57 results on '"Fuleihan RL"'
Search Results
2. Allergy, immunology, and related disorders.
- Author
-
Fuleihan RL
- Published
- 2004
- Full Text
- View/download PDF
3. Allergy, immunology, and related disorders.
- Author
-
Fuleihan RL and Fuleihan, R L
- Published
- 1998
- Full Text
- View/download PDF
4. Allergy, immunology and related disorders.
- Author
-
Fuleihan RL
- Published
- 2005
- Full Text
- View/download PDF
5. Expanding the Clinical Phenotype of Autosomal Recessive Chronic Granulomatous Disease.
- Author
-
Chester JG, Estrella AM, Kuhns DB, Garcia CK, and Fuleihan RL
- Subjects
- Humans, Male, Mutation genetics, Female, Genes, Recessive, Granulomatous Disease, Chronic genetics, Granulomatous Disease, Chronic diagnosis, Phenotype
- Published
- 2024
- Full Text
- View/download PDF
6. Correction: Individuals with JAK1 variants are affected by syndromic features encompassing autoimmunity, atopy, colitis, and dermatitis.
- Author
-
Horesh ME, Martin-Fernandez M, Gruber C, Buta S, Le Voyer T, Puzenat E, Lesmana H, Wu Y, Richardson A, Stein D, Hodeib S, Youssef M, Kurowski JA, Feuille E, Pedroza LA, Fuleihan RL, Haseley A, Hovnanian A, Quartier P, Rosain J, Davis G, Mullan D, Stewart O, Patel R, Lee AE, Rubinstein R, Ewald L, Maheshwari N, Rahming V, Chinn IK, Lupski JR, Orange JS, Sancho-Shimizu V, Casanova JL, Abul-Husn NS, Itan Y, Milner JD, Bustamante J, and Bogunovic D
- Published
- 2024
- Full Text
- View/download PDF
7. Individuals with JAK1 variants are affected by syndromic features encompassing autoimmunity, atopy, colitis, and dermatitis.
- Author
-
Horesh ME, Martin-Fernandez M, Gruber C, Buta S, Le Voyer T, Puzenat E, Lesmana H, Wu Y, Richardson A, Stein D, Hodeib S, Youssef M, Kurowski JA, Feuille E, Pedroza LA, Fuleihan RL, Haseley A, Hovnanian A, Quartier P, Rosain J, Davis G, Mullan D, Stewart O, Patel R, Lee AE, Rubinstein R, Ewald L, Maheshwari N, Rahming V, Chinn IK, Lupski JR, Orange JS, Sancho-Shimizu V, Casanova JL, Abul-Husn NS, Itan Y, Milner JD, Bustamante J, and Bogunovic D
- Subjects
- Humans, Autoimmunity, Inflammation, Janus Kinase 1 genetics, Colitis genetics, Hypersensitivity, Dermatitis
- Abstract
Inborn errors of immunity lead to autoimmunity, inflammation, allergy, infection, and/or malignancy. Disease-causing JAK1 gain-of-function (GoF) mutations are considered exceedingly rare and have been identified in only four families. Here, we use forward and reverse genetics to identify 59 individuals harboring one of four heterozygous JAK1 variants. In vitro and ex vivo analysis of these variants revealed hyperactive baseline and cytokine-induced STAT phosphorylation and interferon-stimulated gene (ISG) levels compared with wild-type JAK1. A systematic review of electronic health records from the BioME Biobank revealed increased likelihood of clinical presentation with autoimmunity, atopy, colitis, and/or dermatitis in JAK1 variant-positive individuals. Finally, treatment of one affected patient with severe atopic dermatitis using the JAK1/JAK2-selective inhibitor, baricitinib, resulted in clinically significant improvement. These findings suggest that individually rare JAK1 GoF variants may underlie an emerging syndrome with more common presentations of autoimmune and inflammatory disease (JAACD syndrome). More broadly, individuals who present with such conditions may benefit from genetic testing for the presence of JAK1 GoF variants., (© 2024 Bogunovic et al.)
- Published
- 2024
- Full Text
- View/download PDF
8. COVID-19 Vaccination in Patients with Inborn Errors of Immunity Reduces Hospitalization and Critical Care Needs Related to COVID-19: a USIDNET Report.
- Author
-
McDonnell J, Cousins K, Younger MEM, Lane A, Abolhassani H, Abraham RS, Al-Tamemi S, Aldave-Becerra JC, Al-Faris EH, Alfaro-Murillo A, AlKhater SA, Alsaati N, Doss AMA, Anderson M, Angarola E, Ariue B, Arnold DE, Assa'ad AH, Aytekin C, Bank M, Bergerson JRE, Bleesing J, Boesing J, Bouso C, Brodszki N, Cabanillas D, Cady C, Callahan MA, Caorsi R, Carbone J, Carrabba M, Castagnoli R, Catanzaro JR, Chan S, Chandra S, Chapdelaine H, Chavoshzadeh Z, Chong HJ, Connors L, Consonni F, Correa-Jimenez O, Cunningham-Rundles C, D'Astous-Gauthier K, Delmonte OM, Demirdag YY, Deshpande DR, Diaz-Cabrera NM, Dimitriades VR, El-Owaidy R, ElGhazali G, Al-Hammadi S, Fabio G, Faure AS, Feng J, Fernandez JM, Fill L, Franco GR, Frenck RW, Fuleihan RL, Giardino G, Galant-Swafford J, Gambineri E, Garabedian EK, Geerlinks AV, Goudouris E, Grecco O, Pan-Hammarström Q, Khani HHK, Hammarström L, Hartog NL, Heimall J, Hernandez-Molina G, Horner CC, Hostoffer RW, Hristova N, Hsiao KC, Ivankovich-Escoto G, Jaber F, Jalil M, Jamee M, Jean T, Jeong S, Jhaveri D, Jordan MB, Joshi AY, Kalkat A, Kanarek HJ, Kellner ES, Khojah A, Khoury R, Kokron CM, Kumar A, Lecerf K, Lehman HK, Leiding JW, Lesmana H, Lim XR, Lopes JP, López AL, Tarquini L, Lundgren IS, Magnusson J, Marinho AKBB, Marseglia GL, Martone GM, Mechtler AG, Mendonca L, Milner JD, Mustillo PJ, Naderi AG, Naviglio S, Nell J, Niebur HB, Notarangelo L, Oleastro M, Ortega-López MC, Patel NR, Petrovic G, Pignata C, Porras O, Prince BT, Puck JM, Qamar N, Rabusin M, Raje N, Regairaz L, Risma KA, Ristagno EH, Routes J, Roxo-Junior P, Salemi N, Scalchunes C, Schuval SJ, Seneviratne SL, Shankar A, Sherkat R, Shin JJ, Siddiqi A, Signa S, Sobh A, Lima FMS, Stenehjem KK, Tam JS, Tang M, Barros MT, Verbsky J, Vergadi E, Voelker DH, Volpi S, Wall LA, Wang C, Williams KW, Wu EY, Wu SS, Zhou JJ, Cook A, Sullivan KE, and Marsh R
- Subjects
- Humans, COVID-19 Vaccines adverse effects, Vaccination, Hospitalization, Critical Care, COVID-19 epidemiology
- Abstract
Background: The CDC and ACIP recommend COVID-19 vaccination for patients with inborn errors of immunity (IEI). Not much is known about vaccine safety in IEI, and whether vaccination attenuates infection severity in IEI., Objective: To estimate COVID-19 vaccination safety and examine effect on outcomes in patients with IEI., Methods: We built a secure registry database in conjunction with the US Immunodeficiency Network to examine vaccination frequency and indicators of safety and effectiveness in IEI patients. The registry opened on January 1, 2022, and closed on August 19, 2022., Results: Physicians entered data on 1245 patients from 24 countries. The most common diagnoses were antibody deficiencies (63.7%). At least one COVID-19 vaccine was administered to 806 patients (64.7%), and 216 patients received vaccination prior to the development of COVID-19. The most common vaccines administered were mRNA-based (84.0%). Seventeen patients were reported to seek outpatient clinic or emergency room care for a vaccine-related complication, and one patient was hospitalized for symptomatic anemia. Eight hundred twenty-three patients (66.1%) experienced COVID-19 infection. Of these, 156 patients required hospitalization (19.0%), 47 required ICU care (5.7%), and 28 died (3.4%). Rates of hospitalization (9.3% versus 24.4%, p < 0.001), ICU admission (2.8% versus 7.6%, p = 0.013), and death (2.3% versus 4.3%, p = 0.202) in patients who had COVID-19 were lower in patients who received vaccination prior to infection. In adjusted logistic regression analysis, not having at least one COVID-19 vaccine significantly increased the odds of hospitalization and ICU admission., Conclusion: Vaccination for COVID-19 in the IEI population appears safe and attenuates COVID-19 severity., (© 2024. The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF
9. CVID-Associated Intestinal Disorders in the USIDNET Registry: An Analysis of Disease Manifestations, Functional Status, Comorbidities, and Treatment.
- Author
-
Franzblau LE, Fuleihan RL, Cunningham-Rundles C, and Wysocki CA
- Subjects
- Humans, Functional Status, Intestines, Registries, Common Variable Immunodeficiency complications, Common Variable Immunodeficiency epidemiology, Common Variable Immunodeficiency therapy, Lymphoma complications
- Abstract
Common variable immunodeficiency (CVID) has been subdivided into five phenotypes, including one marked by non-infectious enteropathies that lead to significant morbidity and mortality. We examined a large national registry of patients with CVID to better characterize this population and understand how the presence of enteropathy influences nutritional status, patient function, and the risk of additional non-infectious disorders in CVID patients. We also sought to illustrate the range of treatment strategies for CVID-associated enteropathies. We extracted patient data from the United States Immunodeficiency Network (USIDNET) database, which included 1415 patients with CVID, and compared those with and without intestinal disorders. Demographic and genetic profiles, functional status, and treatments targeting intestinal disorders are reported. Intestinal disorders were present in 20% of patients with CVID, including chronic diarrhea, inflammatory bowel disease, malabsorption, and others. Compared to those without enteropathies, this patient subset exhibited significantly lower Karnofsky-Lansky functional scores, greater reliance on nutritional support, higher rates of vitamin deficiencies, and increased prevalence of hematologic disorders, liver disease, pulmonary disease, granulomatous disease, and lymphoma. Genetic data were reported for only 5% of the cohort. No mutations segregated significantly to patients with or without intestinal disease. Corticosteroids were most frequently used for treatment. Patients with CVID-associated intestinal disorders exhibit higher rates of autoimmune and inflammatory comorbidities, lymphoma, malnutrition, and debility. We review recent studies implicating specific pathways underlying this immune dysregulation. Further studies are needed to evaluate the role of targeted immunomodulatory therapies for CVID-associated intestinal disorders., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2023
- Full Text
- View/download PDF
10. Respiratory Comorbidities Associated with Bronchiectasis in Patients with Common Variable Immunodeficiency in the USIDNET Registry.
