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O011 Immunoglobulin management approaches in American patients with common variable immune deficiency and autoimmunity
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Abstracts: Oral Concurrent Sessions / Ann Allergy Asthma Immunol 117 (2016) S1eS21
O009 SYSTEMIC MASTOCYTOSIS PRESENTING AS CARDIAC TAMPONADE A. Wong*1, J. Toh2, E. Jerschow1, 1. Bronx, NY; 2. New York, NY. Introduction: Systemic mastocytosis (SM) is a rare disorder characterized by the growth and accumulation of pathologic mast cells in one or more organ systems. We describe a patient with undiagnosed SM who presented with pericardial effusion/cardiac tamponade. Methods: Chart review. Results: A 59-year-old man with a twenty-year history of diffuse lymphadenopathy and hyperpigmented macular rash presented with pleuritic chest pain. Medical history included flushing after drinking alcohol and anaphylaxis after NSAID use. Echocardiogram revealed pericardial effusion/cardiac tamponade. An emergent pericardial window drained 1 liter of fluid. The procedure was complicated by intraoperative hypotension from an anaphylactoid reaction necessitating epinephrine. Initial pericardial fluid analysis and biopsy revealed fibroadipose tissue with chronic inflammation and fibrinous exudate. Additional staining of the fluid showed mast cells with aberrant CD25 expression. An elevated tryptase (115 ng/ml) prompted a bone marrow biopsy, revealing dense aggregates of atypical mast cells with aberrant CD25 expression. Skin biopsy showed telangiectasia macularis eruptiva perstans, a form of cutaneous mastocytosis. A previous gastric biopsy was reevaluated, revealing two clusters (>15 mast cells; c-kit positive) of atypical mast cells with aberrant CD25 expression. These findings and a positive peripheral c-kit mutation (D816V) confirmed the diagnosis of SM. His decreased albumin and hepatomegaly classified his SM as the aggressive variant. Conclusion: This is a rare description of an undiagnosed systemic mastocytosis patient presenting with pericardial effusion/cardiac tamponade, likely due to pericarditis from mast cell mediators causing inflammation and subsequent effusion. This potentially life-threatening condition would be an important clinical presentation of SM.
O010 POST-NATAL MECHANISMS OF HUMAN HEMATOPOIETIC STEM CELL SELF-RENEWAL V. Bundy*, S. Sandoval, C. Seet, C. Parekh, C. Chin, C. He, Y. Zhu, L. Kohn, D. Rao, G. Crooks, Los Angeles, CA. Introduction: Hematopoietic stem cell (HSC) transplantation is the only potentially curative, non-experimental therapy available to treat severe primary immunodeficiency disease. Precise regulatory mechanisms to support and maintain HSCs remain to be elucidated. Micro RNAs (miRNAs) have been shown in many systems to regulate stem cell function. This study focuses on miRNA-specific mechanisms that support and maintain HSCs. Methods: Our laboratory has identified a genomic cluster of miRNAs (miR-99a/let-7c/miR-125b) that is highly coexpressed in hematopoietic stem cells, almost absent in progenitors and mature cells, with an expression pattern specific to postnatal hematopoiesis in the adult bone marrow. To determine the impact of increased miRNA expression in human HSCs, we generated lentiviral vectors to overexpress let-7c, miR-125b, or the entire cluster. Results: Lentiviral expression of let-7c alone decreased the number and frequency of CD34+ cells, reduced long-term culture initiation cells (LTC-ICs) and increased myeloid cell output. In contrast, expression of miR-125b alone expanded CD34+ cells and LTC-ICs. Expression of the entire miRNA cluster revealed a phenotype intermediate between let-7c and mir-125b overexpression. We have now also developed lentiviral “sponge” vectors to inhibit each miRNA individually, and hypothesize that inhibition of let-7c will enhance HSC proliferation due to un-opposed miR-125b. Conclusion: Our data suggests that let-7c may inhibit miR-125binduced proliferation during adult hematopoiesis. Our future goal is to use bioinformatics packages that combine miRNA and gene
expression analyses to identify molecular targets of let-7c and miR125b. We will use RNA-Seq to identify early transcriptional changes that occur after both over-expression and knockdown.
