Abstract
Common variable immunodeficiency (CVID) is the most prevalent antibody deficiency, characterized by remarkable genetic, immunological, and clinical heterogeneity. The diagnosis of pediatric CVID is challenging due to the immaturity of the immune response and sustained actively developing antibody affinity to antigens and immunological memory that may overlap with the inborn error of immunity. Significant progress has been recently done in the field of immunogenetics, yet a paucity of experimental and clinical studies on different systemic manifestations and immunological features of CVID in children may contribute to a delayed diagnosis and therapy. In this review, we aimed at defining the variable epidemiological, etiological, and clinical aspects of pediatric CVID with special emphasis on predominating infectious and non-infectious phenotypes in affected children.Conclusion: While pediatric CVID is a multifaceted and notorious disease, increasing the pediatricians’ awareness of this disease entity and preventing the diagnostic and therapeutic delay are needed, thereby improving the prognosis and survival of pediatric CVID patients.What is Known:• CVID is an umbrella diagnosis characterized by complex pathophysiology with an antibody deficiency as a common denominator.• It is a multifaceted disease characterized by marked genetic, immunological, and clinical heterogeneity..What is New:• The diagnosis of pediatric CVID is challenging due to the immaturity of innate and adaptive immune response.• Increasing the pediatricians’ awareness of CVID for the early disease recognition, timely therapeutic intervention, and improving the prognosis is needed.
Highlights
Common variable immunodeficiency (CVID) belongs to a phenotypically and immunologically heterogeneous and complex group of primary immunodeficiencies (PIDs)
In the light of the persistently aberrant adaptive immune response in CVID and defective clearance of pathogens, these findings suggest an innate immune system activation that may, in turn, predispose CVID-affected children to the development of chronic inflammatory complications
Whereas the genetic landscape of pediatric CVID is being expanded, it is no longer perceived as a spectrum of monogenic diseases, yet polygenic and environmental background, as well as epigenetic regulation of gene expression, has been postulated as relevant mechanism underpinning the immunopathogenesis of CVID
Summary
ADHD Attention deficit/hyperactivity disorder AEFI Adverse effect following vaccination AIDCA Activation-induced cytidine deaminase AIHA Autoimmune hemolytic anemia BACH BTB domain and CNC homolog BAFF B cell-activating factor belonging to the tumor necrosis factor (TNF) family BLK B-lymphoid tyrosine kinase BLNK B-cell linker BTK Bruton tyrosine kinase CARD Caspase recruitment domain family member CCR CC-chemokine receptor CID Combined immunodeficiency CMV Cytomegalovirus CSR Class-switch recombination CTLA Cytotoxic T lymphocyte-associated antigen CTNNBL1 Catenin beta-like CVID Common variable immunodeficiency CXCR CXC-chemokine receptor DCK Dyskerin DCLRE DNA cross-link repair DNMT DNA methyltransferase DOCK Dedicator of cytokinesis EBV Epstein-Barr virus ESID European Society for Immunodeficiencies FOXP Forkhead box protein GATA GATA binding protein GLILD Granulomatous lymphocytic interstitial lung disease HDI Human Development Index HLH Hemophagocytic lymphohistiocytosis HSV Herpes simplex virus IBD Inflammatory bowel disease ICF Immunodeficiency-centromeric instabilityfacial anomalies ICOS Inducible T cell co-stimulator IFN Interferon IGHM Immunoglobulin heavy constant μ IgRT Immunoglobulin replacement therapy IKBKB Inhibitor of nuclear factor κ B (NFκB). Kinase subunit gamma IKZF Ikaros zinc finger IL Interleukin ILD Interstitial lung disease IRF2BP Interferon regulatory factor 2 binding protein ITK Interleukin 2-inducible T-cell kinase ITP Immune thrombocytopenia IVIg Intravenous immunoglobulin KCNN Potassium calcium activate channel subfamily N member
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