Invasive aspergillosis is one of the most important and fatal complications after liver transplant, especially in patients with involvement of the central nervous system. We present a case of a patient who developed cerebral and pulmonary aspergillosis, coinfected with cytomegalovirus, after liver transplant for toxic fulminant hepatitis. The patient was treated successfully with neurosurgical intervention and voriconazole. Voriconazole is considered more effective in cerebral aspergillosis than other anti-fungal agents due to the greater penetration into central nervous system and higher cerebrospinal fluid and brain tissue levels.
Key words : End-stage liver disease, Immunosuppression, Infectious diseases, Invasive aspergillosis
Invasive aspergillosis in liver transplant recipients is uncommon, with frequency from 1% to 8%. However, invasive aspergillosis is one of the most important and often fatal opportunistic fungal infections, with an associated mortality rate > 90%, especially when the central nervous system is affected in liver transplant recipients.1-5 Aspergillus infections usually occur within the first month after transplant, and the most frequent form of invasive aspergillosis is pulmonary aspergillosis. However, 10% to 25% of all cases of invasive aspergillosis have central nervous system involvement, presumably disseminated through the blood stream.3,6 In the past, invasive aspergillosis with central nervous system involvement had a high mortality rate of almost 100%, but survival has been improved with introduction of voriconazole for treatment of cerebral aspergillosis.7 We report our successful treatment of a liver transplant recipient who had cerebral aspergillosis combined with cytomegalovirus (CMV) infection using voriconazole.
A 55-year-old woman underwent deceased-donor liver transplant for fulminant hepatic failure caused by toxic mushroom ingestion. She had no previous history of viral or autoimmune hepatitis, other liver disease, or medication for chronic disease. She was comatose and had Model for End-Stage Liver Disease score of 28 preoperatively on hospital day 8. There was no evidence of infection on microbiologic studies including cultures. In addition, the donor had no evidence of viral, bacterial, or fungus infection. Liver transplant surgery was performed in routine standard manner without complications, and the grafted liver started to function immediately. Immunosuppression consisted of induction with methylprednisolone and basiliximab and maintenance with tacrolimus (target level, 10-12 ng/mL), prednisone, and mycophenolate mofetil.
On postoperative day 4, the patient recovered consciousness and was tapered from the ventilator. Early after surgery, there was intermittent high fever without evidence of infection on microbiologic study and chest radiography. However, intermittent fever spontaneously subsided on postoperative day 5, and the patient recovered without any symptoms or signs of infection or hepatic dysfunction.
On postoperative day 25, the patient developed persistent nausea, vomiting, headache, and visual disturbance without neurologic impairment on examination. On the computed tomography (CT) scan of the chest, a round peripheral enhancing lesion (size, 3 cm) with central necrosis was observed in the right lower lung (Figure 1). Brain magnetic resonance imaging (MRI) scan showed multiple peripheral enhancing nodular lesions with perifocal edema scattered throughout the whole brain (Figure 2). Histopathologic examination of the specimens taken from the lesions of the lung by aspiration, and the brain by excisional biopsy, showed multiple septate hyphae and inclusion bodies typical of CMV (Figure 3), consistent with the diagnosis of invasive pulmonary and cerebral aspergillosis combined with CMV infection.
For the treatment of invasive aspergillosis and CMV infection, intravenous voriconazole (8 mg/kg/d) and ganciclovir (5 mg/kg/d) were used immediately. Fungal cultures from the abscesses grew Aspergillus fumigatus, and CMV antigenemia test showed 106 antigen-expressing cells per 200 000 polymorp-honuclear leukocytes. Tacrolimus was reduced (target level, 5 to 7 ng/mL) and mycophenolate mofetil was stopped. Follow-up CT scans at 1 and 2 months after voriconazole treatment showed decreased size of the lesions in the lung and brain without any newly developed lesion. Headache and visual disturbance improved slowly after treatment was started. After intravenous voriconazole and ganciclovir treatment for 2 months, medication was switched to oral voriconazole (200 mg twice daily) for 6 months and prophylactic valganciclovir (900 mg/d) for 3 months. Multiple abscesses in the brain and the pulmonary lesion were remarkably reduced in size after treatment for 6 months. The patient’s symptoms subsided and the lesions completely disappeared on imaging studies at 18 months after transplant (Figure 1 and 2).
