Common variable immune deficiency or CIVD, is the commonest primary childhood immunodeficiency disorder. It is characterized by recurrent infections and increased susceptibility to autoimmunity and malignancy. With an estimated age-adjusted incidence of about 1 case per 200 000 per year, the average age-adjusted prevalence is 1 case per 91 000 per year. CVID encompasses the largest group of symptomatic primary immunodeficiency. There are regional differences in incidence, with CVID being a rare diagnosis among Asians and Afro-Americans. There is no gender predisposition. The age of onset is usually in the second to third decade of life, although a smaller group of patients already manifest CVID in childhood, and, in general, it can occur at any age.
More than 90% of documented CVID patients lack a definite molecular genetic diagnosis or other causal explanation for their disease. Only 10 to 20% of CVID patients have a positive family history, while most cases occur sporadically. Four out of five CVID families show autosomal dominant inheritance. In some larger pedigrees, individuals with selective IgA deficiency, CVID and intermediate forms can be observed side by side. This finding and cases of progression from IgA deficiency towards CVID indicates a possible common genetic predisposition. Autosomal recessive CVID is rarely seen in Europe and North America but is more frequent in regions.
For many years, abnormalities of CD4+ and CD8+ T-cell numbers or function were known and described in subgroups of CVID patients. In a significant proportion of CVID patients a reduction of total CD4+ T-cell counts was observed. Regulatory T-cells are also diminished in subgroups of CVID patients who present clinically with increased autoimmunity, granulomas, and splenomegaly. The total number of peripheral B-cells is slightly reduced in about 40 to 50% of CVID patients. In some patients elevated numbers of B-cells are reported, often associated with polyclonal lymphoid organ infiltration and autoimmunity. In only about 10% of CVID patients are B-cells dramatically reduced or absent.
The diagnosis is established by recognizing decreased classes of immunoglobulins (Ig) with an impaired vaccination responses. The criteria of CVID of the European Society for Immunodeficiencies and the Pan-American Group for Immunodeficiency include: onset of immunodeficiency at >2 years of age, with absent isohemagglutinins and poor response to vaccination, with a marked decrease of IgG and IgM or IgA levels, and exclusion of other causes of hypogammaglobulinemia. Probable cases can be recognized by marked decreases of IgG, IgM or IgA classes alone. Up to one-half of children develop noninfectious complications including lymphoproliferative disease, granulomatous disease, disturbed immunity and autoimmunity leading to significant morbidity and mortality. Such complications suggest an underlying state of immune dysregulation that results from chronic systemic immune activation.
In recent years, the role of the gut microbiome has emerged as an important driver in the pathogenesis of CIVD-mediated immune dysregulation. The human gut is a unique organ that is home to hundreds of different microbial species, each with a somewhat different habitat and host physiologic function, such as digestion, nutrition, and immunity. Studies have demonstrated crosstalk between the gut microbiota, immunity, and metabolism. There is typically a separation between its microbiome and the epithelial surface and immune cells that patrol it. But normal regular sampling of the microbiome by the immune system influences both the composition of the microbiota and directs immune maturation necessary for immune tolerance and homeostasis. This movement of bacteria or bacterial products across the intestinal membrane into the lymphatics or the visceral circulation enhances the risk of systemic autoimmunity. IgA is a necessary determinant of the composition of the gut microbiome where it limits its growth and invasion by blocking bacteria adhesion to gut epithelial cells and is deficient in CVID leading to leakiness of the gut and increased bacterial translocation and local inflammation. When this occurs, there is the potential for the release of bacterial products such as lipopolysaccharide (LPS), interleukin-2 (IL-2) receptor protein, that show up in the peripheral circulation as evidence of toxemia. In pathological states of increased translocation as a consequence of diminished gut barriers as in CVID, there is resultant chronic inflammation and immune dysregulation, overgrowth of proinflammatory bacteria, and a decrease of anti-inflammatory bacteria that further imbalances the immune system. It is believed that bacterial translocation and alterations in the gut microbiome, superimposed on genetically impaired polysaccharide-specific responses and inherited deficiency of Ig classes, contribute to the pathogenesis of CVID with increased autoimmune and inflammatory manifestations, which represent some of the biggest challenge in their care.
All components of the nervous system are susceptible to the resultant autoimmunity including the brain, spinal cord, peripheral nerves and autonomic function with resultant syndromes of optic neuritis, encephalitis, meningitis, myelitis, peripheral neuritis, and acute dysautonomia alone or in association with concurrent superimposed bacterial, viral, and parasitic infection.
Ig replacement is the mainstay of therapy; 90% of CVID patients are on either intravenous (IVIg) or subcutaneous (SCIg) treatment. The current standard dosage when administered intravenously is 400 to 600 mg/kg every 3 to 4 weeks. For subcutaneous administration, this corresponds to 100 to 150 mg/kg per week. The goal is the control of infections, which is reached at different individual IgG trough levels. Patients with existing chronic lung disease or inflammatory bowel disease often require higher doses of IgG. In chronic sinusitis additional careful local therapy is mandatory.