Symptoms of chronic granulomatous disease

Patients with chronic granulomatous disease suffer from severe recurrent bacterial and fungal infections that primarily affect organs in contact with the external environment (lungs, gastrointestinal tract, skin, and lymph nodes draining these organs). Other organs may then be affected by hematogenous spread of the infection, most commonly the liver, bones, kidneys, and brain.

The first symptoms in 2/3 of patients with chronic granulomatous disease appear in the first year of life (lymphadenitis, pneumonia, rectal abscesses and osteomyelitis), purulent skin lesions (sometimes from birth) and complications from the gastrointestinal tract (vomiting due to obstruction of the antral part of the stomach by granuloma, repeated bleeding against the background of chronic colitis), although later cases of the onset of clinical manifestations of the disease have also been described. A. Lun et al. observed a 43-year-old woman with a typical clinical picture of chronic granulomatous disease, including aspergillosis and the formation of intestinal granuloma, in whom the first signs of the disease developed at the age of 17. Genetic examination of the patient revealed a mutation in the gp91-phox gene with non-randomized lyonization of the X chromosome.

Clinical manifestations can be very variable, some children with chronic granulomatous disease may suffer from several of the complications listed above, while others may have minimal manifestations of the disease. In some cases, the first manifestations of chronic granulomatous disease may be mistaken for other conditions, such as pyloric stenosis, cow's milk protein allergy, iron deficiency anemia. When examining children with chronic granulomatous disease, one can often note a delay in physical development and anemia, especially in the X-linked form of the disease. Usually, children with the X-linked form of chronic granulomatous disease get sick earlier and much more severely than children with an autosomal recessive type of inheritance, especially with p47-phox deficiency.

Staphylococcus aureus, Aspergillus fungi, intestinal gram-negative flora, Burkholderia cepacia (previously called Pseudomonas cepacia) are the most common pathogens causing infectious complications in CGD. Most of these microbes produce catalase. Catalase destroys hydrogen peroxide formed in the process of the microbe's own vital activity, thereby preventing the neutrophil from "borrowing" free radicals for killing. At the same time, catalase-negative microorganisms, such as streptococci, die in the neutrophils of patients with chronic granulomatous disease, destroyed by their own metabolic products - hydrogen peroxide.

Fungal infections are detected in 20% of patients with chronic granulomatous disease, primarily aspergillosis.

Lung damage is the most typical infectious complication encountered in all age groups of patients with chronic granulomatous disease. These are recurrent pneumonias, damage to the hilar lymph nodes, pleurisy, pleural empyema, pulmonary abscesses caused by Staphylococcus aureus, Aspergillus sp., intestinal gram-negative bacteria (Escherichia colli, Salmonella sp., Serratia marcescens, Burkholderia cepacia).

The pathogen responsible for the development of inflammation is not always possible to identify in sputum, therefore, when radiographic changes in the lungs are detected, empirical antibacterial therapy is prescribed, covering the above-described spectrum of microorganisms. Usually, this is a combination of aminoglycosides with ceftazidime. In the event that there is no response to empirical treatment, more invasive diagnostic methods are used (bronchoscopy, fine-needle biopsy of the lungs, open lung biopsy), since when such microorganisms as, for example, Nokardia are detected, specific antibacterial therapy is required. One of the most important pathogens of pulmonary complications in patients with chronic granulomatous disease is Burkholderia cepacia and related bacteria B. gladioli, B. mallei, B. pseudomallei and B. pickettii. These bacteria are unusually virulent in patients with chronic granulomatous disease and are one of the main causes of fatal pneumonia in them. Most Burkholderia bacteria are resistant to caminoglycosides and ceftazidime. Moreover, cultures from the sputum of patients infected with Burkholderia often grow very slowly, which allows the pathogen to proliferate in the patient's body until endotoxic shock develops. In cases where the pathogen can be identified before dissemination of the process, high doses of intravenous trimethoprim-sulfamethoxazole are effective.

Cutaneous abscesses and lymphadenitis are the next most common infectious complications of chronic granulomatous disease, most often caused by S. aureus and gram-negative organisms, including B. cepatia and Serratia morcescens. These infections require prolonged antibiotic therapy and often drainage for complete cure.

Liver and subdiaphragmatic abscesses are also a common complication of chronic granulomatous disease, most often caused by S. aureus. Patients usually experience fever, malaise, weight loss, and loss of appetite. There is usually no pain, even upon palpation of the affected organ, and there are often no laboratory abnormalities in liver function. These conditions also respond to long-term massive antibacterial therapy; in rare cases, surgery is indicated.

The most severe infectious complication of chronic granulomatous disease is aspergillosis. Protocols for the treatment of aspergillosis in chronic granulomatous disease include long-term use of amphotericin B and, if possible, removal of the aspergilloma. However, surgical treatment is not always used, since the localization of the lesion in the lung, vertebral body, ribs, and brain excludes this method. Thus, the main method of treating aspergillosis in patients with chronic granulomatous disease is long-term (4-6 months) conservative therapy using amphotericin B at a dose of 1.5 mg/kg of the patient's weight and its combination with griazole antifungal drugs (itraconazole, voriconazole). In addition, it is important to establish and, if possible, eliminate the source of aspergillosis in the patient's environment, since it is possible to reduce the risk of re-infection.

Osteomyelitis and pararectal abscesses are also typical for patients with chronic granulomatous disease and, like other infectious complications, require long-term intensive antibacterial and antifungal therapy.

Mucosal lesions include ulcerative stomatitis, gingivitis, persistent rhinitis, and conjunctivitis. Enteritis and colitis, which are common in patients with chronic granulomatous disease, may be difficult to differentiate from Crohn's disease. Ament and Ochs (1973) also described perianal fistulas, vitamin B12 malabsorption, and steatorrhea. Histiocytes were found in rectal and jejunal mucosal biopsies in most of these patients.

In addition to infectious complications, autoimmune diseases have been described in some patients with chronic granulomatous disease. Systemic and discoid lupus have been described in patients with both X-linked and autosomal recessive types of the disease. Juvenile rheumatoid arthritis with a positive rheumatoid factor has been described in a girl with p47 deficiency.

Patients with chronic granulomatous disease are usually shorter than their parents or normal siblings. The delay in physical development in such patients may be secondary to severe chronic infections (with growth rate increasing during the asymptomatic period of the disease), to gastrointestinal tract involvement due to nutritional deficiency, and may also be a genetic feature of the disease, reflecting a membrane defect not only in hematopoietic cells but also in other cells in patients with chronic granulomatous disease.

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