- Author
-
Correa-Jimenez O, Restrepo-Gualteros S, Nino G, Cunningham-Rundles C, Sullivan KE, Fuleihan RL, and Gutierrez MJ
- Subjects
- Humans, Middle Aged, Cross-Sectional Studies, Registries, Common Variable Immunodeficiency complications, Common Variable Immunodeficiency epidemiology, Bronchiectasis epidemiology, Pneumonia complications, Lung Diseases, Interstitial etiology, Sinusitis epidemiology, Sinusitis complications
- Abstract
Background: Bronchiectasis is a major respiratory complication in patients with common variable immunodeficiency (CVID) and is associated with recurrent pulmonary infections. However, it is unclear whether other infections or non-infectious respiratory conditions are related to its development., Objective: To identify respiratory comorbidities associated with bronchiectasis in patients with CVID., Methods: A total of 1470 CVID patients enrolled in the USIDNET registry were included in a cross-sectional analysis. The primary outcome of our study was to determine the clinical characteristics and other respiratory conditions associated with respiratory comorbidities and physician-reported bronchiectasis., Results: One hundred ninety-seven CVID patients were noted to have bronchiectasis (13.4%). Affected patients were significantly older than patients without bronchiectasis (median age 54 years vs. 49 years, p = 0.0004). These patients also had lower serum IgA (13 mg/dL IQR 60 mg/dL vs. 28.4 mg/dL IQR 66 mg/dL, p = 0.000). Notably, chronic rhinosinusitis (OR = 1.69 95%CI 1.05-2.75), sinusitis (OR = 2.06 95%CI 1.38-3.09), pneumonia (OR = 2.70 95%CI 1.88-3.88), COPD (OR = 2.66 95%CI 1.51-4.67), and interstitial lung disease (OR = 2.34 95%CI 1.41-3.91) were independently associated with the development of bronchiectasis in this population., Conclusion: These data suggest that lower and upper respiratory infections, chronic lower airway disease, and interstitial lung diseases are independently associated with bronchiectasis in CVID patients. Further study into predisposing conditions related to the development of bronchiectasis in CVID patients may allow prediction and early intervention strategies to prevent the development of this complication., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2023
- Full Text
- View/download PDF
11. Who's your data? Primary immune deficiency differential diagnosis prediction via machine learning and data mining of the USIDNET registry.
- Author
-
Méndez Barrera JA, Rocha Guzmán S, Hierro Cascajares E, Garabedian EK, Fuleihan RL, Sullivan KE, and Lugo Reyes SO
- Subjects
- Humans, Diagnosis, Differential, Machine Learning, Data Mining, Primary Immunodeficiency Diseases, Wiskott-Aldrich Syndrome
- Abstract
Purpose: There are currently more than 480 primary immune deficiency (PID) diseases and about 7000 rare diseases that together afflict around 1 in every 17 humans. Computational aids based on data mining and machine learning might facilitate the diagnostic task by extracting rules from large datasets and making predictions when faced with new problem cases. In a proof-of-concept data mining study, we aimed to predict PID diagnoses using a supervised machine learning algorithm based on classification tree boosting., Methods: Through a data query at the USIDNET registry we obtained a database of 2396 patients with common diagnoses of PID, including their clinical and laboratory features. We kept 286 features and all 12 diagnoses to include in the model. We used the XGBoost package with parallel tree boosting for the supervised classification model, and SHAP for variable importance interpretation, on Python v3.7. The patient database was split into training and testing subsets, and after boosting through gradient descent, the predictive model provides measures of diagnostic prediction accuracy and individual feature importance. After a baseline performance test, we used the Class Weighting Hyperparameter, or scale_pos_weight to correct for imbalanced classification., Results: The twelve PID diagnoses were CVID (1098 patients), DiGeorge syndrome, Chronic granulomatous disease, Congenital agammaglobulinemia, PID not otherwise classified, Specific antibody deficiency, Complement deficiency, Hyper-IgM, Leukocyte adhesion deficiency, ectodermal dysplasia with immune deficiency, Severe combined immune deficiency, and Wiskott-Aldrich syndrome. For CVID, the model found an accuracy on the train sample of 0.80, with an area under the ROC curve (AUC) of 0.80, and a Gini coefficient of 0.60. In the test subset, accuracy was 0.76, AUC 0.75, and Gini 0.51. The positive feature value to predict CVID was highest for upper respiratory infections, asthma, autoimmunity and hypogammaglobulinemia. Features with the highest negative predictive value were high IgE, growth delay, abscess, lymphopenia, and congenital heart disease. For the rest of the diagnoses, accuracy stayed between 0.75 and 0.99, AUC 0.46-0.87, Gini 0.07-0.75, and LogLoss 0.09-8.55., Discussion: Clinicians should remember to consider the negative predictive features together with the positives. We are calling this a proof-of-concept study to continue with our explorations. A good performance is encouraging, and feature importance might aid feature selection for future endeavors. In the meantime, we can learn from the rules derived by the model and build a user-friendly decision tree to generate differential diagnoses., Competing Interests: Declaration of Competing Interest All authors declare no competing interests to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
12. A Registry Study of 240 Patients with X-Linked Agammaglobulinemia Living in the USA.
- Author
-
Hernandez-Trujillo V, Zhou C, Scalchunes C, Ochs HD, Sullivan KE, Cunningham-Rundles C, Fuleihan RL, Bonilla FA, Petrovic A, Rawlings DJ, and de la Morena MT
- Subjects
- Humans, Infant, Child, Preschool, Child, Adolescent, Young Adult, Adult, Middle Aged, Quality of Life, Agammaglobulinaemia Tyrosine Kinase genetics, Mutation genetics, Genetic Diseases, X-Linked diagnosis, Genetic Diseases, X-Linked epidemiology, Genetic Diseases, X-Linked genetics, Agammaglobulinemia diagnosis, Agammaglobulinemia epidemiology, Agammaglobulinemia therapy
- Abstract
Purpose: To understand the natural history and clinical outcomes for patients with X-linked agammaglobulinemia (XLA) in the United States utilizing the United States Immunodeficiency Network (USIDNET) patient registry., Methods: The USIDNET registry was queried for data from XLA patients collected from 1981 to 2019. Data fields included demographics, clinical features before and after diagnosis of XLA, family history, genetic mutation in Bruton's tyrosine kinase (BTK), laboratory findings, treatment modalities, and mortality., Results: Data compiled through the USIDNET registry on 240 patients were analyzed. Patient year of birth ranged from 1945 to 2017. Living status was available for 178 patients; 158/178 (88.8%) were alive. Race was reported for 204 patients as follows: White, 148 (72.5%); Black/African American, 23 (11.2%); Hispanic, 20 (9.8%); Asian or Pacific Islander, 6 (2.9%), and other or more than one race, 7 (3.4%). The median age at last entry, age at disease onset, age at diagnosis, and length of time with XLA diagnosis was 15 [range (r) = 1-52 years], 0.8 [r = birth-22.3 years], 2 [r = birth-29 years], and 10 [r = 1-56 years] years respectively. One hundred and forty-one patients (58.7%) were < 18 years of age. Two hundred and twenty-one (92%) patients were receiving IgG replacement (IgGR), 58 (24%) were on prophylactic antibiotics, and 19 (7.9%) were on immunomodulatory drugs. Eighty-six (35.9%) patients had undergone surgical procedures, two had undergone hematopoietic cell transplantation, and two required liver transplantation. The respiratory tract was the most affected organ system (51.2% of patients) followed by gastrointestinal (40%), neurological (35.4%), and musculoskeletal (28.3%). Infections were common both before and after diagnosis, despite IgGR therapy. Bacteremia/sepsis and meningitis were reported more frequently before XLA diagnosis while encephalitis was more commonly reported after diagnosis. Twenty patients had died (11.2%). The median age of death was 21 years (range = 3-56.7 years). Neurologic condition was the most common underlying co-morbidity for those XLA patients who died., Conclusions: Current therapies for XLA patients reduce early mortality, but patients continue to experience complications that impact organ function. With improved life expectancy, more efforts will be required to improve post-diagnosis organ dysfunction and quality of life. Neurologic manifestations are an important co-morbidity associated with mortality and not yet clearly fully understood., (© 2023. The Author(s).)
- Published
- 2023
- Full Text
- View/download PDF
13. Outcomes among racial and ethnic minority groups with X-linked agammaglobulinemia from the USIDNET registry.
- Author
-
O'Toole D, Groth D, Wright H, Bonilla FA, Cunningham-Rundles C, Sullivan KE, Ochs HD, Marsh RA, Feuille E, and Fuleihan RL
- Subjects
- Humans, Ethnic and Racial Minorities, Registries, Ethnicity, Minority Groups
- Published
- 2023
- Full Text
- View/download PDF
14. Risk Factors of Pneumonia in Primary Antibody Deficiency Patients Receiving Immunoglobulin Therapy: Data from the US Immunodeficiency Network (USIDNET).
- Author
-
Syed MN, Kutac C, Miller JM, Marsh R, Sullivan KE, Cunningham-Rundles C, Fuleihan RL, Kheradmand F, and Hajjar J
- Subjects
- Humans, Splenomegaly complications, Cross-Sectional Studies, Immunization, Passive adverse effects, Immunoglobulins therapeutic use, Risk Factors, Immunologic Deficiency Syndromes diagnosis, Immunologic Deficiency Syndromes epidemiology, Immunologic Deficiency Syndromes complications, Pneumonia diagnosis, Pneumonia epidemiology, Pneumonia etiology, Common Variable Immunodeficiency diagnosis, Common Variable Immunodeficiency epidemiology, Common Variable Immunodeficiency complications, Lung Diseases, Interstitial complications, Respiratory Tract Infections etiology, Hypersensitivity complications, Primary Immunodeficiency Diseases diagnosis, Primary Immunodeficiency Diseases epidemiology
- Abstract
Background: Despite immunoglobulin replacement (IgRT) therapy, some patients with primary antibody deficiency (PAD) continue to develop respiratory infections. Recurrent and severe respiratory infections, particularly pneumonia, can lead to significant morbidity and mortality. Therefore, we sought to determine the risk factors of developing pneumonia in PAD patients, already receiving IgRT., Methods: We evaluated clinical and laboratory features of PAD patients enrolled in the US Immune Deficiency Network (USIDNET) registry by April 2017. Patients were included if they met the following criteria: (1) PAD diagnosis (common variable immunodeficiency (CVID), agammaglobulinemia, hypogammaglobinemia, and specific antibody deficiency (SAD) and (2) available data on infections before and after IgRT. Patients were excluded if they were not receiving IgRT, or if no pre/post infections data were available. Descriptive and multivariable logistic regression analyses were used to identify factors associated with pneumonia post-IgRT., Results: A total of 1232 patients met the inclusion criteria. Following IgRT, 218 patients (17.7%) were reported to have at least one pneumonia episode. Using multivariate logistic regression analysis, we found a statistically significant increased risk of pneumonia in patients with asthma (OR: 2.55, 95% CI (1.69-3.85), p < 0.001) bronchiectasis (OR: 3.94, 95% CI (2.29-6.80), p < 0.001), interstitial lung disease (ILD) (OR: 3.28, 95%CI (1.43-7.56), p < 0.005), splenomegaly (OR: 2.02, 95%CI (1.08-3.76), p < 0.027), allergies (OR: 2.44, 95% CI [1.44-4.13], p = 0.001), and patients who were not on immunosuppressives (OR: 1.61; 95%CI [1.06-2.46]; p = 0.027). For every 50 unit increase in IgA, the odds of reporting pneumonia post IgRT decreased (OR: 0.86, 95% CI [0.73-1.02], p = 0.062). Infectious organisms were reported in 35 of 218 patients who reported pneumonia after IgRT. Haemophilus influenzae was the most frequently reported (n = 11, 31.43%), followed by Streptococcus pneumoniae (n = 7, 20.00%)., Conclusion: Our findings suggest PAD patients with chronic and structural lung disease, splenomegaly, and allergies were associated with persistent pneumonia. However, our study is limited by the cross-sectional nature of the USIDNET database and limited longitudinal data. Further studies are warranted to identify susceptible causes and explore targeted solutions for prevention and associated morbidity and mortality., Clinical Implications: Patients with primary antibody deficiency with structural lung disease, allergies, and splenomegaly are associated with persistent pneumonia post-IgRT., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2022
