- Email: [email protected]
Clinical and Molecular Characterization of Autosomal Recessive Hyper IgE Syndrome in Saudi Arabia
Abstracts AB83
J ALLERGY CLIN IMMUNOL VOLUME 129, NUMBER 2
B, T, and NK Cell Antigen Expression in Patients with Common Variable Immunodeficiency S. A. Gierer1, M. Altrich2, C. Lutgen2, N. Torke2, J. D. Martinez1; 1University of Kansas Medical Center, Kansas City, MO, 2ViraCor-IBT Laboratories, Lee’s Summit, MO. RATIONALE: Common variable immunodeficiency (CVID) is often due to defects in B, T, and NK cells. Classification of CVID to assess clinical manifestations and prognostic markers has not been determined. Researchers have documented reduced numbers of memory CD27+ B cells correlate with an increased risk of complications. Other cell surface marker levels may indicate additional abnormalities. METHODS: We evaluated B, T, and NK cell surface markers by whole blood flow cytometry in patients on chronic IVIg compared to normal donors in a single-center pilot study. Approval was obtained from the University of Kansas IRB and written informed consent was obtained from all research subjects. RESULTS: We found statistically significant lower absolute median numbers of CD19+, class-switched memory, and CD19+CD27-IgD+ mature na€ıve B cells in patients with CVID on IVIg compared to normal controls with 95% confidence intervals. There was a statistically significant difference in the median percentage of CD3+ T cells, possibly relative to the decrease in B cells. There was no statistically significant difference in absolute median number of T and NK cells. CONCLUSIONS: Studies have shown reduced class switched memory B cells. We also found differences in mature na€ıve B cells and percentage of T cells. This may indicate chronic IVIG therapy does not affectrelative numbers of various B cell populations. Additionally, some of our patients have recurrent viral infections, which could not be attributed to a decrease in median absolute T or NK cell counts. We hope further research in this area will lead to screening tools for classification and prognosis.
313
Clinical and Molecular Characterization of Autosomal Recessive Hyper IgE Syndrome in Saudi Arabia Z. Alsum1, A. Hawwari1, S. Al-Hifi1, E. Borrero1, H. Khalak1, N. Ades1, O. Alsmadi1, R. Arnaout1, A. Al-Ghonaium1, S. Al-Muhsen1, H. AlDhekri1, B. Al-Saud1, H. Al-Mousa1,2; 1King Faisal Specialist Hospital and Research Center, Riyadh, SAUDI ARABIA, 2Alfaisal university, Riyadh, SAUDI ARABIA. RATIONAL: Autosomal-recessive hyper-IgE syndrome (AR-HIES) is a combined immunodeficiency characterized by susceptibility to viral infections, eczema and high serum IgE. Mutations in DOCK8 are responsible for many, though not all cases. Further characterization of clinical, immunological and molecular features may improve our understanding of its pathogenesis. METHODS: Clinical data of 25 patients diagnosed with AR-HIES were collected. Eighteen patients screened for STAT3, Tyk2 and Dock8 mutations. RESULTS: Sinopulmonary infections, dermatitis, hepatic disorders, cutaneous and systemic bacterial, fungal and viral infections were the most common clinical features. Autoimmunity, malignancies and allergies are common complications. Twelve patients died with a median age of 10 years. No consistent immunological findings. Two novel DOCK8 mutations were found in nine patients resulted in stop codons. In addition, 4 patients from two separate families were found with 2 gross deletions. In one family the deletions spanned the entire Dock8 gene and the surrounding genes. In the other family, the deletion extended from somewhere at the tip of chromosome 9 to the middle of DOCK8 gene. No mutations found in STAT3 or TYK2 genes. CONCLUSION: Autosomal recessive hyper-IgE disease is a combined immunodeficiency disease characterized by high morbidity and mortality rate. Early consideration of hematopoetic stem cell transplantation might improve the outcome. DOCK8 defect were found in 72% of patients screened. Patients with no identified genetic etiology are likely to carry mutations in the regulatory elements of genes tested or in novel genes that are yet to be discovered.
