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Jørgensen SF, Braadland PR, Ueland T, Fraz MSA, Michelsen AE, Holm K, Osnes LT, Trøseid M, Ueland PM, Fevang B, Aukrust P, Hov JR. Tryptophan-kynurenine metabolites associate with inflammation and immunologic phenotypes in common variable immunodeficiency. J Allergy Clin Immunol 2025:S0091-6749(25)00515-9. [PMID: 40378971 DOI: 10.1016/j.jaci.2025.04.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 04/23/2025] [Accepted: 04/29/2025] [Indexed: 05/19/2025]
Abstract
BACKGROUND A large proportion of patients with common variable immunodeficiency (CVID) have autoimmune and inflammatory manifestations characterized by chronic T-cell- and monocyte/macrophage activation of unknown etiology. The tryptophan-kynurenine pathway has previously been linked to immune activation involving T cells and monocytes/macrophages, as well as with gut microbial dysbiosis in some inflammatory diseases. OBJECTIVE We aimed to characterize the tryptophan-kynurenine pathway in CVID and its potential association with clinical/immunologic phenotype and gut microbial dysbiosis. METHODS Serum concentrations of a set of tryptophan-kynurenine pathway metabolites and neopterin were measured using liquid chromatography-tandem mass spectrometry in a discovery cohort (n = 40), a validation cohort (n = 53), and healthy controls (n = 60). B-cell phenotype was analyzed in both cohorts, whereas inflammatory markers (enzyme immunoassay), lipopolysaccharide, gut microbial composition, and food frequency questionnaire were measured in the discovery cohort. RESULTS Compared to healthy controls, CVID patients had increased metabolism of the tryptophan-kynurenine pathway as assessed by increased kynurenine/tryptophan ratio, quinolinic acid, and 3-hydroxykynurenine in both the discovery and validation cohorts. The findings were most pronounced in the subgroup with autoimmune/inflammatory complications but was to some degree also observed in CVID patients with infection only. In CVID, the metabolites in the tryptophan-kynurenine pathway associated with soluble (s) markers of monocyte (sCD14, sCD163, neopterin) and T-cell (sCD25) activation as well as B-cell phenotype (eg, naïve B cells). Individual gut microbial taxa may influence tryptophan-kynurenine pathway metabolites, but not lipopolysaccharide or diet. CONCLUSION We found altered levels of several metabolites in the tryptophan-kynurenine pathway in two different CVID cohorts associated with systemic inflammation and B-cell phenotype.
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Affiliation(s)
- Silje F Jørgensen
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway.
| | - Peder R Braadland
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Thor Ueland
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Thrombosis Research Center (TREC), Division of Internal Medicine, University Hospital of North Norway, Tromsø, Norway
| | - Mai S A Fraz
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Annika E Michelsen
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Kristian Holm
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Liv T Osnes
- Department of Immunology, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Marius Trøseid
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | | | - Børre Fevang
- Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Pål Aukrust
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Johannes R Hov
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; Section of Gastroenterology, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway
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Aykan FS, Çölkesen F, Evcen R, Kılınç M, Yıldız E, Ergün ÜY, Önalan T, Akkuş FA, Kahraman S, Gerek ME, Arslan Ş. Exploring noninfectious radiological lung findings in adult patients with primary immunodeficiency diseases. Allergol Immunopathol (Madr) 2025; 53:41-50. [PMID: 40342113 DOI: 10.15586/aei.v53i3.1302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Accepted: 03/20/2025] [Indexed: 05/11/2025]
Abstract
Primary immunodeficiency diseases (PIDs) show different patterns of airway involvement, particularly bronchiectasis; however, comparative studies of radiologic manifestations in patients with PIDs are scarce. Hence, the aim of this study to investigate radiologic lung findings in adult patients with PIDs and evaluate the possible relationship between clinical and immunologic features and respiratory function in these patients. In this study, the demographic and clinical characteristics, serum immunoglobulins (Ig), lymphocyte subgroups, high-resolution computed tomography (HRCT), and pulmonary function tests (PFTs) of 116 adult patients with PID were evaluated and those with and without abnormal HRCT were compared. The median age was 40 (28-48) years, and there were 51 (44%) females. Abnormal findings were detected in 55.2% of the HRCTs, but the most common findings were bronchiectasis (30.2%), bilateral involvement (73.5%), and lower lobe predominance. The median age and age of diagnosis were higher in those with HRCT findings. The obstructive pattern was the most common found in the PFTs. Forced vital capacity, maximal mid-expiratory flow at 25-75%, immunoglobulin G (IgG), immunoglobulin A (IgA), immunoglobulin M (IgM), cluster of differentiation (CD)4+ T cell, CD4+/CD8+ ratio, and class-switched memory B (cSMB) cell levels were significantly lower, whereas mortality was higher. Noninfectious pulmonary complications are among the important causes of morbidity and mortality in PID that could result in chronic lung disease despite adequate Ig therapy. Considering the extra radiation dose of HRCT, clinical findings and immunological and PFT parameters accompanying radiological features may be helpful in predicting the diagnosis; it may also be useful in determining additional treatment modalities and reducing mortality.
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Affiliation(s)
- Filiz Sadi Aykan
- Division of Clinical Immunology and Allergy, Department of Internal Medicine, Ankara Health Sciences University Gülhane Training and Research Hospital, Ankara, Türkiye;
| | - Fatih Çölkesen
- Division of Clinical Immunology and Allergy, Department of Internal Medicine, Necmettin Erbakan University Faculty of Medicine, Konya, Türkiye
| | - Recep Evcen
- Division of Clinical Immunology and Allergy, Department of Internal Medicine, Recep Tayyip Erdoğan University Training and Research Hospital, Rize, Türkiye
| | - Mehmet Kılınç
- Division of Clinical Immunology and Allergy, Department of Internal Medicine, Batman Training and Research Hospital, Batman, Türkiye
| | - Eray Yıldız
- Division of Clinical Immunology and Allergy, Department of Internal Medicine, Necip Fazıl City Hospital, Kahramanmaraş, Türkiye
| | - Ümmügülsüm Yılmaz Ergün
- Division of Clinical Immunology and Allergy, Department of Internal Medicine, Necmettin Erbakan University Faculty of Medicine, Konya, Türkiye
| | - Tuğba Önalan
- Division of Clinical Immunology and Allergy, Department of Internal Medicine, Necmettin Erbakan University Faculty of Medicine, Konya, Türkiye
| | - Fatma Arzu Akkuş
- Division of Clinical Immunology and Allergy, Department of Internal Medicine, Necmettin Erbakan University Faculty of Medicine, Konya, Türkiye
| | - Selim Kahraman
- Division of Clinical Immunology and Allergy, Department of Internal Medicine, Necmettin Erbakan University Faculty of Medicine, Konya, Türkiye
| | - Mehmet Emin Gerek
- Division of Clinical Immunology and Allergy, Department of Internal Medicine, Necmettin Erbakan University Faculty of Medicine, Konya, Türkiye
| | - Şevket Arslan
- Division of Clinical Immunology and Allergy, Department of Internal Medicine, Necmettin Erbakan University Faculty of Medicine, Konya, Türkiye
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Lakhal M, El Baroudi T, Rhazari M, Gartini S, Thouil A, Kouismi H. Common Variable Immunodeficiency Revealed by Bronchiectasis: A Case Report. Cureus 2025; 17:e81647. [PMID: 40322360 PMCID: PMC12048885 DOI: 10.7759/cureus.81647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/03/2025] [Indexed: 05/08/2025] Open
Abstract
We report a case of a 38-year-old female with a past medical history of lymph node tuberculosis treated for six months in 2015, history of bronchiectasis from the past six years, and recurrent sinopulmonary infections, who was subsequently diagnosed to have common variable immunodeficiency (CVID). She had reduced levels of immunoglobulins during our diagnostic workup, after ruling out hematological malignancy and solid tumors. CVID is a highly heterogeneous group of disorders characterized by a primary defect in immunoglobulin production and an inability to mount a specific humoral response against exogenous antigens. The most frequently reported pulmonary manifestations of CVID are infectious pneumonias. Bronchiectasis, resulting from recurrent infections, is the third most common pulmonary manifestation observed in CVID patients, following pneumonia and bacterial bronchitis. The therapeutic management of CVID focuses on evaluating complications, with particular emphasis on the risks of bronchial dystrophy (bronchiectasis) and bronchial colonization by antibiotic-resistant pathogens. Respiratory physiotherapy is a key element in the management of bronchial suppuration. Treatment for CVID mainly consists of immunoglobulin replacement therapy, administered intravenously or subcutaneously, which must be given for life.
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Affiliation(s)
- Mohamed Lakhal
- Department of Pulmonology, Research and Medical Sciences Laboratory, Centre Hospitalier Universitaire (CHU) Mohammed VI, Faculty of Medicine and Pharmacy, Mohammed I University, Oujda, MAR
| | - Touria El Baroudi
- Department of Pulmonology, Research and Medical Sciences Laboratory, Centre Hospitalier Universitaire (CHU) Mohammed VI, Faculty of Medicine and Pharmacy, Mohammed I University, Oujda, MAR
| | - Meriem Rhazari
- Department of Pulmonology, Research and Medical Sciences Laboratory, Centre Hospitalier Universitaire (CHU) Mohammed VI, Faculty of Medicine and Pharmacy, Mohammed I University, Oujda, MAR
| | - Sara Gartini
- Department of Pulmonology, Research and Medical Sciences Laboratory, Centre Hospitalier Universitaire (CHU) Mohammed VI, Faculty of Medicine and Pharmacy, Mohammed I University, Oujda, MAR
| | - Afaf Thouil
- Department of Pulmonology, Research and Medical Sciences Laboratory, Centre Hospitalier Universitaire (CHU) Mohammed VI, Faculty of Medicine and Pharmacy, Mohammed I University, Oujda, MAR
| | - Hatim Kouismi
- Department of Pulmonology, Research and Medical Sciences Laboratory, Centre Hospitalier Universitaire (CHU) Mohammed VI, Faculty of Medicine and Pharmacy, Mohammed I University, Oujda, MAR
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Khadka S, Shrestha R, Pandian S, Upadhyay M. From recurrent infections to ulcerative colitis: a case report on the diagnostic challenge of CVID. Ann Med Surg (Lond) 2025; 87:2473-2476. [PMID: 40212137 PMCID: PMC11981455 DOI: 10.1097/ms9.0000000000003164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Accepted: 02/28/2025] [Indexed: 04/13/2025] Open
Abstract
Introduction and importance Common Variable Immunodeficiency (CVID) is a rare primary immunodeficiency with complex presentations, including recurrent infections and autoimmune diseases. Given its rarity and overlapping symptoms with other gastrointestinal and infectious conditions, it is often overlooked. This case underscores the importance of considering CVID as a differential diagnosis when evaluating patients with recurrent infections and persistent gastrointestinal manifestations. It highlights the complexities of diagnosing and managing multifaceted, multisystemic disorders and reinforces the need for a personalized approach to treatment. We present a 68-year-old male with recurrent infections, gastrointestinal symptoms, and a family history of autoimmune disease and consanguinity. Initially diagnosed with malabsorption syndrome, the patient was later found to have ulcerative colitis (UC) and CVID. Case presentation A 68-year-old Asian male with a history of recurrent pulmonary infections, chronic diarrhea, and fatigue presented with a family history of autoimmune diseases. Investigations revealed a marked reduction in immunoglobulin levels, leading to the diagnosis of CVID. Further investigations, including a colonoscopy, confirmed the presence of UC. The patient was treated with intravenous immunoglobulin (IVIG), corticosteroids, and azathioprine. The patient's condition stabilized, and his infection frequency reduced significantly. Discussion This case illustrates the complexity of diagnosing CVID, particularly when accompanied by autoimmune disorders like UC. The patient's overlapping symptoms of chronic infection, gastrointestinal distress and lack of proper follow through led to delayed diagnosis and treatment. Conclusion This case underscores the importance of considering CVID in patients with recurrent infections and unexplained gastrointestinal symptoms, particularly when there is a family history of autoimmune diseases.
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Tsoulis MW, Williams KW. Keeping up with recent developments in immunodeficiency. Ann Allergy Asthma Immunol 2025; 134:259-268. [PMID: 39716531 DOI: 10.1016/j.anai.2024.12.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 12/06/2024] [Accepted: 12/16/2024] [Indexed: 12/25/2024]
Abstract
Inborn errors of immunity (IEIs) are a rapidly expanding group of monogenetic disorders affecting the immune system. Advancements in genetic testing and functional validation studies have accelerated the pace of IEI gene discovery and mechanism of disease, particularly in the past 5 years. To keep up with this rapid expansion, the International Union of Immunological Societies Expert Committee has periodically, since 1999, released updated IEI classifications with corresponding genotypic and phenotypic catalogues with its most recent update in 2022. Now, there are more than 485 monogenetic disorders of the immune system described among 10 main groups of classification. This article reviews recent clinical developments in IEI, including a closer look at some of the more recently described IEI disorders. In particular, we highlight a few disorders with the following clinical phenotypes of IEI: severe atopy, immunodeficiency with immune dysregulation, immune dysregulation with lymphoproliferation, autoinflammation, and innate phenotype. To aid the clinician, we also provide a diagnostic approach to use when there is suspicion of IEI and a discussion of management and treatment.
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Affiliation(s)
- Michael W Tsoulis
- Section of Allergy and Clinical Immunology, Dartmouth-Hitchcock Medical Center, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire
| | - Kelli W Williams
- Division of Pediatric Pulmonology, Allergy and Immunology, Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina.
