Immunoglobulin Supplementation Research Articles

COVID-19 in patients with Good syndrome: report of 4 cases and literature review

Objective: To summarize the clinical characteristics of coronavirus disease 2019 (COVID-19) in patients with Good's syndrome. Methods: We included all cases of COVID-19 in patients with Good's syndrome in the Second Xiangya Hospital of Central South University from January 1, 2023 to August 31, 2023. In addition to our cases, we searched the published literature in Wanfang database and PubMed database using the keywords "Good's syndrome" and "COVID-19". The clinical characteristics, treatment and outcome of the patients were summarized and analyzed. Results: A total of four patients with Good's syndrome complicated by COVID-19 were identified in our hospital, all of them were male, and the days of hospitalization were 17, 23, 7, and 13 days, respectively. Databases were searched for a total of six patients with Good's syndrome complicated by COVID-19, including three females and three males, all foreign patients, with hospitalization days of 12, 22, 13, 25, 21, and 34 days respectively. All ten patients met the diagnostic criteria for severe or critical COVID-19, and three(all middle-aged males) of them died, two from sepsis and one from respiratory failure. They were. Conclusion: COVID-19 in patients with Good's syndrome are prone to develop severe or critical disease and are more likely to be infected with multiple pathogens. Timely immunoglobulin supplementation is the key to treatment.

Long-Term Clinical Outcomes and B Cell Immune Reconstitution Following Allo-HCT With Prophylactic, Post-Transplant Rituximab

BackgroundChronic graft-versus-host disease (cGVHD) remains a significant source of morbidity and mortality following allogeneic hematopoietic cell transplantation (HCT). Post-transplant, prophylactic rituximab has successfully decreased cGHVD rates in clinical trials, but the durability of this strategy is uncertain. The long-terms effect of post-HCT B cell depletion on immune reconstitution, B cell function, and infectious complications are also unknown. ObjectiveIn this study, we provide 10 year follow-up and correlative analyses on patients given post-HCT, prophylactic rituximab. The objective of the study is to examine the durability of cGVHD protection as well as the long-term effect of rituximab prophylaxis on protective immune reconstitution, B cell function, and alloantibody formation. Study DesignWe analyzed 35 patients given prophylactic rituximab on phase II clinical trial. Clinical outcomes included cGVHD development, relapse and survival outcomes, and infectious outcomes. Correlative analyses included B cell subset analysis, development of antibodies to infectious antigens, and, for male patients receiving female donor grafts, development of antibodies to HY antigens. To further investigate the effect of rituximab on immune reconstitution and function, we also analyzed 43 similarly transplanted patients who did not receive post- or peri-HCT rituximab as a comparator group. ResultsFor patients who received rituximab, the 8-year cumulative incidence of cGHVD and freedom from immunosuppression were 20.0% and 76.2%, respectively. Importantly, no late incidences of cGVHD developed beyond 14 months post-HCT. Relative to patients who did not receive rituximab, post-HCT rituximab was associated with increased B cell aplasia at 1 year post-HCT (42.9% vs 11% of patients, p = 0.037); by 3 years post-HCT, this aplasia resolved. Patients who received rituximab also had a significantly lower proportion of IgD+/CD38+ transitional B cells at 3 years post-HCT (78.8% vs 89.9%, p = 0.039); at 10 years post-HCT, this percentage remained markedly decreased at 50.7%. Rituximab prophylaxis altered B cell function. In male patients receiving female donor grafts, fewer patients developed HY antibodies at 3 years post-HCT (20% vs 78%, p = 0.04). At 10 years post-HCT, HY antibody production remained decreased at 33%. Rituximab prophylaxis was also associated with significantly lower antibody response to tetanus and EBV infectious antigens as well as lower IgG levels. Despite these changes, post-HCT was not associated with increased infections, although patients who received rituximab required intravenous immunoglobulin (IVIG) supplementation more frequently than those who did not (62.9% vs 32.6% of patients, p = 0.01). ConclusionsPrior data on the efficacy and feasibility of rituximab prophylaxis are durable, with persistent reduction in cGVHD. Rituximab prophylaxis also results in lasting B cell immunologic changes, with altered B cell subset composition and decreased alloantibody formation. Associated infectious risks were not increased, perhaps mitigated by high IVIG use.