- Full Text
- View/download PDF
15. Eosinophilic gastrointestinal disorders in patients with inborn errors of immunity: Data from the USIDNET registry.
- Author
-
Tran P, Gober L, Garabedian EK, Fuleihan RL, Puck JM, Sullivan KE, Spergel JM, and Ruffner MA
- Subjects
- Eosinophilia, Female, Humans, Male, Registries, Enteritis epidemiology, Enteritis therapy, Eosinophilic Esophagitis diagnosis, Eosinophilic Esophagitis epidemiology, Eosinophilic Esophagitis therapy, Gastritis diagnosis, Gastritis epidemiology
- Abstract
Rationale: Eosinophilic gastrointestinal disorders (EGID), including eosinophilic esophagitis (EoE), are inflammatory disorders of the gastrointestinal mucosa mediated by complex immune mechanisms. Although there have been initial reports of EGID in patients with inborn errors of immunity (IEI), little is known about the presentation of EGID in immunodeficient individuals., Methods: We queried the U.S. Immunodeficiency Network (USIDNET) for patient records including the terms eosinophilic esophagitis, gastritis, enteritis, or colitis. We analyzed 74 patient records from the database, including diagnoses, demographics, infectious history, laboratory findings, genetic studies, therapeutic interventions, and clinical outcomes., Results: We examined 74 patient records. A total of 61 patients had isolated EoE, and 13 had distal gastrointestinal involvement consistent with EGID. The most common IEI were common variable immunodeficiency (43.2%), some form of combined immunodeficiency (21.6%), chronic granulomatous disease (8.1%), hyper-IgE syndrome (6.8%), and autoimmune lymphoproliferative syndrome (6.8%). The median age at presentation with IEI was 0.5 years (IQR 1.725, max 39 years) and 56.76% were male. Approximately 20% of the patients in the cohort received a hematopoietic stem cell transplantation for treatment of IEI, but the timing of the HSCT in relationship to the EGID diagnosis was unknown., Conclusions: Here, we report EGID in a diverse cohort of IEI patients, suggesting that both non-EoE EGID and EoE can be seen as comorbid conditions with a variety of IEI. Our data suggests that EGID may be more common in patients with IEI than would be expected based on estimates of EGID in the general population., Competing Interests: JP receives royalties from UpToDate and her spouse is employed by Invitae, a DNA sequencing company. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tran, Gober, Garabedian, Fuleihan, Puck, Sullivan, Spergel and Ruffner.)
- Published
- 2022
- Full Text
- View/download PDF
16. Ocular Manifestations in Primary Immunodeficiency Disorders: A Report From the United States Immunodeficiency Network (USIDNET) Registry.
- Author
-
Pham MN, Fuleihan RL, Sullivan KE, and Cunningham-Rundles C
- Subjects
- Humans, Prevalence, Registries, United States epidemiology, Conjunctivitis, Immunologic Deficiency Syndromes diagnosis, Primary Immunodeficiency Diseases
- Abstract
Background: Few published studies address eye disease in primary immunodeficiency (PID) despite ocular infections and autoimmune disease being known manifestations of immunodeficient states., Objective: Data from the USIDNET Registry provide a resource to study ocular ailments in subjects with PID., Methods: Ocular manifestations and patient characteristics were determined using data from 4624 patients with PID enrolled in the US Immunodeficiency Network (USIDNET) Registry., Results: A total of 519 (11.2%) patients had recorded ocular diseases. Those with autoinflammatory disorders (n = 4 of 7 [57.1%]), intrinsic and innate immunity defects (n = 9 of 44 [20.5%]), and immune dysregulation (n = 27 of 142 [19.0%]) had the highest percentage of ocular diseases for the PID diagnosis category. Of the 67.6% with infections, 85.5% had conjunctivitis. Bacteria (56.2%) and viruses (27.4%) were the most common microorganisms reported, with Staphylococcus (31.7%), Haemophilus (26.8%), and Streptococcus (22.0%) being the most common bacteria isolated. Those with a history of eye infections had lower immunoglobulin levels, lower CD19 B-cell percentages, and a lower number of protective pneumococcal titers. In patients with noninfectious ocular complications, 30.8% had vision changes, with retina (n = 20 [8.0%]), cataract (n = 16 [6.4%]), and nerve diseases (n = 16 [6.4%]) also being common. Many patients with ocular disease had serious sequelae, with 12.7% undergoing eye surgery and 10.6% having a vision-based disability., Conclusions: Vision loss and conjunctivitis were the most commonly reported ocular complications and pose large quality-of-life issues. Learning more about ocular disease in PID will increase awareness about the importance of addressing and evaluating for these ailments., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
17. X-Linked Agammaglobulinemia: Infection Frequency and Infection-Related Mortality in the USIDNET Registry.
- Author
-
O'Toole D, Groth D, Wright H, Bonilla FA, Fuleihan RL, Cunningham-Rundles C, Sullivan KE, Ochs HD, Marsh R, and Feuille E
- Subjects
- Agammaglobulinaemia Tyrosine Kinase genetics, Humans, Infant, Newborn, Mutation, Registries, Agammaglobulinemia complications, Agammaglobulinemia diagnosis, Agammaglobulinemia epidemiology, Genetic Diseases, X-Linked diagnosis, Genetic Diseases, X-Linked epidemiology, Genetic Diseases, X-Linked genetics, Respiratory Tract Infections epidemiology
- Abstract
X-linked agammaglobulinemia (XLA) is a primary immunodeficiency disorder caused by mutations in the Bruton tyrosine kinase (BTK) gene leading to B lymphocyte deficiency and susceptibility to infection. A potential benefit of earlier diagnosis and treatment initiation on morbidity and mortality in XLA is incompletely understood. In the USIDNET Registry, we describe infection frequency and infection-related mortality in patients with XLA and their relationship to age of diagnosis and treatment initiation. Among the 231 XLA patients enrolled in the Registry, respiratory infections (N = 203, 88%) were the most commonly reported. Among those deceased (N = 20) where cause of death was known (N = 17), mortality was attributed to infection in most (N = 12, 71%). Chronic lung disease, often a consequence of repeated lower respiratory tract infection (LRTI), was also a frequent complication associated with mortality (N = 9, 53%). Age of diagnosis in years was lower for those without LRTI compared to those with (median 1.5 [IQR 0.5-3.3] vs. median 3.0 [IQR 1.0-5.0], p = 0.0026) and among living patients compared to deceased (median 1.8 [IQR 0.5-5.0] vs. median 2.7 [IQR 1.6-6.0], p = 0.04). Age at treatment initiation in years was lower among those without LRTIs compared to those with (median 1.0 [IQR 0.4-2.4] vs. median 2.8 [IQR 1.0-5.4], p = 0.0006). For every year increase in age at start of therapy, the odds of experiencing a LRTI was 1.216 (OR 1.216, 95% CI 1.048-1.411, p = 0.01). Given the expected finding of reduced LRTIs and mortality among those with earlier age at diagnosis, our study findings support inclusion of XLA in newborn screening programs., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2022
- Full Text
- View/download PDF
18. Chronic Granulomatous Disease With Inflammatory Bowel Disease: Clinical Presentation, Treatment, and Outcomes From the USIDNET Registry.
- Author
-
LaBere B, Gutierrez MJ, Wright H, Garabedian E, Ochs HD, Fuleihan RL, Secord E, Marsh R, Sullivan KE, Cunningham-Rundles C, Notarangelo LD, and Chen K
- Subjects
- Humans, Registries, Retrospective Studies, Granulomatous Disease, Chronic diagnosis, Granulomatous Disease, Chronic epidemiology, Granulomatous Disease, Chronic therapy, Hematopoietic Stem Cell Transplantation, Inflammatory Bowel Diseases epidemiology, Inflammatory Bowel Diseases therapy
- Abstract
Background: Chronic granulomatous disease (CGD) is an inborn error of immunity caused by defects in the phagocytic nicotinamide adenine dinucleotide phosphate oxidase complex, leading to increased susceptibility to infection and inflammatory autoimmune diseases. Up to 50% of patients have gastrointestinal (GI) involvement and meet diagnostic criteria for inflammatory bowel disease (CGD-IBD)., Objective: We analyzed patients with CGD from the US Immunodeficiency Network (USIDNET) registry to determine whether IBD changes the presentation, treatment, and outcomes of patients with CGD., Methods: A retrospective evaluation of CGD cases from the USIDNET registry was completed. CGD-IBD was defined as the presence of any major physician-reported inflammatory, noninfectious GI disease manifestation. Demographic information, conditions, infections, antimicrobial therapies, immunomodulator use, and hematopoietic stem cell transplantation data were analyzed., Results: Of 194 patients with a diagnosis of CGD, 96 met criteria for IBD and 98 were categorized in the non-IBD group. Patients with CGD-IBD had an increased rate of infection compared with the non-IBD group (0.66 vs 0.36 infections/patient/year). Enteric organism infections were more common in patients with IBD. Immunomodulators were used at a significantly higher percentage in patients with IBD compared with patients without IBD (80% vs 56%, P < .001). Of the entire CGD cohort, 17 patients died (8.8%), with no significant difference between patients with IBD and patients without IBD (P = 1.00)., Conclusion: Infectious events, enteric organism infections, and use of immunomodulatory drugs were higher in patients with IBD than patients without IBD; however, mortality was not increased. Patients with CGD and concurrent IBD are at increased risk for disease complications, supporting the importance of early recognition, diagnosis, and treatment., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
19. Clinical disparity of primary antibody deficiency patients at a safety net hospital.
- Author
-
Wallace LJ, Ware MS, Cunningham-Rundles C, Fuleihan RL, and Maglione PJ
- Subjects
- Healthcare Disparities, Humans, Medically Uninsured, United States, Primary Immunodeficiency Diseases, Safety-net Providers
- Published
- 2021
- Full Text
- View/download PDF
20. Infection Phenotypes Among Patients with Primary Antibody Deficiency Mined from a US Patient Registry.
- Author
-
Pickett G, Motazedi T, Kutac C, Cahill G, Cunnigham-Rundles C, Fuleihan RL, Sullivan KE, and Rider NL
- Subjects
- Agammaglobulinemia immunology, Female, Humans, Immunologic Deficiency Syndromes complications, Immunologic Deficiency Syndromes immunology, Male, Phenotype, Registries, Retrospective Studies, Infections etiology, Infections immunology, Primary Immunodeficiency Diseases complications, Primary Immunodeficiency Diseases immunology
- Abstract
Purpose: Primary immunodeficiency disorders (PIDs) affect immune system development and/or function, increase infection susceptibility, and cause dysregulation or both. Recognition of PID requires assessment about the normal state of infection frequency and microbiology. To help clarify infection characteristics, we use data mined from the US Immunodeficiency Network (USIDNET) registry among primary antibody deficiency (PAD) patients before diagnosis., Methods: We analyzed PAD patient data from the USIDNET registry prior to ultimate diagnosis. Our analysis included basic descriptive statistics for 8 major infection subtypes and significance testing for comparing infection rate by specific organisms across 7 distinct PAD subtypes., Results: Of 2038 patients reviewed, 1259 (61.8%) had infections reported prior to diagnosis. Most (77.4%) had four or less reported infections prior to diagnosis; however, some suffered up to 16 infections. Infection patterns differed across the PAD subtypes. Patients with agammaglobulinemia differed significantly from patients with all other forms of PAD studied in at least one infection category, whereas patients with CVID differed from 3 other PAD categories in at least one infection category. Patterns of infections in patients with hypogammaglobulinemia, specific antibody deficiency, and transient hypogammaglobulinemia were less unique. For each of the infection types, bacteria were the most prevalent cause of disease., Conclusions: Our data shows that distinct subtypes of PAD display unique infection patterns. We also show that patients with agammaglobulinemia suffer more invasive infections and differ most significantly from all other forms of PAD studied. Our analysis has broad implications about infection surveillance, progression, and vulnerability by PAD subtype.