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Özdemir Ö. Relation between dysbiosis and inborn errors of immunity. World J Methodol 2024; 14:96380. [PMID: 39712559 PMCID: PMC11287548 DOI: 10.5662/wjm.v14.i4.96380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2024] [Revised: 05/27/2024] [Accepted: 06/14/2024] [Indexed: 07/26/2024] Open
Abstract
Inborn errors of immunity (IEI) disorders, formerly primary immune deficiency diseases, are a heterogeneous group of disorders with variable hereditary transitions, clinical manifestations, complications and varying disease severity. Many of the clinical symptoms, signs and complications in IEI patients can be attributed to inflammatory and immune dysregulatory processes due to loss of microbial diversity (dysbiosis). For example, in common variable immunodeficiency patients, the diversity of bacteria, but not fungi, in the gut microbiota has been found to be reduced and significantly altered. Again, this was associated with a more severe disease phenotype. Compromise of the STAT3/Th17 pathway in hyper-IgE syndrome may lead to dysbiosis of the oral microbiota in these patients, causing Candida albicans to switch from commensal to pathogenic. Modification of the microbiota can be used as a therapeutic approach in patients with IEI. Prebiotics, probiotics, postbiotics and fecal microbiota transplantation can be used to restore the balance of the gut microbiota and reduce pathogenicity in IEI patients. Clinical trials are currently underway to understand the impact of this dysbiosis on the phenotype of IEI diseases and its role in their treatment.
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Affiliation(s)
- Öner Özdemir
- Department of Pediatric Allergy and Immunology, Sakarya University, Medical Faculty, Adapazarı 54100, Sakarya, Türkiye
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Cunningham-Rundles C, Casanova JL, Boisson B. Common variable immunodeficiency: autoimmune cytopenias and advances in molecular diagnosis. HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2024; 2024:137-142. [PMID: 39643993 DOI: 10.1182/hematology.2024000538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/09/2024]
Abstract
Common variable immunodeficiency (CVID) is one of the most common groups of human inborn errors of immunity. In addition to infections resulting from insufficient levels of immunoglobulins and antibodies, a significant proportion of patients develop autoimmune cytopenias, especially immune thrombocytopenia, hemolytic anemia, or neutropenia. They may be the initial manifestation of CVID in a patient who has not had significant infections, and similar episodes may recur at intervals over time. Treatment of these hematologic complications includes the use of corticosteroids or other medications, often including rituximab; splenectomy is discouraged. Here we outline the overall occurrence of these blood cytopenias in a cohort of 408 patients, as well as the clinical and genetic associations noted in these individuals.
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MESH Headings
- Humans
- Common Variable Immunodeficiency/diagnosis
- Common Variable Immunodeficiency/genetics
- Neutropenia/diagnosis
- Neutropenia/etiology
- Neutropenia/immunology
- Neutropenia/genetics
- Purpura, Thrombocytopenic, Idiopathic/diagnosis
- Purpura, Thrombocytopenic, Idiopathic/genetics
- Purpura, Thrombocytopenic, Idiopathic/immunology
- Anemia, Hemolytic, Autoimmune/diagnosis
- Anemia, Hemolytic, Autoimmune/immunology
- Female
- Male
- Cytopenia
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Affiliation(s)
- Charlotte Cunningham-Rundles
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
- Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY
- Division of Clinical Immunology, Departments of Medicine and Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Jean-Laurent Casanova
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- Paris Cité University, Imagine Institute, Paris, France
- Department of Pediatrics, Necker Hospital for Sick Children, Paris, France
- Howard Hughes Medical Institute, New York, NY
| | - Bertrand Boisson
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- Paris Cité University, Imagine Institute, Paris, France
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Majety SK, Modh S, Mishra D, Alam N, Suvvari TK, Pagadala CG, Muppana G. The interplay of immunity and growth: a case of combined variable immunodeficiency and growth hormone deficiency. Ann Med Surg (Lond) 2024; 86:6859-6864. [PMID: 39525729 PMCID: PMC11543155 DOI: 10.1097/ms9.0000000000002623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Accepted: 09/23/2024] [Indexed: 11/16/2024] Open
Abstract
Introduction Common variable immunodeficiency (CVID) is one of the more common immunodeficiencies seen in clinical practice with a complex disease pathology; while growth hormone deficiency (GHD) is a disorder characterized by complete or relative absence of the human growth hormone. Case presentation This case report presents a 13-year-old female patient with a long history of recurrent respiratory tract and ear infections, along with a notable failure to hit her developmental milestones early in the second decade of her life. The diagnosis was based on a thorough investigation of serum immunoglobulins for CVID and a GH stimulation test for GHD. For these, the patient was placed on a tailored regimen of IVIGs, somatropin therapy, and antibiotics for the recurrent infections. Case discussion CVID patients characteristically present with recurrent respiratory and ear infections, showing a marked decrease in immunity. Often diagnosed in childhood, GHD typically presents as growth failure along with developmental delays in dentition. There has been a notable rise in the coexistence of immunodeficiency syndromes and endocrinopathies studied in the past few decades. The case highlights and discusses the complex underlying pathology at play that links the two conditions to each other, while also excluding the various differentials. Conclusion The report highlights the various challenges faced by both clinicians and patients when dealing with dual health conditions that may have a relatively nonspecific presentation. Some of which include the diagnostic difficulties, financial strains on the patient leading to poor follow-up, and in the long-term, the development of various complications. This emphasizes the importance of early disease diagnosis and strict management protocols for the said disease, for the overall betterment of the patient's quality of life.
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Affiliation(s)
- Sameer K. Majety
- School of Medicine, Xiamen University, Xiamen, People’s Republic of China
| | - Sagar Modh
- School of Medicine, Xiamen University, Xiamen, People’s Republic of China
| | - Devrakshita Mishra
- School of Medicine, Xiamen University, Xiamen, People’s Republic of China
| | - Nafisa Alam
- School of Medicine, Xiamen University, Xiamen, People’s Republic of China
| | | | | | - Gopichand Muppana
- Vinnitsya National Pirgov Memorial and Medical University, Vinnitsya, Ukraine
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Kahn A, Luque G, Cuestas E, Basquiera A, Ricchi B, Schmitz-Abe K, Charbonnier LM, Benamar M, Motrich RD, Chatila TA, Rivero VE. Immunological biomarkers associated with survival in a cohort of Argentinian patients with common variable immunodeficiency. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. GLOBAL 2024; 3:100311. [PMID: 39282620 PMCID: PMC11393598 DOI: 10.1016/j.jacig.2024.100311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 04/25/2024] [Accepted: 04/30/2024] [Indexed: 09/19/2024]
Abstract
Background Common variable immunodeficiency (CVID) is the most common symptomatic syndrome among inborn errors of immunity. Although several aspects of CVID immunopathology have been elucidated, predictive factors for mortality are incompletely defined. A genetic cause can be identified only in approximately 30% of patients. Objective We sought to develop a mortality predictive score on the basis of the immunophenotypes and genotypes of patients with CVID. Methods Twenty-one patients diagnosed with CVID in Córdoba, Argentina, were analyzed for clinical and laboratory data. Immunophenotyping was done by flow cytometry. CVID-associated mutations were identified by whole-exome sequencing. Results Alive (15) and deceased (6) patients were compared. Univariate analysis showed significant differences in CD4+ T cells (P = .002), natural killer (NK) cells (P = .001), and memory switched B cells (P = .001) between groups. Logistic regression analysis showed a negative correlation between CD4+, NK, and memory switched B-cell counts and probability of survival over a 10-year period (CD4+ T cells: odds ratio [OR], 1.01; 95% CI, 1.001-1.020; NK cells: OR, 1.07; 95% CI, 1.02-1.17; and memory switched B cells: OR, 26.23; 95% CI, 2.06-2651.96). Receiver-operating characteristic curve analysis identified a survival cutoff point for each parameter (CD4+ T cells: 546 cells/mL; AUC, 0.87; sensitivity, 60%; specificity, 100%; memory switched B cells: 0.84 cells/mL; AUC, 0.92; sensitivity, 100%; specificity, 85%; and NK cells: 45 cells/mL; AUC, 0.92; sensitivity, 83%; specificity, 100%). Genetic analysis on 14 (9 female and 5 male) patients from the cohort revealed mutations associated with inborn errors of immunity in 6 patients. Conclusions A score to predict mortality is proposed on the basis of CD4+ T, NK, and memory switched B-cell counts in patients with CVID.
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Affiliation(s)
- Adrian Kahn
- Servicio de Alergia e Inmunología Clínica, Hospital Privado Universitario de Córdoba, Córdoba, Argentina
- Instituto Universitario de Ciencias Biomédicas de Córdoba, Córdoba, Argentina
- FOCIS Center of Excellence Centro de Inmunologia Clinica de Cordoba (CICC), Córdoba, Argentina
| | - Gabriela Luque
- Servicio de Oncohematologia, Hospital Privado Universitario de Córdoba, Córdoba, Argentina
| | - Eduardo Cuestas
- Instituto Universitario de Ciencias Biomédicas de Córdoba, Córdoba, Argentina
- Servicio de Pediatria, Hospital Privado Universitario de Córdoba, Córdoba, Argentina
| | - Ana Basquiera
- Instituto Universitario de Ciencias Biomédicas de Córdoba, Córdoba, Argentina
- Servicio de Oncohematologia, Hospital Privado Universitario de Córdoba, Córdoba, Argentina
| | - Brenda Ricchi
- Servicio de Oncohematologia, Hospital Privado Universitario de Córdoba, Córdoba, Argentina
| | - Klaus Schmitz-Abe
- Division of Immunology, Boston Children’s Hospital, Boston, Mass
- Department of Pediatrics, Harvard Medical School, Boston, Mass
- Manton Center for Orphan Disease Research, Boston Children’s Hospital, Boston, Mass
- Division of Neonatology, Department of Pediatrics, University of Miami Miller School of Medicine and Holtz Children’s Hospital, Jackson Health System, Miami, Fla
| | - Louis-Marie Charbonnier
- Division of Immunology, Boston Children’s Hospital, Boston, Mass
- Department of Pediatrics, Harvard Medical School, Boston, Mass
| | - Mehdi Benamar
- Division of Immunology, Boston Children’s Hospital, Boston, Mass
- Department of Pediatrics, Harvard Medical School, Boston, Mass
| | - Ruben Dario Motrich
- FOCIS Center of Excellence Centro de Inmunologia Clinica de Cordoba (CICC), Córdoba, Argentina
- Centro de Investigaciones en Bioquímica Clínica e Inmunología, CIBICI-CONICET, Córdoba, Argentina
- Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Talal A. Chatila
- Division of Immunology, Boston Children’s Hospital, Boston, Mass
- Department of Pediatrics, Harvard Medical School, Boston, Mass
| | - Virginia E. Rivero
- FOCIS Center of Excellence Centro de Inmunologia Clinica de Cordoba (CICC), Córdoba, Argentina
- Centro de Investigaciones en Bioquímica Clínica e Inmunología, CIBICI-CONICET, Córdoba, Argentina
- Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
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Baxter J, Waters A. CVID With Unusual Peripheral Mononeuropathy and Associated IL-7 Receptor Mutation. Mil Med 2024; 189:e1819-e1822. [PMID: 38126802 DOI: 10.1093/milmed/usad480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 11/09/2023] [Accepted: 12/08/2023] [Indexed: 12/23/2023] Open
Abstract
Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency. It is characterized by hypogammaglobulinemia and can present with a broad range of symptoms including recurrent bacterial infections, autoimmunity, and malignancy. Rarely, it has been implicated with peripheral neuropathy. We present a case of CVID with peripheral neuropathy and a pathogenic heterozygous variant of IL-7 receptor gene. The patient is a 38-year-old female with a history of recurrent infections since childhood including pneumonia and sinus infections status post tonsillectomy and sinus surgery. She subsequently developed severe left leg and lower back pain that progressed to left foot drop and decreased sensation over the left leg. She was found to have severe hypogammaglobulinemia and poor polysaccharide and protein response, thus meeting criteria for CVID. Mononeuropathy is a rare finding in CVID. Genetic panel was performed and was significant for a single pathogenic variant in IL-7 receptor. Disruptions in the IL-7 and IL-7 receptor signaling pathway have been associated with autoimmunity such as rheumatoid arthritis and multiple sclerosis. Further investigation is indicated to determine the clinical significance of this variant.
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Affiliation(s)
- Joseph Baxter
- Department of Allergy and Immunology, Wilford Hall Ambulatory Surgical Center, JBSA-Lackland AFB, TX 78236, USA
| | - Aubri Waters
- Department of Allergy and Immunology, Brooke Army Medical Center, Fort Sam Houston, TX 78234, USA
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Ganapathi L, Cochran RL, Robbins GK, Barmettler S, Holland SM, Ababneh EI. Case 20-2024: A 73-Year-Old Man with Recurrent Fever and Liver Lesions. N Engl J Med 2024; 390:2309-2319. [PMID: 38924735 DOI: 10.1056/nejmcpc2309383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/28/2024]
Affiliation(s)
- Lakshmi Ganapathi
- From the Departments of Pediatrics (L.G.), Radiology (R.L.C.), Medicine (G.K.R., S.B.), and Pathology (E.I.A.), Massachusetts General Hospital, and the Departments of Pediatrics (L.G.), Radiology (R.L.C.), Medicine (G.K.R., S.B.), and Pathology (E.I.A.), Harvard Medical School - both in Boston; and the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD (S.M.H.)
| | - Rory L Cochran
- From the Departments of Pediatrics (L.G.), Radiology (R.L.C.), Medicine (G.K.R., S.B.), and Pathology (E.I.A.), Massachusetts General Hospital, and the Departments of Pediatrics (L.G.), Radiology (R.L.C.), Medicine (G.K.R., S.B.), and Pathology (E.I.A.), Harvard Medical School - both in Boston; and the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD (S.M.H.)
| | - Gregory K Robbins
- From the Departments of Pediatrics (L.G.), Radiology (R.L.C.), Medicine (G.K.R., S.B.), and Pathology (E.I.A.), Massachusetts General Hospital, and the Departments of Pediatrics (L.G.), Radiology (R.L.C.), Medicine (G.K.R., S.B.), and Pathology (E.I.A.), Harvard Medical School - both in Boston; and the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD (S.M.H.)
| | - Sara Barmettler
- From the Departments of Pediatrics (L.G.), Radiology (R.L.C.), Medicine (G.K.R., S.B.), and Pathology (E.I.A.), Massachusetts General Hospital, and the Departments of Pediatrics (L.G.), Radiology (R.L.C.), Medicine (G.K.R., S.B.), and Pathology (E.I.A.), Harvard Medical School - both in Boston; and the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD (S.M.H.)
| | - Steven M Holland
- From the Departments of Pediatrics (L.G.), Radiology (R.L.C.), Medicine (G.K.R., S.B.), and Pathology (E.I.A.), Massachusetts General Hospital, and the Departments of Pediatrics (L.G.), Radiology (R.L.C.), Medicine (G.K.R., S.B.), and Pathology (E.I.A.), Harvard Medical School - both in Boston; and the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD (S.M.H.)
| | - Emad I Ababneh
- From the Departments of Pediatrics (L.G.), Radiology (R.L.C.), Medicine (G.K.R., S.B.), and Pathology (E.I.A.), Massachusetts General Hospital, and the Departments of Pediatrics (L.G.), Radiology (R.L.C.), Medicine (G.K.R., S.B.), and Pathology (E.I.A.), Harvard Medical School - both in Boston; and the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD (S.M.H.)