Teclistamab impairs humoral immunity in patients with heavily pretreated myeloma: importance of immunoglobulin supplementation

AbstractTeclistamab and other B-cell maturation antigen (BCMA)–targeting bispecific antibodies (BsAbs) have substantial activity in patients with heavily pretreated multiple myeloma (MM) but are associated with a high rate of infections. BCMA is also expressed on normal plasma cells and mature B cells, which are essential for the generation of a humoral immune response. The aim of this study was to improve the understanding of the impact of BCMA-targeting BsAbs on humoral immunity. The impact of teclistamab on polyclonal immunoglobulins and B cell counts was evaluated in patients with MM who received once-weekly teclistamab 1.5 mg/kg subcutaneously. Vaccination responses were assessed in a subset of patients. Teclistamabinduced rapid depletion of peripheral blood B cells in patients with MM and eliminated normal plasma cells in ex vivo assays. In addition, teclistamab reduced the levels of polyclonal immunoglobulins (immunoglobulin G [IgG], IgA, IgE, and IgM), without recovery over time while receiving teclistamab therapy. Furthermore, response to vaccines against Streptococcus pneumoniae, Haemophilus influenzae type B, and severe acute respiratory syndrome coronavirus 2 was severely impaired in patients treated with teclistamab compared with vaccination responses observed in patients with newly diagnosed MM or relapsed/refractory MM. Intravenous immunoglobulin (IVIG) use was associated with a significantly lower risk of serious infections among patients treated with teclistamab (cumulative incidence of infections at 6 months: 5.3% with IVIG vs 54.8% with observation only [P < .001]). In conclusion, our data show severe defects in humoral immunity induced by teclistamab, the impact of which can be mitigated by the use of immunoglobulin supplementation. This trial was registered at www.ClinicalTrials.gov as #NCT04557098.

Analysis of vaccine responses after anti-CD20 maintenance in B-cell lymphoma in the Balearic Islands. A single reference center experience.

The use of maintenance approaches with anti-CD20 monoclonal antibodies has improved the outcomes of B-cell indolent lymphomas but may lead to significant peripheral B-cell depletion. This depletion can potentially hinder the serological response to neoantigens. Our objective was to analyze the effect of anti-CD20 maintenance therapy in a reliable model of response to neoantigens: SARS-CoV-2 vaccine responses and the incidence/severity ofCOVID-19 in a reference hospital. In our series (n=118), the rate of vaccination failures was 31%. Through ROC curve analysis, we determined a cutoff for SARS-CoV-2 vaccine serologic response at 24 months from the last anti-CD20 dose. The risk of severe COVID-19 was notably higher within the first 24months following the last anti-CD20 dose (52%) compared to after this period (just 18%) (p=0.007). In our survival analysis, neither vaccine response nor hypogammaglobulinemia significantly affected OS. While COVID-19 led to a modest mortality rate of 2.5%, this figure was comparable to the OS reported in the general immunocompetent population. However, most patients with hypogammaglobulinemia received intravenous immunoglobulin therapy and all were vaccinated. In conclusion, anti-CD20 maintenance therapy impairs serological responses to SARS-CoV-2 vaccines. We report for the first time that patients during maintenance therapy and up to 24 months after the last anti-CD20 dose are at a higher risk of vaccine failure and more severe cases of COVID-19. Nevertheless, with close monitoring, intravenous immunoglobulin supplementation or proper vaccination, the impact on survival due to the lack of serological response in this high-risk population can be mitigated, allowing for the benefits of anti-CD20 maintenance therapy, even in the presence of hypogammaglobulinemia.

Serum-derived bovine immunoglobulin/protein isolate binds to various opportunistic microbes along with associated virulence factors

The gut microbiome consists of a complex population of bacteria, fungi, and viruses that aid the host in various physiological functions. When the microbiota is imbalanced, known as dysbiosis, symbiotic microbes can become opportunistic and excrete virulence factors that decrease intestinal barrier function, causing chronic inflammation that leads to disease. Therefore, maintaining gut microbiome balance is critical to overall health. Endogenous immunoglobulins play a positive role in gut homeostasis and immunoglobulin supplements can assist the body with microbiome maintenance. Serum-derived bovine immunoglobulin/protein isolate (SBI), a spray-dried protein powder enriched in immunoglobulins (IgG, IgA, IgM), is clinically proven to help manage loose and frequent stools associated with gastrointestinal enteropathies. A previous study used an in vitro cell culture model to show that SBI binds and neutralizes pattern-associated molecular patterns by steric/immune exclusion mechanisms. The goal of our study is to expand the list of antigens to which SBI binds. We hypothesize the IgG in SBI binds additional opportunistic microbes found in the gut and their associated virulence factors. Heliobacter pylori ( H. pylori), Shigella dysenteriae, Escherichia coli ( E. coli), and Candida albicans ( C. albicans) are common microbes associated with human gastroenteropathies. Therefore, we initially tested the binding of SBI to H. pylori lysate, H. pylori cytotoxicity-associated immunodominant antigen (CagA), Shiga toxin type-1 (Stx1), E. coli cytolethal distending toxin (CDT), C. albicans lysate, and C. albicans agglutinin-like protein 3 (Als3) by a dot blot method. SBI demonstrated binding to all antigens except the H. pylori lysate. To validate specificity of IgG, further binding studies were completed using a modified ELISA. The absorbance of IgG bound to immobilized antigens increased proportionally to SBI concentration (CagA R 2 =0.98, Stx1 R 2 =0.97, CDT subunit A R 2 =0.99, CDT subunit C R 2 =0.99, C. albicans lysate R 2 =0.99, and Als3 R 2 =0.99). Control experiments verified effective blocking, non-specific binding, and functionality (denatured SBI), as no significant absorbance was measured for any antigen tested. Together, the dot blot and modified ELISA showed the IgG in SBI was found to bind to a variety of opportunistic microbes and their associated virulence factors, including CagA, Stx1, CDT subunit A, CDT subunit C, C. albicans lysate, and Als3. Future work will examine if IgG binding can promote gut microbiome balance. Proliant Health and Biologicals This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

