Agammaglobulinemia in children

Agammaglobulinemia in children is a typical disease with isolated deficiency of antibody production. Genetic defects lead to disruption of early stages of B lymphocyte maturation, and, as a consequence, repeated bacterial infections from the first years of life, severe hypogammaglobulinemia and a sharp decrease or absence of B lymphocytes in the peripheral circulation.

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How does agammaglobulinemia develop in children?

Most patients with agammaglobulinemia (about 85%) have a mutation in the Btk (Bruton's tyrosine kinase) gene located on the X chromosome. The disease is called X-linked (or Bruton's) agammaglobulinemia (XLA). Half of patients with this defect have no family history; mutations are spontaneous. 5% of patients with agammaglobulinemia have a mutation in the alpha heavy chain gene. A small number of patients have defects in other components of the pre-B-cell receptor (surrogate light chain, mu heavy chain), as well as the BLNK signaling protein. All these defects are inherited in an autosomal recessive manner. The absence of one of the above proteins leads to a disruption in signal transmission from the pre-B-cell receptor, and, as a consequence, to a block in the maturation of B lymphocytes.

Symptoms of Agammaglobulinemia in Children

Clinical symptoms of agammaglobulinemia are virtually identical depending on the molecular genetic defect.

An important sign of a B lymphocyte defect in a patient is hypotrophy of the tonsils and lymph nodes. The lymph nodes mainly consist of follicles, which in turn are predominantly represented by B lymphocytes. In the absence of B cells, follicles do not form and the lymph nodes are very small.

In most patients, infections debut in the first year of life, after catabolism of maternal antibodies. However, about 10% of patients are diagnosed after 4 years of age. It is possible that higher residual concentrations of immunoglobulins are observed in this group.

The vast majority of patients with agammaglobulinemia develop recurrent or chronic infections caused by encapsulated bacteria, especially S. pneumoniae and H. influenzae, such as pneumonia, otitis, sinusitis, conjunctivitis, and enterocolitis. More severe infections are somewhat less common: meningitis, osteomyelitis, destructive pleuropneumonia, sepsis, septic arthritis, pyoderma, and purulent infections of the subcutaneous tissue.

In addition to H. influenzae, S. pneumoniae, patients with agammaglobulinemia are characterized by increased susceptibility to infections caused by mycoplasmas and ureaplasmas. Mycoplasmas and ureaplasmas cause the development of chronic pneumonia, purulent arthritis, cystitis, and subcutaneous tissue infections. Giardiasis is often detected with gammaglobulinemia. Patients with humoral defects are highly sensitive to enterovirus infections: ECHO and Coxsackie. The cause of infection can be a vaccine strain of poliomyelitis. Enteroviruses cause both severe acute and chronic encephalitis and encephalomyelitis. Manifestations of enterovirus infections can be dermatomyositis-like syndrome, ataxia, headaches, behavioral disorders.

Among non-infectious symptoms, patients experience non-specific ulcerative colitis, scleroderma-like syndrome, and, paradoxically, symptoms of seasonal and drug allergies.

Patients with agammaglobulinemia often develop neutropenia, which can be complicated by characteristic infections (S. aureus, P. aerogenosa).

Diagnosis of agammaglobulinemia

The diagnostic criteria are a decrease in the serum IgG concentration to less than 2 g/l in the absence of IgA, IgM, and circulating B lymphocytes. Some patients with XLA have an "attenuated" phenotype, in which trace amounts of IgG and IgM can be detected, and the number of B lymphocytes in the peripheral blood is up to 0.5% of all lymphocytes. Typically, such patients have a later onset of the disease.

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Treatment of agammaglobulinemia

The basis of treatment for agammaglobulinemia is replacement therapy with intravenous immunoglobulin. At the beginning of treatment and in the development of severe infections, immunoglobulin is administered at a dose of 0.2-0.3 g/kg of body weight once every 5-7 days for 4-6 weeks. This regimen of immunoglobulin administration allows achieving a normal concentration of IgG in the serum. Regular maintenance therapy is carried out once every 3-4 weeks at a dose of 0.4 g/kg. The pretransfusion IgG level should be at least 4 g/l. In case of enterovirus infection, high-dose therapy with intravenous immunoglobulin (2 g/kg) is indicated once every 5-7 days for 4 weeks.

In the presence of chronic foci of infection (usually in the lungs), patients are prescribed constant prophylactic antibacterial therapy (sulfamethoxazole-trimethoprim as monotherapy or in combination with fluoroquinolones or amoxiclav).

In case of persistent neutropenia accompanied by clinical manifestations, growth factors are used. Stem cell transplantation is not indicated for agammaglobulinemia.

What is the prognosis for agammaglobulinemia in children?

The use of combined therapy for agammaglobulinemia using regular administration of immunoglobulin and antibiotics has significantly improved the prognosis of the disease. Early initiation of adequate replacement therapy with intravenous immunoglobulin helps to avoid the formation of chronic infections and significantly reduces the number of episodes of acute infections and the incidence of other complications. Recently, most patients receiving adequate treatment reach adulthood.