- Published
- 2021
- Full Text
- View/download PDF
21. PROMIS-29 survey confirms major impact of fatigue on health-related quality of life in common variable immunodeficiency.
- Author
-
Zhang S, Kline M, Fuleihan RL, Consortium U, Scalchunes C, Sullivan KE, and Jongco AM 3rd
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Common Variable Immunodeficiency etiology, Fatigue etiology, Female, Humans, Male, Middle Aged, Public Health Surveillance, Registries, United States epidemiology, Young Adult, Common Variable Immunodeficiency epidemiology, Fatigue epidemiology, Quality of Life
- Abstract
Health-related quality of life (HRQOL) is an emerging topic of interest in patients with immunodeficiency. Information about HRQOL in common variable immunodeficiency (CVID) is limited. The primary objective was to compare primary immunodeficiency disease (PIDD) patients with and without common variable immunodeficiency (CVID) on HRQOL domains using Patient-Reported Outcomes Measurement Information System (PROMIS-29) survey data from the United States Immunodeficiency Network (USIDNET) registry. The primary endpoint variables were scores on 7 HRQOL domains. The USIDNET registry was used to select patients with baseline PROMIS-29 data collected between 2015 and 2018. Descriptive statistics, Fisher's exact test, and Student's two-sample t test were used to compare patients with CVID versus patients with non-CVID on demographic and clinical characteristics. The single-sample t test was used to compare sample means to the normed population mean of 50. A general linear model approach to multiple regression with backward selection was used to remove factors that did not contribute significant information to the multivariable models, while controlling for multiple testing. Potential explanatory variables included group (CVID/non-CVID), sex, age, and BMI. Among 184 PIDD patients, 146 (79%) were diagnosed with CVID. Patients had a mean (SD) age of 53 (13.8), were predominantly female (83%), and were Caucasian (98%). PROMIS-29 results revealed a significant effect of group (CVID/non-CVID) on the anxiety, fatigue, and social participation domains, with fatigue being the most statistically significant. Fatigue, anxiety, and social participation may be key factors influencing HRQOL among patients with CVID. Future prospective longitudinal studies using PROMIS-29 will be needed to confirm these findings and to determine the mechanisms through which these factors develop in CVID, and how they can be improved.
- Published
- 2020
- Full Text
- View/download PDF
22. Lymphoproliferative Disease in CVID: a Report of Types and Frequencies from a US Patient Registry.
- Author
-
Yakaboski E, Fuleihan RL, Sullivan KE, Cunningham-Rundles C, and Feuille E
- Subjects
- Adult, Female, Humans, Incidence, Lymphadenopathy, Lymphocytosis, Male, Middle Aged, Prevalence, Pseudolymphoma, Registries, United States epidemiology, Common Variable Immunodeficiency epidemiology, Lymphoma epidemiology, Lymphoproliferative Disorders epidemiology
- Abstract
Purpose: Lymphoproliferative disease in common variable immunodeficiency disease (CVID) is heterogeneous in pathogenesis and ranges from non-malignant lymphoid hyperplasia to lymphoma., Methods: The United States Immunodeficiency Network (USIDNET) patient registry was queried for lymphoproliferative diseases reported in CVID patients. Diagnoses included as possible manifestations of lymphoproliferation included lymphadenopathy, lymphoid hyperplasia, lymphocytic inflammation, lymphocytosis, and gammopathy., Results: Among 1091 CVID patients, lymphoproliferative conditions were reported in 17.2% (N = 188). These conditions included lymphadenopathy (N = 192, 12.3%), lymphoid hyperplasia or lymphocytic inflammation (N = 50, 4.6%), lymphocytosis (N = 3, 0.3%), and gammopathies (N = 3, 0.3%). Of the 188 patients with lymphoproliferative conditions, 15 (8%) also had a diagnosis of lymphoma, while the remaining 173 (92%) did not. Nine (4.8%) had a diagnosis of non-lymphomatous malignancy including basal cell carcinoma (N = 3, 1.6%), thyroid carcinoma (N = 2, 1.1%), gynecologic cancer (N = 2, 1.1%), testicular cancer (N = 1), and vocal cord carcinoma (N = 1). CVID patients with lymphoma were older than patients with lymphoproliferative disease who did not have a diagnosis of lymphoma at the time of analysis (median age 49 vs. 35 years, p = 0.005). CVID patients with lymphoproliferative disease had 2.5 times higher odds of having chronic lung disease compared with those with lymphoma (OR = 0.4, p = 0.049). There were no significant differences in the frequency of autoimmune, gastrointestinal, hepatic, or granulomatous disease between these populations., Conclusions: While CVID patients are at increased risk for lymphoma, lymphoproliferation may be observed in the absence of a concurrent hematologic or solid tumor malignancy.
- Published
- 2020
- Full Text
- View/download PDF
23. Pulmonary Disease Burden in Primary Immune Deficiency Disorders: Data from USIDNET Registry.
- Author
-
Patrawala M, Cui Y, Peng L, Fuleihan RL, Garabedian EK, Patel K, and Guglani L
- Subjects
- Adolescent, Adult, Comorbidity, Female, Humans, Male, Middle Aged, Phenotype, Prevalence, Retrospective Studies, United States epidemiology, Young Adult, Lung Diseases epidemiology, Primary Immunodeficiency Diseases epidemiology, Registries
- Abstract
Purpose: Pulmonary manifestations are common in patients with primary immunodeficiency disorders (PIDs) but the prevalence, specific diseases, and their patterns are not well characterized., Methods: We conducted a retrospective analysis of pulmonary diseases reported in the database of the United States Immunodeficiency Network (USIDNET), a program of the Immune Deficiency Foundation. PIDs were categorized into 10 groups and their demographics, pulmonary diagnoses and procedures, infections, prophylaxis regimens, and laboratory findings were analyzed., Results: A total of 1937 patients with various PIDs (39.3% of total patients, 49.6% male, average age 37.9 years (SD = 22.4 years)) were noted to have a pulmonary disease comorbidity. Pulmonary diseases were categorized into broad categories: airway (86.8%), parenchymal (18.5%), pleural (4.6%), vascular (4.3%), and other (13.9%) disorders. Common variable immune deficiency (CVID) accounted for almost half of PIDs associated with airway, parenchymal, and other pulmonary disorders. Pulmonary procedures performed in 392 patients were mostly diagnostic (77.3%) or therapeutic (16.3%). These patients were receiving a wide variety of treatments, which included immunoglobulin replacement (82.1%), immunosuppressive (32.2%), anti-inflammatory (12.7%), biologic (9.3%), and cytokine (7.6%)-based therapies. Prophylactic therapy was being given with antibiotics (18.1%), antifungal (3.3%), and antiviral (2.2%) medications, and 7.1% of patients were on long-term oxygen therapy due to advanced lung disease., Conclusions: Pulmonary manifestations are common in individuals with PID, but long-term pulmonary outcomes are not well known in this group of patients. Further longitudinal follow-up will help to define long-term prognosis of respiratory comorbidities and optimal treatment modalities.
- Published
- 2020
- Full Text
- View/download PDF
24. A case of aberrant CD8 T cell-restricted IL-7 signaling with a Janus kinase 3 defect-associated atypical severe combined immunodeficiency.
- Author
-
Khanolkar A, Wilks JD, Liu G, Simpson BM, Caparelli EA, Kirschmann DA, Bergerson J, and Fuleihan RL
- Subjects
- Female, Humans, Infant, Infant, Newborn, Phenotype, Phosphorylation, STAT5 Transcription Factor metabolism, Severe Combined Immunodeficiency genetics, Severe Combined Immunodeficiency therapy, Signal Transduction, Exome Sequencing, CD8-Positive T-Lymphocytes immunology, Cord Blood Stem Cell Transplantation, Interleukin-7 metabolism, Janus Kinase 3 genetics, Mutation genetics, Severe Combined Immunodeficiency diagnosis
- Abstract
Severe combined immunodeficiency (SCID) disorders compromise lymphocyte numbers and/or function. One subset of SCID typically affects T cell and Natural Killer (NK) cell development in tandem (T
- B+ NK- ) due to mutations arising in the genes encoding the common γ chain or Janus Kinase 3 (JAK3). In rare circumstances, mutations in the JAK3 gene have been reported to cause atypical SCID that selectively affects T cells (T- B+ NK+ ). Here we describe a case involving a female infant who was referred to our institution on day nine of life following an abnormal newborn screen result for T- SCID. Immunological assessments revealed a T- B+ NK+ phenotype and molecular analyses, including whole exome sequencing, identified compound heterozygous JAK3 variants (R117C and E658K). Pre-transplant phosflow analyses revealed a persistent IL-7 signaling defect, based on phospho-STAT5 measurements, only in CD8 but not CD4 T cells. Intriguingly, phospho-STAT5 signals in response to IL-2 stimulation were not affected in either CD4 or CD8 T cells. The pre-transplant clinical course was unremarkable, and the patient received a cord-blood stem cell transplant on day 716 of life. Post-transplant monitoring revealed that despite normalization of lymphocyte counts, the CD8 T cell-restricted IL-7 signaling defect was still evident at day 627 post-transplant (phospho-STAT5 signal in CD8 T cells was > 60% reduced compared with CD4 T cells). The post-transplant clinical course has also been complicated by identification of autoimmune responses and likely GVHD-induced ichthyosis. To the best of our knowledge, this report represents the third case of JAK3-associated atypical SCID reported in the literature.- Published