A study to assess the etiology, risk factors, distribution, characteristics and outcome of multisystem inflammatory syndrome in children in Hadoti region of Rajasthan

Background: Aim and objectives of the study was to assess the etiology, risk factors, distribution, characteristics and outcome of multisystem inflammatory syndrome in children (MIS-C) in Hadoti region of Rajasthan.Methods: A cross-sectional study was conducted, based on notified suspected cases of MIS-C with COVID-19. The records were then classified according to the definition of a ‘confirmed case. Treatment was also recorded immunoglobulin, antibiotics, corticoid, anticoagulant and oxygen supplementation. The outcome of the subjects was also recorded.Results: Majority of the subjects belonged to 1-6 years (56.6%) with 62.3% males and 37.7% females. Fever, rashes, cough, vomiting, abdominal pain, throat pain, hematuria and decreased appetite was present among 100.0%, 47.2%, 37.7%, 39.6%, 22.6%, 15.1%, 13.2% and 3.8% respectively. C-reactive protein, D-dimer, erythrocyte sedimentation rate (ESR), ferritin and lactate dehydrogenase (LDH) were present among 94.3%, 92.5%, 88.7%, 75.5% and 60.4% respectively. Discharge against medical advice (DAMA) was done for 5.7%, death among 7.5%, discharge among 84.9% and 1.9% were referred to higher centre.Conclusions: The risk of mortality was greater in MIS-C patients in LMICs despite reduced rates of ICU hospitalisation and use of mechanical ventilation. For the causation, ideal preventative and treatment strategies, and long-term results of the MIS-C patients, further proof is required.

P142 Inflammatory bowel diseases associated with primary immunodeficiency: a multicenter study

Abstract Background Inflammatory bowel diseases (IBD) associated with primary immunodeficiency (PID) remain poorly known. We aimed to isolate characteristics of IBD associated with PID. Methods Using a GETAID register, we reviewed medical files of recorded patients with PID and IBD (Crohn’s disease, ulcerative colitis (UC) or microscopic colitis) followed in 9 adult university hospitals. Results of genetic investigations were available for 46 patients (62%). Results 74 patients (30 F, 44M) were included with a mean age of 26 years (median: 24 years) at diagnosis of IBD. Forty-four (59%) patients had Crohn’s disease with anoperineal lesions in 12, 26(35%) patients had microscopic (mainly lymphocytic) colitis and 4 patients had UC. PID was predominantly antibody deficiency in 40(54%) patients [34 common variable immunodeficiency, 4 X-linked agammaglobulinemia, 2 selective IgA deficiencies], disease of immune dysregulation in 18(24%) patients [CTLA4, LRBA, NFKB1, TNFAi3, XIAP deficiencies, STAT3 and STAT1 hyperactivation], phagocytosis deficiency in 15(20%) patients (12 chronic granulomatous diseases (CGD), 3 congenital neutropenia] and C1s deficiency (n=1). In order of frequency, Crohn’s disease was associated with antibody deficiencies (52%), phagocytosis deficiencies (29%) and immune dysregulation (18%), microscopic colitis with antibody deficiencies (65%), immune dysregulation (27%) and more rarely with phagocytosis deficiencies (8%) and UC with antibody deficiencies (75%) and immune dysregulation (25%). 46% of patients received immunoglobulin supplementation, 70% steroids, equally corticosteroids and budesonide, 49% biotherapy mainly anti-TNF-alpha antibody (38%) and ustekinumab (16%), 23% immunosuppressive drugs, mainly azathioprine and sirolimus and 18% aminosalicylates. Three patients (2 CGD, 1 XIAP) had been treated with allogeneic stem cell transplantation (SCT) and one patient (TNFRS13B deficiency) with autologous SCT. Eleven (15%) patients had intestinal surgery, mainly ileocecal resection. During follow-up [mean: 16 years], 51% of patients had transient or sustained clinical remission mainly with an anti-TNF-alpha antibody, ustekinumab, steroids (budesonide) and specific therapy (targeted therapy such as abatacept and ASCT), 41% of patients had severe infections, 22% developed neoplasia mainly gastrointestinal dysplasia and/or cancers (n=8), B cell lymphoma (n=3) and 4 patients died. Conclusion At adulthood in our series, IBD associated with PID are mainly Crohn’s disease and lymphocytic colitis. The first most frequent associated PID is antibody deficiency. Biotherapies (anti-TNF-alpha antibody, ustekinumab), steroids and specific therapies are commonly used to induce clinical remission.

