristics and laboratory results in five patients with Chinese Good's syndrome (thymoma and hypogammaglobulinemia): an 8-year retrospective analysis in a university hospital in China

BackgroundGood's syndrome (GS) is a rare secondary immunodeficiency disease presenting as thymoma and hypogammaglobulinemia. Due to its rarity, the diagnosis of GS is often missed.MethodsWe used the hospital information system to retrospectively screen thymoma and hypogammaglobulinemia patients at the First Affiliated Hospital of Wenzhou Medical University from Apr 2012 to Apr 2020. The clinical, laboratory, treatment, and outcome data for these patients were collected and analyzed.ResultsAmong the 181 screened thymoma patients, 5 thymoma patients with hypogammaglobulinemia were identified; 3 patients had confirmed diagnoses of GS, and the other 2 did not have a diagnosis of GS recorded in the hospital information system. A retrospective review of the clinical characteristics, laboratory results, and follow-up data for these 2 undiagnosed patients confirmed the diagnosis of GS. All 5 GS patients presented with pneumonia, 2 patients presented with recurrent skin abscesses, 2 patients presented with recurrent cough and expectoration, 1 patient presented with recurrent oral lichen planus and diarrhea, and 1 patient presented with tuberculosis and granulomatous epididymitis. In the years after the diagnosis of hypogammaglobulinemia with mild symptoms, all 5 patients had received irregular intravenous immunoglobulin (IVIG) treatment. As the course of the disease progressed, the clinical symptoms of all patients worsened, but the symptoms were partly resolved with IVIG in these patients. However, 4 patients died due to comorbidities.ConclusionGS should be investigated as a possible diagnosis in thymoma patients who present with hypogammaglobulinemia, especially those with recurrent opportunistic infections, recurrent skin abscesses, chronic diarrhea, or recurrent lichen planus.

Infections and Immune System Impairment in Multiple Myeloma: Increasing Frequency of Serious Complications in the “Novel Agents Era”— a Retrospective Real Life Analysis

New treatments options introduced during recent decades have improved the survival of multiple myeloma(MM)patients.Managing the complications of the disease and its treatment, such as infections become more important as MM-patients survive longer. Infections are a significant cause of morbidity and a leading cause of death in MM-patients.Effect of novel therapies on the risk of infection remains to be established and new trials on prophylactic measures are needed.These advances have transformed myeloma into a chronic condition, with multiple relapses resulting in cumulative immunosuppression and higher risk of infection. In addition to the immunodeficiency related to myeloma, the type of anti-myeloma therapy used also plays a role in the development of infectious events.We aimed to study the development of severe infectious events of grade 3-4 requiring often hospitalization in a group of patients under treatment at diagnosis as well as at relapse. We evaluated the impact of the type of anti-myeloma therapy and of the disease features on patients' infectious complications in the context of novel agents.We retrospectively reviewed data from 195 myeloma patients diagnosed from 1999 to 2016 in order to assess type and outcome of infections (Table 1). 7 of these were life-threatening (3 viral interstitial pneumonias and 4 gram negative sepsis)and 103 have resulted in discontinuation of therapy(respectively 73 bacterial, 10 fungal,18 viral and 2 parasitic-infectious-complications). We focus on time of occurrence and number of prior therapeutic lines and on disease biological aggressiveness.Our aim was to define risk-factors and to organize an effective antimicrobial prophylaxis strategy in our cohort of patients.In our analysis 30 patients presented a FUO(fever of unknown origin)without isolation of pathogens.They were 19 elderly-patients and 11 young in a neutropenic phase after chemotherapy. They showed defervescence following antibiotic therapy with piperacillin-tazobactam.165 patients presented infectious complications with a well-known etiology (Figure 1): 100 bacterial, 45 viral, 15 fungal and 5 parasitic infections. Pathogens isolated were:Candida-Albicans followed by C.Parapsylosis and Aspergillus-Flavus among fungal infections,E.Coli,Klebsiella-Pneumoniae and Pseudomonas-aeruginosa between bacterial complications,CMV,HSV,HZV in viral manifestations and Leishmanias among parasitic-events.Advanced age is a meaningful risk-factor togheter with biologically aggressiveness and relapse condition. The majority of patients were older than 65 years (125 as 76%) in a relapse setting (125 as 77%).Kind of anti-myeloma therapy used also plays a role in the development of infection. Specifically the predominant part of patients developing fungal infections(13 as 89%)showed neutropenia after chemotherapy or previous therapy with Imids. The majority of patients with viral infections(39 as 87%) presented lymphopenia and previous therapies bortezomib-based.Bacterial infections have shown mostly prevalent in neutropenic-phases (88 as 88%) usually in relapse phases (78 as 78%)or in hypogammaglobulinemic patients(68 as 68%).Finally most of parasitic infections have been shown after high doses steroid treatment and with more than 2 of therapeutic lines(100%).Severe infections represent a significant comorbidity in MM, often underestimated, in all phases of the disease expecially in refractory/relapsed patients.Immunoglobulin-replacement-therapy or antibiotic-prophylaxis may possible have a protective-role in high risk old patients with high ISS stage and aggressive disease. Variety of factors underlies susceptibility to infections including defects of innate and adaptive-immunity(neutropenia,hypogammaglobulinemia).Need for antimicrobial-prophylaxis depends on risk for and seriousness of infections.Based on our experience,in the first three-months of therapy with IMIDs we now begin prophylactic antibacterial and antifungal therapy (quinolone and fluconazole).All patients treated to date(30 in total)did not require therapy-discontinuation.High-risk-patients should receive antimicrobial-prophylaxis and trials on prophylactic-measures are needed.Key to the management of infection is the understanding of the specific risk factors and periods in order to perform a risk adjusted prophylactic and treatment strategies. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