Cerebral aspergillosis is an uncommon type of invasive aspergillosis, but it is 1 of the most important infectious complications early after liver transplant. Despite high mortality rate, this infectious comp-lication is very difficult to detect early after surgery.8 Most patients with cerebral aspergillosis after organ transplant have few clinical manifestations before developing neurologic symptoms, but most patients have a compatible pulmonary lesion on chest CT scan. Therefore, cerebral aspergillosis usually is revealed by brain CT or MRI performed after developing neuro-logic symptoms. Cerebral aspergillosis generally has multiple brain lesions on the CT or MRI. However the differential diagnosis of multiple brain lesions after organ transplant is broad, and includes systemic embolization from bacterial endocarditis, cerebral aspergillosis or cerebral candidiasis, nocardiosis, toxoplasmosis, and tuberculosis.9 Previous studies reported that brain abscess after liver transplant occurs at 0.6% frequency, and most are fungal, typically Aspergillus species.10 The brain biopsy, histopathology, and microbiologic culture are diagnostic tools for confirming cerebral aspergillosis. However a few case reports or series reported that cerebrospinal fluid galactomannan enzyme immunoassay (GM EIA) may help establish a diagnosis of probable central nervous system invasive aspergillosis when timely brain biopsy is not feasible.11-13
Risk factors for invasive aspergillosis after liver transplant include environmental exposure, immuno-suppression, CMV infection, pretransplant hepatic failure, primary graft failure, retransplant, dialysis after transplant, and high transfusion requirement.4,14-16 In reviewing this case, we observed that the patient had several risk factors for invasive aspergillosis: immuno-suppression, CMV infection, and pretransplant hepatic failure. The patient showed no clinical manifestations before he developed neurologic symptoms including headache and visual disturbance, except he had intermittent high fever that spontaneously subsided early after transplant. The fever early after transplant may have occurred from various factors including infectious and noninfectious causes. In this case, infectious causes were not considered because there was no evidence of infection on serologic tests and microbiologic studies. Moreover, GM EIA test was unavailable. However these negative results were pitfalls in our posttransplant treatment. Blood samples from patients with invasive aspergillosis or other fungal infections rarely are positive for fungal antigens, and blood cultures often are not positive even in patients who have disseminated infection.17-19
Before introduction of voriconazole for antifungal treatment, most patients who had cerebral asper-gillosis died.20 After the introduction of voriconazole for treatment of cerebral aspergillosis, survival rates of 30% were reported in high-risk patients.7 Improved survival rates may be due to the greater penetration of voriconazole across the blood-brain barrier, with higher cerebrospinal fluid and brain tissue levels than other antifungal agents.20,21 In a few case reports and a retrospective study, immediate neurosurgical intervention for diagnosis and therapy also is associated with improved outcomes.5,7,22 In our case, immediate neurosurgical intervention (excisional biopsy) for diagnosis, reduction of immunosuppression, and antifungal treatment with vorico-nazole resulted in successful outcome.
In conclusion, this case indicates that the possibility of invasive aspergillosis should be considered in high-risk patients when fever occurs early after transplant, even when there is no evidence of infection on serologic and microbiologic studies. In patients with cerebral aspergillosis after liver transplant, prompt diagnosis and aggressive treatment including neurosurgical intervention and antifungal medication with voriconazole are most important for a favorable outcome.
Volume : 15
Issue : 1
Pages : 110 - 113
DOI : 10.6002/ect.2014.0233
From the Departments of 1Surgery, 2Internal Medicine,
3Neurosurgery, and 4Pathology, Dongsan Medical Center,
Keimyung University School of Medicine, Daegu, Korea
Acknowledgements: The authors have no conflicts of interest to declare. No funding was received for this study.
Corresponding author: Koo Jeong Kang, MD, PhD, Division of Hepatobiliary & Pancreatic Surgery, Department of Surgery, Keimyung University School of Medicine, 56 Dalseong-Ro, Jung-Gu, Daegu, Korea 700-712
Phone: +82 53 250 7655
Fax: +82 53 250 7322
Figure 1. Chest Computed Tomography (CT) Scans
Figure 2. Magnetic Resonance Imaging of the Head
Figure 3. Histopathology of Brain and Lung Biopsies