O011 IMMUNOGLOBULIN MANAGEMENT APPROACHES IN AMERICAN PATIENTS WITH COMMON VARIABLE IMMUNE DEFICIENCY AND AUTOIMMUNITY K. Kennedy*1, C. Cunningham-Rundles2, M. Morsheimer3, 1. Philadelphia, PA; 2. New York, NY; 3. Wilmington, DE. Introduction: Common variable immune deficiency (CVID) is a primary immune deficiency characterized by B cell dysfunction and paucity of protective specific antibodies. Autoimmunity, and commonly hematologic cytopenias, is also a manifestation. Immunoglobulin replacement therapy is the cornerstone of management; treatment route and dose can be used to modulate the frequency and severity of cytopenias. Typically IV immunoglobulin administration (IVIG) at high doses is required for immunomodulatory benefits, however international experience suggests subcutaneous administration at lower doses can also be successful. We aim to summarize the American experience regarding immunoglobulin route and dosing among CVID subjects with autoimmunity. Methods: A USIDNET enrollment characteristic query of 1494 CVID patients revealed 105 cases with autoimmunity. Variables assessed included sex, autoimmune disorder, transfusion history, adjunctive immunomodulatory medications, and immunoglobulin dose and administration route. STATA performed descriptive statistics. Results: The majority were female (61%) and treated with IVIG (72%). One third had cytopenias, most commonly immune thrombocytopenic purpura (14.2%). Nearly 80% with cytopenias received IVIG (300 to 1300 mg/kg/dose); 67% of these patients required immunomodulatory medications and 18% required transfusions. Approximately 20% with cytopenias were treated with subcutaneous immunoglobulin (SCIG) (100-150mg/kg/dose); 86% of these patients required immunomodulatory medications and 42% required transfusions. Conclusion: Most American CVID patients with cytopenias were managed with IVIG and had lower rates of immunomodulatory medications and transfusions than those on SCIG. There was a wide range of autoimmunity noted in the cohort with the same preference for IVIG noted for non-hematologic complications. Institutional-level data is required to identify characteristics predictive of success on SCIG.
O012 A SINGLE CENTER EXPERIENCE OF SCID NEWBORN SCREENING IN ILLINOIS J. Bergerson*, A. Skoskiewicz, R. Fuleihan, Chicago, IL. Background: Severe combined immunodeficiency (SCID) is primary immunodeficiency that result from the absence or diminished function of T cells. SCID is phenotypically classified by the presence or absence of B and NK cells and each subtype can be caused by defects in a number of different genes. Early diagnosis and prompt treatment of SCID leads to decreased patient mortality from disease complications. In May 2014, Illinois instituted newborn screening (NBS) of all infants for T-cell lymphopenia via Tcell receptor excision circle (TREC) assay. Methods: TREC level was performed as part of the Illinois state NBS program. Infants who had abnormal TREC levels (<300 in year one, and <250 in year two) were referred for further evaluation. Results: We identified patients with SCID, 22q11 deletion syndromes, Trisomy 21, and idiopathic T cell lymphopenia (iTCL) from all infants referred with low TREC levels. Since initiation of statewide newborn screening for SCID we evaluated six infants with absent TREC levels (TREC ¼ 0). Four of these six patients had typical SCID. The two remaining patients had iTCL. One of the patients
Abstracts: Oral Concurrent Sessions / Ann Allergy Asthma Immunol 117 (2016) S1eS21
O009 SYSTEMIC MASTOCYTOSIS PRESENTING AS CARDIAC TAMPONADE A. Wong*1, J. Toh2, E. Jerschow1, 1. Bronx, NY; 2. New York, NY. Introduction: Systemic mastocytosis (SM) is a rare disorder characterized by the growth and accumulation of pathologic mast cells in one or more organ systems. We describe a patient with undiagnosed SM who presented with pericardial effusion/cardiac tamponade. Methods: Chart review. Results: A 59-year-old man with a twenty-year history of diffuse lymphadenopathy and hyperpigmented macular rash presented with pleuritic chest pain. Medical history included flushing after drinking alcohol and anaphylaxis after NSAID use. Echocardiogram revealed pericardial effusion/cardiac tamponade. An emergent pericardial window drained 1 liter of fluid. The procedure was complicated by intraoperative hypotension from an anaphylactoid reaction necessitating epinephrine. Initial pericardial fluid analysis and biopsy revealed fibroadipose tissue with chronic inflammation and fibrinous exudate. Additional staining of the fluid showed mast cells with aberrant CD25 expression. An elevated tryptase (115 ng/ml) prompted a bone marrow biopsy, revealing dense aggregates of atypical mast cells with aberrant CD25 expression. Skin biopsy showed telangiectasia macularis eruptiva perstans, a form of cutaneous mastocytosis. A previous gastric biopsy was reevaluated, revealing two clusters (>15 mast cells; c-kit positive) of atypical mast cells with aberrant CD25 expression. These findings and a positive peripheral c-kit mutation (D816V) confirmed the diagnosis of SM. His decreased albumin and hepatomegaly classified his SM as the aggressive variant. Conclusion: This is a rare description of an undiagnosed systemic mastocytosis patient presenting with pericardial effusion/cardiac tamponade, likely due to pericarditis from mast cell mediators causing inflammation and subsequent effusion. This potentially life-threatening condition would be an important clinical presentation of SM.
