The Experts below are selected from a list of 270 Experts worldwide ranked by ideXlab platform
Donald B Kohn - One of the best experts on this subject based on the ideXlab platform.
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consensus approach for the management of severe combined Immune Deficiency caused by adenosine deaminase Deficiency
The Journal of Allergy and Clinical Immunology, 2019Co-Authors: Donald B Kohn, Jennifer M Puck, Luigi D Notarangelo, Michael S Hershfield, Bobby H Gaspar, Alessandro Aiuti, Annaliesse Blincoe, Eyal GrunebaumAbstract:Inherited defects in adenosine deaminase (ADA) cause a subtype of severe combined immunoDeficiency (SCID) known as severe combined Immune Deficiency caused by adenosine deaminase defects (ADA-SCID). Most affected infants can receive a diagnosis while still asymptomatic by using an SCID newborn screening test, allowing early initiation of therapy. We review the evidence currently available and propose a consensus management strategy. In addition to treatment of the Immune Deficiency seen in patients with ADA-SCID, patients should be followed for specific noninfectious respiratory, neurological, and biochemical complications associated with ADA Deficiency. All patients should initially receive enzyme replacement therapy (ERT), followed by definitive treatment with either of 2 equal first-line options. If an HLA-matched sibling donor or HLA-matched family donor is available, allogeneic hematopoietic stem cell transplantation (HSCT) should be pursued. The excellent safety and efficacy observed in more than 100 patients with ADA-SCID who received gammaretrovirus- or lentivirus-mediated autologous hematopoietic stem cell gene therapy (HSC-GT) since 2000 now positions HSC-GT as an equal alternative. If HLA-matched sibling donor/HLA-matched family donor HSCT or HSC-GT are not available or have failed, ERT can be continued or reinstituted, and HSCT with alternative donors should be considered. The outcomes of novel HSCT, ERT, and HSC-GT strategies should be evaluated prospectively in "real-life" conditions to further inform these management guidelines.
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Adenosine Deaminase (ADA)-Deficient Severe Combined Immune Deficiency (SCID): Molecular Pathogenesis and Clinical Manifestations
Journal of Clinical Immunology, 2017Co-Authors: Kathryn L. Bradford, Federico A. Moretti, Denise A. Carbonaro-sarracino, Hubert B. Gaspar, Donald B KohnAbstract:Deficiency of adenosine deaminase (ADA, EC3.5.4.4), a housekeeping enzyme of purine metabolism encoded by the Ada gene, is a cause of human severe combined Immune Deficiency (SCID). Numerous deleterious mutations occurring in the ADA gene have been found in patients with profound lymphopenia (T^− B^− NK^−), thus underscoring the importance of functional purine metabolism for the development of the Immune defense. While untreated ADA SCID is a fatal disorder, there are multiple life-saving therapeutic modalities to restore ADA activity and reconstitute protective immunity, including enzyme replacement therapy (ERT), allogeneic hematopoietic stem cell transplantation (HSCT) and gene therapy (GT) with autologous gene-corrected hematopoietic stem cells (HSC). We review the pathogenic mechanisms and clinical manifestations of ADA SCID.
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how we manage adenosine deaminase deficient severe combined Immune Deficiency ada scid
Journal of Clinical Immunology, 2017Co-Authors: Donald B Kohn, Bobby H GasparAbstract:Adenosine deaminase-deficient severe combined Immune Deficiency (ADA SCID) accounts for 10-15% of cases of human SCID. From what was once a uniformly fatal disease, the prognosis for infants with ADA SCID has improved greatly based on the development of multiple therapeutic options, coupled with more frequent early diagnosis due to implementation of newborn screening for SCID. We review the various treatment approaches for ADA SCID including allogeneic hematopoietic stem cell transplantation (HSCT) from a human leukocyte antigen-matched sibling or family member or from a matched unrelated donor or a haplo-identical donor, autologous HSCT with gene correction of the hematopoietic stem cells (gene therapy-GT), and enzyme replacement therapy (ERT) with polyethylene glycol-conjugated adenosine deaminase. Based on growing evidence of safety and efficacy from GT, we propose a treatment algorithm for patients with ADA SCID that recommends HSCT from a matched family donor, when available, as a first choice, followed by GT as the next option, with allogeneic HSCT from an unrelated or haplo-identical donor or long-term ERT as other options.
