Intravenous Immunoglobulin Replacement Research Articles

IgA nephropathy in a child with X-linked agammaglobulinemia: a case report

BackgroundX-linked agammaglobulinemia (XLA) is a primary immunodeficiency disease caused by mutations in the Bruton tyrosine kinase (BTK) gene. Individuals diagnosed with XLA are at an increased risk of developing autoimmune diseases. However, renal involvement are rare in cases of XLA.Case presentationIn this report, we discussed a specific case involving a 6-year-old boy with XLA who experienced recurrent upper respiratory tract infections since the age of one. He presented with symptoms of hematuria and proteinuria, and renal pathology confirmed the presence of immunoglobulin (Ig) A nephropathy. Treatment comprised glucocorticoids, mycophenolate mofetil, and intermittent intravenous immunoglobulin replacement therapy. Consequently, there was a remission of proteinuria and a partial improvement in hematuria.ConclusionsIn this study, we describe the first case of IgA nephropathy associated with XLA. This is an interesting phenotype found in XLA, and it provides valuable insights into the process of autoimmunity and the regulation of immune function in individuals with XLA. Based on our findings, we recommend the evaluation of immunoglobulin levels in patients diagnosed with IgA nephropathy.

Rituximab as an effective add-on maintenance therapy for disease activities in childhood-onset systemic lupus erythematosus

ObjectivesSystemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease that can result in high morbidity if not treated. This retrospective study aimed to evaluate the outcomes of rituximab treatment...

Evaluation of Clinical and Immunological Alterations Associated with ICF Syndrome.

Immunodeficiency with centromeric instability and facial anomalies (ICF) syndrome is a rare autosomal recessive combined immunodeficiency. The detailed immune responses are not explored widely. We investigated known and novel immune alterations in lymphocyte subpopulations and their association with clinical symptoms in a well-defined ICF cohort. We recruited the clinical findings from twelve ICF1 and ICF2 patients. We performed detailed immunological evaluation, including lymphocyte subset analyses, upregulation, and proliferation of T cells. We also determined the frequency of circulating T follicular helper (cTFH) and regulatory T (Treg) cells and their subtypes by flow cytometry. There were ten ICF1 and two ICF2 patients. We identified two novel homozygous missense mutations in the ZBTB24 gene. Respiratory tract infections were the most common recurrent infections among the patients. Gastrointestinal system (GIS) involvements were observed in seven patients. All patients received intravenous immunoglobulin replacement therapy and antibacterial prophylaxis; two died during the follow-up period. Immunologically, CD4+ T-cell counts, percentages of recent thymic emigrant T cells, and naive CD4+ T decreased in two, five, and four patients, respectively. Impaired T-cell proliferation and reduced CD25 upregulation were detected in all patients. These changes were more prominent in CD8+ T cells. GIS involvements negatively correlated with CD3+ T-, CD3+CD4+ T-, CD16+CD56+ NK-cell counts, and CD4+/CD8+ T-cell ratios. Further, we observed expanded cTFH cells and reduced Treg and follicular regulatory T cells with a skewing to a TH2-like phenotype in all tested subpopulations. The ICF syndrome encompasses various manifestations affecting multiple end organs. Perturbed T-cell responses with increased cTFH and decreased Treg cells may provide further insight into the immune aberrations observed in ICF syndrome.

Factors Associated with Refractoriness or Relapse after Varnimcabtagene Autoleucel (IMN-003A) in Patients with Relapsed Refractory B Cell Malignancies: Phase 2 First-in-India Industry (IMAGINE) Study