Hypogammaglobulinemia as a Predictive Factor of Postoperative Complications in Pediatric Cardiac Surgery

Hypogammaglobulinemia, developed as a result of cardiac surgery accompanied by cardiopulmonary bypass (CPB), may be caused by hemodilution, destruction of immunoglobulin, extravasation into the interstitial space related to systemic inflammation, and capillary leak syndrome. Therefore, to address this gap, we analyzed the characteristics of the infants who developed hypogammaglobulinemia after cardiac surgery and could benefit from Immunoglobulin supplementation. Methods: This is a retrospective study evaluating infants undergoing surgery for repair of congenital heart defects from October 1, 2019 to June 30th, 2020 in the neonatal unit of our institution. Due to its retrospective design, informed consent was not required. Patients were divided in two groups: Group 1 (IgG &gt;= 340mg/dL) and Group 2 (IgG &lt; 340mg/dL). The value cut point was defined taking into consideration p10 level of Immunoglobulin according to Fujimura. Results: From October 1, 2019 to June 30th, 2020, 62 children were born or admitted in our neonatal unit. Among them, 19 (30%) have their IgG dosed, according to attending physician decision. Among patients with hypogammaglobulinemia, Pseudomonas sp was present in 87.5% of blood stream and/or tracheal secretion cultures. Regarding survival analysis, mortality was not different between Group 1 and 2. Conclusion: Hypogammaglobulinemia has proved to be a predictor factor of postoperative complications in pediatric cardiac surgery. However, prospective trials are needed to determine the incidence of this problem, its real impact on survival, and the appropriate therapy.

Vaccine Titers in Lymphoma Patients Receiving Chimeric Antigen Receptor T Cell Therapy

Background: While CD19 chimeric antigen receptor T cell therapy (CAR-T) therapy does not use myeloablative chemotherapy, patients with aggressive lymphoma treated with CAR-T are immunosuppressed from lymphodepletion chemotherapy, and prolonged B cell aplasia and hypogammaglobulinemia from CAR-T. The impact of CAR-T on immunologic protection from vaccine-preventable diseases (and thus the need to revaccinate) has not been formally studied. We report the vaccine titers of patients treated with CAR-T at Mayo Clinic, Rochester.Methods: We conducted a retrospective chart review of patients who received CAR-T from 9/2018 to 4/2021 for treatment of aggressive lymphoma at Mayo Clinic, Rochester. Data was collected on anti-viral and anti-bacterial titers prior to CAR-T infusion and at month 3 post CAR-T. Clinical assays for vaccine titers were used for patient assessment and threshold for clinical assays was used to define antibody titer as positive or negative.Results: In our cohort of 87 CAR-T patients, 83 (94%) patients were infused with axicabtagene ciloleucel, 4 (5%) patients received brexucabtagene autoleucel and 1 (1%) received tisagenlecleucel. Prior to CAR-T therapy, positive titer rate was highest for tetanus and lowest for Streptococcus pneumoniae (Strep PNA). Similar trends were seen whether patients had autologous stem cell transplant (ASCT) within 2 years of CAR-T (i.e. within immunization timeframe post ASCT) or not (Table 1).At 3 months post CAR-T, overall seropositivity rates were similar when compared to pre-CAR-T levels for the prior transplant and no prior transplant group. For patients who had received intravenous immunoglobulin (IVIG) supplement prophylactically (for IVIG<400 mg/dl), seropositivity rate for Strep PNA remained zero (Table 1). Among the 30 patients who received IVIG, variable rate of conversion from negative to positive titers were seen for measles (1/2, 50%), mumps (3/5, 60%), rubella (3/4, 75%), varicella-zoster (VZV, 4/4, 100%), hepatitis A (8/9, 89%) and hepatitis B (10/12, 83%).For patients who did not receive IVIG prophylaxis after CAR-T, seropositivity rate for hepatitis A and B was low. In addition, some of these patients had a loss of seropositivity for Strep PNA (2/5, 40%) and hepatitis A (1/4, 25%).Conclusion: The presence of protective vaccine titers is variable for patients receiving CAR-T therapy, regardless of recent ASCT. The loss of protective titers post CAR-T was low. The need for immunization post CAR-T may remain important regardless of transplant status prior to CAR-T. Prophylactic IVIG does not confer complete immunization protection. Optimal timing for immunization post CAR-T is probably unknown and may need to be considered earlier for patients not on prophylactic IVIG. Further study with longer follow-up is needed to inform the need for immunization and optimal timing post CAR-T. [Display omitted] DisclosuresBennani: Kymera: Other: Advisory Board; Vividion: Other: Advisory Board; Kyowa Kirin: Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Purdue Pharma: Other: Advisory Board; Verastem: Other: Advisory Board. Paludo: Karyopharm: Research Funding. Wang: LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; MorphoSys: Research Funding; Genentech: Research Funding; Novartis: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Eli Lilly: Membership on an entity's Board of Directors or advisory committees; InnoCare: Research Funding. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding. Lin: Sorrento: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Vineti: Consultancy; Juno: Consultancy; Legend: Consultancy; Gamida Cell: Consultancy; Merck: Research Funding; Bluebird Bio: Consultancy, Research Funding; Novartis: Consultancy; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding.