A clinician survey for management of the secondary immunodeficiency caused by hematological malignancies in China

Unlike Western countries, there are still few clinical immunology specialists in China, and the optimal care for secondary immunodeficiency caused by hematological malignancies is unknown. Therefore, we initiated this clinician survey study to describe the current situation of the care for malignancy patients with hypogammaglobulinemia in China.We adapted a previously published online questionnaire of current clinical practices regarding the management of secondary immunodeficiency caused by hematological malignancies and then distributed the questionnaire to 52 hematologists in China via WeChat mobile software; the survey collected demographic details, starting dosage, target immunoglobulin (Ig) level, monitoring, criteria for stopping Ig replacement, vaccination use, and oral antibiotic prophylaxis for hypogammaglobulinemia patients.Forty-eight hematologists responded. 28(58.33%) respondents had more than 10 years of experience. Nevertheless, 40(83.33%) respondents reported that they did not use any specific criteria for prophylactic Ig replacement in hypogammaglobulinemia patients. However, 27(56.25%) respondents reported that they had used intravenous immunoglobulin (IVIG); however, the starting dose, frequency, and target Ig level were significantly varied. Additionally, the criteria for stopping Ig replacement were significantly varied. Only one respondent (2.08%) used subcutaneous immunoglobulin (SCIG). Moreover, 35(72.92%) respondents reported no vaccination prior to Ig replacement, and 47(97.92%) respondents reported that they had not used antibiotic prophylaxis in secondary hypogammaglobulinemia patients.Official guideline for the care for secondary immunodeficiency (SID) of the hematological malignancies patients should be issued in China, and significant attention of the hematologists should be paid to the use of prophylactic antibiotics and Ig replacement for the care of patients with hypogammaglobulinemia caused by hematological malignancies, as these agents could significantly reduce the infection rate in China.