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12
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Yang M, Kaarbø M, Myhre V, Reims HM, Karlsen TH, Wang J, Rognes T, Halvorsen B, Fevang B, Lundin KEA, Aukrust P, Bjørås M, Jørgensen SF. Altered Genome-Wide DNA Methylation in the Duodenum of Common Variable Immunodeficiency Patients. J Clin Immunol 2024; 44:133. [PMID: 38780872 PMCID: PMC11116262 DOI: 10.1007/s10875-024-01726-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 04/29/2024] [Indexed: 05/25/2024]
Abstract
PURPOSE A large proportion of Common variable immunodeficiency (CVID) patients has duodenal inflammation with increased intraepithelial lymphocytes (IEL) of unknown aetiology. The histologic similarities to celiac disease, lead to confusion regarding treatment (gluten-free diet) of these patients. We aimed to elucidate the role of epigenetic DNA methylation in the aetiology of duodenal inflammation in CVID and differentiate it from true celiac disease. METHODS DNA was isolated from snap-frozen pieces of duodenal biopsies and analysed for differences in genome-wide epigenetic DNA methylation between CVID patients with increased IEL (CVID_IEL; n = 5) without IEL (CVID_N; n = 3), celiac disease (n = 3) and healthy controls (n = 3). RESULTS The DNA methylation data of 5-methylcytosine in CpG sites separated CVID and celiac diseases from healthy controls. Differential methylation in promoters of genes were identified as potential novel mediators in CVID and celiac disease. There was limited overlap of methylation associated genes between CVID_IEL and Celiac disease. High frequency of differentially methylated CpG sites was detected in over 100 genes nearby transcription start site (TSS) in both CVID_IEL and celiac disease, compared to healthy controls. Differential methylation of genes involved in regulation of TNF/cytokine production were enriched in CVID_IEL, compared to healthy controls. CONCLUSION This is the first study to reveal a role of epigenetic DNA methylation in the etiology of duodenal inflammation of CVID patients, distinguishing CVID_IEL from celiac disease. We identified potential biomarkers and therapeutic targets within gene promotors and in high-frequency differentially methylated CpG regions proximal to TSS in both CVID_IEL and celiac disease.
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Affiliation(s)
- Mingyi Yang
- Department of Microbiology, Oslo University Hospital and University of Oslo, Oslo, Norway
- Department of Medical Biochemistry, Oslo University Hospital and University of Oslo, Oslo, Norway
| | - Mari Kaarbø
- Department of Microbiology, Oslo University Hospital and University of Oslo, Oslo, Norway
| | - Vegard Myhre
- Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Henrik M Reims
- Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Tom H Karlsen
- Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
- Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Junbai Wang
- Department of Clinical Molecular Biology (EpiGen), Akershus University Hospital and University of Oslo, Lørenskog, Norway
| | - Torbjørn Rognes
- Department of Microbiology, Oslo University Hospital and University of Oslo, Oslo, Norway
- Centre for Bioinformatics, Department of Informatics, University of Oslo, Oslo, Norway
| | - Bente Halvorsen
- Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Børre Fevang
- Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Knut E A Lundin
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Pål Aukrust
- Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Magnar Bjørås
- Department of Microbiology, Oslo University Hospital and University of Oslo, Oslo, Norway
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, NTNU, Trondheim, Norway
- The Proteomics and Modomics Experimental Core Facility (PROMEC) at Norwegian University of Science and Technology, Trondheim, Norway
| | - Silje F Jørgensen
- Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway.
- Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
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13
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Franzblau LE, Fuleihan RL, Cunningham-Rundles C, Wysocki CA. CVID-Associated Intestinal Disorders in the USIDNET Registry: An Analysis of Disease Manifestations, Functional Status, Comorbidities, and Treatment. J Clin Immunol 2023; 44:32. [PMID: 38133694 DOI: 10.1007/s10875-023-01604-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Accepted: 10/30/2023] [Indexed: 12/23/2023]
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.
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Affiliation(s)
- Lauren E Franzblau
- Department of Internal Medicine, Division of Allergy and Immunology, University of Texas Southwestern, Dallas, TX, USA
| | - Ramsay L Fuleihan
- Department of Pediatrics, Division of Allergy, Immunology and Rheumatology, Columbia University Irving Medical Center, New York-Presbyterian Morgan Stanley Children's Hospital, New York, NY, USA
| | - Charlotte Cunningham-Rundles
- Departments of Medicine and Pediatrics, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Christian A Wysocki
- Departments of Internal Medicine and Pediatrics, Division of Allergy and Immunology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, F4.100B, Dallas, TX, 75390-8859, USA.
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14
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Ansari AG, Haider Mehdi HS, Nasar A. The Importance of Considering Common Variable Immunodeficiency in Patients With Chronic Diarrhea. Cureus 2023; 15:e50556. [PMID: 38222158 PMCID: PMC10787943 DOI: 10.7759/cureus.50556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/15/2023] [Indexed: 01/16/2024] Open
Abstract
Chronic diarrhea poses a diagnostic challenge due to its diverse etiology, encompassing various gastrointestinal disorders. This case report emphasizes the clinical significance of considering common variable immunodeficiency (CVID) as a potential underlying cause in a patient presenting with chronic diarrhea. In this case study, we describe a 36-year-old female with a 9-year history of chronic diarrhea, recurrent sinopulmonary infections, and weight loss for 3 years, where previous evaluations failed to yield a diagnosis. This case underscores the diagnostic hurdles faced by healthcare professionals, often causing a delay in identifying fewer common conditions like immunodeficiency syndromes. Early recognition of CVID is crucial, enabling timely intervention with immunoglobulin replacement therapy, markedly enhancing patients' quality of life and averting complications. This report highlights the necessity for a comprehensive evaluation of non-responsive chronic diarrhea cases and raises awareness about CVID as an essential consideration, facilitating precise diagnoses and tailored treatments.
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Affiliation(s)
- Ahmad G Ansari
- Medicine, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh, IND
| | | | - Ariba Nasar
- Department of Internal Medicine, Jawaharlal Nehru Medical College, Aligarh, IND
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15
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Ergi DG, Kahraman Ü, Akkuş G, Durmaz S, Balcıoğlu Ö, Engin Ç, Yağmur B, Nalbantgil S, Çiçek C, Özbaran M, Yağdı T. Antibody Response to SARS-CoV-2 Vaccination in Heart Failure Patients: Retrospective Single-Center Cohort Study. Diagnostics (Basel) 2023; 13:3460. [PMID: 37998596 PMCID: PMC10670598 DOI: 10.3390/diagnostics13223460] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Revised: 10/28/2023] [Accepted: 11/04/2023] [Indexed: 11/25/2023] Open
Abstract
We sought to investigate the impact of heart failure on anti-spike antibody positivity following SARS-CoV-2 vaccination. Our study included 103 heart failure (HF) patients, including those with and without left ventricular assist devices (LVAD) selected from our institutional transplant waiting list as well as 104 non-heart failure (NHF) patients who underwent open heart surgery at our institution from 2021 to 2022. All the patients received either heterologous or homologous doses of BNT162b2 and CoronaVac. The median age of the HF group was 56.0 (interquartile range (IQR): 48.0-62.5) and the NHF group was 63.0 (IQR: 56.0-70.2) years, and the majority were males in both groups (n = 78; 75.7% and n = 80; 76.9%, respectively). The majority of the patients in both the HF and NHF groups received heterologous vaccinations (n = 43; 41.7% and n = 52; 50.3%, respectively; p = 0.002). There was no difference in the anti-spike antibody positivity between the patients with and without heart failure (p = 0.725). Vaccination with BNT162b2 led to significantly higher antibody levels compared to CoronaVac alone (OR: 11.0; 95% CI: 3.8-31.5). With each passing day after the last vaccine dose, there was a significant decrease in anti-spike antibody positivity, with an OR of 0.9 (95% CI: 0.9-0.9). Furthermore, hyperlipidemia was associated with increased antibody positivity (p = 0.004).
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Affiliation(s)
- Defne Güneş Ergi
- Department of Cardiovascular Surgery, Faculty of Medicine, Ege University, Bornova, 35100 Izmir, Turkey; (D.G.E.); (Ü.K.); (Ç.E.); (M.Ö.)
| | - Ümit Kahraman
- Department of Cardiovascular Surgery, Faculty of Medicine, Ege University, Bornova, 35100 Izmir, Turkey; (D.G.E.); (Ü.K.); (Ç.E.); (M.Ö.)
| | - Gözde Akkuş
- Department of Microbiology, Faculty of Medicine, Ege University, Bornova, 35100 Izmir, Turkey; (G.A.); (C.Ç.)
| | - Seyfi Durmaz
- Department of Public Health, Faculty of Medicine, Ege University, Bornova, 35100 Izmir, Turkey;
| | - Özlem Balcıoğlu
- Department of Cardiovascular Surgery, Near East University Hospital, 99138 Nicosia, Cyprus;
| | - Çağatay Engin
- Department of Cardiovascular Surgery, Faculty of Medicine, Ege University, Bornova, 35100 Izmir, Turkey; (D.G.E.); (Ü.K.); (Ç.E.); (M.Ö.)
| | - Burcu Yağmur
- Department of Cardiology, Faculty of Medicine, Ege University, Bornova, 35100 Izmir, Turkey; (B.Y.); (S.N.)
| | - Sanem Nalbantgil
- Department of Cardiology, Faculty of Medicine, Ege University, Bornova, 35100 Izmir, Turkey; (B.Y.); (S.N.)
| | - Candan Çiçek
- Department of Microbiology, Faculty of Medicine, Ege University, Bornova, 35100 Izmir, Turkey; (G.A.); (C.Ç.)
| | - Mustafa Özbaran
- Department of Cardiovascular Surgery, Faculty of Medicine, Ege University, Bornova, 35100 Izmir, Turkey; (D.G.E.); (Ü.K.); (Ç.E.); (M.Ö.)
| | - Tahir Yağdı
- Department of Cardiovascular Surgery, Faculty of Medicine, Ege University, Bornova, 35100 Izmir, Turkey; (D.G.E.); (Ü.K.); (Ç.E.); (M.Ö.)
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16
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Failing C, Blase JR, Walkovich K. Understanding the Spectrum of Immune Dysregulation Manifestations in Autoimmune Lymphoproliferative Syndrome and Autoimmune Lymphoproliferative Syndrome-like Disorders. Rheum Dis Clin North Am 2023; 49:841-860. [PMID: 37821199 DOI: 10.1016/j.rdc.2023.07.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/13/2023]
Abstract
As a disorder of immune dysregulation, autoimmune lymphoproliferative syndrome (ALPS) stems from pathogenic variants in the first apoptosis signal-mediated apoptosis (Fas) and Fas-ligand pathway that result in elevations of CD3+ TCRαβ+ CD4- CD8- T cells along with chronic lymphoproliferation, a heightened risk for malignancy, and importantly for the rheumatologist, increased risk of autoimmunity. While immune cytopenias are the most encountered autoimmune phenomena, there is increasing appreciation for ocular, musculoskeletal, pulmonary and renal inflammatory manifestations similar to more common rheumatology diseases. Additionally, ALPS-like conditions that share similar clinical features and opportunities for targeted therapy are increasingly recognized via genetic testing, highlighting the need for rheumatologists to be facile in the recognition and diagnosis of this spectrum of disorders. This review will focus on clinical and laboratory features of both ALPS and ALPS-like disorders with the intent to provide a framework for rheumatologists to understand the pathophysiologic drivers and discriminate between diagnoses.
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Affiliation(s)
- Christopher Failing
- Sanford Health, Fargo, ND, USA; University of North Dakota School of Medicine and Health Sciences, Grand Folks, ND, USA.
| | - Jennifer R Blase
- University of Michigan, 1500 East Medical Center Drive, D4202 Medical Professional Building, Ann Arbor, MI 48109, USA
| | - Kelly Walkovich
- University of Michigan, 1500 East Medical Center Drive, D4202 Medical Professional Building, Ann Arbor, MI 48109, USA
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Mertowska P, Mertowski S, Smolak K, Kita G, Guz K, Kita A, Pasiarski M, Smok-Kalwat J, Góźdź S, Grywalska E. Could Immune Checkpoint Disorders and EBV Reactivation Be Connected in the Development of Hematological Malignancies in Immunodeficient Patients? Cancers (Basel) 2023; 15:4786. [PMID: 37835480 PMCID: PMC10572023 DOI: 10.3390/cancers15194786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 08/31/2023] [Accepted: 09/28/2023] [Indexed: 10/15/2023] Open
Abstract
Primary immunodeficiencies (PIDs) and secondary immunodeficiencies (SIDs) are characterized by compromised immune function, rendering individuals susceptible to infections and potentially influencing cancer development. Epstein-Barr virus (EBV), a widespread herpesvirus, has been linked to cancer, particularly in those with weakened immune systems. This study aims to compare selected immune parameters, focusing on immune checkpoint molecules (PD-1/PD-L1, CTLA-4/CD86, CD200R/CD200), and EBV reactivation in patients with chronic lymphocytic leukemia (CLL, a representative of SIDs) and common variable immunodeficiency (CVID, a representative of PIDs). We performed a correlation analysis involving patients diagnosed with CLL, CVID, and a healthy control group. EBV reactivation was assessed using specific antibody serology and viral load quantification. Peripheral blood morphology, biochemistry, and immunophenotyping were performed, with emphasis on T and B lymphocytes expressing immune checkpoints and their serum concentrations. Our findings revealed elevated EBV reactivation markers in both CLL and CVID patients compared with healthy controls, indicating increased viral activity in immunodeficient individuals. Furthermore, immune checkpoint expression analysis demonstrated significantly altered percentages of T and B lymphocytes expressing PD-1/PD-L1, CTLA-4/CD86, and CD200R/CD200 in CLL and CVID patients. This suggests a potential interplay between immune checkpoint dysregulation and EBV reactivation in the context of immunodeficiency. In conclusion, our study underscores the intricate relationship between immune dysfunction, EBV reactivation, and immune checkpoint modulation in the context of immunodeficiency-associated cancers. The altered expression of immune checkpoints, along with heightened EBV reactivation, suggests a potential mechanism for immune evasion and tumor progression. These findings provide insights into the complex interactions that contribute to cancer development in immunocompromised individuals, shedding light on potential therapeutic targets for improved management and treatment outcomes. Further investigations are warranted to elucidate the underlying mechanisms and to explore potential interventions to mitigate cancer risk in these patient populations.
