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Genetic-Molecular Defects in MBL-MASP Pathway and Association with Selective Immunoglobulin Deficiencies: Implications for Host Defense
S12 Abstracts
SATURDAY
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Genetic-Molecular Defects in MBL-MASP Pathway and Association with Selective Immunoglobulin Deficiencies: Implications for Host Defense G. Krishnaswamy, C. W. T. Miller, D. S. Chi; Quillen College of Medicine, Johnson City, TN. RATIONALE: Isolated immunoglobulin (Ig) deficiencies (including IgG4, IgM, and IgE) involve humoral responses and can lead to serious infections. Mannose-binding lectin (MBL) deficiency, the most common immunodeficiency in the general population, is an integral part of host immunity, with deficiency predisposing to infection. Coexistent humoral and MBL deficiency would theoretically lead to graver clinical scenarios, as MBL binds carbohydrates on the surface of immunoglobulins to provide pathways for immune complex clearance and complement activation in response to Ig-covered pathogens. We describe three patients with coincident MBL and selective Ig deficiency. METHODS: Three patients with recurrent infections were assessed for serum Ig and MBL levels. MBL and MASP-2 genotyping was performed in 2 patients (IBT Laboratories, Lenexa, KS). RESULTS: Three patients presented with recurrent chronic rhinosinusitis and bronchitis. All had normal levels of IgG. Two patients, however, had selective IgM deficiency (< 50 mg/dl) and very low MBL levels (<50 ng/mL); genotyping was performed in one patient, revealing a mutated MBL2 promoter (LXPA/LYPB, both haplotypes conferring low serum MBL) and wild-type MASP-2 (A/A). The third patient had severe IgE and IgG4 deficiencies. She had received prior intravenous immunoglobulin therapy for several years for presumed common variable immune deficiency. MBL pathway genotype analysis revealed wild type (A/A) MASP-2 and LXPA/LYPB MBL2. This patient’s IVIG infusion was discontinued. CONCLUSIONS: Patients with recurrent infections may have various combinations of primary immune deficiency, including defects in both the complement (MBL-MASP) and the humoral (Immunoglobulin) pathways. The prevalence and clinical implications of such combinations are unknown and require further study.
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Biologic IgG Level (BIgGL): One Size Does Not Fit All S. A. Siegel, D. W. Rosenthal, V. R. Bonagura; North Shore Long Island Jewish Health System, Great Neck, NY. RATIONALE: The BIgGL is the minimum serum IgG concentration that maintains primary immunodeficiency (PID) patients infection-free. This level varies and should be individualized for each patient and type of PID. METHODS: The medical records of patients with X-linked agammaglobunemia (XLA) and common variable immunodeficiency (CVID) on IVIG were reviewed. The BIgGL was determined by plotting infections vs. IgG levels over time. Target IgG levels for PID patients (AAAAI PID Committee Report) were determined, and differences between BIgGLs and target levels were calculated (DBT) and compared (GraphPad; Instat 3.01). RESULTS: BIgGL were plotted vs. infections over time (n 5 15). For XLA patients (n 5 6), mean pretreatment IgG level 5 6.5 6 3.7 mg/dL, and mean BIgGL 5 791.6 6 129 mg/dL (DBT 5 291.6 mg/dl). For CVID patients with pretreatment IgG levels <250 mg/dL (n 5 3), the mean 5 93.3 6 79.9 mg/dL, and post treatment BIgGL mean 5 960 6 17.3 mg/dL (DBT 5 460 mg/dL). For CVID patients with pretreatment IgG levels >250 (n 5 6), mean IgG 5 427 6 75 mg/dL, and mean BIgGL was 925.8 6 148.4 mg/dL (DBT 5 198.6 mg/dL). DBT IgG levels for 3 groups approached significance (ANOVA; p 5 0.056), and was significant for CVID with pretreatment IgG levels <250 mg/dL vs. XLA (unpaired t-test with Welch correction; p 5 0.02). CONCLUSIONS: BIgGLs are unique within and between PID subgroups. Targeted IgG levels provide starting points, however PID patients commonly require IgG levels greater than target levels to stay infection-free. CVID patients with starting IgG <250 mg/dl, may require higher BIgGL than XLA patients. Our results expand and define BIgGL in PID patients. A multi-center consortium, to increase patient numbers, is underway to determine BIgGLs necessary to prevent recurrent infection and bronchiectasis.