Background: Varnimcabtagene autoleucel (IMN-003A) is an anti-CD19 CAR-T cell immunotherapy for patients with relapsed refractory B cell malignancies (RR BCM) in the Phase 2 IMAGINE study. Some patients (pts) do not respond or relapse early after CD19 directed CAR-T cell therapy. This abstract reviews the factors associated with disease relapse to help improve patient outcomes and development of novel strategies. Methods: Patients (pts) aged 3 to 45 years (B-ALL) and ≥ 18 years (B-NHL) with RR BCM were eligible for IMAGINE study if they had measurable disease, as assessed by lymphoid blasts (B-ALL) or metabolic tumour bulk (B-NHL), received ≥1 prior regimen, refractory to the last line of treatment with good performance status (ECOG 0 to 1). Multiple characteristics for disease progression were reviewed (n=36) and risk stratified as: 1) Baseline parameters (age, lines of treatment, bridging therapy, cytogenetics, blasts, total metabolic tumour volume (TMTV), sum of perpendicular diameter (SPD), refractory, relapse within 6 months, laboratory parameters - haemoglobin, neutrophil count, lymphocyte count, platelet count, CRP, LDH, ferritin, baseline interleukin-6 (IL-6), baseline total T cells, CD4, and CD8 subsets in peripheral blood); 2) Apheresis parameters (total T cells, naïve / central memory in CD4 and CD8 subsets); 3) Final Product characteristics [total CAR+ cells, naïve / central memory in CD4 and CD8 subsets, CD8 (naïve & central memory subsets / tumour burden (TMTV and SPD), product doubling time] and 4) Post Infusion factors (CAR peak & persistence, B cell aplasia, hypogammaglobulinema, infections and intravenous immunoglobulin (IVIg) replacement). These parameters were analyzed using chi-square and appropriate multivariant odds ratio (OR) to examine the association with disease relapse. Results: At data cut-off, of 25 pts enrolled (median age 31 yrs, range 3 - 66) with RR BCM (n=13 B-ALL; n=12 B-NHL), 24 pts received var-cel (1 withdrawal). Median follow-up after IMN-003A administration was 205 days (range 12 - 434). Overall response rate (ORR) was 91.7% (22/24) at D+28 (B-ALL 91.7%; B-NHL 91.7%) and 80.9% (17/21) at D+90 (B-ALL 80%; B-NHL 81.8%). Median progression free survival (PFS, range 12-NR), duration of response (DOR, range 0-NR) and overall survival (OS) were not reached (range 12-NR). Treatment related mortality was 4.2% (n=1/24); 3 pts died of disease progression. Nine pts had relapsed disease (B-ALL 4; B-NHL 5; overall 37.5%; CD19+ 7 pts; CD19- 2 pts; B-ALL: CD20 variable; CD22+ n=4/4; B-NHL PDL1 n=1/5) with median PFS of 178 days (range 28-319). For relapsed pts, median duration of B cell aplasia after primary infusion was 270 days (range 70-NR); var-cel was detected in 1 pt (n=1/4) at relapse and hypogammaglobulinema (IgG <4g/L) was seen in 4 pts. For the 36 multiple parameters studied, age, high risk cytogenetics / genomic aberrations, refractoriness / early relapse <6m, blasts burden in B-ALL, absolute lymphocyte count, inflammatory markers (LDH, ferritin) and baseline T cell subsets did not show association with disease relapse. Ten variables showing some association with disease progression on univariant analysis were: SPD, baseline haemoglobin, platelets, CRP, Apheresis CD8+ T N+CM, Final Product doubling time, CAR-T dosage (B-NHL), CD8 CAR+ T N+CM (weight & dose adjusted), Post Infusion Cmax and IVIg replacement. Multivariant analysis of these parameters showed some statistical significance for following variables: Baseline Platelet count <200 x 10 9/L (overall); Final Product doubling time ≥1 day (B-ALL); baseline SPD ≥2000 mm 2, Hb <12 g/dL, Platelet count <200 x 10 9/L and post infusion IVIg replacement (B-NHL), Table1 & Figure 1. Of these variables, statistically significant association was seen with Final Product doubling time ≥1 day (B-ALL) and baseline SPD ≥2000 mm 2 with Hb <12 g/dL and Platelet count <200 x 10 9/L (B-NHL). The impact of IVIg replacement on efficacy needs further study. Conclusions: In the IMAGINE study, with ORR 80.9% at primary endpoint and median PFS not reached, relapse was seen in 37.5% pts with median PFS of 178 days. Multivariant analysis has identified factors which may predict disease relapse. Further research is needed to identify strategies such as reinfusion or CAR-T targeting a different antigen to achieve cure.

The Bengaluru Score - a Prognostic Predictive Score for Clinical Efficacy Outcomes Based on Discovery Cohort of Patients Treated with Varnimcabtagene Autoleucel (IMN-003A) in the Phase-2 (IMAGINE) Study