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Affiliation(s)
- Paulina Mertowska
- Department of Experimental Immunology, Medical University of Lublin, 20-093 Lublin, Poland; (P.M.); (K.S.); (G.K.); (K.G.); (A.K.); (E.G.)
| | - Sebastian Mertowski
- Department of Experimental Immunology, Medical University of Lublin, 20-093 Lublin, Poland; (P.M.); (K.S.); (G.K.); (K.G.); (A.K.); (E.G.)
| | - Konrad Smolak
- Department of Experimental Immunology, Medical University of Lublin, 20-093 Lublin, Poland; (P.M.); (K.S.); (G.K.); (K.G.); (A.K.); (E.G.)
| | - Gabriela Kita
- Department of Experimental Immunology, Medical University of Lublin, 20-093 Lublin, Poland; (P.M.); (K.S.); (G.K.); (K.G.); (A.K.); (E.G.)
- Student Research Group of Experimental Immunology, Medical University of Lublin, 20-093 Lublin, Poland
| | - Katarzyna Guz
- Department of Experimental Immunology, Medical University of Lublin, 20-093 Lublin, Poland; (P.M.); (K.S.); (G.K.); (K.G.); (A.K.); (E.G.)
- Student Research Group of Experimental Immunology, Medical University of Lublin, 20-093 Lublin, Poland
| | - Aleksandra Kita
- Department of Experimental Immunology, Medical University of Lublin, 20-093 Lublin, Poland; (P.M.); (K.S.); (G.K.); (K.G.); (A.K.); (E.G.)
- Student Research Group of Experimental Immunology, Medical University of Lublin, 20-093 Lublin, Poland
| | - Marcin Pasiarski
- Department of Immunology, Faculty of Health Sciences, Jan Kochanowski University, 25-317 Kielce, Poland;
- Department of Hematology, Holy Cross Cancer Centre, 25-734 Kielce, Poland; (J.S.-K.); (S.G.)
| | - Jolanta Smok-Kalwat
- Department of Hematology, Holy Cross Cancer Centre, 25-734 Kielce, Poland; (J.S.-K.); (S.G.)
| | - Stanisław Góźdź
- Department of Hematology, Holy Cross Cancer Centre, 25-734 Kielce, Poland; (J.S.-K.); (S.G.)
- Institute of Medical Science, Collegium Medicum, Jan Kochanowski University of Kielce, IX Wieków Kielc 19A, 25-317 Kielce, Poland
| | - Ewelina Grywalska
- Department of Experimental Immunology, Medical University of Lublin, 20-093 Lublin, Poland; (P.M.); (K.S.); (G.K.); (K.G.); (A.K.); (E.G.)
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Mane V, Mehta R, Alvarez N, Sharma V, Park S, Fox A, DeCarlo C, Yang X, Perlin DS, Powell RLR. In Vivo Antiviral Efficacy of LCTG-002, a Pooled, Purified Human Milk Secretory IgA product, Against SARS-CoV-2 in a Murine Model of COVID-19. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.08.25.554813. [PMID: 37693438 PMCID: PMC10491103 DOI: 10.1101/2023.08.25.554813] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/12/2023]
Abstract
Immunoglobulin A (IgA) is the most abundant antibody (Ab) in human mucosal compartments including the respiratory tract, with the secretory form of IgA (sIgA) being dominant and uniquely stable in these environments. sIgA is naturally found in human milk, which could be considered a global resource for this biologic, justifying the development of human milk sIgA as a dedicated airway therapeutic for respiratory infections such as SARS-CoV-2. In the present study, methods were therefore developed to efficiently extract human milk sIgA from donors who were either immunologically naïve to SARS-CoV-2 (pooled as a control IgA) or had recovered from a PCR-confirmed SARS-CoV-2 infection that elicited high-titer anti-SARS-CoV-2 Spike sIgA Abs in their milk (pooled together to make LCTG-002). Mass spectrometry determined that proteins with a relative abundance of 1.0% or greater were all associated with sIgA. None of the proteins exhibited statistically significant differences between batches. Western blot demonstrated all batches consisted predominantly of sIgA. Compared to control IgA, LCTG-002 demonstrated significantly higher binding to Spike, and was also capable of blocking the Spike - ACE2 interaction in vitro with 6.3x greater potency compared to control IgA (58% inhibition at ∼240ug/mL). LCTG-002 was then tested in vivo for its capacity to reduce viral burden in the lungs of K18+hACE2 transgenic mice inoculated with SARS-CoV-2. LCTG-002 was demonstrated to significantly reduce SARS-CoV-2 titers in the lungs compared to control IgA when administered at either 250ug/day or 1 mg/day, as measured by TCID50, plaque forming units (PFU), and qRT-PCR, with a maximum reduction of 4.9 logs. This innovative study demonstrates that LCTG-002 is highly pure, efficacious, and well tolerated in vivo, supporting further development of milk-derived, polyclonal sIgA therapeutics against SARS-CoV-2 and other mucosal infections.
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Jorgensen SF, Macpherson ME, Skarpengland T, Berge RK, Fevang B, Halvorsen B, Aukrust P. Disturbed lipid profile in common variable immunodeficiency - a pathogenic loop of inflammation and metabolic disturbances. Front Immunol 2023; 14:1199727. [PMID: 37545531 PMCID: PMC10398391 DOI: 10.3389/fimmu.2023.1199727] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 07/03/2023] [Indexed: 08/08/2023] Open
Abstract
The relationship between metabolic and inflammatory pathways play a pathogenic role in various cardiometabolic disorders and is potentially also involved in the pathogenesis of other disorders such as cancer, autoimmunity and infectious diseases. Common variable immunodeficiency (CVID) is the most common primary immunodeficiency in adults, characterized by increased frequency of airway infections with capsulated bacteria. In addition, a large proportion of CVID patients have autoimmune and inflammatory complications associated with systemic inflammation. We summarize the evidence that support a role of a bidirectional pathogenic interaction between inflammation and metabolic disturbances in CVID. This include low levels and function of high-density lipoprotein (HDL), high levels of triglycerides (TG) and its major lipoprotein very low-density lipoprotein (VLDL), and an unfavorable fatty acid (FA) profile. The dysregulation of TG, VLDL and FA were linked to disturbed gut microbiota profile, and TG and VLDL levels were strongly associated with lipopolysaccharides (LPS), a marker of gut leakage in blood. Of note, the disturbed lipid profile in CVID did not include total cholesterol levels or high low-density lipoprotein levels. Furthermore, increased VLDL and TG levels in blood were not associated with diet, high body mass index and liver steatosis, suggesting a different phenotype than in patients with traditional cardiovascular risk such as metabolic syndrome. We hypothesize that these metabolic disturbances are linked to inflammation in a bidirectional manner with disturbed gut microbiota as a potential contributing factor.
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Affiliation(s)
- Silje F. Jorgensen
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Magnhild E. Macpherson
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Tonje Skarpengland
- Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Rolf K. Berge
- Department of Clinical Science, University of Bergen, Bergen, Norway
- Department of Heart Disease, Haukeland University Hospital, Bergen, Norway
| | - Børre Fevang
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Bente Halvorsen
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Pål Aukrust
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
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20
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Franzblau LE, Fuleihan RL, Cunningham-Rundles C, Wysocki CA. CVID-associated intestinal disorders in the USIDNET registry: An analysis of disease manifestations, functional status, comorbidities, and treatment. RESEARCH SQUARE 2023:rs.3.rs-2838051. [PMID: 37214897 PMCID: PMC10197741 DOI: 10.21203/rs.3.rs-2838051/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
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.
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21
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Macpherson ME, Skarpengland T, Hov JR, Ranheim T, Vestad B, Dahl TB, Fraz MSA, Michelsen AE, Holven KB, Fevang B, Berge RK, Aukrust P, Halvorsen B, Jørgensen SF. Increased Plasma Levels of Triglyceride-Enriched Lipoproteins Associate with Systemic Inflammation, Lipopolysaccharides, and Gut Dysbiosis in Common Variable Immunodeficiency. J Clin Immunol 2023:10.1007/s10875-023-01475-x. [PMID: 36995502 DOI: 10.1007/s10875-023-01475-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 03/15/2023] [Indexed: 03/31/2023]
Abstract
PURPOSE Triglycerides (TG) and their major transport lipoprotein in the circulation (VLDL) appear to be related to inflammation. Patients with common variable immunodeficiency (CVID) have inflammatory complications associated with gut microbial dysbiosis. We hypothesized that CVID patients have disturbed TG/VLDL profiles associated with these clinical characteristics. METHODS We measured plasma concentrations of TGs, inflammatory markers, and lipopolysaccharide (LPS) in 95 CVID patients and 28 healthy controls. Additionally, in 40 CVID patients, we explored plasma lipoprotein profiling, fatty acid, gut microbial dysbiosis, and diet. RESULTS TG levels were increased in CVID patients as compared to healthy controls (1.36 ± 0.53 mmol/l versus 1.08 ± 0.56 [mean, SD], respectively, P = 0.008), particularly in the clinical subgroup "Complications," characterized by autoimmunity and organ-specific inflammation, compared to "Infection only" (1.41 mmol/l, 0.71[median, IQR] versus [1.02 mmol/l, 0.50], P = 0.021). Lipoprotein profile analyses showed increased levels of all sizes of VLDL particles in CVID patients compared to controls. TG levels correlated positively with CRP (rho = 0.256, P = 0.015), IL-6 (rho = 0.237, P = 0.021), IL-12 (rho = 0.265, P = 0.009), LPS (r = 0.654, P = 6.59 × 10-13), CVID-specific gut dysbiosis index (r = 0.315, P = 0.048), and inversely with a favorable fatty acid profile (docosahexaenoic acid [rho = - 0.369, P = 0.021] and linoleic acid [rho = - 0.375, P = 0.019]). TGs and VLDL lipids did not appear to be associated with diet and there were no differences in body mass index (BMI) between CVID patients and controls. CONCLUSION We found increased plasma levels of TGs and all sizes of VLDL particles, which were associated with systemic inflammation, LPS, and gut dysbiosis in CVID, but not diet or BMI.
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Affiliation(s)
- Magnhild E Macpherson
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Tonje Skarpengland
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Johannes R Hov
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Section of Gastroenterology, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway
| | - Trine Ranheim
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Beate Vestad
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Tuva B Dahl
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Department of Acute Medicine, Oslo University Hospital, Oslo, Norway
| | - Mai S A Fraz
- Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Annika E Michelsen
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Kirsten B Holven
- Department of Nutrition, Institute for Basic Medical Sciences, University of Oslo, Oslo, Norway
- Norwegian National Advisory Unit On Familial Hypercholesterolemia, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Børre Fevang
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Centre for Rare Disorders, Oslo University Hospital, Oslo, Norway
| | - Rolf K Berge
- Department of Clinical Science, University of Bergen, N-5020, Bergen, Norway
- Department of Heart Disease, Haukeland University Hospital, N-5021, Bergen, Norway
| | - Pål Aukrust
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Bente Halvorsen
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Silje F Jørgensen
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.
- Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway.
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22
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Fevang B. Treatment of inflammatory complications in common variable immunodeficiency (CVID): current concepts and future perspectives. Expert Rev Clin Immunol 2023; 19:627-638. [PMID: 36996348 DOI: 10.1080/1744666x.2023.2198208] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/01/2023]
Abstract
INTRODUCTION Patients with Common variable immunodeficiency (CVID) have a high frequency of inflammatory complications like autoimmune cytopenias, interstitial lung disease and enteropathy. These patients have poor prognosis and effective, timely and safe treatment of inflammatory complications in CVID are essential, but guidelines and consensus on therapy are often lacking. AREAS COVERED This review will focus on current medical treatment of inflammatory complications in CVID and point out some future perspectives based on literature indexed in PubMed. There are a number of good observational studies and case reports on treatment of specific complications but randomized controlled trials are scarce. EXPERT OPINION In clinical practice, the most urgent issues that need to be addressed are the preferred treatment of GLILD, enteropathy and liver disease. Treating the underlying immune dysregulation and immune exhaustion in CVID is an alternative approach that potentially could alleviate these and other organ-specific inflammatory complications. Therapies of potential interest and wider use in CVID include mTOR-inhibitors like sirolimus, JAK-inhibitors like tofacitinib, the monoclonal IL-12/23 antibody ustekinumab, the anti-BAFF antibody belimumab and abatacept. For all inflammatory complications, there is a need for prospective therapeutic trials, preferably randomized controlled trials, and multi-center collaborations with larger cohorts of patients will be essential.