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primary Immune Deficiency treatment consortium pidtc report
The Journal of Allergy and Clinical Immunology, 2014Co-Authors: Linda M Griffith, Jennifer M Puck, Luigi D Notarangelo, Morton J Cowan, Donald B Kohn, Sungyun Pai, Barbara Ballard, Sarah C Bauer, Jack J Bleesing, Marcia BoyleAbstract:The Primary Immune Deficiency Treatment Consortium (PIDTC) is a network of 33 centers in North America that study the treatment of rare and severe primary immunoDeficiency diseases. Current protocols address the natural history of patients treated for severe combined immunoDeficiency (SCID), Wiskott-Aldrich syndrome, and chronic granulomatous disease through retrospective, prospective, and cross-sectional studies. The PIDTC additionally seeks to encourage training of junior investigators, establish partnerships with European and other International colleagues, work with patient advocacy groups to promote community awareness, and conduct pilot demonstration projects. Future goals include the conduct of prospective treatment studies to determine optimal therapies for primary immunoDeficiency diseases. To date, the PIDTC has funded 2 pilot projects: newborn screening for SCID in Navajo Native Americans and B-cell reconstitution in patients with SCID after hematopoietic stem cell transplantation. Ten junior investigators have received grant awards. The PIDTC Annual Scientific Workshop has brought together consortium members, outside speakers, patient advocacy groups, and young investigators and trainees to report progress of the protocols and discuss common interests and goals, including new scientific developments and future directions of clinical research. Here we report the progress of the PIDTC to date, highlights of the first 2 PIDTC workshops, and consideration of future consortium objectives.
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improving cellular therapy for primary Immune Deficiency diseases recognition diagnosis and management
The Journal of Allergy and Clinical Immunology, 2009Co-Authors: Linda M Griffith, Jennifer M Puck, Luigi D Notarangelo, Morton J Cowan, Rebecca H Buckley, Fabio Candotti, Mary Ellen Conley, Thomas A Fleisher, Bobby H Gaspar, Donald B KohnAbstract:More than 20 North American academic centers account for the majority of hematopoietic stem cell transplantation (HCT) procedures for primary immunoDeficiency diseases (PIDs), with smaller numbers performed at additional sites. Given the importance of a timely diagnosis of these rare diseases and the diversity of practice sites, there is a need for guidance as to best practices in management of patients with PIDs before, during, and in follow-up for definitive treatment. In this conference report of Immune Deficiency experts and HCT physicians who care for patients with PIDs, we present expert guidance for (1) PID diagnoses that are indications for HCT, including severe combined immunoDeficiency disease (SCID), combined immunoDeficiency disease, and other non-SCID diseases; (2) the critical importance of a high degree of suspicion of the primary care physician and timeliness of diagnosis for PIDs; (3) the need for rapid referral to an Immune Deficiency expert, center with experience in HCT, or both for patients with PIDs; (4) medical management of a child with suspicion of SCID/combined immunoDeficiency disease while confirming the diagnosis, including infectious disease management and workup; (5) the posttransplantation follow-up visit schedule; (6) antimicrobial prophylaxis after transplantation, including gamma globulin administration; and (7) important indications for return to the transplantation center after discharge. Finally, we discuss the role of high-quality databases in treatment of PIDs and HCT as an element of the infrastructure that will be needed for productive multicenter clinical trials in these rare diseases.
Charlotte Cunninghamrundles - One of the best experts on this subject based on the ideXlab platform.
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current genetic landscape in common variable Immune Deficiency
Blood, 2020Co-Authors: Lennart Hammarstrom, Hassan Abolhassani, Charlotte CunninghamrundlesAbstract:Abstract Using whole-exome sequencing to examine the genetic causes of Immune Deficiency in 235 common variable immunoDeficiency (CVID) patients seen in the United States (Mount Sinai, New York), 128 patients from Sweden, and 208 from Iran revealed 68 known disease-causing genes underlying this heterogeneous Immune defect. The patients at the time of study ranged from 4 to 90 years of age. Overall, 31%, 36%, and 54% of the patients in the US, Swedish, or Iranian cohorts had mutations. The multiplicity of genes identified in the 571 subjects reflects the complex requirements of B-cell antigen signaling, activation, survival, migration, maturation, and maintenance of antibody-secreting memory B-cell populations to the plasma cell stage. For the US and Swedish cohorts, CVID subjects with noninfectious complications, lymphoid infiltrations, inflamatory conditions, or autoimmunity were somewhat more likely to have an identifiable gene, but in both cohorts, numerous subjects with these medical conditions had no potential gene that could be assigned. Specific clinical patterns of illnesses were also not linked to any given gene defect as there was considerable overlap in clinical presentations. These observations led to a new perspective on the complexity of the immunologic phenotype found in CVID syndrome.