- 2020
- Full Text
- View/download PDF
25. Rituximab-associated Hypogammaglobulinemia in pediatric patients with autoimmune diseases.
- Author
-
Khojah AM, Miller ML, Klein-Gitelman MS, Curran ML, Hans V, Pachman LM, and Fuleihan RL
- Subjects
- Adolescent, Agammaglobulinemia epidemiology, Antirheumatic Agents therapeutic use, Child, Female, Humans, Immunoglobulin G blood, Kaplan-Meier Estimate, Male, Prevalence, Retrospective Studies, Rituximab therapeutic use, Agammaglobulinemia chemically induced, Antirheumatic Agents adverse effects, Autoimmune Diseases drug therapy, Rituximab adverse effects
- Abstract
Background: Despite the increased use of rituximab in treating pediatric patients with autoimmune diseases in the last decade, there are limited data on rituximab safety in those subjects who have a developing immune system. The objective of this study is to determine the prevalence of hypogammaglobulinemia in children with autoimmune disease receiving rituximab within the first three years of treatment in the pediatric rheumatology clinic at a tertiary care center., Methods: We conducted a retrospective chart review of 63 pediatric subjects who received rituximab for the treatment of their autoimmune disease. Immunoglobulin gamma (IgG) levels, immunosuppressive medication and the need for immunoglobulin replacement therapy were evaluated. Hypogammaglobulinemia was defined as a serum IgG level less than two standard deviations below the mean for age-matched healthy controls., Results: Twenty-eight patients (44%) were found to have hypogammaglobulinemia. Hypogammaglobulinemia occurred within the first six months of rituximab treatment in the majority of patients (22 out of 28). The occurrence of hypogammaglobulinemia varied based on the rituximab indication: 46% pediatric Systemic Lupus Erythematosus (SLE), 71% autoimmune CNS disease, 60% ANCA vasculitis, and 12% in the miscellaneous group. Autoimmune CNS disease had more severe hypogammaglobulinemia, more persistent and was associated with more frequent or severe infections. Three patients with autoimmune CNS disease and one with SLE were given IgG replacement therapy to prevent recurrent or severe infections., Conclusions: The prevalence of hypogammaglobulinemia in rituximab treated children with autoimmune disease seems to be higher than published data for adults, especially for children with autoimmune CNS disease. The onset of hypogammaglobulinemia is usually within six months of initiation of rituximab therapy. We recommend: 1) obtaining an IgG level prior to starting rituximab; 2) close monitoring for hypogammaglobulinemia after the use of rituximab in pediatric patients and 3) early institution of immunoglobulin replacement therapy if patients develop recurrent infections.
- Published
- 2019
- Full Text
- View/download PDF
26. Dominant activating RAC2 mutation with lymphopenia, immunodeficiency, and cytoskeletal defects.
- Author
-
Hsu AP, Donkó A, Arrington ME, Swamydas M, Fink D, Das A, Escobedo O, Bonagura V, Szabolcs P, Steinberg HN, Bergerson J, Skoskiewicz A, Makhija M, Davis J, Foruraghi L, Palmer C, Fuleihan RL, Church JA, Bhandoola A, Lionakis MS, Campbell S, Leto TL, Kuhns DB, and Holland SM
- Subjects
- Adolescent, Adult, Animals, Child, Preschool, Cytoskeleton pathology, Female, Gain of Function Mutation, Humans, Infant, Infant, Newborn, Lymphopenia genetics, Mice, Mice, Inbred C57BL, Pedigree, rac GTP-Binding Proteins immunology, RAC2 GTP-Binding Protein, Immunologic Deficiency Syndromes genetics, rac GTP-Binding Proteins genetics
- Abstract
Ras-related C3 botulinum toxin substrate 2 (RAC2), through interactions with reduced NAD phosphate oxidase component p67
phox , activates neutrophil superoxide production, whereas interactions with p21-activated kinase are necessary for fMLF-induced actin remodeling. We identified 3 patients with de novo RAC2[E62K] mutations resulting in severe T- and B-cell lymphopenia, myeloid dysfunction, and recurrent respiratory infections. Neutrophils from RAC2[E62K] patients exhibited excessive superoxide production, impaired fMLF-directed chemotaxis, and abnormal macropinocytosis. Cell lines transfected with RAC2[E62K] displayed characteristics of active guanosine triphosphate (GTP)-bound RAC2 including enhanced superoxide production and increased membrane ruffling. Biochemical studies demonstrated that RAC2[E62K] retains intrinsic GTP hydrolysis; however, GTPase-activating protein failed to accelerate hydrolysis resulting in prolonged active GTP-bound RAC2. Rac2+/E62K mice phenocopy the T- and B-cell lymphopenia, increased neutrophil F-actin, and excessive superoxide production seen in patients. This gain-of-function mutation highlights a specific, nonredundant role for RAC2 in hematopoietic cells that discriminates RAC2 from the related, ubiquitous RAC1.- Published
- 2019
- Full Text
- View/download PDF
27. Prevalence of Granulomas in Patients With Primary Immunodeficiency Disorders, United States: Data From National Health Care Claims and the US Immunodeficiency Network Registry.
- Author
-
Leung J, Sullivan KE, Perelygina L, Icenogle JP, Fuleihan RL, and Lanzieri TM
- Subjects
- Adolescent, Adult, Child, Child, Preschool, Comorbidity, Female, Humans, Infant, Infant, Newborn, Insurance Claim Review, Male, Middle Aged, Prevalence, Registries, United States epidemiology, Young Adult, Granuloma complications, Granuloma epidemiology, Immunologic Deficiency Syndromes complications, Immunologic Deficiency Syndromes epidemiology
- Abstract
Purpose: Granulomas are a potentially severe condition that can last for several years in persons with primary immunodeficiency disorders (PIDD). We assessed the prevalence of granulomas in patients with PIDD., Methods: We used the Truven Health MarketScan® 2005-2015 Commercial Claims and Encounters and 2006-2015 Medicaid databases and the US Immunodeficiency Network (USIDNET) PIDD registry (a program of the Immune Deficiency Foundation). Our study population consisted of persons age < 65 years with PIDD, defined as persons with ≥ 2 claims with a diagnostic code for PIDD in MarketScan databases, or patients enrolled in USIDNET. Granulomas were identified using diagnostic codes in MarketScan or provider report in USIDNET. We calculated annual prevalence of PIDD and of granulomas among PIDD patients., Results: We identified 247,474 and 40,395 persons with PIDD among commercially and Medicaid-insured persons, respectively. PIDD prevalence was 6.0/10,000 in 2005 and 11.7/10,000 in 2015 among commercially insured persons and 5.5/10,000 in 2006 and 9.6/10,000 in 2015 among Medicaid-insured persons. The prevalence of granulomas among PIDD patients was 1.2 and 1.5% among commercially and Medicaid-insured persons, respectively. In USIDNET, prevalence of granulomas was 4.4% (177/4021). The proportion with granulomas was similar across age groups in MarketScan, but varied from 2 to 9% in USIDNET. The reported prevalence of granulomas differed depending on PIDD condition: 1-2% in the MarketScan data and 0-13% in USIDNET., Conclusion: Granuloma prevalence in PIDD patients was 1-4%. Our study provides an estimate of the proportion of PIDD patients and suggests that granulomas are an uncommon occurrence among patients with PIDD.
- Published
- 2018
- Full Text
- View/download PDF
28. Low Serum IgE Is a Sensitive and Specific Marker for Common Variable Immunodeficiency (CVID).
- Author
-
Lawrence MG, Palacios-Kibler TV, Workman LJ, Schuyler AJ, Steinke JW, Payne SC, McGowan EC, Patrie J, Fuleihan RL, Sullivan KE, Lugar PL, Hernandez CL, Beakes DE, Verbsky JW, Platts-Mills TAE, Cunningham-Rundles C, Routes JM, and Borish L
- Subjects
- Adolescent, Adult, Allergens immunology, Child, Cohort Studies, Common Variable Immunodeficiency blood, Common Variable Immunodeficiency immunology, Female, Humans, Immunization, Immunoglobulin E immunology, Immunoglobulin G blood, Immunoglobulin G immunology, Immunoglobulin Isotypes blood, Immunoglobulin Isotypes immunology, Male, Sensitivity and Specificity, Young Adult, Biomarkers, Common Variable Immunodeficiency diagnosis, Immunoglobulin E blood
- Abstract
Although small prior studies have suggested that IgE can be low in common variable immunodeficiency (CVID), the workup for patients with recurrent infections and suspected hypogammaglobulinemia does not include the routine measurement of serum IgE. We sought to test the hypothesis that low/undetectable serum IgE is characteristic of CVID by comparing the frequency of low/undetectable serum IgE in healthy controls and patients with CVID. We measured total serum IgE in a large multi-center cohort of patients with CVID (n = 354) and compared this to large population-based cohorts of children and adults. We further compared IgE levels in patients with CVID to those with other forms of humoral immunodeficiency, and in a subset, measured levels of allergen-specific serum IgE and IgG subclasses. Lastly, we evaluated for the presence of IgE in commercially available immunoglobulin replacement therapy (IgRT) products. An undetectable serum IgE (< 2 IU/ml) occurs in only 3.3% (95% CI, 1.9-5.7%) of the general population. In contrast, an undetectable IgE occurs in 75.6% (95% CI, 65.6-85.7%) of patients with CVID. Conversely, a high IgE (> 180 IU/ml) is very uncommon in CVID (0.3% of patients). IgE is > 2 IU/ml in 91.2% of patients with secondary hypogammaglobulinemia, and thus, an IgE < LLOD is suggestive of a primary humoral immunodeficiency. Allergen-specific IgE is not detectable in 96.5% of patients with CVID. Sufficient quantities of IgE to change the total serum IgE are not contained in IgRT. The IgG1/IgG4 ratio is increased in subjects with low IgE, regardless of whether they are controls or have CVID. These findings support the routine measurement of serum IgE in the workup of patients with hypogammaglobulinemia.
- Published
- 2018
- Full Text
- View/download PDF
29. Autoimmune Cytopenias and Associated Conditions in CVID: a Report From the USIDNET Registry.
- Author
-
Feuille EJ, Anooshiravani N, Sullivan KE, Fuleihan RL, and Cunningham-Rundles C
- Subjects
- Adolescent, Adult, Anemia, Hemolytic diagnosis, Autoimmune Diseases diagnosis, Child, Common Variable Immunodeficiency diagnosis, Female, Humans, Male, Neutropenia diagnosis, Prevalence, Prognosis, Purpura, Thrombocytopenic, Idiopathic diagnosis, United States epidemiology, Young Adult, Anemia, Hemolytic epidemiology, Autoimmune Diseases epidemiology, Common Variable Immunodeficiency epidemiology, Neutropenia epidemiology, Purpura, Thrombocytopenic, Idiopathic epidemiology, Registries
- Abstract
Purpose: Autoimmune cytopenia is frequently a presenting manifestation of common variable immune deficiency (CVID). Studies characterizing the CVID phenotype associated with autoimmune cytopenias have mostly been limited to large referral centers. Here, we report prevalence of autoimmune cytopenias in CVID from the USIDNET Registry and compare the demographics and clinical features of patients with and without this complication., Methods: Investigators obtained demographic, laboratory, and clinical data on CVID patients within the USIDNET Registry. Patients were considered to have autoimmune cytopenia if they had a diagnosis of hemolytic anemia, immune thrombocytopenia (ITP), or autoimmune neutropenia. Baseline characteristics and associated complications of those with autoimmune cytopenia (+AC) and those without (-AC) were compared., Results: Of 990 CVID patients included in the analysis, 10.2% (N = 101) had a diagnosis consistent with autoimmune cytopenia: ITP was diagnosed in 7.4% (N = 73), hemolytic anemia in 4.5% (N = 45), and autoimmune neutropenia in 1% (N = 10). Age at diagnosis, gender, and baseline Ig values did not differ between the +AC and -AC groups. The +AC group was significantly more likely to have one or more other CVID-associated non-infectious complications (OR = 2.9; 95%-CI: 1.9-4.6, P < 0.001), including lymphoproliferation, granulomatous disease, lymphomas, hepatic disease, interstitial lung diseases, enteropathy, and organ-specific autoimmunity., Conclusions: Autoimmune cytopenias are a common manifestation in CVID and are likely to be associated with other non-infectious CVID-related conditions. In light of prior studies showing increased morbidity and mortality in CVID patients with such complications, a diagnosis of autoimmune cytopenia may have prognostic significance in CVID.
