Arthritis and Osteomyelitis due to Aspergillus fumigatus: A 17 years old boy with chronic granulomatous disease
© Bodur et al; licensee BioMed Central Ltd. 2003
Received: 13 November 2002
Accepted: 31 January 2003
Published: 31 January 2003
Invasive Aspergillus infections are frequently seen in immunocompromised patients but arthritis is a rare complication of Aspergillus infections in the absence of immune suppressive therapy, trauma or surgical intervention.
A 17 years old male patient with arthritis and patellar osteomyelitis of the left knee whose further investigations revealed chronic granulomatous disease as the underlying disease is followed. Aspergillus fumigatus was isolated from the synovial fluid and the tissue samples cultures. He was treated with Amphotericin B deoxicolate 0.7 mg/kg/day. Also surgical debridement was performed our patient. Amphotericin B nephrotoxicity developed and the therapy switched to itraconazole 400 mg/day. Itraconazole therapy were discontinued at the 6th month. He can perform all the activities of daily living including.
We think that, chronic granulomatous disease should be investigated in patients who have aspergillar arthritis and osteomyelitis.
Aspergillus causes of infection in immunocompromised patients. In aspergillar arthritis, the immune system is found to be defective frequently. Chronic granulomatous disease (CGD) is the major underlying disease . CGD is a 70 % X-linked recessive disease effecting especially the male patients and characterized by the impaired phagocyte microbicidal activity. Bacterial and fungal infections often begin during infancy and recur throughout childhood and adolescence [2–5].
Arthritis due to aspergillosis is a very rare condition. It can result from the hematogeneous spread from the lungs to the joints and it usually occurs in the setting of an immunocompromised host. Predisposing conditions have been described in the literature, such as chronic granulomatous disease, corticosteroid therapy, post-renal transplantation and idiopathic thrombocytopenic purpura. However, in immunocompetent patients, Aspergillus infection causing arthritis or osteomyelitis usually occurs as an iatrogenic infection after surgery . Our patient did not have any history of trauma or surgical intervention. Moreover, lack of known any immune deficiency state or previous immunosuppressive therapy makes us to think that CGD might be predisposing factor.
Cohen et al. reviewed the records of 245 patients with CGD and found that 20% had a history of fungal infection and Aspergillus accounted for 78% of the fungal infections. Invasive Aspergillus infection in patients with CGD is associated with mortality rates approaching to 50% . Liese et al evaluated the records of 39 patients with CGD and they stated that infections with Aspergillus species have become the major cause of infectious complications and death and among the pneumonia episodes besides Candida species and Pseudomonas aeruginosa, Aspergillus species were the most frequently isolated microorganisms in patients with CGD .
CGD is an 70% X-linked recessive disorder of phagocyte function, in which the phagocytes were unable to generate super oxide anions and other microbicidal oxygen metabolites, resulting in increased susceptibility to infection with a wide variety of bacterial and fungal pathogens [3, 5, 9, 10]. These patients have an inherited phagocyte-killing defect that occurs as a result of biochemical abnormalities in the NADHP oxidase system [9, 10].
The most characteristic pathogens are catalase-positive microorganisms or microorganisms that can not generate hydrogen peroxide. Catalase negative organisms such as Streptococci are normally killed by the phagositic cells of the patients but microorganisms such as S. aureus, S. epidermitis, E. coli, S. marcescens, Klebsiella, Pseudomonas, B. cepecia, Proteus, Salmonella, C. albicans can not be eliminated. Localized and disseminated M. tuberculosis and Aspergillus infections were also commonly seen [2, 5, 9, 10].
Infections may be acute, subacute or chronic. Besides the delay of tissue healing, acute and chronic inflammatory response may be slow and there may be also a granuloma formation [2, 4]. CGD is commonly associated with dermatitis, lymphadenitis, enlargement of liver, spleen and growth retardation [2, 3]. The physical examination of our patient also revealed hepatosplenomegaly, axillar multiple lymphadenopathy and retardation of normal growth and development.
These phagocytes unlike normal phagocytes, fail to reduce the histochemical dye nitroblue tetrazolium (NBT) to a blue-black deposit after stimulation with endo-toxin or phorbol myristate acetate. Definite diagnosis can be established by the NBT test [2, 5, 11] which was also positive in our patient. The normal G6PD levels in our patient make us to think that this is not the autosomal recessive form of this disease. Although the diagnosis of CGD is established at 17 years of age, active Tbc infection when he was 9 years old and a craniotomy operation (probably because of granuloma) and retardation of growth and development shows that our patient has a mild form of CGD for a long time. As we could not reach the biopsy specimen records of the craniotomy operation of the patient when he was three years old, we can not say anything about the nature of the tissue, whether it was due to aspergillus or not. In addition, diagnosis and specific therapy of Tbc were performed in an Education and Research hospital specially dealing with Tbc patients and at this point, we feel confident about the diagnosis of our patient.
Treatment of the arthritis due to Aspergillus infection especially needs surgical drainage. The main difference of these lesions was commonly encountered granulomatous masses. A surgical incision and drainage was performed to our patient's knee joint and the obtained synovial tissue biopsy specimen consisted of granulomatous tissue. Only two antifungal agents which have activity against Aspergillus are licensed-amphotericin B and itraconazole . For the treatment of Aspergillus osteomyelitis, early surgical debridement and amphotericin B is recommended. However, because of the risk of nephrotoxicity the maximum dosage should be 3 grams and the maximum duration of therapy should be 12 weeks . Oral or intravenous itraconazole is a safe and well tolerated agent for the treatment of invasive Aspergillosis . In one case report, itraconazole was used for one year after surgical debriment of the osteomyelitis and resulted clinical recovery . Tsumura et al. reported that the initial treatment consisting of surgical debridement and antibiotic therapy with amphotericin B, itraconazole and flucytosine did not control the infection but after administering recombinant IFN-γ it was found to be effective in controlling the course of severe invasive Aspergillosis . For the treatment of Aspergillus arthritis, Steinfeld et al. performed an arthroscopic debridement and administered intravenous amphotericin B (60 mg iv every 48 hours) over a 6 week period and oral itraconazole (600 mg daily) for 9 months. The follow-up of the patient revealed very good results without evidence of recurrence .
We could not find any report about the caspofungin therapy in CGD in the English literature but we observed three reports about the voriconazole, a large spectrum new triazol, therapy in CGD. van't Hek et al successfully treated a 5 years old patient with CGD and Aspergillus nidulans pneumonia with voriconazole in 10 weeks, which did not respond to amphotericin therapy of 6 weeks . Sevaux et al observed clinical response at the second and radiological response at the third month in an adult patient with CGD and Aspergillus fumigatus pneumonia with voriconazole therapy . In another study, treatment of 13 CGD children with voriconazole an initial dose 6 mg/kg for the first day and then 4 mg/kg two times daily had a success rate of 62% .
Without trauma or surgical intervention, arthritis and osteomyelitis due to Aspergillus cannot occur in healthy individuals. Encountering this situation must remind us an immune system defect and the most common predisposing factor for this defect is the CGD in otherwise normal children, which should be searched.
Written consent was obtained from the patient or their relative for publication of the patient's details.
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