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clonal and constricted t cell repertoire in common variable Immune Deficiency
Clinical Immunology, 2017Co-Authors: Manish Ramesh, David Hamm, Noa Simchoni, Charlotte CunninghamrundlesAbstract:We used high throughput sequencing to examine the structure and composition of the T cell receptor β chain in Common Variable Immune Deficiency (CVID). TCRβ CDR3 regions were amplified and sequenced from genomic DNA of 44 adult CVID subjects and 22 healthy adults, using a high-throughput multiplex PCR. CVID TCRs had significantly less junctional diversity, fewer n-nucleotide insertions and deletions, and completely lacked a population of highly modified TCRs, with 13 or more V-gene nucleotide deletions, seen in healthy controls. The CVID CDR3 sequences were significantly more clonal than control DNA, and displayed unique V gene usage. Despite reduced junctional diversity, increased clonality and similar infectious exposures, DNA of CVID subjects shared fewer TCR sequences as compared to controls. These abnormalities are pervasive, found in out-of-frame sequences and thus independent of selection and were not associated with specific clinical complications. These data support an inherent T cell defect in CVID.
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the many faces of the clinical picture of common variable Immune Deficiency
Current Opinion in Allergy and Clinical Immunology, 2012Co-Authors: Elena S Resnick, Charlotte CunninghamrundlesAbstract:Purpose of reviewTo summarize the recent advancements in common variable Immune Deficiency (CVID), specifically CVID genetics, clinical discoveries and treatment implications.Recent findingsLarge genomic studies have implicated new genes in the pathogenesis of CVID, and basic science studies have co
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morbidity and mortality in common variable Immune Deficiency over 4 decades
Blood, 2012Co-Authors: Elena S Resnick, Erin Moshier, James Godbold, Charlotte CunninghamrundlesAbstract:The demographics, immunologic parameters, medical complications, and mortality statistics from 473 subjects with common variable Immune Deficiency followed over 4 decades in New York were analyzed. Median immunoglobulin levels were IgG, 246 mg/dL; IgA, 8 mg/dL; and IgM, 21 mg/dL; 22.6% had an IgG less than 100 mg/dL. Males were diagnosed earlier (median age, 30 years) than females (median age, 33.5 years; P = .004). Ninety-four percent of patients had a history of infections; 68% also had noninfectious complications: hematologic or organ-specific autoimmunity, 28.6%; chronic lung disease, 28.5%; bronchiectasis, 11.2%; gastrointestinal inflammatory disease, 15.4%; malabsorption, 5.9%; granulomatous disease, 9.7%; liver diseases and hepatitis, 9.1%; lymphoma, 8.2%; or other cancers, 7.0%. Females had higher baseline serum IgM (P = .009) and were more likely to develop lymphoma (P = .04); 19.6% of patients died, a significantly shorter survival than age- and sex-matched population controls (P < .0001). Reduced survival was associated with age at diagnosis, lower baseline IgG, higher IgM, and fewer peripheral B cells. The risk of death was 11 times higher for patients with noninfectious complications (hazard ratio = 10.95; P < .0001). Mortality was associated with lymphoma, any form of hepatitis, functional or structural lung impairment, and gastrointestinal disease with or without malabsorption, but not with bronchiectasis, autoimmunity, other cancers, granulomatous disease, or previous splenectomy.