The Detection by Immunofixation Electrophoresis (IFE) of Monoclonal Proteins in Veteran Patients with Hypogammaglobulinemia on Negative Serum Protein Electrophoresis, the Veteran Affairs Medical Center (VAMC) Experience

Abstract Introduction/Objective Serum protein electrophoresis (SPEP) is the backbone laboratory test for the detection of abnormal monoclonal proteins. However, IFE is a sensitive assay that can sometimes detect monoclonal proteins even when the corresponding SPEP is negative. The fact that IFE is more sensitive than SPEP combined with the need to avoid overutilization of IFE has led to published algorithms for guidance. Hypogammaglobulinemia in a new patient has been recognized in these algorithms as a reason to reflex to IFE when SPEP is negative, though studies on veteran patients are sparse. Therefore, this QA study of the percentage of positive IFEs in negative new SPEP veteran patients with hypogammaglobulinemia was undertaken to ensure reflex IFEs would still be indicated. Methods As part of a quality assurance/quality improvement project, a retrospective Vista/Fileman search of all SPEPs with IFE performed from January 2017 to February 2019 was undertaken to identify cases of SPEPs showing hypogammaglobulinemia (<0.7 g/dL). Diagnostic comments were then analyzed to identify cases of hypogammaglobulinemia along with the M-spike (<0.1 g/dL) to identify negative SPEPs. Only those cases that were consistent with first time hypogammaglobulinemia without an obvious M-spike were included and tabulated for calculations. Any result that was not negative for a monoclonal band was considered as positive. Results There were a total of 194 specimens that met the criteria of SPEP with hypogammaglobulinemia and standard comments consistent with first time analysis and without an obvious M-spike on SPEP. Out of these 194 specimens, 45 had a positive result, either as a monoclonal band comigrating with the beta protein peak or as a very faint gamma or beta monoclonal band. This represented approximately 23% of the specimens, about double the literature published rate for the non-veteran population. Conclusion The performance of IFE on new hypogammaglobulinemia veteran patients appears to be indicated like previously published algorithms and is supported by the fact that about double (23%), compared to the non-veteran population, had positive IFEs despite negative SPEPs. IFE is a helpful tool for new hypogammaglobulinemia patients for the detection of monoclonal proteins despite negative SPEPs.

Increased antiviral response in circulating lymphocytes from hypogammaglobulinemia patients.

B cells play a crucial role during rhinovirus (RV) infections by production of virus-neutralizing antibodies. A main feature of common variable immunodeficiency (CVID) is hypogammaglobulinemia (HG). HG patients have severely reduced levels of antibody-producing B cells and suffer from prolonged virus infections. Here, we addressed whether antiviral response of peripheral blood lymphocytes differs between HG patients and healthy individuals during natural RV infection. Using fluorescence-activated cell sorting, B-cell subsets were analyzed. Simultaneously, CD19+B cells, CD14+monocytes, and CD3+T cells were sorted from frozen peripheral blood mononuclear cells from 11 RV-infected hypogammaglobulinemia patients, 7 RV-infected control subjects, and 14 noninfected control subjects. Real-time PCR was used to study expression of antiviral genes. A pan-RV PCR was used to detect RV genome in all samples. In HG patients, total B-cell numbers, as well as IgA+and IgG+switched memory B cells, were reduced while naïve B cells and T cells were increased. STAT1 expression was increased in HG patients compared to controls in all lymphocyte subsets analyzed. The expression of antiviral genes IFITM1 and MX1 correlated with STAT1 expression in B cells and monocytes. RV RNA was found in 88.9% of monocytes from infected HG patients, 85.7% of monocytes from infected controls, and 7.1% of monocytes from uninfected controls. We demonstrate an increased antiviral response in B cells and monocytes in HG patients and their correlation with STAT1 expression. Monocytes of infected HG patients and infected non-HG controls carry RV RNA.

