Successful Management of Aspergillus Fumigatus Osteomyelitis In A Lung Transplant Recipient
T Allsopp, M Chandratilleke, F Kermeen, D Chambers, P Hopkins
aspergillus osteomyelitis, immuno-suppression, solid organ transplantation
T Allsopp, M Chandratilleke, F Kermeen, D Chambers, P Hopkins. Successful Management of Aspergillus Fumigatus Osteomyelitis In A Lung Transplant Recipient. The Internet Journal of Pulmonary Medicine. 2009 Volume 12 Number 1.
Fungal osteomyelitis is a rare, life threatening complication of solid organ transplantation often associated with long term sequelae. Here we describe the use of a multi-disciplinary management approach including combination antifungal therapy, surgery and hyperbaric oxygen therapy in the successful management of
A 26 year old man underwent bilateral sequential lung transplantation for cystic fibrosis complicated by respiratory failure. The recipient was seropositive for cytomegalovirus (CMV). The peri-operative course was complicated by type 1 hypersensitivity to methylprednisolone leading to cardiac arrest requiring urgent institution of cardiopulmonary bypass via the groin and re-operation for severe intra-thoracic haemorrhage. Post-transplant immunosuppression consisted of cyclosporin (to maintain trough serum levels of 300 – 350 g/l), mycophenolate (1.5g bd) and dexamethasone (1.5mg daily). Basiliximab (Simulect, Novartis pharmaceuticals) was administered day 1 and 5 as a cyclosporine sparing agent given problems with intrapleural haemorrhage and renal impairment. Due to poor absorption, cyclosporin was changed to tacrolimus (target serum levels of 10-15g/l) on day 15 post transplant. Valganciclovir (450mg/day), nebulised amphotericin B (10mg bd) and sulfamethoxazole/trimethoprim (twice weekly) were administered for CMV, fungal and
Fourteen days post transplant, fluconazole was commenced following the isolation of
Three months post transplant, the patient presented in status epilepticus requiring intubation. The blood sugar level was 1.2 mmol/L. Investigation revealed a normal chest x-ray, mild renal impairment, no
The patient’s neurological state rapidly improved and he was extubated. With further clinical history now available, he reported a one week history of a painful, hot and swollen right shoulder. Fluid aspirated from the right shoulder grew
A progress CT of the shoulder ten days after the initial presentation suggested infective collections involving the subscapularis muscle and right posterior glenohumeral head. There was also a cortical break and associated mixed lytic/sclerotic changes in the posterior humeral head confirming septic arthritis and osteomyelitis (Figure 2). Despite this there was clinical improvement and the CRP had fallen to 22 mg/L. Voriconazole was changed to posaconazole due to deranged liver function tests after thirteen days of therapy.
Twenty days after initial presentation the patient complained of increased pain and decreased range of movement of the right shoulder, he became febrile and the CRP increased to 68 mg/L. The radiologic appearance had deteriorated with an increase in the number and size of locules in the subscapularis muscle, the development of a glenohumeral joint effusion, and an air locule in the posterior aspect of the humeral head (Figure 3). Subsequent MRI of the right shoulder showed enhancement and oedema throughout the right humeral head and extending 9.5cm into the proximal humeral shaft (Figure 4). Cyclosporin was decreased with a target C2 (2 hour post-dose) level of 300-400 and intravenous amphotericin was commenced, in addition to the caspofungin and oral posaconazole. An arthroscopic washout of the right shoulder was performed and converted to an open washout with subsequent synovectomy of the biceps sheath with removal of caseous material.
On day 23 the patient commenced daily hyperbaric oxygen therapy. By day 33 the patient had improved and repeat MRI at day thirty-five showed radiological improvement. His recovery was complicated by a lower-respiratory tract infection for which he received meropenem and ciprofloxacin. Forty-six days after admission the amphotericin, caspofungin and meropenem were ceased and the patient was discharged home to continue the hyperbaric oxygen therapy (to a total of 40 treatments) and posaconazole as an outpatient.
Six months after the initial presentation, the patient again presented with worsening pain in the right shoulder. Investigation revealed recurrence of osteomyelitis in the humeral head and he subsequently underwent open debridement of the humeral head and insertion of amphotericin cement beads. Posaconazole was changed back to voriconazole without a significant deterioration in liver function. The patient made a full recovery with a full range of movement at the shoulder joint, and normal allograft function 15 months after initial presentation with
Infections of bone and joints caused by
Traditionally treatment has focused on Amphotericin B and surgical debridement. However, single use of Amphotericin B has fallen out of favour due to its poor bone/joint tissue penetration and the sub-optimal response of infection when used as a single agent. Other medical options for treatment include triazoles: itraconazole, voriconazole, ravuconazole and posaconazole; flucytosine and caspofungin. Fluconazole has no activity against
Our patient was commenced on voriconazole and caspofungin combination therapy but later voriconazole was changed to posaconazole due to deranged liver function tests. Amphotericin B was later added to the regime, although there was initial hesitancy because of pre-existing impaired renal function. In solid organ transplant recipients, whenever possible, consideration should also be given to carefully decreasing the degree of immunosuppression as an adjunct to medical therapy for the treatment of invasive aspergillosis. Despite lowering the patient’s immunosuppression he did not develop acute allograft rejection and graft function remains excellent.
Hyperbaric oxygen (HBO) is claimed to be helpful in refractory osteomyelitis. The functional definition most commonly applied to hyperbaric candidates includes failure to respond to a 4- to 6-week course of appropriate antibiotics (7). A large number of animal data and in vitro experimental studies supports the use of HBO in refractory osteomyelitis (8). Uncontrolled trials of surgery and antibiotics combined HBO in refractory osteomyelitis in the past have shown success rates as high as 85% (9). As yet there are no randomized controlled trials relating to refractory osteomyelitis. Unfortunately randomized controlled trials may be difficult to accomplish, given the relative infrequency of the illness and the varied patient and disease characteristics. HBO therapy is considered safe when used according to standard protocols, with oxygen pressures not exceeding 300 kPa and treatment duration not exceeding 120 minutes (10). Due to rapid pressure changes, adverse effects include barotrauma to the middle ear, cranial sinuses and, in rare cases, the teeth or lungs. HBO-related pulmonary toxicity is thought to be a concern in lung transplant patients due to pre-existing co-morbidities and increased susceptibility to toxic pulmonary injury (10). Throughout treatment our patient’s lung function was stable.
The addition of HBO as an adjunctive therapy significantly increases the upfront cost of treatment. In complicated cases of refractory osteomyelitis, however, the long-term expenses associated with prolonged hospitalization, long courses of antimicrobial therapy, and additional surgery actually offset the differences, frequently making HBO cost effective (8)
To our knowledge, this is the first reported case of osteomyelitis in a solid organ recipient that has included hyperbaric oxygen therapy in the treatment regime and one of the few documented cases of aspergillus osteomyelitis involving a lung transplant patient.
The authors wish to advise that they received no funding from outside sources and declare no conflict of interest in presenting this case.