- Published
- 2018
- Full Text
- View/download PDF
30. CD4 T cell-restricted IL-2 signaling defect in a patient with a novel IFNGR1 deficiency.
- Author
-
Khanolkar A, Kirschmann DA, Caparelli EA, Wilks JD, Cerullo JM, Bergerson JRE, Jennings LJ, and Fuleihan RL
- Subjects
- Biomarkers, Female, Humans, Immunophenotyping, Infant, Lymphocyte Count, Lymphocyte Subsets immunology, Lymphocyte Subsets metabolism, Phenotype, Sequence Analysis, DNA, Interferon gamma Receptor, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes metabolism, Genetic Association Studies, Genetic Predisposition to Disease, Interleukin-2 metabolism, Receptors, Interferon deficiency, Signal Transduction
- Published
- 2018
- Full Text
- View/download PDF
31. Characterization of T and B cell repertoire diversity in patients with RAG deficiency.
- Author
-
Lee YN, Frugoni F, Dobbs K, Tirosh I, Du L, Ververs FA, Ru H, Ott de Bruin L, Adeli M, Bleesing JH, Buchbinder D, Butte MJ, Cancrini C, Chen K, Choo S, Elfeky RA, Finocchi A, Fuleihan RL, Gennery AR, El-Ghoneimy DH, Henderson LA, Al-Herz W, Hossny E, Nelson RP, Pai SY, Patel NC, Reda SM, Soler-Palacin P, Somech R, Palma P, Wu H, Giliani S, Walter JE, and Notarangelo LD
- Abstract
Recombination-activating genes 1 and 2 ( RAG1 and RAG2 ) play a critical role in T and B cell development by initiating the recombination process that controls the expression of T cell receptor (TCR) and immunoglobulin genes. Mutations in the RAG1 and RAG2 genes in humans cause a broad spectrum of phenotypes, including severe combined immunodeficiency (SCID) with lack of T and B cells, Omenn syndrome, leaky SCID, and combined immunodeficiency with granulomas or autoimmunity (CID-G/AI). Using next-generation sequencing, we analyzed the TCR and B cell receptor (BCR) repertoire in 12 patients with RAG mutations presenting with Omenn syndrome ( n = 5), leaky SCID ( n = 3), or CID-G/AI ( n = 4). Restriction of repertoire diversity skewed usage of variable (V), diversity (D), and joining (J) segment genes, and abnormalities of CDR3 length distribution were progressively more prominent in patients with a more severe phenotype. Skewed usage of V, D, and J segment genes was present also within unique sequences, indicating a primary restriction of repertoire. Patients with Omenn syndrome had a high proportion of class-switched immunoglobulin heavy chain transcripts and increased somatic hypermutation rate, suggesting in vivo activation of these B cells. These data provide a framework to better understand the phenotypic heterogeneity of RAG deficiency., (Copyright © 2016, American Association for the Advancement of Science.)
- Published
- 2016
- Full Text
- View/download PDF
32. Serologic response and clinical efficacy of influenza vaccination in children and young adults on chemotherapy for cancer.
- Author
-
Choi DK, Fuleihan RL, and Walterhouse DO
- Subjects
- Adolescent, Child, Child, Preschool, Cohort Studies, Female, Humans, Infant, Influenza, Human epidemiology, Lymphocyte Count, Male, Neoplasms immunology, Prospective Studies, Influenza Vaccines immunology, Neoplasms drug therapy
- Abstract
Background: Influenza is a health risk to children receiving chemotherapy for cancer. An absolute lymphocyte count (ALC) >1,000 cells/mm(3) has been associated with the ability to produce an immune response to influenza vaccine during chemotherapy. However, clinical efficacy of influenza vaccination during chemotherapy remains unclear., Procedure: We conducted a prospective cohort study in children receiving chemotherapy for cancer during two consecutive influenza seasons. Assessments of immune cells and serologic response were measured immediately before and after receiving influenza vaccine. Patients were monitored for influenza or influenza-like illness (ILI)., Results: Two hundred fifty-nine patients were studied over 2 years. The seroresponse rate was 62% (98/157). The median ALC at vaccination was higher in seroresponders than nonresponders, 854 cells/mm(3) versus 602 cells/mm(3) , respectively (P < 0.036). Univariate analysis showed that patients with an ALC <1,000 cells/mm(3) at the time of vaccination were twice as likely to be sero-nonresponders (P < 0.02, OR = 2.4, 95% CI: 1.1-5.0). Twelve percent (31/259) of patients developed influenza, of whom all had fever at presentation, 26% (8/31) required hospitalization, and 81% (25/31) had chemotherapy delays. No deaths were associated with influenza infection. The proportion of patients with influenza was not different between seroresponders and nonresponders., Conclusions: Influenza infection following immunization remains a source of morbidity in children undergoing chemotherapy. Lymphopenia at vaccination predicted sero-nonresponse. Seroresponse was not associated with a decreased frequency of influenza infection or ILI when compared to sero-nonresponders, suggesting clinical effectiveness of vaccination is likely multifactorial. Further investigation into the efficacy of the influenza vaccine is needed to refine immunization recommendations., (© 2016 Wiley Periodicals, Inc.)
- Published
- 2016
- Full Text
- View/download PDF
33. Hyper IgM Syndrome: a Report from the USIDNET Registry.
- Author
-
Leven EA, Maffucci P, Ochs HD, Scholl PR, Buckley RH, Fuleihan RL, Geha RS, Cunningham CK, Bonilla FA, Conley ME, Ferdman RM, Hernandez-Trujillo V, Puck JM, Sullivan K, Secord EA, Ramesh M, and Cunningham-Rundles C
- Subjects
- Adolescent, Adult, Child, Child, Preschool, Diarrhea, Female, Humans, Hyper-IgM Immunodeficiency Syndrome mortality, Hyper-IgM Immunodeficiency Syndrome therapy, Male, Middle Aged, Neutropenia, Survival Analysis, United States, Young Adult, CD40 Ligand genetics, Hematopoietic Stem Cell Transplantation, Hyper-IgM Immunodeficiency Syndrome genetics, Mutation genetics, Registries
- Abstract
Purpose: The United States Immunodeficiency Network (USIDNET) patient registry was used to characterize the presentation, genetics, phenotypes, and treatment of patients with Hyper IgM Syndrome (HIGM)., Methods: The USIDNET Registry was queried for HIGM patient data collected from October 1992 to July 2015. Data fields included demographics, criteria for diagnosis, pedigree analysis, mutations, clinical features, treatment and transplant records, laboratory findings, and mortality., Results: Fifty-two physicians entered data from 145 patients of ages 2 months to 62 years (median 12 years); 131 were males. Using patients' age at last entry, data from 2072 patient years are included. Mutations were recorded for 85 subjects; 82 were in CD40LG. Eighteen subjects had non-X-linked HIGM. 40 % had a normal serum IgM and 15 %, normal IgA. Infections were reported for 91 %, with pulmonary, ear, and sinus infections being the most common. 42 % had Pneumocystis jirovecii pneumonia; 6 % had Cryptosporidium. 41 % had neutropenia. 78 % experienced non-infectious complications: chronic diarrhea (n = 22), aphthous ulcers (n = 28), and neoplasms (n = 8) including colon cancer, adrenal adenoma, liver adenocarcinoma, pancreatic carcinoid, acute myeloid leukemia, hepatoma, and, in a female with an autosomal dominant gain of function mutation in PIK3CD, an ovarian dysgerminoma. Thirteen patients had a hematopoietic marrow or stem cell transplant; three had solid organ transplants. Thirteen were known to have died (median age = 14 years)., Conclusions: Analysis of the USIDNET Registry provides data on the common clinical features of this rare syndrome, and in contrast with previously published data, demonstrates longer survival times and reduced gastrointestinal manifestations.
- Published
- 2016
- Full Text
- View/download PDF
34. Naturally occurring tolerance acquisition to foods in previously allergic children is characterized by antigen specificity and associated with increased subsets of regulatory T cells.
- Author
-
Qamar N, Fishbein AB, Erickson KA, Cai M, Szychlinski C, Bryce PJ, Schleimer RP, Fuleihan RL, and Singh AM
- Subjects
- Adolescent, Antigens, Surface metabolism, Arachis immunology, Case-Control Studies, Child, Child, Preschool, Female, Humans, Immunoglobulin E immunology, Immunophenotyping, Infant, Interleukin-10 biosynthesis, Male, Phenotype, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets metabolism, T-Lymphocytes, Regulatory metabolism, Allergens immunology, CD4 Lymphocyte Count, Food adverse effects, Food Hypersensitivity immunology, Immune Tolerance, T-Lymphocytes, Regulatory immunology
- Abstract
Background: Food allergy affects approximately 6-8% of children, and increasing in prevalence. Some children naturally outgrow their food allergy without intervention, but the mechanisms by which this occurs remain poorly understood. We sought to investigate the role of regulatory T cells in the development of naturally acquired tolerance., Methods: Fifty-eight children (1-18 years) with either egg or peanut allergy, recent acquisition of natural tolerance to egg or peanut, or no food allergy were studied. Peripheral blood mononuclear cells (PBMC) from these groups were stimulated with relevant antigen for 48 h and flow cytometry performed to characterize both surface (CD3, CD4, CD25, CD14, CD19, and CD127) and intracellular markers (IL-10, Foxp3, and IL-5)., Results: Resting PBMC from naturally tolerant patients had significantly increased CD3+CD4+CD25+CD127loFoxp3+ cells, when compared to allergic or control patients (mean 6.36 vs. 2.37 vs. 2.62%, respectively, P < 0.05). Upon stimulation with relevant antigen, naturally tolerant patients also had increased IL-10-expressing CD25+CD127lo cells (6.33 vs. 1.65 vs. 0.7, P < 0.01), Foxp3+ cells (mean 12.6 vs. 5.42 vs. 3%, P < 0.01), and CD4+ cells (mean 4.48 vs. 1.59 vs. 0.87%, P < 0.01); the increase was not observed in PBMCs from allergic or control patients. Additionally, this upregulation was only seen with relevant antigen stimulation and not upon stimulation with unrelated antigen., Conclusion: The increased CD3+CD4+CD25+CD127lo cells at baseline and upon stimulation and increased induction of IL-10-producing cells of several types, including Tr1 cells, from naturally tolerant patients suggests an important role for regulatory T cell subsets in the acquisition of natural tolerance., (© 2015 John Wiley & Sons Ltd.)