314
Safety, Tolerability, and Efficacy of Hizentra Over An Extended Period for the Treatment of Primary Immunodeficiency Disease R. P. Nelson, Jr1,2, I. Melamed3, M. R. Stein4, R. L. Wasserman5,6; 1Melvin and Bren Simon Cancer Center, Indianapolis, IN, 2Indiana University, Indianapolis, IN, 3IMMUNOe International Research Centers, Centennial, CO, 4Allergy Associates of the Palm Beaches, North Palm Beach, FL, 5Allergy/Immunology Research Center of North Texas, Dallas, TX, 6 University of Texas Southwestern Medical School, Dallas, TX. RATIONALE: Previously, a 52-week study demonstrated that 20% immune globulin (HizentraÒ, CSL Behring) administered subcutaneously to subjects with primary immunodeficiencies was associated with protection from serious bacterial infections (SBIs) and was well-tolerated. This extension study assessed longer-term (112104 wk) outcomes, including efficacy, tolerability, and health-related quality-of-life (HRQL) in 21 subjects treated at home. METHODS: Maximum infusion rates were 35 mL/h (1 pump) or 70 mL/h _4 sites/infusion). (2 pumps; maximum volume540 mL/site; < Premedication was not given. Study endpoints included: annual SBI rate; rate of any infections; days hospitalized; missed work/school/or inability to perform normal activities days due to any infection; and days of antibiotic use. HRQL and treatment satisfaction were evaluated using validated questionnaires. Local reactions were assessed by subjects 24 hours postinfusion and documented in a diary. RESULTS: The SBI rate was 0.06/subject-year (2 pneumonia cases), and total infection rate was 2.4/subject-year. Subjects were hospitalized a mean of 0.55 days/subject-year and missed work/school or were unable to perform normal activities a mean of 4.3 days/subject-year. Antibiotics were used a mean of 84 days/subject-year. Mean IgG levels were 11.7212.8 g/L. HRQL scores were consistent with US norms; treatment satisfaction remained high and stable. The local adverse reaction rate was 0.5/infusion; 99.1% were mild. Adverse event and local reaction rates were similar among subjects infused at low (<35 mL/h), medium (35250 mL/ h), and high (>50270 mL/h) rates. CONCLUSIONS: Hizentra was well-tolerated and effective over an extended period in subjects with primary immunodeficiency. Adverse event rates were similar among low, medium, and high infusion rate patients.
315
Clinical Characteristics of Adult Patients with Isolated Low IgG and Abnormal Response to Pneumovax D. F. LaRosa, C. S. Patel; Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA. RATIONALE: ESID defines possible common variable immunodeficiency to include patients with findings compatible with CVID, but with deficiency in only one antibody isotype. We considered that patients with possible common variable immune deficiency limited to the IgG isotype (PCVI-IgG) have an infection-only phenotype, rarely having autoimmune-related complications. METHODS: Records were analyzed in a retrospective cohort study, selecting subjects with the following criteria: IgG < 600 mg/dL and normal IgA and IgM, abnormal Pneumovax response, and no secondary causes of immunodeficiency. Pneumovax response was defined as positive if at least 70% of the 14 serotypes tested were at least 1 ug/mL and had a minimum 2-fold increase from pre-vaccination. RESULTS: 26 subjects were identified with mean age of 52 (range 25-72). Mean IgG was 508 mg/dL (SD 15, range 338-590); mean IgA 138 mg/dL and mean IgM 97 mg/dL. Deficiency in IgG was mostly distributed between the IgG1 and IgG2 subclasses. Responses to protein-conjugated vaccines were unimpaired, but for Pneumovax challenge, 22 of 26 responded to 6 or fewer antigen serotypes, with 2 having no response. The most common infections were chronic sinusitis and pneumonia (21 of 26) and 8 had bronchiectasis. No subjects had history of immune thrombocytopenia or hemolytic anemia; only one subject had mild splenomegaly. Fourteen were treated with IgG replacement and all reported a decreased frequency of upper respiratory tract infections. CONCLUSIONS: PCVI-IgG may represent a clinical phenotype more akin to an infection-only CVID. Infections primarily involve the upper respiratory tract. IgG replacement may be indicated to reduce respiratory tract infections.
