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ASPERGILLUS OSTEOMYELITIS IN CHRONIC GRANULOMATOUS DISEASE: TREATMENT WITH RECOMBINANT GAMMA-INTERFERON AND ITRACONAZOLE

1996; Lippincott Williams & Wilkins; Volume: 15; Issue: 9 Linguagem: Inglês

10.1097/00006454-199609000-00021

1532-0987

Srdjan Pasic, Mario Abinun, Boris S. Pistignjat, Bozidar Vlajic, Jelena Gudelj Rakić, Ljudmila Sarjanović, N. Ostojić,

Antifungal resistance and susceptibility

Chronic granulomatous disease (CGD) is a rare inherited disorder of phagocyte function caused by mutations of the genes coding for components in the multienzyme complex, phagocytic nicotinamide dinucleotide phosphate oxidase.1, 2 The production of superoxide and related oxygen metabolites is absent or severely impaired resulting in decreased intracellular killing of catalase-positive microorganisms, so that patients with CGD are unusually susceptible to infections with Staphylococcus, Aspergillus and Candida. We report a child with CGD with a less common pattern of Aspergillus osteomyelitis occurring after untreated pulmonary infection. Case report. A 10-year-old boy with the diagnosis of CGD was referred to Mother and Child Health Institute because of unsolved fever lasting for 2 months, dry cough and the right hip pain. This episode was initially treated with ceftriaxone and amikacin, but because the right upper lobe consolidation persisted on chest radiograph, treatment was changed to vancomycin and antituberculous medication (isoniazid, rifampin). The past medical history revealed localized Bacillus Calmette-Guérin infection at the site of inoculation in infancy; a 6-month course of combined antituberculous therapy for bilateral pneumonia at the age of 3 years and an episode of submandibular suppurative lymphadenitis at the age of 8 years. This last episode raised the suspicion of primary immunodeficiency. The nitroblue tetrazolium test confirmed the diagnosis of CGD and treatment with prophylactic trimethoprim-sulfamethoxazole was begun. The X-linked inheritance of CGD was presumed because his maternal uncle died of unexplained septicemia at the age of 6 months; the presumption was supported with evidence that mother's phorbol acetate myristate-stimulated nitroblue tetrazolium test showed only 17% of neutrophils reducing the dye. On admission his weight and height were at the 25th percentile; he was pale, febrile and had a nonproductive cough with right apical tubular breath sounds, chronic rhinitis, submandibular scars, left axillary lymphadenitis, hepatosplenomegaly and limping because of a painful and swollen right inguinal area. Laboratory findings showed an erythrocyte sedimentation rate (ESR) of 72 mm/h and C-reactive protein of 98 mg/l (normal, <10 mg/l), hemoglobin 9.5 g/dl and white blood cell count 13 800/mm3 with 78% neutrophils, normal liver function tests and negative blood cultures. Bronchoalveolar lavage culture was negative. Chest radiograph showed right apical infiltration and calcified left axillary lymph node (Fig. 1). Thoracic computerized tomography scan showed no evidence of osseal or mediastinal involvement, and the right hip radiograph was normal. An abdominal ultrasound showed only an enlarged spleen. At the time of admission antibiotics were changed to chloramphenicol and cloxacillin, but because sputum culture grew Aspergillus fumigatus the patient was also given amphotericin B (1 mg/kg/day). During the next few days the hip pain intensified, and repeated hip radiograph revealed metaphysial lytic lesions. Open bone biopsy of right femur yielded A. fumigatus on culture; histology showed granulomatous osteomyelitis with periodic acid-Schiff-positive hyphae. During a 5-week course of amphotericin B (cumulative dose, 30 mg/kg), significant toxicity was observed consisting of cramping muscle pains, fever and chills. However, there was no clinical improvement, the ESR and C-reactive protein values increased further to 100 mm/h and 138 mg/l, respectively, and there was progression of metaphysial lesions with an extension to diaphysis seen on a subsequent hip radiograph (Fig. 2). As a result antibiotics and amphotericin B were stopped and itraconazole (10 mg/kg/day) and recombinant gamma-interferon (Immukin-lB®; Boehringer Ingelheim; 50 μg/m2 s.c. three times weekly) were started. After 5 weeks of this treatment he became afebrile, thigh swelling reduced, repeated radiographs showed regression of the right upper lobe lesion and healing of osteomyelitis and ESR and C-reactive protein values decreased (68 mm/h and 22 mg/l, respectively). Recombinant gamma-interferon treatment was stopped after 6 weeks, but itraconazole was continued in conjunction with trimethoprim-sulfamethoxazole as long term prophylaxis. During the 18 months of follow-up he has been symptom-free. Discussion. The distant femoral Aspergillus osteomyelitis development in our patient after presumed Aspergillus pneumonitis demonstrates a hazard in delay of correct diagnosis and treatment caused by this less common pattern of fungal dissemination. An overall incidence of fungal infections in CGD has been reported to be 20%,3Aspergillus being the most common pathogen (78% of all fungal infections). Osteomyelitis is a relatively frequent complication of Aspergillus infection in these patients. In a review by Sponseller et al.4 of 13 CGD patients with osseous involvement, Aspergillus was the most common cause accounting for 7 of 20 infections. Lungs are the common portal of entry for Aspergillus spores, and untreated lung infection has a propensity for invasive spread. Usually the surrounding bones, pleura and mediastinum are affected in this direct spread common to fungi or mycobacteria. Hematogenous spread common with bacteria is less often a pattern of fungal spread.5 Itraconazole is efficient in the treatment of invasive aspergillosis in CGD patients and was well-tolerated in the dosage of 10 mg/kg/day.6, 7 Recombinant gamma-interferon has been used for prophylaxis8 and as an adjunct therapy of severe infections in CGD9, 10 including Aspergillus osteomyelitis.11, 12 Surgical debridement, the mainstay of treatment of invasive aspergillosis in CGD, was not necessary in this case. We used recombinant gamma-interferon as adjunct therapy with itraconazole for 6 weeks and believe that this therapy improved the outcome of this severe infection. However, the persistently elevated ESR is suggestive of chronic infection and because aspergillosis is known to recur in CGD, long term itraconazole prophylaxis is mandatory.7 Srdjan Pasic, M.D., M.Sc.; Mario Abinun, M.D. M.Sc.; Boris Pistignjat, M.D.; Bozidar Vlajic, M.D.; Jelena Rakic, M.D., M.Sc.; Ljudmila Sarjanovic, M.D.; Nikola Ostojic, M.D. Mother and Child Health Institute Belgrade, Yugoslavia (SP, BP, BV, JR, LS, NO) Department of Paediatrics Newcastle General Hospital Newcastle upon-Tyne, UK (MA)FIG. 1: Chest roentgenogram. Right apical granulomatous infiltration; calcified left axillary lymph node (previous B. Calmette-Guérin lymphadenitis).FIG. 2: Right hip roentgenogram showing femoral osteomyelitis.