- Published
- 2015
- Full Text
- View/download PDF
35. Signaling impairments in maternal T cells engrafted in an infant with a novel IL-2 receptor γ mutation.
- Author
-
Khanolkar A, Wilks JD, Jennings LJ, Davies JL, Zollett JA, Lott LL, Fullmer ER, Bensen NE, Carlson-Leuer KM, Tse WT, and Fuleihan RL
- Subjects
- Adult, Child, Female, Humans, Immunophenotyping, Infant, Male, Phenotype, T-Lymphocytes immunology, Cell Transplantation, Interleukin Receptor Common gamma Subunit genetics, Mutation, Signal Transduction, T-Lymphocytes metabolism, T-Lymphocytes transplantation
- Published
- 2015
- Full Text
- View/download PDF
36. Cytokine responses to egg protein in previously allergic children who developed tolerance naturally.
- Author
-
Fishbein AB, Qamar N, Erickson KA, Kwasny MJ, Cai M, Szychlinski C, Singh AM, and Fuleihan RL
- Subjects
- Adolescent, Biomarkers metabolism, Cells, Cultured, Child, Child, Preschool, Cross-Sectional Studies, Egg Hypersensitivity metabolism, Female, Humans, Immunoglobulin E metabolism, Immunoglobulin G metabolism, Interferon-gamma metabolism, Interleukin-10 metabolism, Interleukin-4 metabolism, Interleukin-5 metabolism, Leukocytes, Mononuclear immunology, Male, Egg Hypersensitivity immunology, Immune Tolerance, Leukocytes, Mononuclear metabolism, Ovalbumin pharmacology
- Published
- 2014
- Full Text
- View/download PDF
37. Transplantation outcomes for severe combined immunodeficiency, 2000-2009.
- Author
-
Pai SY, Logan BR, Griffith LM, Buckley RH, Parrott RE, Dvorak CC, Kapoor N, Hanson IC, Filipovich AH, Jyonouchi S, Sullivan KE, Small TN, Burroughs L, Skoda-Smith S, Haight AE, Grizzle A, Pulsipher MA, Chan KW, Fuleihan RL, Haddad E, Loechelt B, Aquino VM, Gillio A, Davis J, Knutsen A, Smith AR, Moore TB, Schroeder ML, Goldman FD, Connelly JA, Porteus MH, Xiang Q, Shearer WT, Fleisher TA, Kohn DB, Puck JM, Notarangelo LD, Cowan MJ, and O'Reilly RJ
- Subjects
- CD3 Complex blood, Female, Graft vs Host Disease epidemiology, Humans, Immunoglobulin A blood, Incidence, Infant, Lymphocyte Count, Male, Retreatment, Retrospective Studies, Severe Combined Immunodeficiency immunology, Severe Combined Immunodeficiency mortality, Siblings, Survival Rate, T-Lymphocytes immunology, Transplantation Conditioning, Treatment Outcome, Hematopoietic Stem Cell Transplantation adverse effects, Hematopoietic Stem Cell Transplantation mortality, Severe Combined Immunodeficiency therapy
- Abstract
Background: The Primary Immune Deficiency Treatment Consortium was formed to analyze the results of hematopoietic-cell transplantation in children with severe combined immunodeficiency (SCID) and other primary immunodeficiencies. Factors associated with a good transplantation outcome need to be identified in order to design safer and more effective curative therapy, particularly for children with SCID diagnosed at birth., Methods: We collected data retrospectively from 240 infants with SCID who had received transplants at 25 centers during a 10-year period (2000 through 2009)., Results: Survival at 5 years, freedom from immunoglobulin substitution, and CD3+ T-cell and IgA recovery were more likely among recipients of grafts from matched sibling donors than among recipients of grafts from alternative donors. However, the survival rate was high regardless of donor type among infants who received transplants at 3.5 months of age or younger (94%) and among older infants without prior infection (90%) or with infection that had resolved (82%). Among actively infected infants without a matched sibling donor, survival was best among recipients of haploidentical T-cell-depleted transplants in the absence of any pretransplantation conditioning. Among survivors, reduced-intensity or myeloablative pretransplantation conditioning was associated with an increased likelihood of a CD3+ T-cell count of more than 1000 per cubic millimeter, freedom from immunoglobulin substitution, and IgA recovery but did not significantly affect CD4+ T-cell recovery or recovery of phytohemagglutinin-induced T-cell proliferation. The genetic subtype of SCID affected the quality of CD3+ T-cell recovery but not survival., Conclusions: Transplants from donors other than matched siblings were associated with excellent survival among infants with SCID identified before the onset of infection. All available graft sources are expected to lead to excellent survival among asymptomatic infants. (Funded by the National Institute of Allergy and Infectious Diseases and others.).
- Published
- 2014
- Full Text
- View/download PDF
38. The hyper IgM syndromes.
- Author
-
Qamar N and Fuleihan RL
- Subjects
- Animals, CD40 Antigens genetics, CD40 Ligand genetics, Genetic Testing, Humans, Hyper-IgM Immunodeficiency Syndrome genetics, Immunoglobulin Class Switching genetics, Signal Transduction genetics, B-Lymphocytes immunology, CD40 Antigens metabolism, CD40 Ligand metabolism, Hyper-IgM Immunodeficiency Syndrome immunology, Stem Cell Transplantation, T-Lymphocytes immunology
- Abstract
The hyper IgM syndromes are a group of rare inherited immune deficiency disorders characterized by impairment of immunoglobulin isotype switching resulting from defects in the CD40 ligand/CD40 signaling pathway. X-linked forms of hyper IgM are caused by defects in the CD40 ligand gene or NF-κB essential modulator, while autosomal recessive forms of hyper IgM are caused by defects in CD40 or downstream signaling molecules including activation-induced cytidine deaminase, uracil N glycosylase or postmeiotic segregation increased 2. The loss of interaction between CD40 and its ligand results in an impairment of T cell function, of B cell differentiation and of monocyte function while only B cell differentiation appears to be affected in defects of sinaling molecules downstream of CD40 with the exception of defects of the NF-κB complex, which mediates signaling via multiple receptor pathways. With many genetic defects in the hyper IgM syndrome identified, it is possible to diagnose patients definitively, to perform genetic screening, and to delineate the clinical manifestations of the different diseases in this syndrome. Stem cell transplantation is an available therapeutic option for defects that result in a combined immunodeficiency while antibody replacement appears sufficient for the strictly humoral immunodeficiencies.
- Published
- 2014
- Full Text
- View/download PDF
39. A systematic analysis of recombination activity and genotype-phenotype correlation in human recombination-activating gene 1 deficiency.
- Author
-
Lee YN, Frugoni F, Dobbs K, Walter JE, Giliani S, Gennery AR, Al-Herz W, Haddad E, LeDeist F, Bleesing JH, Henderson LA, Pai SY, Nelson RP, El-Ghoneimy DH, El-Feky RA, Reda SM, Hossny E, Soler-Palacin P, Fuleihan RL, Patel NC, Massaad MJ, Geha RS, Puck JM, Palma P, Cancrini C, Chen K, Vihinen M, Alt FW, and Notarangelo LD
- Subjects
- Alleles, B-Lymphocytes immunology, B-Lymphocytes metabolism, Child, Child, Preschool, Gene Order, Gene Rearrangement, Homeodomain Proteins metabolism, Humans, Immunoglobulin Heavy Chains genetics, Infant, Infant, Newborn, Mutation, Phenotype, Severe Combined Immunodeficiency immunology, Severe Combined Immunodeficiency metabolism, T-Lymphocytes immunology, T-Lymphocytes metabolism, Genetic Association Studies, Homeodomain Proteins genetics, Severe Combined Immunodeficiency genetics, V(D)J Recombination
- Abstract
Background: The recombination-activating gene (RAG) 1/2 proteins play a critical role in the development of T and B cells by initiating the VDJ recombination process that leads to generation of a broad T-cell receptor (TCR) and B-cell receptor repertoire. Pathogenic mutations in the RAG1/2 genes result in various forms of primary immunodeficiency, ranging from T(-)B(-) severe combined immune deficiency to delayed-onset disease with granuloma formation, autoimmunity, or both. It is not clear what contributes to such heterogeneity of phenotypes., Objective: We sought to investigate the molecular basis for phenotypic diversity presented in patients with various RAG1 mutations., Methods: We have developed a flow cytometry-based assay that allows analysis of RAG recombination activity based on green fluorescent protein expression and have assessed the induction of the Ighc locus rearrangements in mouse Rag1(-/-) pro-B cells reconstituted with wild-type or mutant human RAG1 (hRAG1) using deep sequencing technology., Results: Here we demonstrate correlation between defective recombination activity of hRAG1 mutant proteins and severity of the clinical and immunologic phenotype and provide insights on the molecular mechanisms accounting for such phenotypic diversity., Conclusions: Using a sensitive assay to measure the RAG1 activity level of 79 mutations in a physiologic setting, we demonstrate correlation between recombination activity of RAG1 mutants and the severity of clinical presentation and show that RAG1 mutants can induce specific abnormalities of the VDJ recombination process., (Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
40. Chapter 27: Approach to primary immunodeficiency.
- Author
-
Uzzaman A and Fuleihan RL
- Subjects
- DiGeorge Syndrome diagnosis, DiGeorge Syndrome etiology, DiGeorge Syndrome therapy, Humans, Immunologic Deficiency Syndromes etiology, Infant, Newborn, Neonatal Screening, Immunologic Deficiency Syndromes diagnosis, Immunologic Deficiency Syndromes therapy
- Abstract
Primary immunodeficiency diseases (PID) are inherited defects of the innate or adaptive arms of the immune system that lead to an increase in the incidence, frequency, or severity of infections. There may be defects in the adaptive arm of the immune system that include combined immunodeficiency and antibody deficiency syndromes or by abnormalities in innate immunity such as disorders of phagocytes, the complement pathway, or Toll-Like receptor (TLR) mediated signaling. Recurrent sinopulmonary infections with encapsulated bacteria such as Haemophilus influenza type B or Streptococcus pneumoniae may be characteristic of an IgG antibody deficiency or dysfunction. Frequent viral, fungal, or protozoal infections may suggest T lymphocyte dysfunction. Multiple staphylococcal skin infections and fungal infections may imply neutrophil dysfunction or the hyper-IgE syndrome, and recurrent neisserial infection is a characteristic manifestation of late complement component (C5-9, or the membrane attack complex) defects. Recurrent viral or pyogenic bacterial infections often without the presence of a significant inflammatory response suggest a defect in TLR signaling. Mycobacterial infections are characteristic of defects in interleukin (IL)-12, interferon (IFN) gamma, or their receptors. Screening of newborns for T-cell lymphopenia using a polymerase chain reaction to amplify T-cell receptor excision circles (TRECs), which are formed when a T cell rearranges the variable region of its receptor, serves as a surrogate for newly synthesized naïve T cells. Because of very low numbers of TRECs, severe combined immunodeficiency, DiGeorge syndrome, and other causes of T-cell lymphopenia have been identified in newborns.
