Clinical Heterogeneity of Common Variable Immunodeficiency

Common variable immunodeficiency (CVID) is the most common, clinically relevant, primary immunodeficiency (PID). In the western world the incidence of this disease is about 1:50000. CVID is characterized by hypogammaglobulinemia which involves in all cases immunoglobulin G (IgG), in about 70-80% of cases immunoglobulin A (IgA) and in about 50% of cases immunoglobulin M (IgM). Additionally, patients with CVID develop weak or no immunization responses against polysaccharide (mainly) and protein antigens. Clinical manifestations of CVID may present either early in childhood or late in adulthood, usually between the third and fourth decade of life. The range of CVID clinical manifestations is broad. Underlying CVID should be considered mainly in cases of patients who present with recurrent or persistent bacterial infections of the upper or lower respiratory tract. The possibility of underlying CVID has also to be examined during laboratory investigation of various clinical syndromes, such as lymphadenopathy, hepatosplenomegaly, chronic diarrhea, or malabsorption, and also of autoimmune cytopenias such as idiopathic thrombocytopenic purpura and autoimmune hemolytic anemia. It is noteworthy, that autoimmune diseases and malignancies in the form of lymphoma and neoplasm of the gastrointestinal tract occur with increased incidence in CVID patients in comparison to the general population. Treatment strategy of CVID patients should not be limited to immunoglobulin substitution therapy (administered either intravenously or subcutaneously), but it also has to target effective management of infections and early diagnosis of occurring malignancies (lymphomas and gastrointestinal tumors) through systematic patient monitoring. With regard to life expectancy of CVID patients, two recently published large retrospective studies showed that CVID patients suffering only from infections had prolonged overall survival compared to those who presented with other CVID clinical manifestations. Exclusion of all potential causes of secondary hypogammaglobulinemia is mandatory for establishing the diagnosis of CVID. Also, in some CVID cases, differential diagnosis from other PID may be required, such as X-linked agammaglobulinemia (XLA), antibody deficiency with increased IgM (Hyper-IgM syndrome), and X-linked lymphoproliferative syndrome (XLP)