Background: Recurrence of disease is seen in some patients post CD19 targeted CAR-T cell therapy. There is a need to develop CAR-specific efficacy risk-classification systems as established parameters of disease relapse are not predictive. In the Phase-2 IMAGINE study, multiple variables that may predict clinical outcomes were studied and the relevant clinical, laboratory and translational information were integrated. This abstract reviews the development of the Bengaluru Score as a predictive prognostic score for clinical efficacy outcomes based on discovery cohort of patients treated with varnimcabtagene autoleucel (IMN-003A). Methods: Multiple characteristics for disease progression were reviewed (n=36) and risk stratified as: 1) Baseline parameters (age, lines of treatment, bridging therapy, cytogenetics, blasts, total metabolic tumour volume (TMTV), sum of perpendicular diameter (SPD), refractory, relapse within 6m, laboratory parameters - haemoglobin, neutrophil count, lymphocyte count, platelet count, CRP, LDH, ferritin, baseline interleukin-6 (IL-6), baseline total T cells, CD4, and CD8 subsets in peripheral blood); 2) Apheresis (total T cells, naïve / central memory in CD4 and CD8 subsets); 3) Final Product characteristics [total CAR+ cells, naïve / central memory in CD4 and CD8 subsets, CD8 (naïve & central memory subsets / tumour burden (TMTV and SPD), product doubling time] and 4) Post Infusion (CAR peak & persistence, B cell aplasia, hypogammaglobulinemia, infections and intravenous immunoglobulin (IVIg) replacement). These parameters were analyzed using chi-square and appropriate multivariant odds ratio (OR) to examine the association with disease progression. Independent risk factors were identified and weighted score allocated for OR ≥10 to obtain a multifactorial prediction model - The Bengaluru Score. The specificity and sensitivity of this model was then studied in the discovery cohort. Results: In the IMAGINE study, with ORR 80.9% at primary endpoint (n=17/21) and median PFS not reached (range 12 to NR), relapse was seen in 37.5% (n=9/24) pts with median PFS of 178 days (range 28 to 319). Multivariant analysis of these parameters showed some statistical significance for following variables: Baseline Platelet count <200 x 10 9/L (overall); Final Product doubling time ≥1 day (B-ALL); Baseline SPD ≥2000 mm 2, Hb <12 g/dL, Platelet count <200 x 10 9/L and post infusion IVIg replacement (B-NHL), Of these variables, statistically significant association was seen with Final Product doubling time ≥1 day (B-ALL) and Baseline SPD ≥2000 mm 2 with Hb <12 g/dL and Platelet count <200 x 10 9/L (B-NHL). The impact of IVIg replacement on efficacy needs further study. A multiple factor-based prognostic score system - The Bengaluru Score was developed classifying patients into B-ALL low-risk (1 point) and high-risk (3 points) and for B-NHL low risk (<5 points) and high-risk (≥5 points), Table 1. The Bengaluru Score when applied to discovery cohort in the IMAGINE study was able to risk stratify patients for disease progression with Sensitivity, Specificity, Positive Predictive Value and Accuracy of 100.00%, 66.67%, 60.00% and 77.78% respectively (for B-ALL) and 100.00%, 100.00%, 100.00% and 100.00% respectively (for B-NHL), Table 2. Conclusions: The Bengaluru Score is probably the first predictive prognostic score for clinical efficacy outcomes and is based on multivariant statistical analysis in the discovery cohort of patients in the IMAGINE study integrating clinical, laboratory and translational data with a very high sensitivity, specificity and accuracy. The score highlights the role of overall T cell expansion in the final product for B-ALL (but not the T N+CM subsets on its own) and for B-NHL, disease burden and haematological reserve. This suggests that earlier use of varnimcabtagene autoleucel may positively influence efficacy outcome but needs to be proven in the real-world setting. The Bengaluru Score can guide informed treatment decisions and evolve clinical strategies, such as reinfusion, CAR-T targeting a different antigen or allogeneic transplant (if applicable), to reduce the risk of relapse / disease progression in high-risk patients. The Bengaluru Score needs validation in a larger cohort of patients following treatment with varnimcabtagene autoleucel and other CD19 targeted CAR-T cell therapies.

Patterns of Outpatient IVIG Use before and during the COVID Pandemic in Patients with Multiple Myeloma

Background: Infections in patients with multiple myeloma are a frequent cause of morbidity and mortality. Intravenous immunoglobulin (IVIG) replacement is a preventative strategy for infection risk reduction. The NCCN guidelines recommend IVIG therapy should be considered in the setting of recurrent serious infection and/or hypogammaglobinemia. The IMWG suggests a targeted use, limiting replacement to patients with IgG concentrations less than 400mg/dl and who have serious recurrent encapsulated bacterial infections. In this study, we sought to describe patterns of IVIG use prior to and during the COVID-19 epidemic. Methods: In this cross-section study, we sought to describe real-world patterns of outpatient IVIG use before and during the COVID-19 pandemic using the IBM MarketScan Commercial Claims and Encounters (CCAE) and Medicare Supplemental and Coordination of Benefits (COB, a.k.a. MDCR) databases. MarketScan is an administrative database of diagnostic and treatment data for more than 30 million commercially insured individuals in the United States. Patients included in this study had private insurance or were enrolled in a Medicare advantage plan. IVIG administration data was grouped by patient age, sex, geographic region, and metropolitan area defined by the Census Metropolitan Statistical Area,. Pre-pandemic time period is defined as the time prior to March 2020. Results: Our study showed changes in patterns of IVIG use with respect to patient age, sex, geographic region, and location of care delivery. A total of 12,893 patients were identified with multiple myeloma during this study period. Patients greater than age 65 made up 31.3% of the cohort. Location of IVIG administration was outpatient hospital (32.6%), Office (40.2%), Patient home (14.9%) and other (0.9%). Pre-pandemic IVIG usage rate in this cohort was 3.37 IVIG administrations per 100 patients studied compared to post-pandemic usage rate increased to 3.6 per 100 patients (p=0.038). A significant increase in utilization is noted by age with usage rate in patients over age 65 increasing from 1.96 to 2.54 (p<0.001). Prior to the pandemic, usage rate for males was 2.2 and increased to 2.51 after the pandemic (p<0.001). For females, usage rate also increased from 2.42 to 2.58 (p=0.07). Changes in utilization also occurred regionally with increased use in the Northeast and West. Usage rates in the Northeast prior to the pandemic were 2.37 compared to 3.28 IVIG administration (p<0.001). Similarly, pre-pandemic utilization rates in the West were 2.55 and increased to 3.21 (p<0.001). Usage rates were stable in the North Central region, only increasing from 2.09 to 2.15 (p=0.54). Interestingly, usage rates decreased slightly in the Southern region from 2.32 to 2.24 post pandemic (p=0.38). Metropolitan service areas saw a slight increase in utilization from 2.41 to 2.56 (p=0.06). However, non-metropolitan service areas had an increase from 2.1 to 2.56 (p<0.001). Conclusions: This study describes the variation in outpatient IVIG use by age, geographic region, sex and location of treatment before and during the COVID-19 pandemic. During the COVID-19 pandemic, there was significant uncertainty regarding optimal infection risk mitigation strategies for patients with multiple myeloma. In this real-world review of clinical practice patterns, variations in outpatient use of IVIG can be seen to vary most based on geographic region and patient age. Statistically significant increases are also seen in males and in non-metropolitan areas. Patients in regions impacted earliest and hardest by increase in COVID-19 infections saw the greatest increase in the use of IVIG while other regions saw stable or decreased utilization. Additionally, patients over age 65, who were at greatest risk for negative outcomes of COVID-19 infections saw the greatest increase in utilization compared to pre-pandemic rates. In the post pandemic time period, patients over age 65 continued to have statistically significant increased rates of utilization while patients less than age 65 also increased rates of utilization that was not statistically significantly increased. This study is limited by lack of clinical information including COVID 19 infection status and concomitant myeloma therapy. The variation in utilization of IVIG illustrates the need for prospective studies to guide its use.