SUNDAY
312
J ALLERGY CLIN IMMUNOL VOLUME 129, NUMBER 2
B, T, and NK Cell Antigen Expression in Patients with Common Variable Immunodeficiency S. A. Gierer1, M. Altrich2, C. Lutgen2, N. Torke2, J. D. Martinez1; 1University of Kansas Medical Center, Kansas City, MO, 2ViraCor-IBT Laboratories, Lee’s Summit, MO. RATIONALE: Common variable immunodeficiency (CVID) is often due to defects in B, T, and NK cells. Classification of CVID to assess clinical manifestations and prognostic markers has not been determined. Researchers have documented reduced numbers of memory CD27+ B cells correlate with an increased risk of complications. Other cell surface marker levels may indicate additional abnormalities. METHODS: We evaluated B, T, and NK cell surface markers by whole blood flow cytometry in patients on chronic IVIg compared to normal donors in a single-center pilot study. Approval was obtained from the University of Kansas IRB and written informed consent was obtained from all research subjects. RESULTS: We found statistically significant lower absolute median numbers of CD19+, class-switched memory, and CD19+CD27-IgD+ mature na€ıve B cells in patients with CVID on IVIg compared to normal controls with 95% confidence intervals. There was a statistically significant difference in the median percentage of CD3+ T cells, possibly relative to the decrease in B cells. There was no statistically significant difference in absolute median number of T and NK cells. CONCLUSIONS: Studies have shown reduced class switched memory B cells. We also found differences in mature na€ıve B cells and percentage of T cells. This may indicate chronic IVIG therapy does not affectrelative numbers of various B cell populations. Additionally, some of our patients have recurrent viral infections, which could not be attributed to a decrease in median absolute T or NK cell counts. We hope further research in this area will lead to screening tools for classification and prognosis.
313
Clinical and Molecular Characterization of Autosomal Recessive Hyper IgE Syndrome in Saudi Arabia Z. Alsum1, A. Hawwari1, S. Al-Hifi1, E. Borrero1, H. Khalak1, N. Ades1, O. Alsmadi1, R. Arnaout1, A. Al-Ghonaium1, S. Al-Muhsen1, H. AlDhekri1, B. Al-Saud1, H. Al-Mousa1,2; 1King Faisal Specialist Hospital and Research Center, Riyadh, SAUDI ARABIA, 2Alfaisal university, Riyadh, SAUDI ARABIA. RATIONAL: Autosomal-recessive hyper-IgE syndrome (AR-HIES) is a combined immunodeficiency characterized by susceptibility to viral infections, eczema and high serum IgE. Mutations in DOCK8 are responsible for many, though not all cases. Further characterization of clinical, immunological and molecular features may improve our understanding of its pathogenesis. METHODS: Clinical data of 25 patients diagnosed with AR-HIES were collected. Eighteen patients screened for STAT3, Tyk2 and Dock8 mutations. RESULTS: Sinopulmonary infections, dermatitis, hepatic disorders, cutaneous and systemic bacterial, fungal and viral infections were the most common clinical features. Autoimmunity, malignancies and allergies are common complications. Twelve patients died with a median age of 10 years. No consistent immunological findings. Two novel DOCK8 mutations were found in nine patients resulted in stop codons. In addition, 4 patients from two separate families were found with 2 gross deletions. In one family the deletions spanned the entire Dock8 gene and the surrounding genes. In the other family, the deletion extended from somewhere at the tip of chromosome 9 to the middle of DOCK8 gene. No mutations found in STAT3 or TYK2 genes. CONCLUSION: Autosomal recessive hyper-IgE disease is a combined immunodeficiency disease characterized by high morbidity and mortality rate. Early consideration of hematopoetic stem cell transplantation might improve the outcome. DOCK8 defect were found in 72% of patients screened. Patients with no identified genetic etiology are likely to carry mutations in the regulatory elements of genes tested or in novel genes that are yet to be discovered.