Long-Term Experience of Subcutaneous Immunoglobulin Therapy in Pediatric Primary Immunodeficient Patients with Low and Normal Body Weight.

The aim was to review the compliance, side effects and effectiveness of subcutaneous immunoglobulin (SCIG) supplementation in patients with primary immunodeficiencies (PID) who had previously received intravenous immunoglobulin (IVIG) therapy and subsequently switched to SCIG, as well as to compare these parameters in patients while considering body weight. Demographic data, clinical and laboratory findings, SCIG dose, and side effects of 87 patients were retrospectively obtained from patient files. In patients who first received IVIG and then SCIG, the monthly SCIG dose was calculated by multiplying the IVIG dose by 1.37. The total monthly SCIG dose was distributed via injection across three or four doses per month, thus every 7 or 10days. Of the 87 patients aged between one and 22years, 50 were male (57.5%) and 37 were female (42.5%). The serum IgG levels of the SCIG group were higher and more stable than those of the IVIG group. The number of hospitalizations and infections decreased significantly after initiation of SCIG. Thirteen patients (14.9%) had low body weight (LBW) for their age, seven of whom were male (53.8%). Serum IgG levels of the LBW cohort were significantly elevated and more stable during the SCIG period than the IVIG period. Mild, local side effects were detected in 153 administrations (3.3%) in 30 patients with normal body weight, while no local reactions were recorded in the patients with LBW. SCIG supplementation is an effective treatment for pediatric patients with PID. The preliminary data from the present study suggest that such treatment is also safe for LBW children. The numbers of patient hospitalizations and family visits to clinics were reduced, allowing our patients and their parents to live more normal lives.

Prevalence of hypogammaglobulinemia and its management with subcutaneous immunoglobulin supplementation in patients after allogeneic hematopoietic stem cell transplantation\u2014a single-center analysis

Secondary immunodeficiencies are frequently observed after allo-HSCT. The efficacy of subcutaneous IgG preparations in this population is unknown. A retrospective single-institution study involved 126 adult patients transplanted in 2012–2019 for hematological malignancies. Patients were tested every 2–3 weeks for plasma IgG concentration during the 1st year after transplantation and supplemented with facilitated subcutaneous immunoglobulin when they either had IgG concentration < 500 mg/dl or between 500 and 700 mg/dl and recurrent infection. The IgG concentration < 500 mg/dL was diagnosed in 41 patients, while 500–700 mg/dL in 25 and altogether 53 patients received IgG supplementation. The median number of IgG administrations was 2. The median time to the first IgG administration after allo-HSCT was 4.1 months, while to the next administration (if more than one was required) 53 days (prophylactic group) and 32 days (group with infections). We did not observe any significant toxicity. Two situations were associated with increased probability of meeting criteria for IgG supplementation: diagnosis of either acute lymphoblastic leukemia (ALL) or chronic lymphocytic leukemia (CLL) (83.8% versus 39.3% for other diagnosis, p = 0.000) and the systemic use of corticosteroids (64.2% versus 31.5% for patients without systemic corticosteroids, p = 0.005). Over 40% of the adult recipients may require at least incidental immunoglobulin supplementation during the first year after allo-HSCT. Low IgG concentrations are associated with inferior outcomes. The subcutaneous route of IgG administration appeared to be safe and may allow for long persistence.