Hypogammaglobulinemia and Infection Risk in Relapsed Refractory B Cell Malignancy Patients Treated with Varnimcabtagene Autoleucel (IMN-003A), a CD19-Directed Chimeric Antigen Receptor T (CAR-T) Cell Therapy, in the Phase-2 Study (IMAGINE)

Background: Varnimcabtagene autoleucel (IMN-003A) is an anti-CD19 CAR-T cell immunotherapy for patients with relapsed refractory B cell malignancies (RR BCM) in the Phase 2 IMAGINE study. Hypogammaglobinemia can result from normal CD19+ B cell depletion (on-target, off-site effect) by CD19 directed CAR-T cells. RR BCM patients (pts) are already at risk for infections due to impaired immune function, lymphodepletion preparative regimen and prior immunosuppressive therapies. Intravenous immunoglobulin (IVIg) replacement is used to reduce the risk of infections due to hypogammaglobulinemia. We report the impact of var-cel on hypogammaglobinemia, infectious complications, risk factors, IVIg usage and clinical outcomes for RR BCM patients treated in first-in-India industry study (CTRI/2022/03/041162). Methods: RR BCM pts treated with var-cel in this study were reviewed. Hypogammaglobulinemia was defined as IgG <4 g/L. Infections reported during pre-apheresis (post screening), D0 to D+28 post CAR-T infusion and beyond D+29 for study duration were analyzed. IVIg usage for hypogammaglobulinemia was at investigator discretion. Patients were monitored for infection events. RR BCM response was assessed as per NCCN (B-ALL) and IWG (B-NHL) criteria. Appropriate statistical tools were used for data analysis. Results: At data cut-off, of 25 pts enrolled (median age 31 yrs, range 3 - 66) with RR BCM (n=13 B-ALL; n=12 B-NHL), 24 pts received var-cel (1 withdrawal). Median follow-up after IMN-003A administration was 205 days (range 12 - 434). Overall response rate (ORR) was 91.7% (22/24) at D+28 (B-ALL 91.7%; B-NHL 91.7%) and 80.9% (17/21) at D+90 (B-ALL 80%; B-NHL 81.8%). Treatment related mortality was 4.2% (n=1/24); 3 pts died of disease progression. Of the 24 pts, none had hypogammaglobulinemia (IgG <4g/L) at baseline. Eleven pts (45.8%) developed hypogammaglobulinemia post var-cel infusion. Of these, 10 pts (90.9%) received prophylactic intravenous immunoglobulin (IVIg). In total, 70.8% (n=17/24) pts received IVIg infusions (Table 1). The median time to initiation of IVIg after var-cel infusion was 58 days (range 15 to 189 days). Of evaluable pts, IVIg was used in 15 of 17 (88.2%) responders at D+90 (CR / PR) vs 0 of 4 (0%) in non-responders (SD / PD) (p=0.06). 52.9% (n=9/17) pts on prophylactic IVIg reported infections. Patients who received IVIg had more infections (30 events; p=0.76). The mean number of infections with and without IVIg was 1.8 and 1.6 respectively. The median overall survival was significantly higher in pts who received IVIg prophylaxis (p=0.02). There was no difference in survival observed based on presence or absence of hypogammaglobulinemia post var-cel infusion (p=0.46). A total of 41 infections were reported in 13 pts. Of these, the incidence from screening to D-1; D0 to D+28 and beyond D+29 were 9 events (4 pts); 12 (11) and 20 (7) respectively. Bacterial, viral and fungal infections reported were 28 events (11 pts); 12 (8) and 1 (1) respectively. Bacterial infections were sepsis (n=7); urinary tract infections (n=5), respiratory (n=14) and central line (n=2). There were 12 viral events, 11 of respiratory origin and one involving conjunctiva. There was one episode of probable fungal candidemia. Stool surveillance detected 27 positive events in 13 pts. Table 2 summarizes the reported infectious organisms. There were 23 infections documented in 13 patients who did not develop hypogammaglobulinemia (median 2 infections; mean 1.8; range 1 - 6). Of 11 pts with hypogammaglobulinemia, there were 18 infections (median 3.5; mean 1.6; range 1 - 9). Complete and partial responders had more infections compared to non-responders (p = 0.05). Conclusions: This is the first-in-India report evaluating hypogammaglobulinemia and infection risk post CAR-T cell infusion. The IVIg usage and documented infections was more in responders. The safety and efficacy outcomes of varnimcabtagene autoleucel (IMN-003A) are consistent with reported outcomes of approved CD19 directed CAR-T cell therapies. The use of prophylactic IVIg, often led by individual practice, to reduce the number of infections and its impact on efficacy outcomes remains uncertain. Potential strategies to reduce infection risk may help improve outcomes.