314
Safety, Tolerability, and Efficacy of Hizentra Over An Extended Period for the Treatment of Primary Immunodeficiency Disease R. P. Nelson, Jr1,2, I. Melamed3, M. R. Stein4, R. L. Wasserman5,6; 1Melvin and Bren Simon Cancer Center, Indianapolis, IN, 2Indiana University, Indianapolis, IN, 3IMMUNOe International Research Centers, Centennial, CO, 4Allergy Associates of the Palm Beaches, North Palm Beach, FL, 5Allergy/Immunology Research Center of North Texas, Dallas, TX, 6 University of Texas Southwestern Medical School, Dallas, TX. RATIONALE: Previously, a 52-week study demonstrated that 20% immune globulin (HizentraÒ, CSL Behring) administered subcutaneously to subjects with primary immunodeficiencies was associated with protection from serious bacterial infections (SBIs) and was well-tolerated. This extension study assessed longer-term (112104 wk) outcomes, including efficacy, tolerability, and health-related quality-of-life (HRQL) in 21 subjects treated at home. METHODS: Maximum infusion rates were 35 mL/h (1 pump) or 70 mL/h _4 sites/infusion). (2 pumps; maximum volume540 mL/site; < Premedication was not given. Study endpoints included: annual SBI rate; rate of any infections; days hospitalized; missed work/school/or inability to perform normal activities days due to any infection; and days of antibiotic use. HRQL and treatment satisfaction were evaluated using validated questionnaires. Local reactions were assessed by subjects 24 hours postinfusion and documented in a diary. RESULTS: The SBI rate was 0.06/subject-year (2 pneumonia cases), and total infection rate was 2.4/subject-year. Subjects were hospitalized a mean of 0.55 days/subject-year and missed work/school or were unable to perform normal activities a mean of 4.3 days/subject-year. Antibiotics were used a mean of 84 days/subject-year. Mean IgG levels were 11.7212.8 g/L. HRQL scores were consistent with US norms; treatment satisfaction remained high and stable. The local adverse reaction rate was 0.5/infusion; 99.1% were mild. Adverse event and local reaction rates were similar among subjects infused at low (<35 mL/h), medium (35250 mL/ h), and high (>50270 mL/h) rates. CONCLUSIONS: Hizentra was well-tolerated and effective over an extended period in subjects with primary immunodeficiency. Adverse event rates were similar among low, medium, and high infusion rate patients.
315
Clinical Characteristics of Adult Patients with Isolated Low IgG and Abnormal Response to Pneumovax D. F. LaRosa, C. S. Patel; Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA. RATIONALE: ESID defines possible common variable immunodeficiency to include patients with findings compatible with CVID, but with deficiency in only one antibody isotype. We considered that patients with possible common variable immune deficiency limited to the IgG isotype (PCVI-IgG) have an infection-only phenotype, rarely having autoimmune-related complications. METHODS: Records were analyzed in a retrospective cohort study, selecting subjects with the following criteria: IgG < 600 mg/dL and normal IgA and IgM, abnormal Pneumovax response, and no secondary causes of immunodeficiency. Pneumovax response was defined as positive if at least 70% of the 14 serotypes tested were at least 1 ug/mL and had a minimum 2-fold increase from pre-vaccination. RESULTS: 26 subjects were identified with mean age of 52 (range 25-72). Mean IgG was 508 mg/dL (SD 15, range 338-590); mean IgA 138 mg/dL and mean IgM 97 mg/dL. Deficiency in IgG was mostly distributed between the IgG1 and IgG2 subclasses. Responses to protein-conjugated vaccines were unimpaired, but for Pneumovax challenge, 22 of 26 responded to 6 or fewer antigen serotypes, with 2 having no response. The most common infections were chronic sinusitis and pneumonia (21 of 26) and 8 had bronchiectasis. No subjects had history of immune thrombocytopenia or hemolytic anemia; only one subject had mild splenomegaly. Fourteen were treated with IgG replacement and all reported a decreased frequency of upper respiratory tract infections. CONCLUSIONS: PCVI-IgG may represent a clinical phenotype more akin to an infection-only CVID. Infections primarily involve the upper respiratory tract. IgG replacement may be indicated to reduce respiratory tract infections.
SUNDAY
312