A case of invasive aspergillosis in CGD patient successfully treated with Amphotericin B and INF-γ
© Mamishi et al; licensee BioMed Central Ltd. 2005
Received: 12 December 2004
Accepted: 03 March 2005
Published: 03 March 2005
Chronic granulomatous disease (CGD) is a rare disorder of phagocytes in which absence of superoxide and hydrogen peroxide production in phagocytes predisposes patients to bacterial and fungal infections. The most common fungal infections in these patients are caused by Aspergillus species.
Here, we describe Aspergillus osteomyelitis of the ribs and hepatic abscess in a 5-year-old boy. The patient was successfully treated with Amphotericin B and INF-γ.
With respect to the high frequency of aspergillosis in the CGD patient, immune deficiency should be investigated in patients with invasive aspergillosis. Moreover, using antifungal drugs as prophylaxis can improve the quality of life in these patients.
Chronic granulomatous disease (CGD) is a rare inherited disorder of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex of phagocytic cells resulting in failure to generate reactive oxidants and the absence of a respiratory burst . The disease is characterized by recurrent or persistent intra-cellular bacterial and fungal infections. Approximately, the incidence of fungal infections in CGD patients has been reported up to 20% of infections . Aspergillus spp are ubiquitous saprophytic fungi and are considered as the major causative fungal agent in these patients [2, 3]. The spectrum of infection caused by Aspergillus species varies from flu-like pneumonia to life-threatening invasive aspergillosis . The most common form of the aspergillosis in CGD patients is Aspergillus pneumonia which can be accompanied by dissemination to the ribs, chest wall and soft tissues [1, 2]. Here, we describe a case of invasive aspergillosis in CGD patient with hepatic abscesses and osteomyelitis.
A 5-year-old male patient was admitted to Children Medical Center (CMC) with inflammation and swelling in his left mandible and wrist without a history of trauma. In the past, he had suffered from several episodes of pneumonia which started at the age of seven months. On admission, laboratory findings included erythrocyte sedimentation rate (ESR) 84 mm/h, WBC count 12100/mm3 (61% neutrophils, 39% lymphocytes), hemoglobin 11.3 gr/dl and thrombocyte 386000/mm3. As the CRP analysis displayed 20 mg/dl, cephalexin (150 mg/kg/day) was initiated. In his roentgenogram, osteolytic lesions in the distal metaphase of hand and maxillary bone were observed. Considering history of several infections and multifocal osteomyelitis, bone biopsy was performed and his immune system function was evaluated. In the bone biopsy, non-necrotizing granulomatoid lesions were seen. The induration of purified protein derivative reaction was 10 mm diameter. Besides, HIV, hepatitis B surface antigen (HBs), rheumatoid factor and brucella agglutination tests were all negative. The serum IgG level was 1650 mg/dl (normal: 441–1135 mg/dl). IgM and IgA were in high normal range at 250 and 175 mg/dl, respectively. Because no defect was found in his humeral and cellular immunity, the phagocytic cells function was tested with a nitroblue-tetrazolium (NBT) slide test. Based on his hematological and immunological tests (NBT = 0), CGD was considered as underlying disease in this case. Regarding his NBT test, antibiotic therapy was changed from cephalexin to co-trimoxazole (20 mg/kg/day, iv) plus (along with) interferon-γ (50 microgram/m2 every other day). After two weeks of treatment, the patient's condition improved and he was discharged with prescription of both cephalexin (100 mg/kg/day) and co-trimoxazole (10 mg/kg/day) to be taken orally as prophylaxis.
CGD is a rare inherited immune disorder whose prevalence is estimated to be about 1/1,100,000 – 1/1,300,000 individuals worldwide . Similar to the presented case, the most common form of CGD is X-linked recessive that consists of about two thirds of cases and the rest are autosomal recessive .
In the absence of minimal oxidative metabolism in CGD which can be ascertained easily using nitro blue tetrazolium (NBT) slide test, other immune mechanisms are triggered . The relative evaluated immunoglobulin levels in the above-mentioned case might be due to persistent antigenic stimulation and it is a common phenomenon in all chronic infections.
This defect is characterized by recurrent or persistent infections due to catalase-positive fungal and bacterial agents despite aggressive antibiotic therapy [1, 6]. The incidence of aspergillosis in these patients has been reported to be 78% of all fungal infections . Among Aspergillus spp, Aspergillus fumigatus is considered to be the predominant cause of invasive aspergillosis in CGD patients [1, 7]. Pulmonary aspergillosis has been reported in CGD patients infected with Aspergillus fumigatus. As shown in this case, Aspergillus might spread from lungs to the bones of thoracic wall and cause osteomyelitis [7–9]. Although Aspergillus fumigatus is considered to be the most isolated species, Aspergillus nidulans osteomyelitis is reported to have a higher incidence and more mortality rate in these patients [7, 9].
The treatment of infections in CGD patients is not easy. Since the underlying immunodeficiency is the most important factor with respect to the outcome of treatment, these patients should be treated either with immunomudulative agents such as recombinant INF-γ or with stimulating factors . Recently, on the basis of cytochrome b (558) expression and NADPH oxidase activity, three different sub-type of X-linked chronic granulomatous disease were described . Therefore, therapeutic response to INF-γ in this case and other X-linked CGD patients might be elucidated. Besides, similar to other systemic fungal infections, antifungal drugs such as amphotericin B should be added to therapeutic regimen of CGD patients with established invasive aspergillosis. Our patient responded to the above-mentioned therapeutic protocol and was discharged with long term anti-microbial and immunomudulatory prophylactic treatment as well as anti fungal drug  to enhance the quality of life and lessen the risk of re-infection.
Written consent was obtained from the patient or their relative for publication of the study.
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