J ALLERGY CLIN IMMUNOL FEBRUARY 2009
31
Subcutaneous Use of Immune Globulin in Patients with Primary Immune Deficiency: A Retrospective Claims Database Analysis J. M. Li-McLeod1, H. S. Friedman2, P. O. Bonnet1; 1Baxter Healthcare Corporation, Westlake Village, CA, 2Analytic Solutions, New York, NY. RATIONALE: Intravenous Immune Globulin (IVIG) products are used in clinical practice to treat a wide variety of disorders. Dosage and frequency vary depending on the condition being treated and the route of administration. The objective of this study was to describe the use of Immune Globulins when administered subcutaneously and examine dosing and frequency of administration. METHODS: Pharmacy claims for two IVIG brands (Gammagard Liquid and Gammagard S/D, Baxter Healthcare Corporation) were extracted from a homecare company dataset for the year 2006. Only claims for patients with Primary Immune Deficiency (PI) -ICD9 code 279.XX- receiving IVIG subcutaneously were selected. For each claim, the following information was available: patients’ age and weight, dose dispensed, frequency of administration and diagnosis code. Dose per claim (in mg/kg) and frequency of administration were examined across the patients included in the sample. Descriptive statistics were utilized in this analysis. RESULTS: The database included 1,600 PI patients with 13,945 IVIG claims. 12.8% (204) of the patients were prescribed Immune Globulin subcutaneously on 1,094 occasions (10.5% of the total claims). The mean and the median doses administered were 148 mg/kg and 119 mg/kg, respectively; corresponding to a dose in grams ranging between 8.3 and 10.4 for a 70 kg patient. In 75% of the cases, IVIG was administered subcutaneously on a weekly basis. CONCLUSIONS: This database analysis demonstrated that these IVIG products are commonly administered subcutaneously in patients with PI and provided insight on commonly used doses when this route of administration is utilized.
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(1) Long-term Reversal of Hypogammaglobulinemia in two Common Variable Immunodeficiency (CVID) Patients after Discontinuation of Intravenous Immunoglobulin (IVIG) P. Chirichella1, J. P. Guo1, B. McGoey1, M. Michelis2,1; 1Division of Allergy, Asthma and Immune Disorders, Department of Medicine, Hackensack University Med Cntr, Hackensack, NJ, 2UMDNJ, Newark, NJ. RATIONALE: Life long immunoglobulin supplementation is required to maintain a normal IgG in CVID patients. Normal immunoglobulins after discontinuation of IVIG in 2 adults is reported. METHODS: Chart review of 2 CVID patients who had normalization of their IgA and IgM observed were followed after stopping IVIG. RESULTS: Patient A 33 year old female presented with frequent sinopulmonary infections including pneumonias. Initial IgG, IgA, and IgM in mg/ dL were 325, 0, and 0, normal B lymphocytes and Tcell subsets. She received IVIG for 22 years and when stopped 3 years ago, her IgG has been at 601 to 823 (mg/dL), her IgA and IgM at 188 to 265 (mg/dL) and 99.5 to 138 (mg/dL), with normal response to immunizations and no recurrent infections; Patient B 50 year old female presented with frequent cutaneous and sinopulmonary infections, dermatits and alopecia. She had reduced IgG 258, IgA 28.3 and IgM 13.4, lymphopenia with 130 CD4 cells, 30 CD8 cells, no NK cells but 220 B lymphocytes, no lymphocytoxic antibodies and depressed lymphocyte proliferation. She received IVIG for five years. Over the 6 years since discontinuation, her IgG has been 670 - 1310 (mg/dL) and IgA and IgM levels stayed at 233 to 627 (mg/dL) and 38.3 to 92 (mg/dL) with normal antibody vaccine responses. Recurrent infections, dermatits and alopecia resolved. No HIV infection, multiple myeloma, lymphoma, malignancy or any autoimmune disorders have developed. CONCLUSIONS: Hypogammaglobulinemia in some CVID patients may be reversible and measurements of IgA and IgM during therapy may detect this rare outcome.