Cytokine dysregulation despite immunoglobulin replacement therapy in common variable immunodeficiency (CVID).

Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary immunodeficiency. CVID is a heterogeneous disorder with a presumed multifactorial etiology. Intravenous or subcutaneous immunoglobulin replacement therapy (IgRT) can prevent severe infections but not underlying immune dysregulation. In this study, we evaluated the serum concentrations of proinflammatory (TNF-α, IL-1β, IL-6) and immunoregulatory cytokines (IL-10), as well as lipopolysaccharide (LPS) and soluble CD14 (sCD14) in CVID individuals with infectious only (INF-CVID), and those with additional systemic autoimmune and inflammatory disorders (NIC-CVID), and healthy donors (HD). Our results showed increased serum concentrations of TNF-α, IL-1β, IL-6, and IL-10 in both INF-CVID and NIC-CVID subjects compared to HD. However, elevations of TNF-α, IL-1β, IL-6, and IL-10 were significantly more marked in NIC-CVID than INF-CVID. Additionally, LPS concentrations were increased only in NIC-CVID but not in INF-CVID compared to HD. Circulating levels of sCD14 were significantly increased in NIC-CVID compared to both INF-CVID and HD. These findings indicate persistent cytokine dysregulation despite IgRT in individuals with CVID. Moreover, the circulating cytokine profile reveals the heterogeneity of immune dysregulation in different subgroups of CVID subjects.

Safety of Intravenous Immunoglobulin Replacement Therapy in a Group of Patients with Primary Immune Deficiency

Background Intravenous immunoglobulin (IVIG) has been used as antibody replacement therapy in primary immunodeficiency diseases for more than 50 years. Most routinely, IVIG is used in patients with predominantly antibody deficiency and combined immunodeficiency. Aim To evaluate the safety of regular intravenous immunoglobulin (IVIG) among patients with primary immunodeficiency diseases who receive IVIG as a replacement treatment. Methods Our study included 40 patients with primary immunodeficiency following up regularly in the Pediatric Allergy and Immunology Unit, Children’s Hospital, Ain Shams University, These patients were followed up for one year in order to evaluate the incidence of occurrence of adverse reactions among the patients who received IVIG monthly, Once patients with adverse reactions have been identified, the following data were taken and reviewed : a specific type of adverse reaction to IVIG; the time interval between onset of adverse reaction and beginning of IVIG infusion; IVIG preparation, dose and infusion rate; medical management done during side effects . Statistics were used to analyze and interpret the data. Results This study included 40 PID patients. They were 31 males (77.5%) and 9 females 22.5% with a male to female ratio of 3.4:1. At time of enrolment in the study, the median age was 73.5 months (14 – 218 months). In our studied population the median age of symptoms onset was 23 months (1 – 187 months), and age at diagnosis was 25 months (2-192 months). This made the diagnostic lag to have a median of 9 months (0-56 months). From our studied population only one patient (2.5%) out of the study groups developed anaphylaxis and was shifted to another brand. Conclusion IVIG is a safe drug for patients with primary antibody deficiency with minimal reported side effects.

Practise of Immunoglobulin Replacement Therapy in Primary and Secondary Immunodeficiencies: A Single Centre Experience from Malaysia.

Intravenous immunoglobulin (IVIG) replacement therapy is increasingly in demand. This study focused on the characteristics of IVIG usage and associated factors toward the frequency status of IVIG among patients in Hospital Kuala Lumpur. A retrospective cross-sectional study was performed on patients who received IVIG in Hospital Kuala Lumpur. Data were extracted from the request forms for IVIG recorded in the Pharmacy Department from January 2018 until December 2019. Chi-squared test and t-test analysis were used for statistical analysis, and a P-value of < 0.05 was considered significant. A total of 482 patients received IVIG in Hospital Kuala Lumpur. There were 243 (50.4%) females and 228 (47.3%) males with median age of the patients was 27 years old. The highest indications for IVIG among all patients were hypogammaglobulinemia and other deficiency states in 127 patients (26.3%). The most common indication for one-off treatment in adults was hypogammaglobulinemia and other deficiency states, 35%; whereas in paediatrics, it was Kawasaki disease, 20.3%. The highest indication for regular therapy among adult patients was chronic inflammatory demyelinating polyneuropathy (23.4%), while in paediatrics it was sepsis (31.1%). The clinical category was associated with the frequency status of IVIG usage in both adult and paediatric cohorts with P = 0.004 and P = 0.017, respectively. There were significant differences between the indication of one-off treatment and regular therapy among adult and paediatric patients. A national guideline on the prescription of IVIG for patients is instantly needed to help clinicians in prescribing IVIG appropriately.

