Chronic granulomatous disease

Chronic granulomatous disease is a hereditary disease caused by a defect in the formation system of the superoxide anion in neutrophils in response to stimulation by microorganisms. This disease is based on genetically programmed changes in the structure or deficiency of the enzyme NADPH oxidase, which catalyzes the reduction of oxygen to its active form - superoxide. Superoxide - the main component of a respiratory explosion, leading to the destruction of microorganisms. Due to a genetic defect, the intracellular death of bacteria and fungi that are capable of producing its own catalase (catalase-positive - Staphylococcus aureus, Burkholderia cepacia, Aspergillus spp.) Is blocked . Depending on the severity of the defect, 4 main types of chronic granulomatous disease are distinguished: complete absence of education (X-linked form - 75% of cases), partial deficiency, structural defect leading to impaired function or regulation of NADPH oxidase formation. The localization and character of the gene rearrangements underlying the disease and the clinical features of the variants are known.

The incidence of chronic granulomatous disease is from 1: 1 000 000 to 1: 250 000 population (1 per 200 000-250 000 live births). Mostly boys are ill, much less often girls.

History of chronic granulomatous disease

Two years after the description of Bruton in 1952, anamaglio6ylinemia. Janeway with a group of colleagues (1954) described five children with severe repeated life-threatening infections caused by staphylococcus, a proteus or Pseudomonas aeruginosa. At the same time there was an increase in the level of serum immunoglobulins. In 1957, in two independent reports (Landing and Shirkey and Good and colleagues), and then Berendes and Bridges in 1957, several boys with purulent lymphadenitis, hepatosplenomegaly, severe pulmonary diseases, purulent skin lesions, hypergammaglobulinemia were described. A specific antibody response was normal at the same time, and an increase in the concentration of gamma globulins corresponded to the severity of the infectious process. The early mortality of all children, despite intensive treatment, gave rise to Bridges et at. In 1959, call this syndrome a "fatal granulomatosis of childhood". In 1967, Jonston and McMurry described five boys and summarized 23 previously described patients with a clinical syndrome of hepatosplenomegaly, repeated purulent infections and hypergammaglobulinemia. All patients were boys, 16 of them had a brother or brothers with similar clinical symptoms, which indicated an X-linked inheritance of the disease. Jonston and McMurry suggested calling this syndrome "chronic fatal granulomatosis." In the same year Quie et al. Described violations of intracellular bacterial killing in neutrophils, and since then the term "Chronic granulomatous disease" has been used. It is interesting that in French this disease is called "granulomatose septique chronique", which means "chronic septic granulomatosis".

Pathogenesis of chronic granulomatous disease

Chronic granulomatous disease develops as a result of a defect in the enzyme NADP oxidase, which catalyzes a "respiratory explosion," which normally accompanies phagocytosis in all cells of the myeloid series. "Respiratory explosion" leads to the formation of free radicals of oxygen, which play a critical role in intracellular killing of pathogenic bacteria and fungi. In connection with the violation of digestion of microorganisms with preserved phagocytosis, hematogenous dissemination of infection by neutrophils occurs. As a result, patients with chronic granulomatous disease suffer from severe recurrent infections caused by intracellular pathogens. In addition, against this background, patients with chronic granulomatous disease develop diffuse granulomatosis of internal organs (esophagus, stomach, biliary system, ureter, bladder), which often causes obstructive or painful symptoms.

The enzyme NADPH oxidase consists of 4 subunits: gp91-phox and p22-phox, which are cytochrome b558, and 2 cytosolic components - p47-phox and p67-phox. The cause of chronic granulomatous disease may be a defect of any of these components. The mutation in the gene gp91-phox, which is localized on the short arm of the X chromosome (Chp21.1), leads to the development of the X-linked variant of the disease and is found in 65% of all patients with chronic granulomatous disease. The remaining 35% of cases of chronic granulomatous disease are inherited autosomally-recessively (AR). The gene encoding the subunit p47-phox is localized in chromosome 7 till.23 (25% of the AR of the HBB), p67-phox is localized in the lq25 chromosome (5% of the AR of the HBB) and p22-phox is localized in chromosome 16q24 (5% ).

Symptoms of chronic granulomatous disease

Clinical manifestations of chronic kidney disease - as a rule, during the first 2 years of life, children develop severe repeated bacterial or fungal infections. Frequency and severity vary depending on the variant of chronic granulomatous disease. Girls become ill at an older age, the course of the disease is mild and moderate. The main clinical sign is the formation of granules. Primarily affected are lungs, skin, mucous, lymph nodes. Characterized by hepatic and hepatic abscesses, osteomyelitis, perianal abscesses and fistulas. There may be meningitis, stomatitis, sepsis. Pneumonia caused by B. Cepatia, are acute, with a high probability of death with improper treatment with antibiotics; fungal infections, especially aspergillosis, are also extremely dangerous, have a prolonged chronic course with lymphadenitis, hepatosplenomegaly, colitis, kidney damage, bladder, esophagus.

Symptoms of chronic granulomatous disease

Diagnosis of chronic granulomatous disease

The main diagnostic criterion for chronic granulomatous disease is the NBT test (NitroBlue Tetrazolium - test with tetrasolium nitrosinim) or the chemiluminescence study of neutrophils. The methods are highly sensitive, but require careful research and interpretation of its results to avoid diagnostic errors. In rarer variants of the disease, neutrophil extracts for cytochrome b _{55 8} content are examined by immunoblotting or by spectral analysis. The most accurate, but less accessible, molecular biological methods for diagnosing chronic granulomatous disease with the determination of structural defects of the corresponding genes.

Diagnosis of chronic granulomatous disease

[1], [2], [3], [4], [5], [6], [7]

Treatment of chronic granulomatous disease

With timely diagnosis, adequate prevention and proper treatment for children with chronic granulomatous disease, a satisfactory quality of life can be ensured. In case of severe course and risk of development of disability, a radical method of treatment is the allogeneic transplantation of hematopoietic stem cells, the decision to conduct it depends on many factors and is taken collectively; such treatment is carried out in highly specialized clinics. Approaches to gene therapy are being developed, but so far this is a purely experimental method.

Treatment of chronic granulomatous disease