Common variable immune deficiency: symptoms, diagnosis, treatment

Common variable immune deficiency (CVID) is a heterogeneous group of diseases characterized by a defect in antibody synthesis. The prevalence of CVID varies from 1:25,000 to 1:200,000, with an equal sex ratio.

Pathogenesis of common variable immunodeficiency

The molecular defect of most patients is unknown, and this group probably combines several entities. Most cases of CVID are sporadic, but familial variants have been observed, as well as cases of common variable immune deficiency and selective IgA deficiency in the same family, suggesting that these two diseases may be allelic variants of a single gene mutation.

Numerous attempts to find the genetic basis of common variable immunodeficiency led to the identification of the first defect in this group, a mutation in the inducible costimulatory molecule (ICOS) gene located on the long arm of chromosome 2. ICOS is expressed by activated T lymphocytes, and its interaction with its ligand on B lymphocytes is necessary for late B-cell differentiation and the formation of memory B cells. Nine patients with this mutation have been described to date.

More recently, a mutation in the TNFRSF13B gene encoding the transmembrane activator and modulator of calcium (TACI) was found in 17 patients with CVID (out of 181 screened). TACI is expressed by B lymphocytes and is important for their interaction with macrophages and dendritic cells.

At present, common variable immune deficiency is classified by WHO experts as a group of immunodeficiencies with a predominant disorder of antibody production, however, a lot of data has been revealed indicating damage to T-lymphocytes. Thus, the decrease in the production of immunoglobulins is probably associated with a disorder of T-cell regulation of their synthesis, that is, CVID is to a greater extent a combined immunodeficiency,

Lab changes

As a rule, in common variable immune deficiency, the concentrations of three main classes of immunoglobulins are reduced; it is possible to reduce only two, for example, IgA and IgG or even one IgG. All patients have a violation of specific antibody formation,

The number of B-lymphocytes in most patients is not changed, but they often have an immature phenotype with limited hypermutations, as well as a decrease in the number of memory B cells.

Many patients have T-lymphopenia, an abnormal CD4/CD8 ratio (due to a decrease in CD4+ and an increase in CD8+), and a limited T-lymphocyte repertoire. Lymphocyte proliferation and IL-2 production under the influence of nonspecific and, especially, specific mitogens are significantly impaired in patients with CVID. There is evidence of a decrease in the expression of the CD40 ligand by activated T cells and defects in signal transmission through the costimulatory molecules CD40-CD40L and CD28-B7, which causes impaired B-cell differentiation in some patients with common variable immune deficiency.

A significant role in the development of a cascade of cellular disorders in common variable immune deficiency is played by a defect in the macrophage link, in the form of an increase in the number of monocytes containing intracellular IL-12, which is associated with an increase in the number of IFN-y-positive T cells. This imbalance shifts the immune response to the Th1 type and also explains the inability of T cells in common variable immune deficiency to form antigen-specific memory cells and the tendency of patients to develop chronic inflammation and granulomatous complications.

In addition, there is evidence of impaired maturation and differentiation of dendritic cells, resulting in impaired antigen presentation necessary for the effective functioning of T lymphocytes.

Symptoms of common variable immunodeficiency

The first symptoms of common variable immune deficiency can appear at any age, usually common variable immune deficiency is diagnosed at the age of 20-40 years. In children, common variable immune deficiency often debuts in adolescence, but the appearance of the first symptoms at an early age is not excluded, as is the case with agammaglobulinemia.

The spectrum of clinical manifestations on the basis of which one can suspect common variable immunodeficiency is very wide: in some patients the first clinical manifestations are repeated pneumonias, in others - thrombocytopenic purpura, autoimmune hemolytic anemia, or colitis.

Infectious complications of common variable immune deficiency are mainly represented by bacterial lesions of the respiratory and gastrointestinal tracts, purulent meningitis, and giardiasis. Pneumonia is one of the most common manifestations of common variable immune deficiency. They are often accompanied by the formation of bronchiectasis or a tendency to chronicity. In addition to banal bacterial infections, opportunistic infections such as pneumocystis pneumonia can also develop.