Hypogammaglobulinemia in Adolescents and Young Adults with Acute Lymphoblastic Leukemia

Hypogammaglobulinemia is a poorly described complication of chemotherapy in adolescents and young adults (AYAs, 15-39 years) with acute lymphoblastic leukemia (ALL). The majority of AYAs treated on a Berlin-Frankfurt-Munster-based ALL regimen experienced hypogammaglobulinemia (65.0% [13/20]). Febrile neutropenia episodes (throughout the treatment course) and infectious events during maintenance occurred more frequently in hypogammaglobulinemic patients compared with patients with normal immunoglobulin G levels (n = 7) (median 1.0 vs. 0.0, p = 0.02; 7.0 vs. 3.0, p = 0.02, respectively). Hypogammaglobulinemia did not impact overall or event-free survival. Further studies are needed to elucidate the etiology of hypogammaglobulinemia and to establish criteria for immunoglobulin replacement in these patients.

The Natural History of Untreated Primary Hypogammaglobulinemia in Adults: Implications for the Diagnosis and Treatment of Common Variable Immunodeficiency Disorders (CVID).

Background: Adults with primary hypogammaglobulinemia are frequently encountered by clinicians. Where IgG levels are markedly decreased, most patients are treated with subcutaneous or intravenous immunoglobulin (SCIG/IVIG), because of the presumed risk of severe infections. The natural history of untreated severe asymptomatic hypogammaglobulinemia is thus unknown. Similarly, there are no long-term prospective studies examining the natural history of patients with moderate reductions in IgG.Methods: In 2006, we began a prospective cohort study of patients with symptomatic and asymptomatic reductions in IgG who were not immediately commenced on SCIG/IVIG. Over the course of 12 years, 120 patients were enrolled in the NZ hypogammaglobulinemia study (NZHS) including 59 who were asymptomatic.Results: Five patients with profound primary hypogammaglobulinemia (IgG < 3 g/l), who were not on regular SCIG/IVIG have remained well for a mean duration of 139 months. This study has also shown most asymptomatic patients with moderate hypogammaglobulinemia (IgG 3.0–6.9 g/l) have been in good health for a mean observation period of 96 months. We have only identified one asymptomatic patient with moderate hypogammaglobulinemia who experienced progressive decline in IgG levels to <3 g/l and was accepted for IVIG replacement. Prospective monitoring has shown that none have suffered catastrophic infections or any of the severe autoimmune or inflammatory sequelae associated with Common Variable Immunodeficiency Disorders (CVID). Unexpectedly, 18.1% of asymptomatic and 41.6% of symptomatic hypogammaglobulinemic patients spontaneously increased their IgG into the normal range (≥7.0 g/l) on at least one occasion, which we have termed transient hypogammaglobulinemia of adulthood (THA). In this study, vaccine challenge responses have correlated poorly with symptomatic state and long-term prognosis including subsequent SCIG/IVIG treatment.Conclusions: In spite of our favorable experience, we recommend patients with severe asymptomatic hypogammaglobulinemia are treated with SCIG/IVIG because of the potential risk of severe infections. Patients with moderate asymptomatic hypogammaglobulinemia have a good prognosis. Patients with symptomatic hypogammaglobulinemia are a heterogeneous group where some progress to SCIG/IVIG replacement, while many others spontaneously recover. This study has implications for the diagnosis and treatment of CVID.

An X-Linked Hyper-IgM Patient Followed Successfully for 23 Years without Hematopoietic Stem Cell Transplantation