SATURDAY
29
Genetic-Molecular Defects in MBL-MASP Pathway and Association with Selective Immunoglobulin Deficiencies: Implications for Host Defense G. Krishnaswamy, C. W. T. Miller, D. S. Chi; Quillen College of Medicine, Johnson City, TN. RATIONALE: Isolated immunoglobulin (Ig) deficiencies (including IgG4, IgM, and IgE) involve humoral responses and can lead to serious infections. Mannose-binding lectin (MBL) deficiency, the most common immunodeficiency in the general population, is an integral part of host immunity, with deficiency predisposing to infection. Coexistent humoral and MBL deficiency would theoretically lead to graver clinical scenarios, as MBL binds carbohydrates on the surface of immunoglobulins to provide pathways for immune complex clearance and complement activation in response to Ig-covered pathogens. We describe three patients with coincident MBL and selective Ig deficiency. METHODS: Three patients with recurrent infections were assessed for serum Ig and MBL levels. MBL and MASP-2 genotyping was performed in 2 patients (IBT Laboratories, Lenexa, KS). RESULTS: Three patients presented with recurrent chronic rhinosinusitis and bronchitis. All had normal levels of IgG. Two patients, however, had selective IgM deficiency (< 50 mg/dl) and very low MBL levels (<50 ng/mL); genotyping was performed in one patient, revealing a mutated MBL2 promoter (LXPA/LYPB, both haplotypes conferring low serum MBL) and wild-type MASP-2 (A/A). The third patient had severe IgE and IgG4 deficiencies. She had received prior intravenous immunoglobulin therapy for several years for presumed common variable immune deficiency. MBL pathway genotype analysis revealed wild type (A/A) MASP-2 and LXPA/LYPB MBL2. This patient’s IVIG infusion was discontinued. CONCLUSIONS: Patients with recurrent infections may have various combinations of primary immune deficiency, including defects in both the complement (MBL-MASP) and the humoral (Immunoglobulin) pathways. The prevalence and clinical implications of such combinations are unknown and require further study.
30
Biologic IgG Level (BIgGL): One Size Does Not Fit All S. A. Siegel, D. W. Rosenthal, V. R. Bonagura; North Shore Long Island Jewish Health System, Great Neck, NY. RATIONALE: The BIgGL is the minimum serum IgG concentration that maintains primary immunodeficiency (PID) patients infection-free. This level varies and should be individualized for each patient and type of PID. METHODS: The medical records of patients with X-linked agammaglobunemia (XLA) and common variable immunodeficiency (CVID) on IVIG were reviewed. The BIgGL was determined by plotting infections vs. IgG levels over time. Target IgG levels for PID patients (AAAAI PID Committee Report) were determined, and differences between BIgGLs and target levels were calculated (DBT) and compared (GraphPad; Instat 3.01). RESULTS: BIgGL were plotted vs. infections over time (n 5 15). For XLA patients (n 5 6), mean pretreatment IgG level 5 6.5 6 3.7 mg/dL, and mean BIgGL 5 791.6 6 129 mg/dL (DBT 5 291.6 mg/dl). For CVID patients with pretreatment IgG levels <250 mg/dL (n 5 3), the mean 5 93.3 6 79.9 mg/dL, and post treatment BIgGL mean 5 960 6 17.3 mg/dL (DBT 5 460 mg/dL). For CVID patients with pretreatment IgG levels >250 (n 5 6), mean IgG 5 427 6 75 mg/dL, and mean BIgGL was 925.8 6 148.4 mg/dL (DBT 5 198.6 mg/dL). DBT IgG levels for 3 groups approached significance (ANOVA; p 5 0.056), and was significant for CVID with pretreatment IgG levels <250 mg/dL vs. XLA (unpaired t-test with Welch correction; p 5 0.02). CONCLUSIONS: BIgGLs are unique within and between PID subgroups. Targeted IgG levels provide starting points, however PID patients commonly require IgG levels greater than target levels to stay infection-free. CVID patients with starting IgG <250 mg/dl, may require higher BIgGL than XLA patients. Our results expand and define BIgGL in PID patients. A multi-center consortium, to increase patient numbers, is underway to determine BIgGLs necessary to prevent recurrent infection and bronchiectasis.