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how i treat common variable Immune Deficiency
Blood, 2010Co-Authors: Charlotte CunninghamrundlesAbstract:Common variable immunoDeficiency is a rare Immune Deficiency, characterized by low levels of serum immunoglobulin G, A, and/or M with loss of antibody production. The diagnosis is most commonly made in adults between the ages of 20 and 40 years, but both children and older adults can be found to have this Immune defect. The range of clinical manifestations is broad, including acute and chronic infections, inflammatory and autoImmune disease, and an increased incidence of cancer and lymphoma. For all these reasons, the disease phenotype is both heterogeneous and complex. Contributing to the complexity is that patient cohorts are generally small, criteria used for diagnosis vary, and the doses of replacement Immune globulin differ. In addition, routines for monitoring patients over the years and protocols for the use of other biologic agents for complications have not been clarified or standardized. In the past few years, data from large patient registries have revealed that both selected laboratory markers and clinical phenotyping may aid in dissecting groups of subjects into biologically relevant categories. This review presents my approach to the diagnosis and treatment of patients with common variable immunoDeficiency, with suggestions for the use of laboratory biomarkers and means of monitoring patients.
Luigi D Notarangelo - One of the best experts on this subject based on the ideXlab platform.
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Immune dysregulation in patients with rag Deficiency and other forms of combined Immune Deficiency
Blood, 2020Co-Authors: Ottavia M Delmonte, Anna Villa, Luigi D NotarangeloAbstract:Traditionally, primary Immune deficiencies have been defined based on increased susceptibility to recurrent and/or severe infections. However, Immune dysregulation, manifesting with autoimmunity or hyperinflammatory disease, has emerged as a common feature. This is especially true in patients affected by combined Immune Deficiency (CID), a group of disorders caused by genetic defects that impair, but do not completely abolish, T-cell function. Hypomorphic mutations in the recombination activating genes RAG1 and RAG2 represent the prototype of the broad spectrum of clinical and immunological phenotypes associated with CID. The study of patients with RAG Deficiency and with other forms of CID has revealed distinct abnormalities in central and peripheral T- and B-cell tolerance as the key mechanisms involved in Immune dysregulation. Understanding the pathophysiology of autoimmunity and hyperinflammation in these disorders may also permit more targeted therapeutic interventions.
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consensus approach for the management of severe combined Immune Deficiency caused by adenosine deaminase Deficiency
The Journal of Allergy and Clinical Immunology, 2019Co-Authors: Donald B Kohn, Jennifer M Puck, Luigi D Notarangelo, Michael S Hershfield, Bobby H Gaspar, Alessandro Aiuti, Annaliesse Blincoe, Eyal GrunebaumAbstract:Inherited defects in adenosine deaminase (ADA) cause a subtype of severe combined immunoDeficiency (SCID) known as severe combined Immune Deficiency caused by adenosine deaminase defects (ADA-SCID). Most affected infants can receive a diagnosis while still asymptomatic by using an SCID newborn screening test, allowing early initiation of therapy. We review the evidence currently available and propose a consensus management strategy. In addition to treatment of the Immune Deficiency seen in patients with ADA-SCID, patients should be followed for specific noninfectious respiratory, neurological, and biochemical complications associated with ADA Deficiency. All patients should initially receive enzyme replacement therapy (ERT), followed by definitive treatment with either of 2 equal first-line options. If an HLA-matched sibling donor or HLA-matched family donor is available, allogeneic hematopoietic stem cell transplantation (HSCT) should be pursued. The excellent safety and efficacy observed in more than 100 patients with ADA-SCID who received gammaretrovirus- or lentivirus-mediated autologous hematopoietic stem cell gene therapy (HSC-GT) since 2000 now positions HSC-GT as an equal alternative. If HLA-matched sibling donor/HLA-matched family donor HSCT or HSC-GT are not available or have failed, ERT can be continued or reinstituted, and HSCT with alternative donors should be considered. The outcomes of novel HSCT, ERT, and HSC-GT strategies should be evaluated prospectively in "real-life" conditions to further inform these management guidelines.
