Lymphadenopathy at the crossroad between immunodeficiency and autoinflammation: An intriguing challenge

Costagliola, Giorgio; Consolini, Rita

doi:10.1111/cei.13620

Cited by 19 publications

(28 citation statements)

References 110 publications

(189 reference statements)

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“…In our study group showing lymphoproliferative disorders, the clinical diagnoses included lymphadenopathy, GLILD (as shown in Figure 6 ), hepatosplenomegaly, and cutaneous granulomas. It is worth noting that, in all our patients with CVID presenting with GLILD, other extrapulmonary, systemic features of immune dysregulation have been observed, in the form of lymphadenopathy, granulomatous liver and spleen disease, and cutaneous granulomatosis, supporting the hypothesis of the generalized nature of the granulomatous disease in CVID ( 9 , 10 , 42 , 43 ). It is also worth pointing out that, in our patients with pediatric CVID, same as in children with autoimmune cytopenias reported in ( 36 ), either GLILD or any other granulomatous lymphoproliferative manifestations were not associated with increased numbers of immature B-cell subset with CD19+CD21lo immunophenotype, in which expansion has been hypothesized to be a predictor of granulomatous complications in CVID ( 8 , 44 , 45 ).…”

Section: Discussionsupporting

confidence: 80%

Immune Dysregulation in Pediatric Common Variable Immunodeficiency: Implications for the Diagnostic Approach

et al. 2022

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Infections and infectious complications are hallmarks of common variable immunodeficiency (CVID) and the leading cause of morbidity and mortality in affected patients at any age. However, the pediatric CVID is no longer perceived as a primary immunodeficiency associated solely with infectious manifestations; autoimmune, allergic, lymphoproliferative, and malignant disorders and organ-specific immunopathology also characterize the spectrum of non-infectious complications. In this study, we sought to determine the role of immune dysregulation and frequency of non-infectious sequelae in children affected with CVID. We also aimed at providing an insight into the pathogenesis of non-infectious complications and at delineating the diagnostic approach to pediatric CVID with immune dysregulation. An in-depth retrospective analysis of clinical manifestations and their correlations with selected immune parameters was performed in a group of 39 CVID children, followed by our pediatric immunology department. Whereas recurrent sinopulmonary infections were present in all (100%) of the children studied, an unexpectedly high rate of non-infectious disorders and immune dysregulation phenotypes were observed in as many as 32 (82.05%) patients, compared with infection-only phenotypes limited to 7 (17.95%) male patients. The most common inflammatory comorbidity was asthma, diagnosed in 21 (53.85%) patients. The second most frequent immune dysregulation group was autoimmune disorders, present in 18 (46.15%) of the children studied with a high rate of autoimmune thyroiditis in as many as 10 (25.64%) of the CVID-affected children. Lymphoproliferation was seen in 14 children (35.90%), and, among them, lymphadenopathy occurred in nine (23.08%) cases and granulomatous lymphocytic interstitial lung disease in seven (17.95%) cases. Finally, malignancies occurred in two female patients (5.13%), papillary thyroid cancer in the first one and T-cell lymphoblastic leukemia in the other one. The most prominent abnormalities in the B- and T-cell compartment contributing to complex immune deficiency and immune dysregulation phenotypes were seen in the autoimmunity group, showing significant reductions in the switched memory B cell, naive T helper cell, and regulatory T-cell subsets. Herein, we document the previously unreported high rate of immune dysregulation in pediatric CVID as a clinical and diagnostic challenge with the variability of defects in the humoral and cellular immune responses.

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Section: Discussionsupporting

confidence: 80%

Immune Dysregulation in Pediatric Common Variable Immunodeficiency: Implications for the Diagnostic Approach

et al. 2022

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“…Clinically, this often presents as generalized lymphadenopathy and splenomegaly. The challenge is to differentiate it from lymphoma [ 5 ]. In 20% of patients with a CVID-like phenotype, monogenic defects responsible for immune deregulation have been identified.…”

Section: Introductionmentioning

confidence: 99%

Patients with Common Variable Immunodeficiency Complicated by Autoimmune Phenomena Have Lymphopenia and Reduced Treg, Th17, and NK Cells

Więsik-Szewczyk

Rutkowska

Kwiecień

et al. 2021

JCM

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Most patients with primary immune deficiency suffer from recurrent infections; however, paradoxical autoimmune phenomena can also manifest. The aim of this study was to identify immunological markers of autoimmune phenomena associated with common variable immunodeficiency (CVID). The study included 33 adults with CVID divided into two groups: (1) those with noninfectious autoimmune complications (CVID-C (n = 24)) and (2) those with only infectious symptoms (CVID-OI (n = 9)). Flow cytometry of peripheral blood was performed and compared with systemic lupus erythematosus (SLE) patients (n = 17) and healthy controls (n = 20). We found that all lymphocytes were lower in CVID-C and SLE. NK cells were lowest in CVID-C. Th17 cells were significantly reduced in CVID-C and SLE. Tregs were significantly lower in CVID-C and SLE. Bregs did not significantly differ between any groups. Class-switched memory B cells were significantly lower in CVID-C and CVID-OI. Lastly, plasmablasts were significantly higher in SLE. Among the T cell subsets, CVID-C patients had lower naive and recent thymic emigrant CD4+ T cells. In conclusion, reduced Treg, Th17, and NK cells are features of CVID with autoimmune complications, and class-switched memory B cells can help distinguish patients with different causes of autoimmunity. Future studies are needed to confirm whether reductions of Treg, Th17, and NK cells might be a biomarker of more complicated CVID cases.

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“…Clinical symptoms are non-specific and mimic those of an infection, inflammation, or neoplasia. The clinical features are characterized by chronic or recurrent lymphadenopathy, hepatosplenomegaly, extranodal infiltration, and/or peripheral blood lymphocytosis ( 4 ). In certain immune disorders such as autoimmune lymphoproliferative syndrome (ALPS) and X-linked lymphoproliferation (XLP), LP is the predominant feature at disease onset.…”

Section: Clinical Issuesmentioning

confidence: 99%

Lymphoproliferation in Inborn Errors of Immunity: The Eye Does Not See What the Mind Does Not Know

et al. 2022

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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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Lymphadenopathy at the crossroad between immunodeficiency and autoinflammation: An intriguing challenge

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri bution-NonCo mmercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 19 publications

References 110 publications

Immune Dysregulation in Pediatric Common Variable Immunodeficiency: Implications for the Diagnostic Approach

Immune Dysregulation in Pediatric Common Variable Immunodeficiency: Implications for the Diagnostic Approach

Patients with Common Variable Immunodeficiency Complicated by Autoimmune Phenomena Have Lymphopenia and Reduced Treg, Th17, and NK Cells

Lymphoproliferation in Inborn Errors of Immunity: The Eye Does Not See What the Mind Does Not Know

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