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"Child`s Health" 4 (47) 2013

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Chronic granulomatous disease – the experience of diagnostic and treatment in children

Authors: Chernyshova L.I. 1, Volokha A.P. 1, Bondarenko A.V. 1, Gilfanova A.M. 1, Chernyshov V.P. 2, 1 National Medical Academy of Postgraduate Education named P.L.Shupyk, 2 SI “Institute of Gynecology, Obstetrics and Pediatrics NAMS Ukraine”

Categories: Pediatrics/Neonatology

Sections: Specialist manual

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Chronic granulomatous disease, primary immunodeficiency, children.

Resume. Chronic granulomatous disease – primary immunodeficiency with X-linked or autosomal recessive inheritance in genes encoding subunits of the phagocyte NADPH oxidase. These genetic defects results in failure to produce antimicrobial oxidant metabolites and cause defect of bactericidal function of phagocytes. Chronic granulomatous disease characterized by recurrent life-threatening bacterial and fungal infections of skin, lymph nodes, lung, and liver and excessive inflammation with granuloma formation. Early diagnosis of chronic granulomatous disease and rapid treatment of infections are critical.

The article described firstly in Ukraine two cases of chronic granulomatous disease in children with typical clinical fenotype of severe recurrent bacterial infections with different localizations and early manifestation.

 Case 1. The 8 years girl is four years under our observation. She manifested at 3 months from local BCG-itis with regional lymphadenitis, was treated by isoniazid for 3 months. Three episodes of bilateral purulent cervical lymphadenitis developed at 6, 9 and 11 months of age treated with wide spectrum antibiotics. Since 12 months child demonstrated periodic fever of uknown origin with progressive hepatosplenomegaly, loss of weight, progressive anemia, inflammatory changes in the common blood. Treatment with wide spectrum antibiotics for several months had insufficient effect. Antimycobacterial treatment with amycacinum, rifampin and izoniazid started ex juvantibus with positive effect after 6 months course: the fever has stopped, the sizes of lymph nodes, liver and spleen decreased, the body weight was normalized.  In two months after ending of treatment the child developed pneumonia with positive result to new course of antimycobacterial treatment. At 4 years old underwent generalized Salmonella infection. 1-2 times per year child has recurrent cervical lymphadenitis. Traditional anti-mycobacterial therapy courses, which girl receives up to 6 months, are insufficient in controlling of infectious syndrome, because after the end of treatment disease relapses. At the age of 7 during the unexplained fever multiple formations were identified in the liver, biopsy showed caseous mass, histologically confirming the mycobacterial nature of lesion. Combined therapy with anti-TB drugs and interferon-gamma provides slow positive dynamics of focal liver lesions.

All immunological investigation did not revealed changes despite decrease of NBT-test  (2-5%) and phagocytic activity 4-28%. The child was genetically tested at INSERM clinic (Paris, France) and autosomal recessive CGD was confirmed based on absent expression of p22phox protein and CYBA gene mutation.

Given the clinical manifestations of infection syndrome (complications of BCG vaccination, recurrent purulent lymphadenitis, systemic disease at the age of 1 year with a good response to anti-TB drugs), the generalized BCG infection should be suspected in girl with immunodeficiency with impaired bactericidal function of phagocytes - chronic granulomatous disease.

Case 2. The boy manifested at the first month of life with recurrent suppurative paraproctitis. During first year he had several episodes of purulent lymphadenitis. Since 12 months fever of uknown origin accompanied by hyperleukocytosis, neutrophylosis, accelerated ESR, anemia continues for 2 months. In the second year of life the boy observed four episodes of pneumonia, the latter two cases of pneumonia complicated by atelectasis of the upper lobe of right lung, recurrent balanoposthitis and cervical lymphadenitis, hepatosplenomegaly. After histological examination of lymph node suspected tuberculosis, received specific chemotherapy. In 3 years boy again contracted pneumonia with foci in the left lower lobe, and in six months - polysegmental pneumonia with reactive pleurisy. Antibody deficiency, autoimmune process, cystic fibrosis were excluded.

The child was evaluated at the Department of Pediatric Infectious Diseases and Immunology at 4 year of age. The diagnosis of primary immunodeficiency - chronic granulomatous disease was suspected due to clinical manifestations in the form of recurrent purulent lymphadenitits, recurrent pneumonia with prolonged course, complication of BCG vaccination in the form of left-axillary lymphadenitis. The physical exam of the child revealed generalized lymphadenopathy, hepatosplenomegaly, failure to thrive. The child had hypochromic anemia, leukocytosis with neutrophylosis, accelerated ESR of 49 mm/h,  high level of CRP. The immunological investigation demonstrated normal amount of lymphocytes subpopulations. Serum immunoglobulin were IgG 10,6 g/l, IgM 4,2 g/l, IgA 3,2 g/l, IgE 30 IU/ml). HIV infection excluded. NBT-test spontaneous was 12% (normal 5-12%).  Determination of expression of adhesion molecules CD11b/CD18 on leukocytes showed no abnormalities. More revealing were the results of the test oxidation of dyhidrorodamin-123 by flow cytometry («Burst-test»), which showed a sharp decrease in the bactericidal function of phagocytes and confirmed diagnosis of chronic granulomatous disease (tab.).

An X-ray of the chest: reduced pneumatization in segments of the left lung, enlarged intrathoracic lymph nodes, in the left groin area - calcification. The boy receives antibiotic therapy, but is having difficulty with the assessment of treatment efficacy, as X-ray picture remained virtually unchanged, but 22 days of hospitalization boy weight increased by 1.7 kg, normalized size of the spleen and liver, data of hemogram.

The patients with chronic granulomatous disease have increased susceptibility to mycobacterial infections caused by Mycobacterium tuberculosis or atypical mycobacteria like Mycobacterium bovis BCG sp. Difficulties in diagnostics of BCG infection require administration of anti-tuberculosis drugs in suspicious cases.

The question of early diagnostic and optimal treatment of chronic granulomatous disease is very important today in Ukraine. Improvements of diagnostic of primary immunodeficiency which need radical treatment as transplantation of hematopoietic stem sells arised the question of organization of allogeneic hematopoietic sells transplantation in Ukraine.

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