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IMMUNOBIOLOGY Brief report Lack of iNKT cells in patients with combined Immune Deficiency due to hypomorphic RAG mutations
2016Co-Authors: Anna Villa, Cristina Sobacchi, Patricia Cortes, Dale T. Umetsu, Luigi D NotarangeloAbstract:Hypomorphic mutations of the RAG genes in humans are associated with a spec-trum of clinical and immunologic presen-tations that range from T B severe combined Immune Deficiency (SCID) to Omenn syndrome. In most cases, re-sidual V(D)J recombination activity al-lows for development of few T-cell clones, which expand in the periphery and infil-trate target organs, resulting in tissue damage. Invariant natural killer T (iNKT) cells play an important immunoregula-tory role and have been associated with protection against autoimmunity. We now report on 5 unrelated cases of combined Immune Deficiency due to hypomorphic RAG mutations, and demonstrate the ab-sence of iNKT cells in all 5 patients. These findings suggest that lack of this impor-tant immunoregulatory cell population may contribute to the pathophysiology o
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primary Immune Deficiency treatment consortium pidtc report
The Journal of Allergy and Clinical Immunology, 2014Co-Authors: Linda M Griffith, Jennifer M Puck, Luigi D Notarangelo, Morton J Cowan, Donald B Kohn, Sungyun Pai, Barbara Ballard, Sarah C Bauer, Jack J Bleesing, Marcia BoyleAbstract:The Primary Immune Deficiency Treatment Consortium (PIDTC) is a network of 33 centers in North America that study the treatment of rare and severe primary immunoDeficiency diseases. Current protocols address the natural history of patients treated for severe combined immunoDeficiency (SCID), Wiskott-Aldrich syndrome, and chronic granulomatous disease through retrospective, prospective, and cross-sectional studies. The PIDTC additionally seeks to encourage training of junior investigators, establish partnerships with European and other International colleagues, work with patient advocacy groups to promote community awareness, and conduct pilot demonstration projects. Future goals include the conduct of prospective treatment studies to determine optimal therapies for primary immunoDeficiency diseases. To date, the PIDTC has funded 2 pilot projects: newborn screening for SCID in Navajo Native Americans and B-cell reconstitution in patients with SCID after hematopoietic stem cell transplantation. Ten junior investigators have received grant awards. The PIDTC Annual Scientific Workshop has brought together consortium members, outside speakers, patient advocacy groups, and young investigators and trainees to report progress of the protocols and discuss common interests and goals, including new scientific developments and future directions of clinical research. Here we report the progress of the PIDTC to date, highlights of the first 2 PIDTC workshops, and consideration of future consortium objectives.
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improving cellular therapy for primary Immune Deficiency diseases recognition diagnosis and management
The Journal of Allergy and Clinical Immunology, 2009Co-Authors: Linda M Griffith, Jennifer M Puck, Luigi D Notarangelo, Morton J Cowan, Rebecca H Buckley, Fabio Candotti, Mary Ellen Conley, Thomas A Fleisher, Bobby H Gaspar, Donald B KohnAbstract:More than 20 North American academic centers account for the majority of hematopoietic stem cell transplantation (HCT) procedures for primary immunoDeficiency diseases (PIDs), with smaller numbers performed at additional sites. Given the importance of a timely diagnosis of these rare diseases and the diversity of practice sites, there is a need for guidance as to best practices in management of patients with PIDs before, during, and in follow-up for definitive treatment. In this conference report of Immune Deficiency experts and HCT physicians who care for patients with PIDs, we present expert guidance for (1) PID diagnoses that are indications for HCT, including severe combined immunoDeficiency disease (SCID), combined immunoDeficiency disease, and other non-SCID diseases; (2) the critical importance of a high degree of suspicion of the primary care physician and timeliness of diagnosis for PIDs; (3) the need for rapid referral to an Immune Deficiency expert, center with experience in HCT, or both for patients with PIDs; (4) medical management of a child with suspicion of SCID/combined immunoDeficiency disease while confirming the diagnosis, including infectious disease management and workup; (5) the posttransplantation follow-up visit schedule; (6) antimicrobial prophylaxis after transplantation, including gamma globulin administration; and (7) important indications for return to the transplantation center after discharge. Finally, we discuss the role of high-quality databases in treatment of PIDs and HCT as an element of the infrastructure that will be needed for productive multicenter clinical trials in these rare diseases.
Hans D. Ochs - One of the best experts on this subject based on the ideXlab platform.