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Affiliation(s)
- Børre Fevang
- Centre for Rare Disorders, Oslo University Hospital, Oslo, Norway
- Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Oslo, Norway
- Research Institute for Internal Medicine, Oslo University Hospital, Oslo, Norway
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23
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Nishimura M, Miyata J, Tanigaki T, Nomura S, Serizawa Y, Igarashi S, Itou K, Ohno T, Kurata Y, Kimizuka Y, Fujikura Y, Sekinaka Y, Sekinaka K, Matsukuma S, Nonoyama S, Kawana A. Successful Treatment of Granulomatous-lymphocytic Interstitial Lung Disease in a Patient with CTLA-4 Deficiency. Intern Med 2023; 62:871-875. [PMID: 35945007 PMCID: PMC10076143 DOI: 10.2169/internalmedicine.0076-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Common variable immunodeficiency (CVID) causes granulomatous-lymphocytic interstitial lung disease (GLILD) and has a poor prognosis. We herein report a case of GLILD in a 49-year-old woman with CTLA-4 deficiency-associated CVID. The patient presented with dyspnea that had worsened over the past two years. A laboratory examination revealed hypoglobulinemia and pancytopenia. Chest computed tomography showed diffuse infiltrative and granular shadows in the bilateral interstitium. A flow cytometric analysis of blood cells and genetic testing confirmed CTLA-4 deficiency. We performed video-assisted thoracoscopic surgery for the pathological diagnosis of GLILD and to exclude infection and malignancy. Corticosteroid treatment successfully improved the condition of the patient.
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Affiliation(s)
- Masashi Nishimura
- Division of Infectious Diseases and Respiratory Medicine, Department of Internal Medicine, National Defense Medical College, Japan
| | - Jun Miyata
- Division of Infectious Diseases and Respiratory Medicine, Department of Internal Medicine, National Defense Medical College, Japan
| | - Tomomi Tanigaki
- Division of Infectious Diseases and Respiratory Medicine, Department of Internal Medicine, National Defense Medical College, Japan
| | - Sakika Nomura
- Division of Infectious Diseases and Respiratory Medicine, Department of Internal Medicine, National Defense Medical College, Japan
| | - Yusuke Serizawa
- Division of Infectious Diseases and Respiratory Medicine, Department of Internal Medicine, National Defense Medical College, Japan
| | - Syunya Igarashi
- Division of Infectious Diseases and Respiratory Medicine, Department of Internal Medicine, National Defense Medical College, Japan
| | - Koki Itou
- Division of Infectious Diseases and Respiratory Medicine, Department of Internal Medicine, National Defense Medical College, Japan
| | - Tomohiro Ohno
- Division of Infectious Diseases and Respiratory Medicine, Department of Internal Medicine, National Defense Medical College, Japan
| | - Yuhei Kurata
- Division of Infectious Diseases and Respiratory Medicine, Department of Internal Medicine, National Defense Medical College, Japan
| | - Yoshifumi Kimizuka
- Division of Infectious Diseases and Respiratory Medicine, Department of Internal Medicine, National Defense Medical College, Japan
| | - Yuji Fujikura
- Division of Infectious Diseases and Respiratory Medicine, Department of Internal Medicine, National Defense Medical College, Japan
| | - Yujin Sekinaka
- Department of Pediatrics, National Defense Medical College, Japan
| | - Kanako Sekinaka
- Department of Pediatrics, National Defense Medical College, Japan
| | - Susumu Matsukuma
- Department of Pathology and Laboratory Medicine, National Defense Medical College, Japan
| | | | - Akihiko Kawana
- Division of Infectious Diseases and Respiratory Medicine, Department of Internal Medicine, National Defense Medical College, Japan
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24
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Kaarbø M, Yang M, Hov JR, Holm K, de Sousa MML, Macpherson ME, Reims HM, Kran AMB, Halvorsen B, Karlsen TH, Aukrust P, Lundin KEA, Fevang B, Bjørås M, Jørgensen SF. Duodenal inflammation in common variable immunodeficiency has altered transcriptional response to viruses. J Allergy Clin Immunol 2023; 151:767-777. [PMID: 36220400 DOI: 10.1016/j.jaci.2022.09.029] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 09/19/2022] [Accepted: 09/29/2022] [Indexed: 11/15/2022]
Abstract
BACKGROUND A substantial proportion of common variable immunodeficiency (CVID) patients has duodenal inflammation of largely unknown etiology. However, because of its histologic similarities with celiac disease, gluten sensitivity has been proposed as a potential mechanism. OBJECTIVE We aimed to elucidate the role of the duodenal microenvironment in the pathogenesis of duodenal inflammation in CVID by investigating the transcriptional, proteomic, and microbial signatures of duodenal biopsy samples in CVID. METHODS DNA, total RNA, and protein were isolated from snap-frozen pieces of duodenal biopsy samples from CVID (with and without duodenal inflammation), healthy controls, and patients with celiac disease (untreated). RNA sequencing, mass spectrometry-based proteomics, and 16S ribosomal DNA sequencing (bacteria) were then performed. RESULTS CVID separated from controls in regulation of transcriptional response to lipopolysaccharide and cellular immune responses. These differences were independent of mucosal inflammation. Instead, CVID patients with duodenal inflammation displayed alterations in transcription of genes involved in response to viral infections. Four proteins were differently regulated between CVID patients and healthy controls-DBNL, TRMT11, GCHFR, and IGHA2-independent of duodenal inflammation. Despite similar histology, there were major differences in CVID with duodenal inflammation and celiac disease both at the RNA and protein level. No significant difference was observed in the bacterial gut microbial signature between CVID, celiac, and healthy controls. CONCLUSION Our findings suggest the existence of altered functions of the duodenal epithelium, particularly in response to lipopolysaccharide and viruses. The latter finding was related to duodenal inflammation, suggesting that viruses, not gluten sensitivity, could be related to duodenal inflammation in CVID.
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Affiliation(s)
- Mari Kaarbø
- Department of Microbiology, Oslo University Hospital and University of Oslo, Oslo, Norway
| | - Mingyi Yang
- Department of Microbiology, Oslo University Hospital and University of Oslo, Oslo, Norway; Department of Medical Biochemistry, Oslo University Hospital and University of Oslo, Oslo, Norway
| | - Johannes R Hov
- Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway; Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
| | - Kristian Holm
- Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway
| | - Mirta Mittelstedt Leal de Sousa
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, NTNU, Trondheim, Norway; Proteomics and Modomics Experimental Core Facility (PROMEC) at Norwegian University of Science and Technology, Trondheim, Norway
| | - Magnhild E Macpherson
- Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Department of Infectious Diseases, Oslo University Hospital, Ullevål, Oslo, Norway
| | - Henrik M Reims
- Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Anne-Marte Bakken Kran
- Department of Microbiology, Oslo University Hospital and University of Oslo, Oslo, Norway
| | - Bente Halvorsen
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway
| | - Tom H Karlsen
- Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway; Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
| | - Pål Aukrust
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Knut E A Lundin
- Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway; K. G. Jebsen Celiac Disease Research Centre, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Børre Fevang
- Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Magnar Bjørås
- Department of Microbiology, Oslo University Hospital and University of Oslo, Oslo, Norway; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, NTNU, Trondheim, Norway
| | - Silje Fjellgård Jørgensen
- Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
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25
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Zhang S, Cunningham-Rundles C. Primary Antibody Immunodeficiency and the Pregnant Patient. Immunol Allergy Clin North Am 2023; 43:133-144. [PMID: 36410999 DOI: 10.1016/j.iac.2022.07.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
An overview of primary antibody immunodeficiency in pregnancy is presented. Indications for immunoglobulin replacement therapy (IGRT), dosing, and safety considerations are highlighted. Uses of immunizations and antimicrobial therapy are also discussed. In general, IGRT, both intravenous and subcutaneous, is considered safe in pregnancy.
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Affiliation(s)
- Shouling Zhang
- Division of Allergy and Immunology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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26
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Milota T, Smetanova J, Bartunkova J. Clinical Outcome of Coronavirus Disease 2019 in Patients with Primary Antibody Deficiencies. Pathogens 2023; 12:pathogens12010109. [PMID: 36678457 PMCID: PMC9860966 DOI: 10.3390/pathogens12010109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 12/30/2022] [Accepted: 01/04/2023] [Indexed: 01/11/2023] Open
Abstract
In 2019, the novel coronavirus, SARS-CoV-2, caused a worldwide pandemic, affecting more than 630 million individuals and causing 6.5 million deaths. In the general population, poorer outcomes have been associated with older age, chronic lung and cardiovascular diseases, and lymphopenia, highlighting the important role of cellular immunity in the immune response against SARS-CoV-2. Moreover, SARS-CoV-2 variants may have a significant impact on disease severity. There is a significant overlap with complications commonly found in inborn errors of immunity (IEI), such as primary antibody deficiencies. The results of various studies have provided ambiguous findings. Several studies identified risk factors in the general population with a minor impact on SARS-CoV-2 infection. However, other studies have found a significant contribution of underlying immunodeficiency and immune-system dysregulation to the disease course. This ambiguity probably reflects the demographic differences and viral evolution. Impaired antibody production was associated with prolonged viral shedding, suggesting a critical role of humoral immunity in controlling SARS-CoV-2 infection. This may explain the poorer outcomes in primary antibody deficiencies compared to other IEIs. Understanding coronavirus disease 2019 (COVID-19) pathogenesis and identifying risk factors may help us identify patients at high risk of severe COVID-19 for whom preventive measures should be introduced.
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27
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Løken RØ, Fevang B. Cellular immunity in COVID-19 and other infections in Common variable immunodeficiency. Front Immunol 2023; 14:1124279. [PMID: 37180118 PMCID: PMC10173090 DOI: 10.3389/fimmu.2023.1124279] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 04/13/2023] [Indexed: 05/15/2023] Open
Abstract
COVID-19 has shed light on the role of cellular immunity in the absence of humoral response in different patient groups. Common variable immunodeficiency (CVID) is characterized by impaired humoral immunity but also an underlying T-cell dysregulation. The impact of T-cell dysregulation on cellular immunity in CVID is not clear, and this review summarizes available literature on cellular immunity in CVID with a particular focus on COVID-19. Overall mortality of COVID-19 in CVID is difficult to assess, but seems not significantly elevated, and risk factors for severe disease mirrors that of the general population, including lymphopenia. Most CVID patients have a significant T-cell response to COVID-19 disease with possible cross-reactivity to endemic coronaviruses. Several studies find a significant but impaired cellular response to basal COVID-19 mRNA vaccination that is independent of an antibody response. CVID patients with infection only have better cellular responses to vaccine in one study, but there is no clear association to T-cell dysregulation. Cellular response wane over time but responds to a third booster dose of vaccine. Opportunistic infection as a sign of impaired cellular immunity in CVID is rare but is related to the definition of the disease. CVID patients have a cellular response to influenza vaccine that in most studies is comparable to healthy controls, and annual vaccination against seasonal influenza should be recommended. More research is required to clarify the effect of vaccines in CVID with the most immediate issue being when to booster the COVID-19 vaccine.
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Affiliation(s)
- Ragnhild Øye Løken
- Section of Clinical Immunology and Infectious Diseases, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital, Oslo, Norway
| | - Børre Fevang
- Section of Clinical Immunology and Infectious Diseases, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital, Oslo, Norway
- Centre for Rare Disorders, Division of Paediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway
- *Correspondence: Børre Fevang,
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28
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Hepatitis E infection in adults with primary immunodeficiency with or without immunoglobulin replacement therapy. BLOOD TRANSFUSION = TRASFUSIONE DEL SANGUE 2022; 20:516-524. [PMID: 35175187 PMCID: PMC9726618 DOI: 10.2450/2022.0258-21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 12/10/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND In a context of secondary immunodeficiency, hepatitis E virus (HEV) infection can be responsible for chronic liver disease. MATERIALS AND METHODS We investigated HEV infection in patients with primary immunodeficiency treated (or not) with immunoglobulin (Ig) replacement therapy (IgRT) in France, a country with a high seroprevalence of HEV. In a nationwide study of individuals with primary immunodeficiency, 533 patients (349 and 184 receiving IgRT or not, respectively) were tested for HEV RNA and anti-HEV antibodies. In addition, 23 batches of five different commercially available immunoglobulin preparations were screened for anti-HEV IgG. RESULTS Three of the 533 patients displayed markers of a recent HEV infection (HEV RNA in one case, and anti-HEV IgG and IgM in two) but no evidence of chronic liver disease. The overall seroprevalence of HEV was 50% (266 out of 533), with values of 68% and 16% in patients receiving IgRT or not, respectively (p<0.001). Anti-HEV IgG were detected in all batches of immunoglobulin preparations, although the titer varied from 3 to 127 IU/g IgG. Seroconversion was observed in 15 of the 22 (68%) patients tested before and after IgRT. DISCUSSION No cases of chronic HEV-related disease were detected among patients with primary immunodeficiency and hypogammaglobulinemia, whether they received IgRT or not. This confirms that patients with primary immunodeficiency have a low risk of chronic infection despite a seroprevalence close to that observed in the French general population and that IgRT, which confers a high HEV seroprevalence, might play a key role in protection against chronic infection.
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Mateti NR, Vaddepally RK, Chandra AB, Skaria PE. Myelodysplastic Syndrome in a Patient With Common Variable Immunodeficiency: A Rare Occurrence. Cureus 2022; 14:e28690. [PMID: 36199647 PMCID: PMC9526999 DOI: 10.7759/cureus.28690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/01/2022] [Indexed: 11/05/2022] Open
Abstract
Common variable immunodeficiency (CVID) is a primary immunodeficiency disorder caused by impaired B-cell function and antibody production. It commonly presents with chronic sinopulmonary and gastrointestinal manifestations. It is also associated with transformation to acute myeloid leukemia. However, the association of CVID with myelodysplastic syndrome (MDS) is rare. This case report aims to present one such rare association in a 26-year-old patient presenting with severe thrombocytopenia. Bone marrow biopsy revealed hypercellular marrow with 80-90% cellularity along with an increase in CD34 blasts. Cytogenetics revealed loss of the Y chromosome. Diagnosis of MDS with excess blasts-2 was confirmed with a Revised International Prognostic Scoring System score of 4, placing the patient in the intermediate-risk category. The patient was started on azacitidine, a hypomethylating agent. A referral to a bone marrow transplant was also done for the consideration of an allogeneic stem cell transplant.