Patients with CVID are prone to developing purulent arthritis caused by mycoplasmas and ureaplasmas. Septic arthritis often develops in patients with CVID who already suffer from rheumatoid arthritis. A case of septic arthritis against the background of generalized infection Penirittium marneffe is described, the treatment of which with a combination of antifungal and replacement therapy proved effective.

Viral hepatitis (especially hepatitis C) is severe (sometimes fatal) in general variable immune deficiency, with pronounced clinical and laboratory abnormalities, and quickly leads to complications in the form of chronic active hepatitis and can recur even after liver transplantation. In CVID, Herpes simplex infection is common and can be severe.

Patients with CVID, as well as with other forms of humoral defects, are highly sensitive to enteroviruses. Enteroviral encephalomyelitis is extremely severe and poses a serious threat to life; enteroviral poliomyelitis and dermatomyositis-like diseases, skin and mucous membrane lesions are possible.

Other viruses can also cause serious illnesses. For example, parvovirus B19 can cause erythroid aplasia.

In addition to infectious lung lesions, noncaseating granulomas have been described in patients with CVID, which have much in common with sarcoidosis. Aseptic noncaseating and caseating granulomas can occur in the lungs, skin, liver, and spleen. The cause of granulomatous inflammation that occurs in various organs of patients with common variable immune deficiency is probably a violation of T-cell regulation of macrophage activation.

Autoimmune manifestations are severe and can determine the prognosis. Sometimes autoimmune disorders are the first clinical manifestations of CVID: arthritis, nonspecific ulcerative colitis and Crohn's disease, sclerosing cholangitis, malabsorption and enteropathy, systemic lupus erythematosus, nephritis, myositis, autoimmune lung disease in the form of lymphoid interstitial pneumonitis, neutropenia, thrombocytopenic purpura, hemolytic anemia, pernicious anemia, total alopecia, retinal vasculitis. One patient may develop several autoimmune syndromes at once, for example: arthritis, alopecia and cytopenia, or systemic lupus erythematosus, and later - enteropathy and nephritis.

Gastroenterological pathology occupies a significant place among the symptoms of common variable immune deficiency. In 25% of cases of common variable immune deficiency, gastroenterological disorders are detected in the form of ulcerative colitis, proctitis and Crohn's disease, nodular lymphoid hyperplasia of the intestine, malabsorption, giardiasis, protein-losing enteropathy, sprue-like syndrome, campylobacteriosis and other rarer syndromes. Along with infectious, autoimmune mechanisms of development of gastroenterological lesions certainly play a significant role.

Patients with CVID have a significantly increased incidence of malignant neoplasms, sarcoid-like granulomas, and non-malignant lymphoproliferation. In general variable immune deficiency, not only peripheral but also intrathoracic lymph node enlargement is often detected. When analyzing the incidence of malignant neoplasms, various tumors were detected in 15% of cases. An increased incidence of non-Hodgkin's lymphomas and gastric adenocarcinomas has been proven; Hodgkin's lymphomas, intestinal cancer, breast cancer, prostate cancer, and ovarian cancer are also encountered.

Diagnosis of common variable immunodeficiency

Since confirmatory molecular genetic studies are not available in most cases of common variable immunodeficiency, it is especially important to exclude other causes of hypogammaglobulinemia.

Based on the criteria of the European Society for the Study of Immunodeficiencies (ESID), the diagnosis of common variable immunodeficiency is highly probable with a significant decrease (more than 2 SD from the median) in two or three major immunoglobulin isotypes (IgA, IgG, IgM) in individuals of both sexes in combination with one of the following features:

• onset of immunodeficiency at the age of over 2 years;
• absence of isohemagglutinins and/or poor response to vaccines;
• other well-known causes of agammaglobulinemia must be excluded.

Treatment of common variable immunodeficiency

As with other humoral defects, the basis of treatment for common variable immune deficiency is immunoglobulin replacement therapy. However, in most cases, it does not prevent all infectious problems, and therefore many patients require prophylactic antibacterial therapy. Corticosteroids are used in the treatment of granulomatous disease. In the treatment of autoimmune and tumor pathology, protocols appropriate to the disease are used. Transplantation of hematopoietic stem cells in common variable immune deficiency is not performed.

Forecast

When carrying out replacement and antibacterial therapy, the average age of death in patients with common variable immune deficiency, according to one study, is 42 years. The main causes of death are tumors and chronic lung diseases.

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