When caring for patients with life-limiting diseases, improving survival and optimizing quality of life are the primary goals. For patients with X-linked hyper-IgM syndrome (XHIGM), the treatment modality has to be decided for a particular patient regarding hematopoietic stem cell transplantation or intravenous immunoglobulin replacement therapy with P. jiroveci prophylaxis. A seven-year-old male patient was admitted with recurrent upper and lower respiratory tract infections and recurrent otitis media. His initial immunologic evaluation revealed low IgG and normal IgA and IgM levels with normal lymphocyte phenotyping and inadequate specific antibody responses. He was diagnosed as common variable immunodeficiency and began to receive intravenous immunoglobulin (IVIG) (0.5 gm/kg) with four-week intervals. During follow-up for 23 years under IVIG therapy, he was extremely well and never had severe infections. In 2017, targeted next generation sequencing was performed in order to understand his molecular pathology. A previously described hemizygous c.31C>T(p.Arg11Ter) mutation was found in CD40LG gene. The mother was heterozygous carrier for this mutation and his sister did not have any mutation. Flow cytometric analysis for CD40LG expression on activated T cells showed highly decreased, but not absent, CD40LG expression. In conclusion, diagnostic delay is a clinical problem for patients with CD40LG deficiency, because of low or normal IgM levels, showing that all the hypogammaglobulinemic patients, not only with high serum IgM levels, but also with normal to low IgM levels, have to be examined for CD40LG expression on activated T lymphocytes. Secondly, type of CD40LG mutations leads to enormous interpatient variations regarding serum IgM levels, CD40LG levels on activated T cells, age at diagnosis, severity of clinical findings, and follow-up therapies with or without hematopoietic stem cell therapy.

BRWD1 orchestrates epigenetic landscape of late B lymphopoiesis

Transcription factor (TF) networks determine cell fate in hematopoiesis. However, how TFs cooperate with other regulatory mechanisms to instruct transcription remains poorly understood. Here we show that in small pre-B cells, the lineage restricted epigenetic reader BRWD1 closes early development enhancers and opens the enhancers of late B lymphopoiesis to TF binding. BRWD1 regulates over 7000 genes to repress proliferative and induce differentiation programs. However, BRWD1 does not regulate the expression of TFs required for B lymphopoiesis. Hypogammaglobulinemia patients with BRWD1 mutations have B-cell transcriptional profiles and enhancer landscapes similar to those observed in Brwd1-/- mice. These data indicate that, in both mice and humans, BRWD1 is a master orchestrator of enhancer accessibility that cooperates with TF networks to drive late B-cell development.

Effectiveness of immunoglobulin prophylaxis in reducing clinical complications of hematopoietic stem cell transplantation: a systematic review and meta-analysis.

Prophylactic immunoglobulin has been used with varying efficacy to reduce complications in hematopoietic stem cell transplant recipients. A systematic review and meta-analysis was conducted of randomized controlled trials that assessed clinical outcomes (overall survival, transplant-related mortality, graft-versus-host disease [GVHD], veno-occlusive disease [VOD], interstitial pneumonitis, disease relapse, cytomegalovirus [CMV] infection and disease, non-CMV infection) of immunoglobulin prophylaxis versus placebo in hematopoietic stem cell transplant recipients. MEDLINE, EMBASE, EBM Reviews, and the Cochrane Central Register of Controlled Trials were searched up to June 2017. Quality of included studies and outcomes were evaluated via Risk of Bias assessment and Grading of Recommendations, Assessment, Development and Evaluation criteria, respectively. Of 899 citations screened, 27 studies (n = 3934) were included. Immunoglobulin prophylaxis had no impact on survival (risk ratio [RR], 0.94; 95% confidence interval [CI], 0.88-1.01; 11 studies, n = 1962) but decreased risk of acute GVHD (RR, 0.78; 95% CI, 0.65-0.94; eight studies, n = 1097) and CMV disease (RR, 0.52; 95% CI, 0.28-0.97; two studies, n = 167). Meta-analysis revealed increased risk of VOD (RR, 3.04; 95% CI, 1.10-8.41; three studies, n = 384) and disease relapse (RR, 1.26; 95% CI, 1.07-1.49; seven studies, n = 1647). Other outcomes were small in sample size or nonsignificant. Results should be interpreted cautiously given the low quality of studies and evidence of outcomes. Immunoglobulin prophylaxis did not have a significant effect on survival. Positive clinical effects were shown for acute GVHD and CMV disease and negative effects against VOD and disease relapse. No studies examined the effect of immunoglobulin treatment in hypogammaglobulinemic patients despite current guidelines, warranting further studies in this population.

Prevalence of Hypogammaglobulinemia in Adult Invasive Pneumococcal Disease.