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Fraz MSA, Michelsen AE, Moe N, Aaløkken TM, Macpherson ME, Nordøy I, Aukrust P, Taraldsrud E, Holm AM, Ueland T, Jørgensen SF, Fevang B. Raised Serum Markers of T Cell Activation and Exhaustion in Granulomatous-Lymphocytic Interstitial Lung Disease in Common Variable Immunodeficiency. J Clin Immunol 2022; 42:1553-1563. [PMID: 35789314 PMCID: PMC9255534 DOI: 10.1007/s10875-022-01318-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 06/23/2022] [Indexed: 11/05/2022]
Abstract
Purpose
About 20–30% of patients with common variable immunodeficiency (CVID) develop granulomatous-lymphocytic interstitial lung disease (GLILD) as one of several non-infectious complications to their immunodeficiency. The purpose of this study was to identify biomarkers that could distinguish GLILD from other non-infectious complications in CVID. Methods We analyzed serum biomarkers related to inflammation, pulmonary epithelium injury, fibrogenesis, and extracellular matrix (ECM) remodeling, and compared three subgroups of CVID: GLILD patients (n = 16), patients with other non-infectious complications (n = 37), and patients with infections only (n = 20). Results We found that GLILD patients had higher levels of sCD25, sTIM-3, IFN-γ, and TNF, reflecting T cell activation and exhaustion, compared to both CVID patients with other inflammatory complications and CVID with infections only. GLILD patients also had higher levels of SP-D and CC16, proteins related to pulmonary epithelium injury, as well as the ECM remodeling marker MMP-7, than patients with other non-infectious complications. Conclusion GLILD patients have elevated serum markers of T cell activation and exhaustion, pulmonary epithelium injury, and ECM remodeling, pointing to potentially important pathways in GLILD pathogenesis, novel targets for therapy, and promising biomarkers for clinical evaluation of these patients. Supplementary Information The online version contains supplementary material available at 10.1007/s10875-022-01318-1.
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Affiliation(s)
- Mai Sasaki Aanensen Fraz
- Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Rikshospitalet, Oslo, Norway. .,Centre for Rare Diseases, Oslo University Hospital, Oslo, Norway.
| | - Annika Elisabet Michelsen
- Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Natasha Moe
- Department of Radiology and Nuclear Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Trond Mogens Aaløkken
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Department of Radiology and Nuclear Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Magnhild Eide Macpherson
- Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.,Department of Infectious Diseases, Oslo University Hospital Ullevål, Oslo, Norway
| | - Ingvild Nordøy
- Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Rikshospitalet, Oslo, Norway.,Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Pål Aukrust
- Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Rikshospitalet, Oslo, Norway.,Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Faculty of Health Sciences, K.G. Jebsen TREC, University of Tromsø, Tromsø, Norway
| | - Eli Taraldsrud
- Department of Immunology, Oslo University Hospital, Oslo, Norway
| | - Are Martin Holm
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Department of Pulmonary Medicine, Oslo University Hospital, Oslo, Norway
| | - Thor Ueland
- Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Faculty of Health Sciences, K.G. Jebsen TREC, University of Tromsø, Tromsø, Norway
| | - Silje Fjellgård Jørgensen
- Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Rikshospitalet, Oslo, Norway.,Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Børre Fevang
- Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Rikshospitalet, Oslo, Norway.,Centre for Rare Diseases, Oslo University Hospital, Oslo, Norway.,Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
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Clinical and Phenotypic Characterization of Common Variable Immunodeficiency Diagnosed in Younger and Older Adults. J Clin Immunol 2022; 42:1270-1279. [PMID: 35588029 DOI: 10.1007/s10875-022-01290-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 05/06/2022] [Indexed: 10/18/2022]
Abstract
PURPOSE Common variable immunodeficiency (CVID) is the most prevalent symptomatic immunodeficiency in adults. Little is known about the manifestations of CVID presenting in older adults. Herein, we performed a phenotypic characterization of patients diagnosed older than age 40. METHODS A retrospective chart review of 79 patients seen at UF Health between 2006 and 2020 with a verified diagnosis of CVID per the ICON 2016 criteria was conducted. Patients were classified according to four phenotypes: no-disease-related complications, autoimmune cytopenias, polyclonal lymphoproliferation, and unexplained enteropathy. Patients diagnosed with CVID from age 2 to 40 (n = 41, "younger cohort") were compared to patients diagnosed with CVID age 41 and older (n = 38, "older cohort"). RESULTS Among the younger cohort, pathologic genetic variants, positive family history for immunodeficiency, autoimmunity (49% vs 24%, p = 0.03), and splenomegaly (46% vs 16%, p = 0.004) were more common, as was the "autoimmune cytopenias" phenotype (24% vs 3%, p = 0.007). Among the older cohort, lymphoma (11% vs 0%, p = 0.049) and the "no disease-related complications" phenotype (79% vs 57%, p = 0.03) were more commonly seen. Comorbidities such as bronchiectasis (27% vs 21%, p = 0.61), GI involvement (34% vs 24%, p = 0.33), and GLILD (5% vs 8%, p = 0.67) were equally present among both the younger and older cohorts, respectively. CONCLUSION The lower incidence of autoimmunity and splenomegaly, as well as overlapping clinical features with immunosenescence, may make diagnosing CVID in older patients more challenging; however, the disease is not more indolent as the risks for lymphoma, bronchiectasis, and GLILD are similar to those of younger patients.
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Sharma S, Pilania RK, Anjani G, Sudhakar M, Arora K, Tyagi R, Dhaliwal M, Vignesh P, Rawat A, Singh S. Lymphoproliferation in Inborn Errors of Immunity: The Eye Does Not See What the Mind Does Not Know. Front Immunol 2022; 13:856601. [PMID: 35603189 PMCID: PMC9114776 DOI: 10.3389/fimmu.2022.856601] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 04/11/2022] [Indexed: 11/13/2022] Open
Abstract
Inborn errors of immunity (IEIs) are a group of heterogeneous disorders characterized by a broad clinical spectrum of recurrent infections and immune dysregulation including autoimmunity and lymphoproliferation (LP). LP in the context of IEI may be the presenting feature of underlying immune disorder or may develop during the disease course. However, the correct diagnosis of LP in IEI as benign or malignant often poses a diagnostic dilemma due to the non-specific clinical features and overlapping morphological and immunophenotypic features which make it difficult to treat. There are morphological clues to LP associated with certain IEIs. A combination of ancillary techniques including EBV-associated markers, flow cytometry, and molecular assays may prove useful in establishing a correct diagnosis in an appropriate clinical setting. The present review attempts to provide comprehensive insight into benign and malignant LP, especially the pathogenesis, histological clues, diagnostic strategies, and treatment options in patients with IEIs.
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Affiliation(s)
- Saniya Sharma
- Department of Pediatrics (Clinical Immunology and Rheumatology), Postgraduate Institute of Medical Education and Research, Chandigarh, India
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Antolí A, Rocamora-Blanch G, Framil M, Mas-Bosch V, Navarro S, Bermudez C, Martinez-Yelamos S, Dopico E, Calatayud L, Garcia-Muñoz N, Hernández-Benítez LH, Riera-Mestre A, Bas J, Masuet-Aumatell C, Rigo-Bonnin R, Morandeira F, Solanich X. Evaluation of Humoral and Cellular Immune Responses to the SARS-CoV-2 Vaccine in Patients With Common Variable Immunodeficiency Phenotype and Patient Receiving B-Cell Depletion Therapy. Front Immunol 2022; 13:895209. [PMID: 35572562 PMCID: PMC9098934 DOI: 10.3389/fimmu.2022.895209] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Accepted: 03/31/2022] [Indexed: 12/14/2022] Open
Abstract
Introduction SARS-CoV-2 vaccines' effectiveness is not yet clearly known in immunocompromised patients. This study aims to assess the humoral and cellular specific immune response to SARS-CoV-2 vaccines and the predictors of poor response in patients with common variable immunodeficiency (CVID) phenotype and in patients treated with B-cell depletion therapies (BCDT), as well as the safety of these vaccines. Methods From March to September 2021, we performed a prospective study of all adult patients who would receive the SARS-CoV-2 vaccination and were previously diagnosed with (i) a CVID syndrome (CVID phenotype group; n=28) or (ii) multiple sclerosis (MS) treated with B-cell depleting therapies three to six months before vaccination (BCD group; n=24). Participants with prior SARS-CoV-2 infection; or prior SARS-CoV-2 vaccine administration; or use of any immunosuppressant (except BCDT in MS group) were excluded. A group of subjects without any medical condition that confers immunosuppression and who met all study criteria was also assessed (control group; n=14). A chemiluminescence immunoassay was used to determine pre- and post-SARS-CoV-2 vaccine anti-S IgG antibodies. T-cell specific response was assessed by analysis of pre- and post-SARS-CoV-2 vaccination blood samples with an interferon-gamma release assay. The baseline blood sample also included several biochemical, haematological and immunological analyses. Results SARS-CoV-2 vaccines are safe in immunocompromised patients, although their effectiveness was lower than in healthy individuals. CVID phenotype patients showed impaired humoral (29%) and cellular (29%) response, while BCD patients fundamentally presented humoral failure (54%). Low IgA values, low CD19+ peripheral B cells, low switched memory B cells, and a low CD4+/CD8+ ratio were predictors of inadequate specific antibody response in CVID phenotype patients. No factor was found to predict poor cellular response in CVID phenotype patients, nor a defective humoral or cellular response in BCD patients. Conclusion The effectiveness of SARS-CoV-2 vaccines in CVID phenotype and BCD patients is lower than in healthy individuals. Knowledge of predictive factors of humoral and cellular response failure in immunocompromised patients could be very useful in clinical practice, and thus, studies in this regard are clearly needed.
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Affiliation(s)
- Arnau Antolí
- Department of Internal Medicine, Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Spain
- Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Spain
- Adults Primary Immunodeficiency Unit (UFIPA), Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Spain
| | - Gemma Rocamora-Blanch
- Department of Internal Medicine, Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Spain
- Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Spain
- Adults Primary Immunodeficiency Unit (UFIPA), Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Spain
| | - Mario Framil
- Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Spain
- Adults Primary Immunodeficiency Unit (UFIPA), Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Spain
- Department of Immunology, Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Spain
| | - Virgínia Mas-Bosch
- Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Spain
- Adults Primary Immunodeficiency Unit (UFIPA), Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Spain
- Department of Immunology, Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Spain
| | - Sergio Navarro
- Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Spain
- Adults Primary Immunodeficiency Unit (UFIPA), Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Spain
- Department of Immunology, Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Spain
| | - Carla Bermudez
- Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Spain
- Adults Primary Immunodeficiency Unit (UFIPA), Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Spain
| | - Sergio Martinez-Yelamos
- Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Spain
- Department of Neurology, Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Spain
- Faculty of Medicine and Health Sciences, Universitat de Barcelona, Barcelona, Spain
| | - Eva Dopico
- Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Spain
- Deparment of Microbiology, Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Spain
| | - Laura Calatayud
- Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Spain
- Deparment of Microbiology, Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Spain
- CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain
| | - Nadia Garcia-Muñoz
- Blood Bank Department - Banc de Sang i Teixits (BST), Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Spain
| | | | - Antoni Riera-Mestre
- Department of Internal Medicine, Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Spain
- Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Spain
- Faculty of Medicine and Health Sciences, Universitat de Barcelona, Barcelona, Spain
| | - Jordi Bas
- Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Spain
- Adults Primary Immunodeficiency Unit (UFIPA), Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Spain
- Department of Immunology, Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Spain
| | - Cristina Masuet-Aumatell
- Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Spain
- Adults Primary Immunodeficiency Unit (UFIPA), Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Spain
- Department of Preventive Medicine, Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Spain
| | - Raúl Rigo-Bonnin
- Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Spain
- Department of Clinical Laboratory, Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Spain
| | - Francisco Morandeira
- Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Spain
- Adults Primary Immunodeficiency Unit (UFIPA), Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Spain
- Department of Immunology, Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Spain
| | - Xavier Solanich
- Department of Internal Medicine, Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Spain
- Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Spain
- Adults Primary Immunodeficiency Unit (UFIPA), Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Spain
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YUCE INEL T, CAN G. Common variable immunodeficiency from the perspective of rheumatology. JOURNAL OF HEALTH SCIENCES AND MEDICINE 2022. [DOI: 10.32322/jhsm.1053500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
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Lee EY, Betschel S, Grunebaum E. Monitoring patients with uncomplicated common variable immunodeficiency: a systematic review. ALLERGY, ASTHMA, AND CLINICAL IMMUNOLOGY : OFFICIAL JOURNAL OF THE CANADIAN SOCIETY OF ALLERGY AND CLINICAL IMMUNOLOGY 2022; 18:21. [PMID: 35264237 PMCID: PMC8908590 DOI: 10.1186/s13223-022-00661-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 02/20/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND Non-infectious complications have become a major cause of morbidity and mortality in patients with Common Variable Immunodeficiency (CVID). The monitoring of patients with CVID prior to the development of non-infectious complications is not well defined. OBJECTIVE Our objectives were to systematically review the current literature on the monitoring of CVID patients without non-infectious complications and to develop recommendations for such monitoring. METHODS MEDLINE and EMBASE were searched from January 1st, 2000 to March 25th, 2021. Studies on any aspects of CVID monitoring were included. Studies that included only children, on monitoring CVID patients with existing non-infectious complications, or in the format of case reports were excluded. RESULTS Nine studies on CVID monitoring, including 3 cohort studies, 3 experts' opinions, 2 consensus statements and a single guideline report were identified. These studies revealed that clinical assessment and bloodwork were preformed every 6 to 12 months in asymptomatic patients. Some centers performed computerized tomography scan of the chest every 2-5 years to identify chronic lung disease, although the majority did chest imaging in accordance with clinical indications. Pulmonary function tests were done annually at most centers. Most studies did not address the role of abdominal imaging to screen for liver diseases or endoscopy to screen for gastric cancer in asymptomatic patients with uncomplicated CVID. CONCLUSIONS There is paucity of evidence-based information to guide the routine monitoring of CVID patients without non-infectious complications. Prospective studies are needed to determine the best monitoring practices in this group of patients.
