Chronic granulomatous disease is a rare form of primary immunodeficiency, in which the bactericidal function of phagocytes is disrupted. It is a hereditary disease, mainly transmitted by the X-linked recessive type. Pathology is manifested by recurrent infections of the lungs, gastrointestinal tract, skin and other organs. Flow cytometry, genetic testing, and microbiological studies are used for diagnosis. Treatment includes antibiotic therapy, antifungal drugs, immunomodulators, in some cases bone marrow transplantation is recommended.
D82.8 Immunodeficiency associated with other specified significant defects
The disease has been known since 1954 thanks to scientist C.A. Janeway and his colleagues, and the genetic causes of pathology began to be studied only in the 1980s. Chronic granulomatous disease (CGD) is rare, in the USA it is registered in 1 child per 200-250 thousand newborns. The rarity of the problem, insufficient awareness of pediatricians and therapists, difficulties in selecting adequate supportive therapy — all this causes the great relevance of this chronic hereditary disease in medicine.
The disease is caused by genetic mutations that are inherited. The most common variant is an X-linked mutation in the gp91-fox gene (60-70%). Men are sick, and women are carriers of the defective gene. The remaining cases fall on an autosomal recessive type of inheritance associated with gene mutations p22-fox, p47-fox, p67-fox. This subtype of the disease can affect patients of both sexes.
Chronic granulomatous disease is based on the deficiency of the NADPH-oxidase complex, which is formed with the participation of cytosolic and membrane-binding protein units. Due to gene mutation, the formation of these proteins is disrupted, enzymes capable of converting molecular oxygen into active forms — superoxide anion, hydrogen peroxide, singlet oxygen are not synthesized in the patient’s body.
These oxidants are normally produced by granulocytes (phagocytes), form the basis of the oxygen-dependent stage of phagocytosis. It is necessary for the digestion of certain types of bacteria and fungi that produce the enzyme catalase (for example, Klebsiella sp, Candida albicans, Aspergillus niger). The remaining links of cellular immunity are not violated, so viral and parasitic infections are not more common than on average in the population.
Children with CGD are born healthy, clinical signs of the disease appear in their first 2 years of life. In atypical cases, symptoms of the X-linked variant of chronic pathology manifest by the age of 5, and in autosomal recessive inheritance – by the age of 9. The main sign of the disease are infections caused by catalase-positive Gram+ (Staphylococcus aureus) or Gram-bacteria (E. coli, Serratia liquefaciens, Klebsiella sp., P. aeruginosa, Proteus sp.).
Primary immunodeficiency in 70-80% of cases manifests with recurrent bacterial infections of the respiratory tract: tonsillitis, bronchitis, pneumonia. Infectious diseases are characterized by a severe course, a moderate response to standard antibiotic therapy, and a frequent transition to suppurative processes. In this case, bullae, abscesses, gangrene of the lung are formed.
In the future, 75-100% of patients develop chronic purulent lymphadenitis, which are manifested by redness, swelling, and tenderness of the lymph nodes. When the axillary or inguinal nodes are affected, sharp pain is bothered by movements of the limbs. Purulent inflammation of the liver is formed in 24-41% of cases, recurrent gastrointestinal infections, bacterial and fungal bone lesions are observed in 20-30% of patients.
A characteristic feature of granulomatous disease is generalized “besezhitis”, which occurs as a complication after the first BCG vaccination, manifested 1-2 months after immunization. Pathology is associated with the insufficiency of cellular immunity with the introduction of weakened Koch mycobacteria. Also, after vaccination, there is a possibility of the onset of osteitis, a form of bone tuberculosis.
A dangerous consequence of chronic granulomatous disease is aspergillosis of the lungs, which provokes up to 25% of deaths among patients. Liver abscess are fraught with the development of severe hepatolienal syndrome. The lesion of bone tissue by a fungal process, especially in the spine and ribs, is associated with massive dissemination of the pathogen, and has an extremely unfavorable prognosis.
A typical complication of immunodeficiency in granulomatous disease sufferers are uncontrolled microbial infections that spread through the body with the occurrence of sepsis, septicemia, septic shock. With a critical decrease in immunity, lack of timely help, these diseases end with the death of the patient. Also, with granulomatous disease in children, growth retardation, lag in physical development are noted.
At the initial diagnosis, general signs of immunodeficiency are established, family history and the degree of risk of genetic pathology are found out. During physical examination, pathognomonic manifestations of chronic granulomatous disease are not determined. To make a diagnosis, a comprehensive laboratory and instrumental examination is required:
- Cytometry of respiratory flushes. The main diagnostic method by which the level of production of active oxygen radicals is assessed. It is suitable for 100% confirmation of chronic genetic pathology, as well as for the identification of asymptomatic women carriers of the gene with the X-linked variant of inheritance.
- Genetic research. It is recommended according to indications, more often for scientific purposes when selecting experimental methods of treatment. The analysis is performed by genome sequencing, FISH hybridization. CGD is indicated by mutations in the genes CYBB, CYBA, NCF1, NCF2 and NCF4.
- Microbiological diagnostics. To identify catalase-producing microorganisms, bacterioscopy is performed, back-seeding on nutrient media. To choose a rational antibiotic therapy, an antibiotic sensitivity test is performed.
- Instrumental visualization. To detect purulent lesions of organs, ultrasound of the pleural and abdominal cavities, lymph nodes is prescribed. X-ray examinations (radiography, CT), endoscopic methods (bronchoscopy, EGDS, colonoscopy) are also used.
In acute episodes of microbial infections that have occurred in patients with CGD, standard antibiotics from the class of macrolides, cephalosporins, fluoroquinolones are prescribed. For the treatment of fungal lesions, amphotericin B is most effective, which is taken in long courses. Supportive care, which is aimed at reducing the risk of infectious complications, includes the following medications:
- Bactericidal preparations. To prevent bacterial diseases, long-term intake of sulfonamides, macrolides is recommended.
- Antimycotics. They are used to reduce the risk of aspergillosis, the most dangerous fungal infection in chronic granulomatous disease.
- Gamma interferon. The immunomodulator is used to increase the body’s resistance to infectious agents, enhance the production of superoxide radicals by neutrophils.
Hematopoietic stem cell transplantation is considered to be the most promising method of therapy for patients with chronic granulomatous disease in order to fully restore normal immune protection. However, transplantation is associated with a high risk of complications, so it is carried out only within the framework of research programs. Various methods of gene therapy are under development.
Prognosis and prevention
Despite the treatment methods used, systemic fungal and bacterial infections often develop with a fatal outcome. The prognosis is relatively unfavorable, there is a deterioration in the quality and a decrease in the life expectancy of patients. Prevention of complications involves the provision of constant maintenance therapy, vaccination in full (with the exception of BCG), maximum protection of the patient from infections.