Patients with humoral immune deficiency are susceptible to invasive pneumococcal disease (IPD). This study estimates the prevalence of underlying hypogammaglobulinemia in admitted IPD cases and examines whether IPD cases had received preventative treatment. All adult IPD cases (Streptococcus pneumoniae in blood or cerebrospinal fluid) admitted to The Ottawa Hospital (TOH) from January 2013 to December 2015 were identified through the Eastern Ontario Regional Laboratory. Documented clinical demographics, S. pneumoniae serotype, serum immunoglobulins measured previously or in convalescence, and vaccination status of the cases were collected retrospectively for descriptive analyses. There were 134 IPD in 133 patients (47.4% male; mean age 63, standard deviation [SD] = 15.6 years) during a 3-year observation period. All-cause mortality rate was 22.6% over a mean follow-up time of 362, SD = 345 days. Fifty-seven patients (42.9%) had serum immunoglobulin levels measured. Eighteen were either found to have hypogammaglobulinemia in convalescence (8/18) or previously known to have hypogammaglobulinemia (10/18). None of the known hypogammaglobulinemic patients had received antibiotic prophylaxis and/or immunoglobulin replacement therapy within 4 months prior to IPD. The high and low estimates of prevalence of hypogammaglobulinemia were 31.6% (of all measured) and 13.5% (of all cases). Among 18 patients with hematological malignancies in our cohort, 13 had hypogammaglobulinemia. Many isolates were vaccine serotypes; however, only 8 had documented previous pneumococcal vaccination. IPD has high mortality, and hypogammaglobulinemia was present in at least 13.5% of IPD cases. Secondary hypogammaglobulinemia is especially common in cases with hematological malignancy and IPD.

Ureaplasma urealyticum necrotizing soft tissue infection

Ureaplasma urealyticum is a urogenital commensal and often associated with localised infection. With the advent of monoclonal immunosuppressive therapy and improved diagnostic methods, reports of non-urogenital infections are accumulating. We report a rare case of U.urealyticum necrotizing soft tissue infection and left hip septic arthritis in a hypogammaglobulinaemic patient. Consideration of this organism as an etiological agent, and potential early use of nucleic-acid diagnostic investigation with empiric therapy including activity against Ureaplasma in this patient population may be warranted.

Pulmonary complications in primary hypogammaglobulinemia: a survey by high resolution CT scan

Primary hypogammaglobulinemia disorders are a group of heterogeneous immunodeficiency syndromes with an increased susceptibility to pulmonary complications. The aim of this study was to evaluate the extent of lung abnormalities in primary hypogammaglobulinaemic patients by high resolution computed tomography (HRCT) scan and pulmonary function test (PFT). HRCT and PFT were performed in 22 Iranian patients with primary hypogammaglobulinemia. Pathological bronchial findings were observed in thirteen patients: three patients showed only peribronchial thickening and the remaining ten patients suffered from both bronchiectasis and peribronchial wall thickening. Mild type of bronchiectasis and peribronchial wall thickening were the most common type, predominantly observed in the right middle and both right and left lower lobe segments of lungs. Although bullae were not found, emphysema, air-trapping, and collapse/consolidation were observed in two patients. Bronchial involvement was mostly limited to 1 up to 5 bronchopulmonary segments; only one HRCT indicated bronchial involvement in more than nine bronchopulmonary segments. Pathological bronchial findings mostly observed in the proximal bronchi; meanwhile the involvement of the distal bronchi was less common. Decreasing FEVI and FVC were observed in 65% and 55% of patients, respectively. There was a significant correlation between the HRCT score and the predicted values by PFT. The delay of diagnosis in patients with bronchiectasis was significantly higher than those without bronchiectasis. It seems that the majority of hypogammaglobulinaemic patients suffer from the mild type of bronchiectasis, which is mostly observed in the proximal bronchi of the lower lobe segments. The delay of diagnosis plays an important role in the occurrence of this complication in these patients.