Probiotic Bacillus Spores Together with Amino Acids and Immunoglobulins Exert Protective Effects on a Rat Model of Ulcerative Colitis.

In inflammatory bowel disease (IBD), experimental models have proven to be important tools for evaluating potential therapeutic agents and for investigating the mechanisms of pathogenesis. Oxidative stress and the immune response have been associated with acetic acid (AA)-induced ulcerative colitis (UC). Our study aimed to evaluate, for the first time, the ability of a spore-based probiotic and an amino acid and immunoglobulin supplement in reducing tissue damage and inflammatory responses in an experimental animal model of UC. Forty-two Wistar rats were divided into six groups, receiving 1% carboxymethylcellulose, 4% AA, MegaSporeBiotic™ (MSB; 1 × 109 colony forming units/day) and MegaMucosa™ (MM; 70 mg/100 g/day). Pretreatment with MSB or MM alone and in combination significantly lowered inflammation and reduced damage to the colonic mucosa. Pretreatment with these agents resulted in levels of proinflammatory cytokines, vascular tight junction proteins, and measures of oxidative stress similar to those reported for methylprednisolone, one of the first-line therapies for moderate to severe activity of UC. The protection was further confirmed by histologic analysis of the colon tissue. In conclusion, pretreatment with probiotic spore-forming Bacillus strains and a supplement of amino acids in combination with immunoglobulins exhibited anti-inflammatory and antioxidant effects in an AA-induced rat model of UC.

Clinical, Immunologic and Molecular Spectrum of Patients with Immunodeficiency, Centromeric Instability, and Facial Anomalies (ICF) Syndrome: A Systematic Review.

Immunodeficiency, centromeric instability and facial dysmorphism (ICF) syndrome is a rare autosomal recessive immune disorder presenting with hypogammaglobulinemia, developmental delay, and facial anomalies. The ICF type 1, type 2, type 3 and type 4 are characterized by mutations in DNMT3B, ZBTB24, CDCA7 or HELLS gene, respectively. This study aimed to present a comprehensive description of the clinical, immunologic and genetic features of patients with ICF syndrome. PubMed, Web of Science, and Scopus were searched systemically to find eligible studies. Forty-eight studies with 118 ICF patients who met the inclusion criteria were included in our study. Among these patients, 60% reported with ICF-1, 30% with ICF-2, 4% with ICF-3, and 6% with ICF-4. The four most common symptoms reported in patients with ICF syndrome were: delay in motor development, low birth weight, chronic infections, and diarrhea. Intellectual disability and preterm birth among patients with ICF-2 and failure to thrive, sepsis and fungal infections among patients with ICF-1 were also more frequent. Moreover, the median levels of all three immunoglobulins (IgA, IgG, IgM) were markedly reduced within four types of ICF syndrome. The frequency of diagnosed patients with ICF syndrome has increased. Early diagnosis of ICF is important since immunoglobulin supplementation or allogeneic stem cell transplantation can improve the disease-free survival rate.

Investigation of immunoglobulin (IgE, IgA, IgG, IgM) concentrations in calves naturally infected with coccidiosis

The aim of this study was to determine immunoglobulin (IgA), immunoglobulin (IgE), immunoglobulin (IgG) and immunoglobulin (IgM) levels of calves naturally infected with coccidiosis and to determine the relationship between infection and calf immunity. The material of this study consisted of 30 calves (21-44 days old) which were brought to clinics of Van Yuzuncu Yil University, Faculty of Veterinary Medicine, of which 20 calves that were diagnosed as coccidiosis by detecting Eimeria spp. oocysts according to native faecal examination and 10 healthy calves as control group. For hematological and biochemical analysis, blood samples were taken from all animals from the v. jugularis before treatment. According to statistical analyses; there was a statistically significant increase in hematological parameters such as white blood cell count (WBC), hematocrit value (Hct), mean corpuscular volume (MCV), monocyte count (Mon) (P&amp;lt;0.05) and neutrophil (Neu) percentage (p&amp;lt;0.01), whereas there was a statistical decrease in lymphocyte (Lym) percentage and mean corpuscular hemoglobin concentration (MCHC) (P&amp;lt;0.05) levels. Besides, there was a significant increase in urea and creatinine (P &amp;lt;0.05) levels of calves with coccidiosis compared to control group. IgA, IgE, IgG and IgM concentrations of calves with coccidiosis were significantly lower than the control group (P &amp;lt;0.001). As a result; there was a relationship between calf immunity and the risk of infection of calves with coccidiosis. It was concluded that determining passive transfer failure levels and oral immunoglobulin supplementation to calves with passive transfer failure would reduce the risk of coccidiosis in newborn calves.

A young woman with a transfusion-related pregnancy complication.