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cancer in primary immunoDeficiency diseases cancer incidence in the united states Immune Deficiency network registry
The Journal of Allergy and Clinical Immunology, 2018Co-Authors: P C Mayor, Elizabeth Garabedian, Kevin H Eng, Kelly L Singel, Scott I Abrams, Kunle Odunsi, Kirsten B Moysich, Ramsay L Fuleihan, Patricia L Lugar, Hans D. OchsAbstract:Background We evaluated the overall and site-specific incidence of cancer in subjects with primary immunoDeficiency diseases (PIDD) enrolled in the United States Immune Deficiency Network (USIDNET) registry compared with age-adjusted cancer incidence in the Surveillance, Epidemiology and End Results Program (SEER) database. Objective We hypothesized that subjects with PIDD would have an increased incidence of cancer due to impaired Immune function. Methods Overall and site-specific cancer incidence rates were evaluated in subjects with PIDD ( n = 3658) enrolled in the USIDNET registry from 2003 to 2015 and compared with age-adjusted incidence rates in the SEER database. Results We observed a 1.42-fold excess relative risk of cancer in subjects with PIDD compared with the age-adjusted SEER population ( P P P P Conclusions Excess incidence of cancer occurred in subjects with PIDD. An excess of lymphoma in specific PIDD populations principally drove this increased incidence, while no increased risk of the most common solid tumor malignancies was observed. These data point to a restricted role of the Immune system in protecting from specific cancers.
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Primary Immune Deficiency disorders presenting as autoImmune diseases: IPEX and APECED.
Journal of Clinical Immunology, 2008Co-Authors: Dewton Moraes-vasconcelos, Beatriz Tavares Costa-carvalho, Troy R. Torgerson, Hans D. OchsAbstract:Background Several primary Immune Deficiency disorders are associated with autoimmunity and malignancy, suggesting a state of Immune dysregulation. The concept of Immune dysregulation as a direct cause of autoimmunity in primary Immune Deficiency disorders (PIDDs) has been strengthened by the recent discovery of distinct clinical entities linked to single-gene defects resulting in multiple autoImmune phenomena including Immune dysregulation, polyendocrinopathy, enteropathy and X-linked (IPEX) syndrome, and autoImmune polyendocrinopathy, candidiasis and ectodermal dystrophy (APECED) syndrome.
Richard Steele - One of the best experts on this subject based on the ideXlab platform.
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new diagnostic criteria for common variable Immune Deficiency cvid which may assist with decisions to treat with intravenous or subcutaneous immunoglobulin
Pediatric Hematology Oncology and Immunopathology, 2014Co-Authors: Rohan Ameratunga, Seetarn Woon, David Gillis, Wikke Koopmans, Richard SteeleAbstract:Common variable Immune Deficiency (CVID) is the most frequent symptomatic primary Immune Deficiency in adults. The standard of care is intravenous immunoglobulin (IVIG) or subcutaneous immunoglobulin (scIG) therapy. The cause of CVID is currently unknown, and there is no universally accepted definition of CVID. This creates problems in determining which patients will benefit from IVIG/scIG treatment. In this paper, we review the difficulties with the commonly used European Society of Immune Deficiencies (ESID) and the Pan American Group for ImmunoDeficiency (PAGID) definition of CVID. We propose new criteria for the diagnosis of CVID, which are based on recent scientific discoveries. Improved diagnostic precision will assist with treatment decisions including IVIG/scIG replacement. We suggest that asymptomatic patients with mild hypogammaglobulinaemia are termed hypogammaglobulinaemia of uncertain significance (HGUS). These patients require long-term follow-up, as some will evolve into CVID.
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new diagnostic criteria for common variable Immune Deficiency cvid which may assist with decisions to treat with intravenous or subcutaneous immunoglobulin
Clinical and Experimental Immunology, 2013Co-Authors: Rohan Ameratunga, Seetarn Woon, David Gillis, Wikke Koopmans, Richard SteeleAbstract:Common variable Immune Deficiency (CVID) is the most frequent symptomatic primary Immune Deficiency in adults. The standard of care is intravenous immunoglobulin (IVIG) or subcutaneous immunoglobulin (scIG) therapy. The cause of CVID is currently unknown, and there is no universally accepted definition of CVID. This creates problems in determining which patients will benefit from IVIG/scIG treatment. In this paper, we review the difficulties with the commonly used European Society of Immune Deficiencies (ESID) and the Pan American Group for Immune Deficiency (PAGID) definition of CVID. We propose new criteria for the diagnosis of CVID, which are based on recent scientific discoveries. Improved diagnostic precision will assist with treatment decisions including IVIG/scIG replacement. We suggest that asymptomatic patients with mild hypogammaglobulinaemia are termed hypogammaglobulinaemia of uncertain significance (HGUS). These patients require long-term follow-up, as some will evolve into CVID.
