Successful, combined long-term treatment of cerebral aspergillosis in a liver transplant patient

Tsitsopoulos, Parmenion P.; Tsoulfas, Georgios; Tsonidis, Christos; Ιmvrios, G.; Papanikolaou, Vasilios; Giakoustidis, Dimitrios; Marinopoulos, Dimitrios; Takoudas, D; Tsitsopoulos, Phillipos D.

doi:10.4161/viru.1.5.13110

Cited by 15 publications

(11 citation statements)

References 22 publications

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“…These findings are consistent with reported evidence of clinical efficacy for voriconazole in Aspergillus infections of the CNS (7). Multiple case reports have been published documenting successful treatment of rhinocerebral aspergillosis (14), cerebellar abscesses (15), cerebral aspergillosis associated with liver transplant (16), and sellar Aspergillus abscesses (17). A retrospective analysis of 81 cases of aspergillosis of the CNS treated with voriconazole indicated that voriconazole treatment combined with neurosurgery is the most effective treatment for this type of infection (5).…”

Section: Discussionmentioning

confidence: 99%

Quantification of Brain Voriconazole Levels in Healthy Adults Using Fluorine Magnetic Resonance Spectroscopy

Henry

Bolo

Chen

et al. 2013

Antimicrob Agents Chemother

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Voriconazole is more effective for aspergillosis infections with central nervous system involvement than other antifungal agents. The clinical efficacy of voriconazole for central nervous system infections has been attributed to its ability to cross the bloodbrain barrier. However, pharmacokinetic studies are limited to plasma and cerebrospinal fluid, so it remains unclear how much of the drug enters the brain. Fluorinated compounds such as voriconazole can be quantified in the brain using fluorine-19 magnetic resonance spectroscopy (MRS). Twelve healthy adult males participated in a pharmacokinetic analysis of voriconazole levels in the brain and plasma. Open-label voriconazole was dosed per clinical protocol with a loading dose of 400 mg every 12 h on day 1, followed by 200 mg every 12 h administered orally over a 3-day period. MRS was performed before and after dosing on the third day. Voriconazole levels in the brain exceeded the MIC for Aspergillus. The brain/plasma ratios were 3.0 at steady state on day 3 (predose) and 1.9 postdose. We found that voriconazole is able to penetrate the brain tissue, which can be quantified using a noninvasive MRS technique. (This study has been registered at ClinicalTrials.gov under registration no. NCT00300677.) C entral nervous system (CNS) fungal infections often occur in immunocompromised individuals and historically have been associated with high mortality rates. Although invasive aspergillosis only involves the CNS in 4 to 6% of cases, the mortality rates range from 80% to close to 100% (1). The number of cases of invasive aspergillosis has risen in recent decades due to greater numbers of transplant patients, as well as more aggressive chemotherapy and immunosuppressive treatments (1). Historically, amphotericin B was the standard of care with itraconazole as an alternative (2). However, the clinical efficacy of standard antifungal agents, including amphotericin B, triazoles, and echinocandins, is generally poor for CNS infections. Most antifungal agents are large molecules that cannot easily penetrate the blood-brain barrier and enter the CNS (3).Voriconazole is a newer broad-spectrum derivative of fluconazole that can be administered both intravenously and orally (4). It is indicated as a first-line treatment for invasive aspergillosis, as well as for other fungal infections that are refractory to other treatments. It is better tolerated and has been associated with improved survival rates in CNS infections compared to other antifungal agents (5). A randomized clinical trial comparing voriconazole to amphotericin B for invasive aspergillosis, including patients with cerebral infections, demonstrated a higher response rate and survival rate for patients who received voriconazole, with fewer serious adverse events (6). The ability of voriconazole to penetrate the blood-brain barrier more effectively than other antifungal agents likely accounts for its greater clinical efficacy.A variety of techniques have been used to study the ability of antifungal medications, inclu...

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Section: Discussionmentioning

confidence: 99%

Quantification of Brain Voriconazole Levels in Healthy Adults Using Fluorine Magnetic Resonance Spectroscopy

Henry

Bolo

Chen

et al. 2013

Antimicrob Agents Chemother

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“…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.…”

Section: Discussionmentioning

confidence: 66%

“…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][2][3][4][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.…”

Section: Introductionmentioning

confidence: 99%

Untitled

Kim

Ahn²,

Kim³

et al. 2017

Exp Clin Transplant

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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 antifungal agents due to the greater penetration into central nervous system and higher cerebrospinal fluid and brain tissue levels.

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“…Voriconazole, which can penetrate effectively into the CSF and brain tissue, was proved to be superior to amphotericin B in terms of the response rate, the survival rate and safety [11]. In recent years, multiple case reports revealed that neurosurgical interventions and combination antifungal therapies might improve the outcome in CA [12,13]. The standard strategy and drug formulations need to be evaluated in future studies.…”

Section: Discussionmentioning

confidence: 97%

A fatal case of cerebral aspergillosis in a diabetes mellitus patient

et al. 2015

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A 64-year-old right-handed diabetic man was presented into our hospital with 1 week history of left-sided limb weakness. One month ago he had been diagnosed with diabetes mellitus and the blood glucose level was poorly controlled. He compulsively reduced his intake and experienced unintentional weight loss. Apart from his limb weakness, he complained fever and progressive headaches in the last 2 weeks. His highest temperature was 40°C. Past medical history was negative for tuberculosis, bone marrow and solid organ transplantation and malignancy. Moreover, there was no history of steroid or other immunosuppressive drug consumption.On physical examination, his general condition was poor as a result of malnutrition. The neurological examination revealed that left hemiplegia and meningeal irritation signs were positive. The serum complete blood count showed a white cell count of 10,210/mm 3 with 76.4 % neutrophils. The glucose level was 632 mg/dL. Viral markers were negative. Lumbar puncture was performed and the opening pressure was 245 cm H 2 O. Cerebrospinal fluid (CSF) contained a white cell count of 522/mm 3 (94 % neutrophils), a protein concentration of 102.2 mg/dL, and a glucose concentration of 95 mg/dL. The chest X-ray was normal. After admission, cranial computed tomography (CT) scan showed a hypointense lesion on right basal ganglia area. Diffusion magnetic resonance imaging (MRI) showed restricted diffusion in the same area.He was initially treated for an acute ischaemic stroke and administered aspirin and rosuvastatin, but his condition sharply deteriorated. Three days after presentation, the second CT scan revealed a hyperintense lesion with surrounding brain edema (Fig. 1). Two days later, he slipped into a coma. Subsequent MRI revealed an occupying lesion with high density and moderate mass in the frontal lobe, with edema in the surrounding area. The lesion showed slightly low signal intensity in T1-weighted sequences with strong enhancement.A right pterional approach craniotomy was performed for pathologic diagnosis and excision of brain abscess. The surgical specimens showed many vessels thrombosis,haemorrhage, inflammatory granulation tissue. Periodic acid-Schiff stain demonstrated a small vessel invasion by septate hyphae of aspergillosis (Fig. 2). During the postoperative period, the patient was treated with intravenous voriconazole. Unfortunately, his health condition deteriorated and he died on hospital day 27.

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Successful, combined long-term treatment of cerebral aspergillosis in a liver transplant patient

Cited by 15 publications

References 22 publications

Quantification of Brain Voriconazole Levels in Healthy Adults Using Fluorine Magnetic Resonance Spectroscopy

Quantification of Brain Voriconazole Levels in Healthy Adults Using Fluorine Magnetic Resonance Spectroscopy

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A fatal case of cerebral aspergillosis in a diabetes mellitus patient

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