Individuals with the K0 phenotype are extremely rare. They may develop anti-Ku antibodies, which react with all antigens of the Kell blood group system, thereby leading to haemolytic transfusion reactions and haemolytic disease of the fetus and newborn. A primigravida who was transfused with one unit of red blood cells due to iron deficiency anaemia developed anti-Ku antibodies. The pregnancy was closely monitored by ultrasound and antibody titres. Maternal autologous blood collection was performed twice during the last trimester as back-up in case of maternal peripartum bleeding, and a few frozen K0 red blood cell units were provided in case of severe fetal anaemia. At gestational week 36+6, labour was induced due to increasing antibody titres and high blood velocities in the fetal middle cerebral artery during systole. The woman was delivered vaginally without need for transfusion. The infant was diagnosed with haemolytic disease of the fetus and newborn and treated with phototherapy, repeated infusions of intravenous immunoglobulin and iron supplements until normalisation of haemoglobin at three months of age. Iron deficiency anaemia should be treated primarily with iron supplementation before considering blood transfusions, which pose the risk of developing alloantibodies that can cause transfusion complications and haemolytic disease of the fetus and newborn.

Accuracy of in-house alcohol-dissolved wheat extract for diagnosing IgE-mediated wheat allergy.

The standard method for diagnosing immediate wheat allergy is oral food challenge test (OFC). However, OFC can provoke anaphylaxis during the challenge process. Skin prick test (SPT) using commercial wheat extract yielded unsatisfactory result for diagnosis of wheat allergy. As a result, an in-house, alcohol-dissolved (Coca-10% EtOH) wheat extract was developed to improve accuracy of the SPT. To determine the accuracy of in-house, alcohol-dissolved wheat extract in children with immediate wheat allergy. This prospective cross-sectional study included children with history of immediate reaction after wheat ingestion. SPTs with commercial and in-house Coca-10% EtOH wheat extract were performed and wheat and omega-5 (ω-5) gliadin specific IgE (sIgE) were measured. Patients with no history of recent anaphylaxis after wheat ingestion underwent OFC with 31 grams of wheat flour. Thirty children were recruited. Thirteen of those had history of anaphylaxis after wheat ingestion. Eleven of the remaining 17 children (64.7%) had a positive result for wheat challenge test. Wheal size of 3 mm for both in-house and commercial wheat extract yielded the best accuracy for the test. Using these cutoff parameters, in-house Coca-10% EtOH wheat extract yielded 91.7% sensitivity, 66.7% specificity, and 86.7% accuracy. Comparatively, the commercial extract yielded 70.8% sensitivity, 100% specificity, and 76.6% accuracy. SPT using in-house Coca-10% EtOH wheat extract yielded better accuracy than commercial extract for diagnosing immediate type wheat allergy in children.

Total absence of the pericardium associated with hypogammaglobulinemia and bronchiectasis in a girl.

We report the case of an 8-years-old girl with recurrent pulmonary infections and wheezing since infancy, in whom asthma and immunoglobulin-G deficiency were diagnosed at the age of 7 months. Since then, the patient was treated for asthma without any satisfactory control of the disease. Cardiomegaly was finally diagnosed radiologically that led to cardiac assessment. Echocardiography suggested left sided partial anomalous pulmonary venous return that was not confirmed at angio-computed tomography scan and cardiac magnetic resonance imaging. Instead, total absence of the pericardium with relative left lung hypoplasia and left-sided bronchiectasis was diagnosed. Immune defect was confirmed. Adequate treatment by immunoglobulin supplementation and observance of the recommended care of bronchiectasis allowed favorable evolution. This case of an unusual association between an exceptional pericardial malformation and immune deficiency causing lower respiratory tract infections complicated by leftsided bronchiectasis highlights the absolute necessity to explore further any child with insufficient asthma control.

Immune Reconstitution and Long-Term Outcomes Following Allo-HCT with TLI-ATG and Post-Transplant Rituximab