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Affiliation(s)
- Erika Yue Lee
- Division of Clinical Immunology and Allergy, Department of Medicine, St. Michael's Hospital, 30 Bond Street, Toronto, ON, M5B 1W8, Canada. .,Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
| | - Stephen Betschel
- Division of Clinical Immunology and Allergy, Department of Medicine, St. Michael's Hospital, 30 Bond Street, Toronto, ON, M5B 1W8, Canada.,Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Eyal Grunebaum
- Division of Immunology and Allergy, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada.,Faculty of Medicine, University of Toronto, Toronto, ON, Canada
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Ferenc T, Vilibić-Čavlek T. COMMON VARIABLE IMMUNODEFICIENCY: PREDISPOSING OR PROTECTIVE FACTOR FOR SEVERE COMPLICATIONS OF COVID-19? Acta Clin Croat 2022; 61:107-114. [PMID: 36398083 PMCID: PMC9616023 DOI: 10.20471/acc.2022.61.01.13] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Accepted: 09/06/2021] [Indexed: 08/11/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) is an emerging infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The usual presentation of the disease is a common cold-like illness but it can present with more severe and sometimes fatal manifestations. Immunocompromised patients such as those with common variable immunodeficiency (CVID) also are among the infected population. A limited number of reports have been published concerning CVID patients with COVID-19. The main reported symptoms were fever, cough, dyspnea and fatigue while the median duration of illness was 19 (interquartile range 14-26.5) days. Total recovery rate was 88.4%. It is still unknown whether primary immunodeficiency interacts as a predisposing or protective factor against the severe forms of COVID-19. Substitute immunoglobulin (IG) therapy is the only treatment option for CVID. Some reports suggest that early administration of intravenous IGs or convalescent plasma infusion may positively influence the outcome of COVID-19 in these patients.
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Affiliation(s)
- Thomas Ferenc
- Department of Diagnostic and Interventional Radiology, Merkur University Hospital, Zagreb, Croatia
| | - Tatjana Vilibić-Čavlek
- School of Medicine, University of Zagreb, Zagreb, Croatia
- Department of Virology, Croatian Institute of Public Health, Zagreb, Croatia
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Abstract
INTRODUCTION There is a wide spectrum of noninfectious gastrointestinal pathology, causing considerable morbidity and mortality in CVID, where both etiology and effective therapy are under debate. AREAS COVERED This review will focus on the noninfectious inflammation in the GI tract in CVID patients, covering the both the upper and lower GI tract inflammation, including the liver. The controversy of the CVID enteropathy definition and that of gluten-free diet for celiac-like disease in CVID will be discussed. Furthermore, the review will cover the link between GI inflammation and GI cancer. Finally, the role of gut microbiota, IgA, and genetics and its relationship with CVID enteropathy is scrutinized. The authors reviewed literature from PubMed. EXPERT OPINION The heterogeneity and the unknown mechanism behind CVID enteropathy, and thereby the lack of effective treatment, is one of the key challenges in the field of CVID. Celiac-like disease in CVID is due to immune dysregulation, and a gluten-free diet is therefore not indicated. Gut microbial dysbiosis and mucosal IgA can initiate systemic and local inflammation and is involved in the immune dysregulation in CVID. Considering the heterogeneity of CVID enteropathy, personalized medicine is probably the future for these patients.
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Affiliation(s)
- I M Andersen
- Section of Clinical Immunology and Infectious Diseases, Department of Rheumatology, Dermatology and Infectious Diseases, Oslo University Hospital, Rikshospitalet, Norway
| | - S F Jørgensen
- Section of Clinical Immunology and Infectious Diseases, Department of Rheumatology, Dermatology and Infectious Diseases, Oslo University Hospital, Rikshospitalet, Norway.,Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Rikshospitalet, Norway
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Nordin J, Solís L, Prévot J, Mahlaoui N, Chapel H, Sánchez-Ramón S, Ali A, Seymour JW, Pergent M. The PID Principles of Care: Where Are We Now? A Global Status Report Based on the PID Life Index. Front Immunol 2021; 12:780140. [PMID: 34868053 PMCID: PMC8637458 DOI: 10.3389/fimmu.2021.780140] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 10/29/2021] [Indexed: 11/13/2022] Open
Abstract
A global gold standard framework for primary immunodeficiency (PID) care, structured around six principles, was published in 2014. To measure the implementation status of these principles IPOPI developed the PID Life Index in 2020, an interactive tool aggregating national PID data. This development was combined with a revision of the principles to consider advances in the field of health and science as well as political developments since 2014. The revision resulted in the following six principles: PID diagnosis, treatments, universal health coverage, specialised centres, national patient organisations and registries for PIDs. A questionnaire corresponding to these principles was sent out to IPOPI’s national member organisations and to countries in which IPOPI had medical contacts, and data was gathered from 60 countries. The data demonstrates that, regardless of global scientific progress on PIDs with a growing number of diagnostic tools and better treatment options becoming available, the accessibility and affordability of these remains uneven throughout the world. It is not only visible between regions, but also between countries within the same region. One of the most urgent needs is medical education. In countries without immunologists, patients with PID suffer the risk of remaining undiagnosed or misdiagnosed, resulting in health implications or even death. Many countries also lack the infrastructure needed to carry out more advanced diagnostic tests and perform treatments such as hematopoietic stem cell transplantation or gene therapy. The incapacity to secure appropriate diagnosis and treatments affects the PID environment negatively in these countries. Availability and affordability also remain key issues, as diagnosis and treatments require coverage/reimbursement to ensure that patients with PID can access them in practice, not only in theory. This is still not the case in many countries of the world according to the PID Life Index. Although some countries do perform better than others, to date no country has fully implemented the PID principles of care, confirming the long way ahead to ensure an optimal environment for patients with PID in every country.
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Affiliation(s)
- Julia Nordin
- The International Patient Organisation for Primary Immunodeficiencies, Downderry, United Kingdom
| | - Leire Solís
- The International Patient Organisation for Primary Immunodeficiencies, Downderry, United Kingdom
| | - Johan Prévot
- The International Patient Organisation for Primary Immunodeficiencies, Downderry, United Kingdom
| | - Nizar Mahlaoui
- Pediatric Immunology-Hematology and Rheumatology Unit, Necker Children's University Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.,French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Children's University Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
| | - Helen Chapel
- Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Silvia Sánchez-Ramón
- Department of Clinical Immunology, Instituto de Medicina del Laboratorio (IML) and Instituto de Investigación Clínico San Carlos (IdISSC), Hospital Clínico San Carlos, Madrid, Spain.,Department of Immunology, ENT and Ophthalmology, Complutense University School of Medicine, Madrid, Spain
| | - Adli Ali
- Clinical Immunology Unit, Department of Paediatrics, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia.,Institute of IR4.0, Universiti Kebangsaan Malaysia, Bangi, Malaysia
| | - John W Seymour
- The International Patient Organisation for Primary Immunodeficiencies, Downderry, United Kingdom.,Department of Counseling and Student Personnel, Minnesota State University, Mankato, MN, United States
| | - Martine Pergent
- The International Patient Organisation for Primary Immunodeficiencies, Downderry, United Kingdom
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Khan S. Interstitial lung disease in common variable immunodeficiency. Br J Hosp Med (Lond) 2021; 82:1. [PMID: 34983218 DOI: 10.12968/hmed.2021.0467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Affiliation(s)
- Sujoy Khan
- Department of Immunology and Allergy, Hull University Teaching Hospitals NHS Trust, Queen's Centre, Castle Hill Hospital, Cottingham, UK
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Smets I, Giovannoni G. Derisking CD20-therapies for long-term use. Mult Scler Relat Disord 2021; 57:103418. [PMID: 34902761 DOI: 10.1016/j.msard.2021.103418] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Revised: 09/15/2021] [Accepted: 11/20/2021] [Indexed: 11/16/2022]
Abstract
Anti-CD20 have quickly become the mainstay in the treatment of multiple sclerosis (MS) and other neuroinflammatory conditions. However, when they are used as a maintenance therapy the balance between risks and benefits changes. In this review, we suggested six steps to derisk anti-CD20. Firstly and secondly, adequate infectious screening followed by vaccinations before starting anti-CD20 are paramount. Third, family planning needs to be discussed upfront with every woman of childbearing age. Fourth, infusion reactions should be adequately managed to avoid treatment interruption. After repeated infusions, it becomes important to detect and prevent anti-CD20-related adverse events. Fifth, we recommended measuring immunoglobulin levels and reviewing vaccinations annually as well as counselling adequate fever management. For female patients, we emphasised the importance to engage with the local breast cancer screening programs. Sixth, to fundamentally derisk anti-CD20 therapies, we need evidence-based approaches to reduce dosing intervals and guide retreatment.
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Affiliation(s)
- Ide Smets
- Blizard Institute, Centre for Neuroscience, Surgery and Trauma, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark St, Whitechapel, London E1 2AT, United Kingdom; Clinical Board Medicine (Neuroscience), Royal London Hospital, Barts Health NHS Trust, Whitechapel Road, London E1 1FR, United Kingdom
| | - Gavin Giovannoni
- Blizard Institute, Centre for Neuroscience, Surgery and Trauma, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark St, Whitechapel, London E1 2AT, United Kingdom; Clinical Board Medicine (Neuroscience), Royal London Hospital, Barts Health NHS Trust, Whitechapel Road, London E1 1FR, United Kingdom.
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Perlman DM, Sudheendra MT, Racilla E, Allen TL, Joshi A, Bhargava M. Granulomatous-Lymphocytic Interstitial Lung Disease Mimicking Sarcoidosis. SARCOIDOSIS VASCULITIS AND DIFFUSE LUNG DISEASES 2021; 38:e2021025. [PMID: 34744421 PMCID: PMC8552568 DOI: 10.36141/svdld.v38i3.11114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 03/12/2021] [Indexed: 11/07/2022]
Abstract
Common variable immunodeficiency (CVID) is one of the most common primary immunodeficiency disorders characterized by hypogammaglobulinemia and inadequate antibody response to immunizations. The impaired antibody response occurs due to the failure of B cells to differentiate into plasma cells resulting in low immunoglobulins levels and increased frequency of infections. Granulomatous and Lymphocytic Interstitial Lung Disease (GLILD) is a non-infectious complication of CVID that is seen in 10-30% of cases. GLILD is a multisystem inflammatory disease involving the lungs, lymph node, liver, spleen and gastrointestinal tract that mimics sarcoidosis. This report describes a series of cases who presented with dyspnea, recurrent respiratory infections or autoimmunity and on further evaluation revealed features suggestive of GLILD. There is very limited understanding of GLILD in terms of clinical presentation, the histo-pathological logical findings, and the diagnostic criteria by itself are limited. A diagnosis of GLILD is established in cases of CVID when there is evidence of lymphoproliferation, cytopenia, autoimmune processes and a lung biopsy demonstrating lymphocytic interstitial pneumonia, follicular bronchiolitis, lymphoid hyperplasia, and/or non-necrotizing granulomas. We review the treatment strategies, including replacement of immunoglobulin and agents targeting B and T lymphocytes. Systematic characterization of GLILD cases and long term follow up studies are sorely needed to understand the natural history of GLILD.
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Affiliation(s)
- David M Perlman
- Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine University of Minnesota Medical School, Minneapolis, MN, USA
| | - Muthya Tejasvini Sudheendra
- Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine University of Minnesota Medical School, Minneapolis, MN, USA
| | - Emilian Racilla
- Department of Lab Medicine and Pathology, University of Minnesota Medical School, Minneapolis MN, USA
| | - Tadashi L Allen
- Department of Radiology, University of Minnesota Medical School, Minneapolis MN, USA
| | - Avni Joshi
- Division of Allergy and Immunology, Mayo Clinic, Rochester, MN, USA
| | - Maneesh Bhargava
- Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine University of Minnesota Medical School, Minneapolis, MN, USA
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Common variable immunodeficiency disorders: What generalists should know. Afr J Thorac Crit Care Med 2021; 27. [PMID: 34734174 PMCID: PMC8547339 DOI: 10.7196/ajtccm.2021.v27i3.228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/08/2021] [Indexed: 11/09/2022] Open
Abstract
Primary immune deficiency disorders (PIDDs) are common and underdiagnosed. Predominant antibody deficiencies (PADs) are the
most common type of immune deficiency and comprise 55% of the immune deficiencies diagnosed.[1] Although immunoglobulin A (IgA)
deficiency remains the most common type of PID, common variable immunodeficiency disorders remain the most common symptomatic
PID for which medical therapy is sought.
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Altered Plasma Fatty Acids Associate with Gut Microbial Composition in Common Variable Immunodeficiency. J Clin Immunol 2021; 42:146-157. [PMID: 34669143 PMCID: PMC8821409 DOI: 10.1007/s10875-021-01146-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2021] [Accepted: 09/27/2021] [Indexed: 12/11/2022]
Abstract
PURPOSE Fatty acid (FA) abnormalities are found in various inflammatory disorders and have been related to disturbed gut microbiota. Patients with common variable immunodeficiency (CVID) have inflammatory complications associated with altered gut microbial composition. We hypothesized that there is an altered FA profile in CVID patients, related to gut microbial dysbiosis. METHODS Plasma FAs were measured in 39 CVID patients and 30 healthy controls. Gut microbial profile, a food frequency questionnaire, and the effect of the oral antibiotic rifaximin were investigated in CVID patients. RESULTS The n-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA) (1.4 [1.0-1.8] vs. 1.9 [1.2-2.5], median (IQR), P < 0.05), and docosahexaenoic acid (DHA) (3.2 [2.4-3.9] vs. 3.5 [2.9-4.3], P < 0.05), all values expressed as weight percent of total plasma FAs, were reduced in CVID compared to controls. Also, n-6 PUFAs (34.3 ± 3.4 vs. 37.1 ± 2.8, mean ± SD, P < 0.001) and linoleic acid (LA) (24.5 ± 3.3 vs. 28.1 ± 2.7, P < 0.0001) and the FA anti-inflammatory index (98.9 [82.1-119.4] vs. 117.0 [88.7-153.1], median (IQR), P < 0.05) were reduced in CVID. The microbial alpha diversity was positively associated with plasma n-6 PUFAs (r = 0.41, P < 0.001) and LA (r = 0.51, P < 0.001), but not n-3 PUFAs (P = 0.78). Moreover, a 2-week course of rifaximin significantly reduced the proportion of n-6 PUFAs (P = 0.04, UNIANOVA). Serum immunoglobulin G (IgG) levels correlated with plasma n-3 PUFAs (rho = 0.36, P = 0.03) and DHA (rho = 0.41, P = 0.009). CONCLUSION We found a potentially unfavorable FA profile in CVID, related to low IgG levels. High plasma n-6 PUFAs were related to increased gut microbial diversity and altered by rifaximin therapy.