Subcutaneous immunoglobulin therapy for adult patients with primary immunodeficiency disease: Qatar experience.

Subcutaneous immunoglobulin (SCIG) and intravenous immunoglobulin (IVIG) are used for the treatment of primary immunodeficiency (PIDD). SCIG is as effective as IVIG in preventing infections.1 However, SCIG has advantages over IVIG as it causes fewer systemic reactions and can be infused at home by the patient leading to improved quality of life.2 Methods: We retrospectively analyzed adult patients with PIDD who received SCIG in an Adult Allergy Clinic in Qatar. Patients who received IVIG before SCIG and are naïve to IgG replacement were included. We compared Serum IgG levels, the number of antibiotic courses received, and the number of hospital admissions one year before and one year after starting SCIG. SF36 score was used to compare health-related quality of life scores before SCIG and after one year of SCIG. Twenty patients were included in the study, of which 17 were on prior IVIG replacement, and three were naive to replacement. SCIG replacement resulted in the maintenance of serum IgG levels in those who received IVIG prior. SCIG resulted in a statistically significant reduction in the number of antibiotics prescribed and hospitalization in the naïve subgroup but no substantial change in the prior IVIG group. 6/20 patients developed side effects like injection site pain, swelling, and headache. No patients developed significant systemic side effects. 10/20 patients discontinued the SCIG therapy, four patients due to side effects, and others due to noncompliance and financial reasons. SF36 Score was compared for the five patients in IVIG prior group and showed no significant improvement in individual score but improvement in the overall score (p=0.003) Conclusions: In our experience, SCIG therapy effectively prevents recurrent infection in PIDD patients, and patients did not experience any significant systemic side effects. There is a substantial improvement in the quality of life. However, compliance continues to be a problem.

Heterozygous TCF3-Related Disease Presenting as X-linked Agammaglobulinemia Mimicry in a Male Toddler with B-cell Aplasia, Agammaglobulinemia, and Severe Neutropenia

IntroductionDisease associated with TCF3 variants are rare and associated with autosomal dominant inheritance agammaglobulinemia. Patients present with profound reduction in CD19+ cells and a block in B cell development at the common lymphoid precursor to pro–B cell phase of differentiation. Severe neutropenia is frequently described in X-linked agammaglobulinemia (XLA) patients but not yet described as a presenting finding in TCF3-related disease. Case ReportThis case describes a 13-month-old full term male with a history of reactive airway disease and recurrent infections including multiple bouts of acute otitis media, hand -foot-mouth, and viral upper respiratory illnesses who presented with fever and persistent severe neutropenia (absolute neutrophil count <100 cell/uL) necessitating hospital admission. Given his infectious history and severe neutropenia, he underwent evaluation for an underlying inborn error of immunity with the following pertinent findings: undetectable IgG (<16 mg/dL), IgM (<10 mg/dL), IgA (<2 mg/dL) and IgE (<2 kU/L), negative pneumococcal, tetanus and diphtheria vaccine titers despite vaccination, lymphocyte subsets with normal CD3, CD4, CD8, and CD16/56 absolute values but extremely low CD19 level (38 cells/cmm), and negative anti-neutrophil antibodies. Patient Bruton tyrosine kinase (Btk) protein flow cytometry results in monocytes were similar to an experimental control, while B-cell subset analysis was unable to be obtained given low B-cell numbers. Comprehensive genetic testing subsequently identified a heterozygous pathogenic TCF3 variant, c.1663G>A, p. (Glu555Lys). Following initiation of intravenous immunoglobulin (IVIG) replacement, our patient's neutropenia resolved quickly and completely. He continues to receive monthly IVIG with goal IgG troughs >800 mg/dL and resultant significant improvement in infections. ConclusionAs in XLA, our patient's severe neutropenia rapidly resolved with initiation of immunoglobulin replacement. While it has been shown that neutrophil development is somewhat dependent on the Btk protein, further study into the importance of the TCF3 protein and additionally adequate immunoglobulin levels in neutrophil expansion is needed. Finally, germline inborn errors of immunity, including TCF3 variants, should be considered in children with a history of recurrent infections and persistent neutropenia.