Post-transplant, prophylactic rituximab has been associated with low incidence of chronic graft-versus host disease (cGVHD) by significantly reducing B-cell allogeneic immunity. However, the long-term effects of B-cell depletion on immune reconstitution and the long-term overall survival (OS) and incidence of cGVHD remain unknown. We describe 35 patients with mantle cell lymphoma (MCL; n = 13) or high-risk chronic lymphocytic leukemia (CLL; n = 22) treated with allogeneic hematopoietic cell transplantation (HCT) with total lymphocyte irradiation/anti-thymocyte globumin (TLI-ATG) conditioning and prophylactic rituximab. The median follow up time was 9.9 years. As a comparison group, we analyzed 43 patients of various histologies transplanted during the same time period who received TLI-ATG conditioning but no prophylactic rituximab. Overall survival and progression-free survival (PFS) at 8 years for CLL were 54.5% and 22.7%, respectively; for MCL patients 8-year OS and PFS were 53.8% and 23.1%, respectively. The 8-year cumulative incidence of cGHVD and freedom from immunosuppression for all patients treated with prophylactic rituximab were 22.8% and 65.7%, respectively, compared to 34.9% and 48.8% for the comparison group. To assess B-cell alloimmunity, we examined formation of antibodies targeting Y-chromosome encoded protein (HY Abs) in male patients receiving grafts from female donors (F à M). At 3 years post-HCT, 20% of F à M patients receiving rituximab had formed HY Abs compared to 78% of F à M patients in the comparison group (p = 0.04). At 10 year follow up, only 33% of F à M patients who received rituximab had formed HY Abs. B-cell alloimmunity was also assessed by development of antibodies to common infectious antigens. At 3 years post-HCT, patients who received rituximab had significantly lower tetanus (3.29 vs 3.74 fold, p = .017) and EBV (3.36 vs 3.76 fold; p = 0.045) titers than patients who did not. At 10-year follow up, tetanus and EBV titers patients who received rituximab had not significantly changed. Importantly, patients who received prophylactic rituximab had significantly lower IgG levels at both 3 years (498 vs 843 mg/dL, p = 0.009) and 5 years (357 vs 724 mg/dL, p = 0.041) post-HCT. For patients receiving prophylactic rituximab, at 10 years post-transplant, the median IgG was 603, and 20% of patients had IgG &lt; 400 mg/dL. More patients receiving rituximab required intravenous immunoglobulin (IVIG) supplementation than patients not receiving rituximab (62.9% vs 32.6%, p = 0.01). Of the patients who required IVIG, patients receiving rituximab did so for a longer amount of time (median duration of use 3.9 vs 0.6 years, p = 0.002). Despite decreased IgG levels, use of rituximab was not associated with a significant increase in hospitalizations for infectious etiologies or febrile neutropenia. Rituximab treatment after allogeneic transplantation provides significantly decreased incidence of chronic GVHD and reduction in B cell alloimmunity, but associates with prolonged hypogammaglobulinemia without increased infection risk. Figure Disclosures Miklos: Kite-Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; AlloGene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Precision Bioscience: Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotech: Membership on an entity's Board of Directors or advisory committees; Becton Dickinson: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees.

Lentiviral Hematopoietic Stem and Progenitor Cell Gene Therapy for Wiskott-Aldrich Syndrome (WAS): Up to 8 Years of Follow up in 17 Subjects Treated Since 2010

Lentiviral Hematopoietic Stem and Progenitor Cell Gene Therapy for Wiskott-Aldrich Syndrome (WAS): Up to 8 Years of Follow up in 17 Subjects Treated Since 2010

2016 - GENE EDITED STEM CELLS COMBINED WITH TARGETED IMMUNOTHERAPY: A NOVEL APPROACH TO TREAT MYELOID MALIGNANCIES

Despite improvements in supportive care and bone marrow transplantation, only 25% of patients diagnosed with Acute Myeloid Leukemia will survive beyond 5 years. While the emergence of targeted immunotherapy has opened new possibilities, clinical studies with chimeric antigen T-cells (CAR-T) cells have shown limited success beyond CD19-targeted immunotherapy, due to lack of unique targetable cell surface antigens and the possible management of B cell aplasia with immunoglobulin supplements. To be an ideal candidate for immunotherapy, an antigen should be unique to cancer cells, indispensable for their survival and not expressed on normal cells. Frequent expression of CD33 on AML blasts and leukemic stem cells have made it an attractive target for AML therapy. The recently reapproved anti-CD33 drug conjugate gemtuzumab ozogamicin (GO) shows promising results but leads to neutropenia and low platelets because of its off-tumor effects targeting CD33 expressed on normal cells. We have designed a novel approach combining immunotherapy targeting a lineage specific antigen expressed by cancer cells with the transplantation of hematopoietic stem cells (HSCs) lacking that lineage specific antigen. As a proof of concept, using CRISPR/Cas 9 technology, we have deleted all CD33 isoforms in human CD34+ stem cells, generating CD34+33Del human stem cells. After confirming in vivo, that the deletion of CD33 in HSCs doesn't impair their ability to engraft and to repopulate a fully functional hematopoietic system overtime, we demonstrate that leukemic humanized mice transplanted with CD34+33Del stem cells and treated with CD33-targeted immunotherapy (anti-CD33-CART cells and/or GO) show full remission and full engraftment of CD34+33- stem cells overtime. With the present study, we have demonstrated a pioneering new approach to improve targeted immunotherapies to treat blood disorders