Indian Pediatrics 1999; 36:594-596 

Chronic Granulomatous Disease

Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder characterized by susceptibility to recurrent infections because of dysfunctional NADPH oxidase and defective microbicidal action of phagocytic cells(l). To the best of our know- ledge this disease has not been described from India. Here we are reporting two cases of CGD, which we have managed recently.

Case Reports

Case 1: A 20-month-old child presented with recurrent respiratory infections since one year of age. He had an episode of loose motions at the age of 12 months from which he recovered uneventfully. At 13 months he developed pneumonia, for which injectable penicillin was given but response was poor. At this time he also received a six month course of antitubercular therapy, but without any significant improvement. At 20 months of age, he developed pneumonia again for which he received parenteral pencillin, cloxacillin and chloramphenicol prior to being referred to our institute. At presentation he weighed 10 kg and had bilateral cervical and axillary lymphadenopathy. Chest examination showed dull percussion note and de- creased air entry in right interscapular region. Liver edge was palpable 4 cm below right costal margin in mid clavicular line. Spleen was palpable 2 cm below left costal margin. Laboratory examination showed hemoglobin of 10 g/dl, total leukocyte count of 11,000/cu mm and erythrocyte sedimentation rate was 53 mm in first hour. Renal and liver functions were normal. Mantoux test was non reactive and gastric aspirates did not reveal any acid fast bacilli on staining and culture. X-ray chest showed consolidation in apical segment of right lower lobe. Blood culture revealed Aspergillus fumigatus and serology was also suggestive for the same fungus. Urine and stool showed confluent growth of Candida albicans. Trachea "and bronchi had normal appearance on bronchoscopy and smear from the aspirate showed pus cells and Gram positive cocci, the cultures being non- contributory. Antifungal therapy was deferred, but antituberculosis therapy was continued as the child appeared to be responding to treatment. After 4 months the child again developed fever and tachypnea. X-ray chest again showed consolidation in apical segment of right lower lobe. He was readmitted for a complete immunological evaluation. Serum electrophoresis showed mild hypergammaglobulinemia, quantitative serum immunoglobulin estimation showed IgM of 31 0 mg/dl (N = 58±23 mg/dl),IgG of 1240 mg/dl (N = 762±209 mg/dl) and IgA of 48 mg/dl (N = 50±24 mg/dl). Nitroblue tetrazolium (NBT) dye reduction test showed absolutely no reduction of dye. NBT dye reduction test done on both parents showed a normal result. Lung aspirate revealed Candida albicans, whereas Gram staining and cultures of this aspirate did not show any organism. He was given 3 weeks course of itraconazole and was started on long term cotrimoxazole prophylaxis. He remained well till four and a half years of age when he had another episode of bronchopneumonia which responded to antibiotics. At six years of age he developed' bronchopneumonia again. Blood culture grew yeast species; a 6 weeks course of amphotericin was administered. On his last follow up at 6V2 years of age he was asymptomatic. His weight was 18 kg (expected 20 kg) and height was 112.5 cm (expected 113 cm). He continues to take prophylactic cotrimoxazole (2 mg/kglday of trimethoprim).

Case 2: A 9-year-old girl (sister of case I) came to us with complaints of fever for two weeks and cough with respiratory distress for a week. She had been treated for pulmonary tuberculosis at the age of five years. On examination her weight Was 15 kg (expected 29 kg) and height was 107 cm (expected 118 cm). She had pallor and clubbing. Systemic examination was unremarkable except for respiratory system. She had tachypnea, a dull percussion note and bronchial breathing in right interscapular area and creptitations were present bilaterally. Laboratory investigations revealed hemoglobin of 9.2 g/dl, totalleukocyte counts of 18,500/cu mm and erythrocyte sedimentation rate of 18 mm in first hour. Mantoux test was non reactive. Chest X-ray was suggestive of bronchopneumonia. Blood cultures for bacteria as well as fungi were sterile. Her NBT dye reduction test showed no reduction of dye. As she was very sick at admission, she was started on intravenous augmentin and amphotericin together on which she showed gradual improvement. She was discharged on cotrimoxazole prophylaxis. At follow up after 4 months, she was asymptomatic and systemic examination was unremarkable.