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Berbers RM, van der Wal MM, van Montfrans JM, Ellerbroek PM, Dalm VASH, van Hagen PM, Leavis HL, van Wijk F. Chronically Activated T-cells Retain Their Inflammatory Properties in Common Variable Immunodeficiency. J Clin Immunol 2021; 41:1621-1632. [PMID: 34247288 PMCID: PMC8452589 DOI: 10.1007/s10875-021-01084-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 06/07/2021] [Indexed: 12/04/2022]
Abstract
Purpose Immune dysregulation complications cause significant morbidity and mortality in common variable immunodeficiency (CVID), but the underlying pathophysiology is poorly understood. While CVID is primarily considered a B-cell defect, resulting in the characteristic hypogammaglobulinemia, T-cells may also contribute to immune dysregulation complications. Here, we aim to further characterize T-cell activation and regulation in CVID with immune dysregulation (CVIDid). Methods Flow cytometry was performed to investigate T-cell differentiation, activation and intracellular cytokine production, negative regulators of immune activation, regulatory T-cells (Treg), and homing markers in 12 healthy controls, 12 CVID patients with infections only (CVIDio), and 20 CVIDid patients. Results Both CD4 + and CD8 + T-cells in CVIDid showed an increased activation profile (HLA-DR + , Ki67 + , IFNγ +) when compared to CVIDio, with concomitant upregulation of negative regulators of immune activation PD1, LAG3, CTLA4, and TIGIT. PD1 + and LAG3 + subpopulations contained equal or increased frequencies of cells with the capacity to produce IFNγ, Ki67, and/or GzmB. The expression of PD1 correlated with serum levels of CXCL9, 10, and 11. Treg frequencies were normal to high in CVIDid, but CVIDid Tregs had reduced CTLA-4 expression, especially on CD27 + effector Tregs. Increased migratory capacity to inflamed and mucosal tissue was also observed in CVIDid T-cells. Conclusion CVIDid was characterized by chronic activation of peripheral T-cells with preserved inflammatory potential rather than functional exhaustion, and increased tissue migratory capacity. While Treg numbers were normal in CVIDid Tregs, low levels of CTLA-4 indicate possible Treg dysfunction. Combined studies of T-cell dysfunction and circulating inflammatory proteins may direct future treatment strategies. Supplementary Information The online version contains supplementary material available at 10.1007/s10875-021-01084-6.
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Affiliation(s)
- Roos-Marijn Berbers
- Department of Rheumatology and Clinical Immunology, University Medical Center and Utrecht University, Utrecht, The Netherlands
| | - M Marlot van der Wal
- Center for Translational Immunology, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands
| | - Joris M van Montfrans
- Department of Pediatric Immunology and Infectious Diseases, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands
| | - Pauline M Ellerbroek
- Department of Internal Medicine and Infectious Diseases, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands
| | - Virgil A S H Dalm
- Department of Internal Medicine, Division of Clinical Immunology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.,Department of Immunology, Academic Center for Rare Immunological Diseases (RIDC), Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - P Martin van Hagen
- Department of Internal Medicine, Division of Clinical Immunology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.,Department of Immunology, Academic Center for Rare Immunological Diseases (RIDC), Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Helen L Leavis
- Department of Rheumatology and Clinical Immunology, University Medical Center and Utrecht University, Utrecht, The Netherlands.
| | - Femke van Wijk
- Center for Translational Immunology, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands
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Jain P, Mishra A, Gupta D, Kulkarni S. Chronic enteropathy-related malabsorption syndrome in an adult with common variable immunodeficiency and symptomatic norovirus infection of the gut. BMJ Case Rep 2021; 14:14/5/e241752. [PMID: 34016632 DOI: 10.1136/bcr-2021-241752] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Common variable immunodeficiency (CVID) causes a chronic debilitating syndrome in affected patients and often leads to high morbidity and mortality. Among its several presentations, chronic enteropathy leading to malabsorption syndrome continues to offer a major diagnostic dilemma. Lately, higher testing for norovirus infection in patients with CVID enteropathy has correlated its presence to chronic diarrhoeas, severe villous atrophy and malabsorption syndromes. There have been no such reports of its clinical and histopathological manifestations in CVID from India. Here, we demonstrate the significance of testing for norovirus in the gut with multiplex PCRs in an adult patient with a chronic undiagnosed CVID enteropathy and its response to monthly intravenous immunoglobulin (IVIG) therapy. Our patient responded after three cycles of monthly IVIG with a complete clinical recovery of his bowel functions, leading to a significant improvement in his quality of life and performance status.
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Affiliation(s)
- Punit Jain
- Hematology Oncology and Bone Marrow Transplant Unit, Apollo Hospitals (AHNM), Navi Mumbai, India .,HematCare-Speciality Hematology Clinic, Mumbai, India
| | - Anand Mishra
- General Medicine, Apollo Hospitals (AHNM), Navi Mumbai, India
| | | | - Satish Kulkarni
- Gastroenterology, Apollo Hospitals (AHNM), Navi Mumbai, India
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46
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Late-onset and long-lasting autoimmune neutropenia: an analysis from the Italian Neutropenia Registry. Blood Adv 2021; 4:5644-5649. [PMID: 33206964 DOI: 10.1182/bloodadvances.2020002793] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Accepted: 09/03/2020] [Indexed: 12/14/2022] Open
Abstract
Primary autoimmune neutropenia (pAN) is typified by onset in early infancy and a mild/moderate phenotype that resolves within 3 years of diagnosis. In contrast, secondary AN is classically an adult disease associated with malignancy, autoimmunity, immunodeficiency, viral infection, or drugs. This study describes a cohort of 79 children from the Italian Registry who, although resembling pAN, did not fully match the criteria for pAN because neutropenia either appeared after age 5 years (LO-Np) or lasted longer than 3 years (LL-Np). These 2 categories compared with classical pAN showed a far inferior rate of resolution (P < .001), lower severity of neutropenia (P = .03), leukopenia (P < .001), lymphopenia (P < .001) with low B+ (P = .001), increased need of granulocyte colony-stimulating factor (P = .04), and increased frequency of autoimmunity over the disease course (P < .001). A paired comparison between LO-Np and LL-Np suggested that LO-Np had a lower rate of resolution (P < .001) and lower white blood cell (P < .001) and lymphocyte (P < .001) values, higher occurrence of apthae (P = .008), and a stronger association with autoimmune diseases/markers (P = .001) than LL-Np, thus suggesting a more pronounced autoimmune signature for LO-Np. A next-generation sequencing panel applied in a small subgroup of LO-Np and LL-Np patients identified variants related to immune dysregulations. Overall, these findings indicate that there are important differences among pAN LL-Np and LO-Np. Forms rising after 3 years of age, with low tendency to resolution, require tight monitoring and extensive immune investigations aimed to early identify underlying immunologic disease.
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Ibrahim H, Walsh J, Casey D, Murphy J, Plant BJ, O'Leary P, Murphy DM. Recurrent asthma exacerbations: co-existing asthma and common variable immunodeficiency. J Asthma 2021; 59:1177-1180. [PMID: 33902374 DOI: 10.1080/02770903.2021.1922913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/30/2022]
Abstract
Common variable immunodeficiency is characterized by impaired B-cell differentiation and defective immunoglobulin production manifesting as recurrent respiratory tract infections. While the condition can masquerade as asthma, late diagnosis of CVID in known asthmatic is rarely reported. We present the case of a 43-year-old lady with recurrent episodes of wheeze, cough, sinusitis and multiple lower respiratory tract infections. Transiently responsive to antibiotics and steroids. These episodes had been occurring for many years and she had a longstanding clinical diagnosis of asthma. As part of her work up for recurrent respiratory tract infections a CT thorax was performed and demonstrated bronchiectasis. Further tests including Immunoglobulin levels revealed critically low IgG, IgM, and IgA levels. Immunoglobulin replacement therapy was commenced with a reduction in exacerbation frequency and severity, and objective improvement of asthma control. Subsequent lung function tests demonstrated reversible airflow limitation (obstructive lung function with 13% reversibility in FEV1 post-bronchodilator) consistent with asthma. Our case illustrates the importance of searching for alternate and co-existent diagnoses in patients diagnosed with asthma who are unresponsive to conventional therapy. We believe that serum immunoglobulin measurement should form a component of such a workup.
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Affiliation(s)
- H Ibrahim
- The Department of Respiratory Medicine, Cork University Hospital, Cork, Ireland
| | - J Walsh
- The Department of Respiratory Medicine, Cork University Hospital, Cork, Ireland
| | - D Casey
- The Department of Respiratory Medicine, Cork University Hospital, Cork, Ireland
| | - J Murphy
- The Department of Respiratory Medicine, Cork University Hospital, Cork, Ireland
| | - B J Plant
- The Department of Respiratory Medicine, Cork University Hospital, Cork, Ireland.,The HRB funded Clinical Research Facility, University College Cork, Cork, Ireland
| | - P O'Leary
- The Department of Medicine, School of Medicine, University College Cork, Cork, Ireland
| | - D M Murphy
- The Department of Respiratory Medicine, Cork University Hospital, Cork, Ireland.,The HRB funded Clinical Research Facility, University College Cork, Cork, Ireland
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48
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ŞENOL M, ÖZÇELİK N, ÖZYURT S, DÖNMEZ H, GÜMÜŞ A, ŞAHİN Ü. COMMON VARIABLE IMMUNODEFICIENCY AT ADULT AGE. CLINICAL AND EXPERIMENTAL HEALTH SCIENCES 2021. [DOI: 10.33808/clinexphealthsci.852785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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Guo H, Zhang H, Sheng N, Wang J, Chen J, Dai J. Perfluorooctanoic acid (PFOA) exposure induces splenic atrophy via overactivation of macrophages in male mice. JOURNAL OF HAZARDOUS MATERIALS 2021; 407:124862. [PMID: 33360190 DOI: 10.1016/j.jhazmat.2020.124862] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 11/27/2020] [Accepted: 12/12/2020] [Indexed: 06/12/2023]
Abstract
Perfluorooctanoic acid (PFOA), a synthetic and widely used chemical, has aroused wide public concern due to its persistence, bioaccumulation, and potential toxicity. To investigate splenic atrophy induced by PFOA, male mice were exposed to 0, 0.4, 2, or 10 mg/kg/d PFOA for 28 d. Results demonstrated that spleen weight and relative spleen weight (RSW) decreased in the 2 and 10 mg/kg/d PFOA exposure groups. Iron levels in the spleen and serum were also reduced in all PFOA exposure groups. Weighted gene co-expression network analysis (WGCNA) of 7 043 genes highlighted enrichment in cell cycle, autoimmunity, and anemia in the spleen. In addition, changes in the levels of hemoglobin, platelets, bilirubin, and heme oxygenase-1 were consistent with anemia. The ratio of total macrophages to M1 macrophages in the spleen, phagocytic ability of macrophages, and levels of cytokines such as TNF-α, IL-1β, and IL-6 all increased, thus suggesting the occurrence of autoimmune disorder. Therefore, we concluded that overactivation of macrophages may be an important reason for splenic atrophy induced by PFOA exposure.
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Affiliation(s)
- Hua Guo
- Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Hongxia Zhang
- Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - Nan Sheng
- Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - Jinghua Wang
- Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - Jiamiao Chen
- Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - Jiayin Dai
- Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
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50
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Lee TK, Gereige JD, Maglione PJ. State-of-the-art diagnostic evaluation of common variable immunodeficiency. Ann Allergy Asthma Immunol 2021; 127:19-27. [PMID: 33716149 DOI: 10.1016/j.anai.2021.03.005] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 03/01/2021] [Accepted: 03/09/2021] [Indexed: 02/06/2023]
Abstract
OBJECTIVE To summarize the current understanding of diagnostic and postdiagnostic evaluation of common variable immunodeficiency (CVID). DATA SOURCES PubMed Central database. STUDY SELECTIONS Original research articles and review articles from 2015 to 2020 including seminal articles that shaped the diagnostic and postdiagnostic evaluation of CVID were incorporated. This work focuses on initial diagnosis of CVID, genetic evaluations, and postdiagnostic assessment of respiratory, gastrointestinal, and hepatobiliary diseases including spleen and lymph node enlargement. RESULTS CVID presents not only with frequent infections but also with noninfectious complications such as autoimmunity, gastrointestinal disease, chronic lung disease, granulomas, liver disease, lymphoid hyperplasia, splenomegaly, or malignancy. The risk of morbidity and mortality is higher in patients with CVID and noninfectious complications. Detailed diagnostic approaches, which may incorporate genetic testing, can aid characterization of individual CVID cases and shape treatment in some instances. Moreover, continued evaluation after CVID diagnosis is key to optimal management of this complex disorder. These postdiagnostic evaluations include pulmonary function testing, radiologic studies, and laboratory evaluations that may be conducted at frequencies determined by disease activity. CONCLUSION Although the diagnosis can be achieved similarly in all patients with CVID, those with noninfectious complications have distinct concerns during clinical evaluation. State-of-the-art workup of CVID with noninfectious complications typically includes genetic analysis, which may shape precision therapy, and thoughtful application of postdiagnostic tests that monitor the presence and progression of disease in the myriad of tissues that may be affected. Even with recent advancements, knowledge gaps in diagnosis, prognosis, and treatment of CVID persist, and continued research efforts are needed.
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Affiliation(s)
- Theodore K Lee
- Section of Pulmonary, Allergy, Sleep & Critical Care Medicine, Department of Medicine, Boston University School of Medicine, Boston Medical Center, Boston, Massachusetts
| | - Jessica D Gereige
- Section of Pulmonary, Allergy, Sleep & Critical Care Medicine, Department of Medicine, Boston University School of Medicine, Boston Medical Center, Boston, Massachusetts
| | - Paul J Maglione
- Section of Pulmonary, Allergy, Sleep & Critical Care Medicine, Department of Medicine, Boston University School of Medicine, Boston Medical Center, Boston, Massachusetts.
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