- Published
- 2012
- Full Text
- View/download PDF
41. DOCK8 deficiency, T cell receptor excision circles and newborn screening.
- Author
-
Fuleihan RL
- Subjects
- Female, Humans, Male, DNA, Circular blood, Frameshift Mutation, Gene Rearrangement, T-Lymphocyte, Guanine Nucleotide Exchange Factors genetics, Job Syndrome genetics, Neonatal Screening methods
- Published
- 2011
- Full Text
- View/download PDF
42. Impaired B cell development and function in mice with a targeted disruption of the homeobox gene Hex.
- Author
-
Bogue CW, Zhang PX, McGrath J, Jacobs HC, and Fuleihan RL
- Subjects
- Animals, Antigens, CD19 analysis, Homeodomain Proteins physiology, Immunoglobulin G biosynthesis, Immunoglobulin M biosynthesis, Leukocyte Common Antigens analysis, Mice, Mice, Inbred C57BL, Transcription Factors, B-Lymphocytes physiology, Genes, Homeobox physiology, Homeodomain Proteins genetics, Lymphopoiesis
- Abstract
Hex is a homeobox gene that is expressed in all stages of B cell development except plasma cells. We studied lymphocyte development in the absence of Hex by using the RAG1-deficient blastocyst complementation system because homozygous disruption of Hex is embryonic lethal. Hex(-/-);RAG1(-/-) chimeric mice had severely reduced numbers of mature B cells, pre-B cells, and CD5(+) B cells with a striking 15-fold increase in the percentage of B220(-)CD19(+) cells in the bone marrow. Hex(-/-);RAG1(-/-) chimeric mice failed to generate IgG antibodies to T cell-independent antigens, although their serum IgM levels and antibody responses to T cell-dependent antigens were intact. Therefore, Hex is necessary for B cell development and function and its absence results in a dramatic increase in B220(-)CD19(+) cells.
- Published
- 2003
- Full Text
- View/download PDF
43. The hygiene hypothesis and atopic disease.
- Author
-
Fuleihan RL
- Subjects
- Allergens adverse effects, Animals, Animals, Domestic, Asthma etiology, Asthma prevention & control, Child, Child Day Care Centers, Endotoxins adverse effects, Environmental Exposure adverse effects, Humans, Hypersensitivity prevention & control, Siblings, Hygiene, Hypersensitivity etiology
- Published
- 2002
- Full Text
- View/download PDF
44. CD40 ligand-deficient T cells from X-linked hyper-IgM syndrome carriers have intrinsic priming capability.
- Author
-
Lobo FM, Scholl PR, and Fuleihan RL
- Subjects
- CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes metabolism, CD40 Ligand biosynthesis, Cytokines biosynthesis, Female, Flow Cytometry, Genetic Carrier Screening, Genetic Linkage, Humans, Immunologic Deficiency Syndromes genetics, Immunologic Deficiency Syndromes immunology, Interphase genetics, Interphase immunology, Leukocyte Common Antigens biosynthesis, Male, T-Lymphocyte Subsets pathology, CD40 Ligand genetics, Hypergammaglobulinemia genetics, Hypergammaglobulinemia immunology, Immunoglobulin M biosynthesis, Lymphocyte Activation genetics, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets metabolism, X Chromosome genetics
- Abstract
Deficiency in CD40 ligand (CD40L) expression is associated with impaired T cell immunity in mouse models and in humans. Previous studies have indicated that this is due to the failure of induction of extrinsic costimulatory molecules. However, other studies have suggested that CD40L is an intrinsic costimulatory molecule. The X-linked hyper-IgM syndrome (XHIM) is a primary immunodeficiency caused by mutations in CD40L, resulting in impaired Ab production and T cell immunity. CD4+ T cells from female carriers of XHIM express a variable degree of normal CD40L based on random X chromosome inactivation. We have examined T cells from XHIM carriers to investigate whether CD40L supports T cell function by acting as an intrinsic costimulator or by induction of other costimulatory molecules by examining coexpression of CD40L and markers of T lymphocyte priming. These carriers provide a unique model for comparison of CD40L-expressing and -nonexpressing lymphocytes in that all factors, including immunological experience, are equivalent between the two populations. Our results show that compared with CD40L-deficient T cells, T cells that express CD40L normally have a minimal advantage in becoming primed, as defined by CD45 RO isoform expression and production of IFN-gamma and TNF-alpha. Conversely, CD40L-deficient T lymphocytes clearly were capable of becoming primed as defined by the same parameters. These findings imply that the intrinsic costimulatory activity of CD40L is not required for attaining primed status, and that CD40L primarily supports T cell function by inducing extrinsic factors that can be shared by CD40L-deficient cells.
- Published
- 2002
- Full Text
- View/download PDF
45. Hyper IgM syndrome: the other side of the coin.
- Author
-
Fuleihan RL
- Subjects
- Antigen-Presenting Cells immunology, Child, Ectodermal Dysplasia immunology, Humans, Hypergammaglobulinemia diagnosis, Hypergammaglobulinemia therapy, Mutation, CD40 Antigens metabolism, CD40 Ligand immunology, Hypergammaglobulinemia immunology, Immunoglobulin M blood
- Abstract
The hyper IgM syndrome is a rare, inherited immune deficiency disorder resulting from defects in the CD40 ligand/CD40-signaling pathway. X-linked hyper IgM is caused by defects in the CD40 ligand gene that prevent it from delivering an activation signal to antigen-presenting cells via CD40. Over the past year, defects in molecules involved in CD40 signaling have been shown to cause other forms of hyper IgM. These newly identified defects emphasize the importance of interaction between CD40 and its ligand in immunity and the role of these molecules in the pathogenesis of immune deficiency. With genetic defects in the hyper IgM syndrome identified, it is possible to diagnose patients definitively, to perform genetic screening, and to delineate the clinical manifestations of this syndrome. Further research may lead to novel and definitive therapeutic options for patients with hyper IgM syndrome.
- Published
- 2001
- Full Text
- View/download PDF
46. The hyper IgM syndrome.
- Author
-
Fuleihan RL
- Subjects
- CD40 Ligand genetics, Humans, Hypergammaglobulinemia therapy, Syndrome, Hypergammaglobulinemia etiology, Immunoglobulin M blood
- Abstract
The hyper IgM syndrome is a rare, inherited immune deficiency disorder resulting from defects in the CD40 ligand/CD40-signaling pathway. X-linked hyper IgM is caused by defects in the CD40 ligand gene, while autosomal recessive hyper IgM is caused by defects in the CD40-activated RNA-editing enzyme, activation-induced cytidine deaminase, which is required for immunoglobulin isotype switching and somatic hypermutation in B cells. The loss of interaction between CD40 and its ligand in X-linked hyper IgM results in an impairment of T cell function, of B cell differentiation, and of monocyte function, while only B cell differentiation appears to be affected in autosomal recessive hyper IgM. With genetic defects in the hyper IgM syndrome identified, it is possible to diagnose patients definitely, to perform genetic screening, and to delineate the clinical manifestations of this syndrome. Further research may lead to novel and definitive therapeutic options for patients with hyper IgM syndrome.
- Published
- 2001
- Full Text
- View/download PDF
47. A rare polyadenylation signal mutation of the FOXP3 gene (AAUAAA-->AAUGAA) leads to the IPEX syndrome.
- Author
-
Bennett CL, Brunkow ME, Ramsdell F, O'Briant KC, Zhu Q, Fuleihan RL, Shigeoka AO, Ochs HD, and Chance PF
- Subjects
- Cells, Cultured, DNA Mutational Analysis, DNA-Binding Proteins biosynthesis, Female, Forkhead Transcription Factors, Genetic Linkage, Humans, Male, Pedigree, RNA, Messenger analysis, Reverse Transcriptase Polymerase Chain Reaction, T-Lymphocytes metabolism, X Chromosome, DNA-Binding Proteins genetics, Mutation, Poly A metabolism, Polyendocrinopathies, Autoimmune genetics
- Abstract
The mouse scurfy gene, Foxp3, and its human orthologue, FOXP3, which maps to Xp11.23-Xq13.3, were recently identified by positional cloning. Point mutations and microdeletions of the FOXP3 gene were found in the affected members of eight of nine families with IPEX (immune dysfunction, polyendocrinopathy, enteropathy, X-linked; OMIM 304930). We evaluated a pedigree with clinically typical IPEX in which mutations of the coding exons of FOXP3 were not detected. Our reevaluation of this pedigree identified an A-->G transition within the first polyadenylation signal (AAUAAA-->AAUGAA) after the stop codon. The next polyadenylation signal is not encountered for a further 5.1 kb. This transition was not detected in over 212 normal individuals (approximately 318 X chromosomes), excluding the possibility of a rare polymorphism. We suggest that this mutation is causal of IPEX in this family by a mechanism of nonspecific degradation of the FOXP3 gene message.
- Published
- 2001
- Full Text
- View/download PDF
48. Transcriptional activity of the distal CD40 ligand promoter.
- Author
-
Lobo FM, Xu S, Lee C, and Fuleihan RL
- Subjects
- Base Sequence, Cyclosporine pharmacology, DNA Primers, DNA-Binding Proteins metabolism, Genes, Reporter, Humans, Jurkat Cells, NFATC Transcription Factors, Protein Binding, Transcription Factors metabolism, CD40 Ligand genetics, Nuclear Proteins, Promoter Regions, Genetic, Transcription, Genetic
- Abstract
CD40 ligand (CD40L, CD154) is a T cell cytokine with highly regulated expression that requires the transcription factor nuclear factor of activated T cells (NF-AT) to bind at two sites in the proximal CD40L promoter. We have determined that the distal CD40L promoter (-500 to -1300 bp from start of transcription) conveys superior promoter activity in reporter gene assays. Within the distal promoter, we have identified a third NF-AT binding site, at -761 to -756. Oligonucleotides incorporating each of the three NF-AT sites cross-compete for binding of nuclear extracts from activated T cells and bind NF-ATc2 by antibody supershift. Mutation of the distal NF-AT site reduces activity of the 1300 bp CD40L promoter construct to that of the proximal 500 bp construct, which includes only two NF-AT sites. This suggests that the newly identified NF-AT site is the major mediator of transcriptional activation in the distal CD40L promoter., (Copyright 2000 Academic Press.)
- Published
- 2000
- Full Text
- View/download PDF
49. Allergy, immunology, and related disorders.
- Author
-
Fuleihan RL
- Subjects
- Child, Genetic Therapy, Humans, Hypersensitivity therapy
- Published
- 2000
- Full Text
- View/download PDF
50. When you hear hoof beats...do not forget the zebras.
- Author
-
Klock B, Pham T, Smith LS, Beris S, Lobo FM, Martin PL, Rappeport J, and Fuleihan RL
- Subjects
- Bone Marrow Transplantation, CD40 Antigens blood, Humans, Hypergammaglobulinemia diagnosis, Hypergammaglobulinemia immunology, Hypergammaglobulinemia therapy, Infant, Male, Syndrome, Hypergammaglobulinemia genetics, Immunoglobulin M, X Chromosome genetics
- Published
- 2000
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.