J ALLERGY CLIN IMMUNOL FEBRUARY 2009
31
Subcutaneous Use of Immune Globulin in Patients with Primary Immune Deficiency: A Retrospective Claims Database Analysis J. M. Li-McLeod1, H. S. Friedman2, P. O. Bonnet1; 1Baxter Healthcare Corporation, Westlake Village, CA, 2Analytic Solutions, New York, NY. RATIONALE: Intravenous Immune Globulin (IVIG) products are used in clinical practice to treat a wide variety of disorders. Dosage and frequency vary depending on the condition being treated and the route of administration. The objective of this study was to describe the use of Immune Globulins when administered subcutaneously and examine dosing and frequency of administration. METHODS: Pharmacy claims for two IVIG brands (Gammagard Liquid and Gammagard S/D, Baxter Healthcare Corporation) were extracted from a homecare company dataset for the year 2006. Only claims for patients with Primary Immune Deficiency (PI) -ICD9 code 279.XX- receiving IVIG subcutaneously were selected. For each claim, the following information was available: patients’ age and weight, dose dispensed, frequency of administration and diagnosis code. Dose per claim (in mg/kg) and frequency of administration were examined across the patients included in the sample. Descriptive statistics were utilized in this analysis. RESULTS: The database included 1,600 PI patients with 13,945 IVIG claims. 12.8% (204) of the patients were prescribed Immune Globulin subcutaneously on 1,094 occasions (10.5% of the total claims). The mean and the median doses administered were 148 mg/kg and 119 mg/kg, respectively; corresponding to a dose in grams ranging between 8.3 and 10.4 for a 70 kg patient. In 75% of the cases, IVIG was administered subcutaneously on a weekly basis. CONCLUSIONS: This database analysis demonstrated that these IVIG products are commonly administered subcutaneously in patients with PI and provided insight on commonly used doses when this route of administration is utilized.
32
(1) Long-term Reversal of Hypogammaglobulinemia in two Common Variable Immunodeficiency (CVID) Patients after Discontinuation of Intravenous Immunoglobulin (IVIG) P. Chirichella1, J. P. Guo1, B. McGoey1, M. Michelis2,1; 1Division of Allergy, Asthma and Immune Disorders, Department of Medicine, Hackensack University Med Cntr, Hackensack, NJ, 2UMDNJ, Newark, NJ. RATIONALE: Life long immunoglobulin supplementation is required to maintain a normal IgG in CVID patients. Normal immunoglobulins after discontinuation of IVIG in 2 adults is reported. METHODS: Chart review of 2 CVID patients who had normalization of their IgA and IgM observed were followed after stopping IVIG. RESULTS: Patient A 33 year old female presented with frequent sinopulmonary infections including pneumonias. Initial IgG, IgA, and IgM in mg/ dL were 325, 0, and 0, normal B lymphocytes and Tcell subsets. She received IVIG for 22 years and when stopped 3 years ago, her IgG has been at 601 to 823 (mg/dL), her IgA and IgM at 188 to 265 (mg/dL) and 99.5 to 138 (mg/dL), with normal response to immunizations and no recurrent infections; Patient B 50 year old female presented with frequent cutaneous and sinopulmonary infections, dermatits and alopecia. She had reduced IgG 258, IgA 28.3 and IgM 13.4, lymphopenia with 130 CD4 cells, 30 CD8 cells, no NK cells but 220 B lymphocytes, no lymphocytoxic antibodies and depressed lymphocyte proliferation. She received IVIG for five years. Over the 6 years since discontinuation, her IgG has been 670 - 1310 (mg/dL) and IgA and IgM levels stayed at 233 to 627 (mg/dL) and 38.3 to 92 (mg/dL) with normal antibody vaccine responses. Recurrent infections, dermatits and alopecia resolved. No HIV infection, multiple myeloma, lymphoma, malignancy or any autoimmune disorders have developed. CONCLUSIONS: Hypogammaglobulinemia in some CVID patients may be reversible and measurements of IgA and IgM during therapy may detect this rare outcome.