O010 POST-NATAL MECHANISMS OF HUMAN HEMATOPOIETIC STEM CELL SELF-RENEWAL V. Bundy*, S. Sandoval, C. Seet, C. Parekh, C. Chin, C. He, Y. Zhu, L. Kohn, D. Rao, G. Crooks, Los Angeles, CA. Introduction: Hematopoietic stem cell (HSC) transplantation is the only potentially curative, non-experimental therapy available to treat severe primary immunodeficiency disease. Precise regulatory mechanisms to support and maintain HSCs remain to be elucidated. Micro RNAs (miRNAs) have been shown in many systems to regulate stem cell function. This study focuses on miRNA-specific mechanisms that support and maintain HSCs. Methods: Our laboratory has identified a genomic cluster of miRNAs (miR-99a/let-7c/miR-125b) that is highly coexpressed in hematopoietic stem cells, almost absent in progenitors and mature cells, with an expression pattern specific to postnatal hematopoiesis in the adult bone marrow. To determine the impact of increased miRNA expression in human HSCs, we generated lentiviral vectors to overexpress let-7c, miR-125b, or the entire cluster. Results: Lentiviral expression of let-7c alone decreased the number and frequency of CD34+ cells, reduced long-term culture initiation cells (LTC-ICs) and increased myeloid cell output. In contrast, expression of miR-125b alone expanded CD34+ cells and LTC-ICs. Expression of the entire miRNA cluster revealed a phenotype intermediate between let-7c and mir-125b overexpression. We have now also developed lentiviral “sponge” vectors to inhibit each miRNA individually, and hypothesize that inhibition of let-7c will enhance HSC proliferation due to un-opposed miR-125b. Conclusion: Our data suggests that let-7c may inhibit miR-125binduced proliferation during adult hematopoiesis. Our future goal is to use bioinformatics packages that combine miRNA and gene
expression analyses to identify molecular targets of let-7c and miR125b. We will use RNA-Seq to identify early transcriptional changes that occur after both over-expression and knockdown.
O011 IMMUNOGLOBULIN MANAGEMENT APPROACHES IN AMERICAN PATIENTS WITH COMMON VARIABLE IMMUNE DEFICIENCY AND AUTOIMMUNITY K. Kennedy*1, C. Cunningham-Rundles2, M. Morsheimer3, 1. Philadelphia, PA; 2. New York, NY; 3. Wilmington, DE. Introduction: Common variable immune deficiency (CVID) is a primary immune deficiency characterized by B cell dysfunction and paucity of protective specific antibodies. Autoimmunity, and commonly hematologic cytopenias, is also a manifestation. Immunoglobulin replacement therapy is the cornerstone of management; treatment route and dose can be used to modulate the frequency and severity of cytopenias. Typically IV immunoglobulin administration (IVIG) at high doses is required for immunomodulatory benefits, however international experience suggests subcutaneous administration at lower doses can also be successful. We aim to summarize the American experience regarding immunoglobulin route and dosing among CVID subjects with autoimmunity. Methods: A USIDNET enrollment characteristic query of 1494 CVID patients revealed 105 cases with autoimmunity. Variables assessed included sex, autoimmune disorder, transfusion history, adjunctive immunomodulatory medications, and immunoglobulin dose and administration route. STATA performed descriptive statistics. Results: The majority were female (61%) and treated with IVIG (72%). One third had cytopenias, most commonly immune thrombocytopenic purpura (14.2%). Nearly 80% with cytopenias received IVIG (300 to 1300 mg/kg/dose); 67% of these patients required immunomodulatory medications and 18% required transfusions. Approximately 20% with cytopenias were treated with subcutaneous immunoglobulin (SCIG) (100-150mg/kg/dose); 86% of these patients required immunomodulatory medications and 42% required transfusions. Conclusion: Most American CVID patients with cytopenias were managed with IVIG and had lower rates of immunomodulatory medications and transfusions than those on SCIG. There was a wide range of autoimmunity noted in the cohort with the same preference for IVIG noted for non-hematologic complications. Institutional-level data is required to identify characteristics predictive of success on SCIG.
O012 A SINGLE CENTER EXPERIENCE OF SCID NEWBORN SCREENING IN ILLINOIS J. Bergerson*, A. Skoskiewicz, R. Fuleihan, Chicago, IL. Background: Severe combined immunodeficiency (SCID) is primary immunodeficiency that result from the absence or diminished function of T cells. SCID is phenotypically classified by the presence or absence of B and NK cells and each subtype can be caused by defects in a number of different genes. Early diagnosis and prompt treatment of SCID leads to decreased patient mortality from disease complications. In May 2014, Illinois instituted newborn screening (NBS) of all infants for T-cell lymphopenia via Tcell receptor excision circle (TREC) assay. Methods: TREC level was performed as part of the Illinois state NBS program. Infants who had abnormal TREC levels (<300 in year one, and <250 in year two) were referred for further evaluation. Results: We identified patients with SCID, 22q11 deletion syndromes, Trisomy 21, and idiopathic T cell lymphopenia (iTCL) from all infants referred with low TREC levels. Since initiation of statewide newborn screening for SCID we evaluated six infants with absent TREC levels (TREC ¼ 0). Four of these six patients had typical SCID. The two remaining patients had iTCL. One of the patients