Discussion

The initial description of this disease were a clinical entity of unknown cause consisting of recurrent suppurative lymphadenitis, hepatosplenomegaly, pyogenic skin lesion, severe pulmonary disease and hyper-gammaglobulinemia. In 1967 the inability of such patient's granulocytes to destroy ingested bacteria was demonstrated(2). The term 'chronic granulomatous disease' (CGD) is being used since then. CGD is a rare disorder and occurs in less than 1 in 25,000 individuals(3). The most common mode of inheritance is X-linked recessive(3,4). However, in 40% of patients with CGD, disease is inherited with an autosomal recessive pattern. Mutation of 4. genes corresponding to 4 different proteins have been identified in CGD. 91-kDa protein is abnormal in X-linked CGD and 22-kDa protein is absent in one form of autosomal recessive form of CGD. Two other proteins 47 and 67-kDa are abnormal in other autosomal recessive forms of CGD(3). The chromosomal location of each of these genes has been identified.

CGD normally presents in first few months of life, though age of onset can be as late as until adolescence or even adult- hood(1). While the brother had disease onset in the first year itself, his sister remained apparently well up to six years of life. Skin, lungs and perianal tissue are the areas which are primarily involved in CGD(l). Both of our patients had significant lung involvment. It is known that abscesses can form in any organ of body, particularly. in the liver, spleen, lungs and bones. Hepatomegaly is often quite prominent in such patients, as was the case in our first patient. Infections in patients having CGD are usually due to catalase positive organisms like Staphylococcus aureus, Pseudomonas cepacia and Aspergillus species(l). We cultured Aspergillus fumigatus in the first case. In the second case we were unable to grow any organism in the blood cultures. Lung involvement in these patients may be in form of hilar lymphadenopathy, bronchopneumonia, empyema and lung abscess. Laboratory findings in CGD include leukocytosis, anemia, increased ESR and hypergammaglobulinemia. Though various diagnostic tests have been used for CGD, the simplest of these is the NBT dye reduction test. In this test oxidase activity of leukocytes is tested during phagocytosis. This test gives percentage of neutrophils stained by the dye. This percentage is close to zero in affected cases, close to 100% in normal subjects, and 20-80% in heterozygotes. Both of our patients had a positive NBT test, i.e., no reduction of the dye(1). Other tests used for diagnosis of CGD are absent chemiluminescence and immunoblot for NADPH oxidase production(3).

Prevention and cure of infections is the primary aim of management in CGD. Sulfamethoxazole-trimethoprim as prophylaxis is standard therapy nowadays for CGD and this this treatment modality has revolutionized the management of this condition (l). We have started this drug in both of our cases. Patients who remain on this therapy have significantly less infections necessitating hospitalization. In 4 years of follow up our first patient required only one hospitalization. Infections in these patients require vigorous as well as aggressive early antimicrobial therapy. A short course of granulocyte transfusions has been used for persistent infection(3). Use of recombinant IFNy reduces the frequency of infections in CGD by stimulating the function of phagocytes. There is a risk of serious blood tranfusion reactions in patients with CGD who lack Kell associated red cell antigens. Therefore, a patient with CGD should be tested for the presence of Kell antigen before blood transfusion(5). Bone marrow transplantation has also been used in these patients. In vitro correction of gene defect has also been tried in B cells of these patients. Similar experiments in vivo are in progress(3,5).

CGD must be considered in the differential diagnosis of children who present with recurrent bacterial and/or fungal infections. The diagnosis can be confirmed by a simple and inexpensive laboratory test and prophylactic long term cotrimoxazole has dramatically improved the long-term prognosis.
 

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