Thalidomide as an Effective Treatment in Sideroblastic Anemia, Immunodeficiency, Periodic Fevers, and Developmental Delay (SIFD)

PurposeSideroblastic anemia, immunodeficiency, periodic fevers, and developmental delay (SIFD) is an autosomal recessive syndrome caused by biallelic loss-of-function variant of tRNA nucleotidyl transferase 1 (TRNT1). Efficacious methods to treat SIFD are lacking. We identified two novel mutations in TRNT1 and an efficacious and novel therapy for SIFD.MethodsWe retrospectively summarized the clinical records of two patients with SIFD from different families and reviewed all published cases of SIFD.ResultsBoth patients had periodic fever, developmental delay, rash, microcytic anemia, and B cell lymphopenia with infections. Whole-exome sequencing of patient 1 identified a previously unreported homozygous mutation of TRNT1 (c.706G > A/p.Glu236Lys). He received intravenous immunoglobulin (IVIG) replacement and antibiotics, but died at 1 year of age. Gene testing in patient 2 revealed compound heterozygous mutations (c.907C > G/p.Gln303Glu and c.88A > G/p.Met30Val) in TRNT1, the former of which is a novel mutation. Periodic fever was controlled in the first month after adalimumab therapy and IVIG replacement, but recurred in the second month. Adalimumab was discontinued and replaced with thalidomide, which controlled the periodic fever and normalized inflammatory markers effectively. A retrospective analysis of reported cases revealed 69 patients with SIFD carrying 46 mutations. The male: female ratio was 1: 1, and the mean age of onset was 3.0 months. The most common clinical manifestations in patients with SIFD were microcytic anemia (82.6%), hypogammaglobulinemia/B cell lymphopenia (75.4%), periodic fever (66.7%), and developmental delay (60.0%). In addition to the typical tetralogy, SIFD features several heterogeneous symptoms involving multiple systems. Corticosteroids, immunosuppressants, and anakinra have low efficacy, whereas etanercept suppressed fever and improved anemia in reports. Bone-marrow transplantation can be used to treat severe SIFD, but carries a high risk. In total, 28.2% (20/71) of reported patients died, mainly because of multi-organ failure. Biallelic mutations located in exon1-intron5 lead to more severe phenotypes and higher mortality. Furthermore, 15.5% (11/71) patients survived to adulthood. The symptoms could be resolved spontaneously in five patients.ConclusionsThalidomide can control the inflammation of SIFD and represents a new treatment for SIFD.

XMEN DISEASE: MAGT1 MUTATION IN A CHILD WITH HYPOGAMMAGLOBULINEMIA

<h3>Introduction</h3> X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection, and neoplasia (XMEN) disease is a rare disorder caused by mutations in the MAGT1 gene, which codes for a magnesium transporter important in CD8+ T cells and their response. These cells are not activated efficiently in the setting of EBV infection, increasing the likelihood of developing lymphoma. <h3>Case Description</h3> A 9-month-old was evaluated at the hospital due to upper respiratory symptoms. Patient was born at 39 weeks and spent 16 days in NICU due to thrombocytopenia. Physical exam was remarkable for low weight. Laboratories revealed anemia, thrombocytopenia, and hypogammaglobulinemia. Lymphocyte subset panel was normal. Genetic testing showed a pathogenic hemizygous mutation in MAGT1, associated with XMEN disease. Patient was started on intravenous immunoglobulin replacement which he tolerated well. Since then, no other infections have been reported. At 3 years old, patient developed transaminitis. Abdominal ultrasound, hepatitis serology and inflammatory markers were normal. He is being evaluated by Gastroenterology. <h3>Discussion</h3> Regardless of EBV serological status, the cellular and clinical phenotype of XMEN patients is similar, implying that the virus is not responsible for the pathogenesis. Management is based on the individual clinical manifestations. Some patients may require immunoglobulin replacement or prophylactic antibiotic therapy. Recommendations include routine EBV serologies and viral load assessment and malignancy surveillance. A small, controlled trial evaluating the role of magnesium supplementation found no benefit in these patients. Given its rarity and broad spectrum of clinical presentations, there is need to increase awareness of this disease and further investigate possible therapies for these patients.

Primary antibody deficiencies represent an underestimated comorbidity in asthma patients: efficacy of immunoglobulin replacement therapy in asthma control

Objective Primary antibody deficiencies (PAD) are an underestimated comorbidity in asthma and its treatment could improve disease control. Methods a retrospective cohort of asthmatics, affected by IgG subclass deficiency or unclassified antibody deficiency and treated with low-dose intravenous immunoglobulin replacement therapy (IRT) was recruited. Demographic and clinical data, chest CT scan, blood eosinophils, atopy, chronic oral corticosteroid (OCS) therapy were evaluated at baseline. Asthma exacerbations, lower respiratory tract infections (LRTI), upper respiratory tract infections (URTI) and asthma-related hospitalizations were assessed after one and two years of IRT. Results 57 moderate-to-severe asthmatics were enrolled, mostly affected by T2 low asthma (39/57, 68.4%). After one year, IRT was effective in improving, irrespective of bronchiectasis, atopy, eosinophils and PAD type: 1) trough IgG (826.9 ± 221.3 vs 942.2 ± 195.1 mg/dl; p < 0.0001) and IgG subclasses (IgG1 355.4 ± 88.4 vs 466.7 ± 122.3, p < 0.0001; IgG2 300.1 ± 130.1 vs 347.6 ± 117.3, p < 0.0005) serum levels. 2) asthma exacerbations (6.4 ± 4.1 vs 2.4 ± 1.9, p < 0.0001), LRTI (4.3 ± 3.9 vs 1.3 ± 1.5, p < 0.0001) and hospitalization rate (0.26 ± 0.7 vs 0.05 ± 0.2, p < 0.01). These results persisted after 2 years of therapy. Estimated mean cumulative OCS exposure was reduced by 4500 mg over the 2-year period. Conclusions low-dose IRT is effective in improving asthma control and lessening OCS burden in asthmatics affected by PAD.

Critical role of diagnostic SARS-CoV-2 T cell assays for immunodeficient patients

After almost 3 years of intense study, the immunological basis of COVID-19 is better understood. Patients who suffer severe disease have a chaotic, destructive immune response. Many patients with severe...

Heterozygous Variants in the DNA-binding Domain of c-Myb May Affect Normal B/T Cell Development.

Heterozygous Variants in the DNA-binding Domain of c-Myb May Affect Normal B/T Cell Development.

Long Term Norovirus Infection in a Patient with Severe Common Variable Immunodeficiency.

Norovirus is the most common cause of acute non-bacterial gastroenteritis. Immunocompromised patients can become chronically infected, with or without symptoms. In Europe, common variable immunodeficiency (CVID) is one of the most common inborn errors of immunity. A potentially severe complication is CVID-associated enteropathy, a disorder with similar histopathology to celiac disease. Studies suggest that chronic norovirus infection may be a contributor to CVID enteropathy, and that the antiviral drug ribavirin can be effective against norovirus. Here, a patient with CVID-like disease with combined B- and T-cell deficiency, had chronic norovirus infection and enteropathy. The patient was routinely administered subcutaneous and intravenous immunoglobulin replacement therapy (SCIg and IVIg). The patient was also administered ribavirin for ~7.5 months to clear the infection. Stool samples (collected 2013–2016) and archived paraffin embedded duodenal biopsies were screened for norovirus by qPCR, confirming a chronic infection. Norovirus genotyping was done in 25 stool samples. For evolutionary analysis, the capsid (VP1) and polymerase (RdRp) genes were sequenced in 10 and 12 stool samples, respectively, collected before, during, and after ribavirin treatment. Secretor phenotyping was done in saliva, and serum was analyzed for histo-blood group antigen (HBGA) blocking titers. The chronic norovirus strain formed a unique variant subcluster, with GII.4 Den Haag [P4] variant, circulating around 2009, as the most recent common ancestor. This corresponded to the documented debut of symptoms. The patient was a secretor and had HBGA blocking titers associated with protection in immunocompetent individuals. Several unique amino acid substitutions were detected in immunodominant epitopes of VP1. However, HBGA binding sites were conserved. Ribavirin failed in treating the infection and no clear association between ribavirin-levels and quantity of norovirus shedding was observed. In conclusion, long term infection with norovirus in a patient with severe CVID led to the evolution of a unique norovirus strain with amino acid substitutions in immunodominant epitopes, but conservation within HBGA binding pockets. Regularly administered SCIg, IVIg, and ~7.5-month ribavirin treatment failed to clear the infection.

Immediate adverse events to intravenous immunoglobulin in pediatric patients with inborn errors of immunity: A longitudinal study with a pre-infusion protocol

Immunoglobulin represents the main therapy for patients with inborn errors of immunity (IEI) and it is a safe procedure, but adverse events (AEs) can occur with variable frequencies. To evaluate the frequency of immediate AEs to intravenous immunoglobulin (IVIG) regular therapy in a pediatric cohort with IEI after a pre-IVIG infusion protocol. This was a longitudinal study from 2011 to 2019 at a tertiary pediatric hospital in Brazil. A total of 1736 infusions were studied in 70 patients with IEI, 46 (65.7%) of whom were males and whose median age was 5.8 years old (range: 6 mo - 18 yo). Seven different brands of IVIG were used with the median loading dose of 0.57g/kg (range: 0.23 - 0.88g/Kg). According to the protocol, pre-medication and step-up infusion rate, were performed in 1305 (75.2%) infusions. Immediate AEs were noted in 10 children (14.3%) and in 22 (1.2%) infusions. Skin reactions (rash or urticaria) were the most common AE with 14 episodes (0.8% of all infusions). Almost all AEs were mild (19/86.4%), with no severe ones being observed. The majority of the AEs (81.8%) was identified at a 0.04ml/kg/min infusion rate. Gender, age at first infusion, presence of infection on the infusion day and change of the IVIG brand were evaluated and none of them were associated with AEs. The low frequency of immediate AEs in children with IEI highlights the safety and tolerability of intravenous immunoglobulin replacement with the procedures established at our center.

SARS-CoV-2 symptomatic reinfection among patients with primary antibody deficiency

SARS-CoV-2 symptomatic reinfection among patients with primary antibody deficiency