Lung aspergilloma with pituitary invasive aspergillosis presenting as headache and hyponatraemia.

Fungal infections involving the pituitary gland are rare and can be life threatening. A 75-year-old man with hypertension and diabetes mellitus presented with headache and hyponatraemia. Imaging study showed right upper lung mass, and mass resection showed aspergilloma without tissue invasion on histology. The patient developed visual impairment a few weeks later, and MRI of the brain revealed bilateral sphenoid sinusitis and pituitary invasion. The trans-sphenoidal biopsy confirmed invasive Aspergillus infection. His sphenoidal sinuses were endoscopically debrided, and he was treated with oral voriconazole. Pituitary aspergillosis should be considered in the differential diagnosis in patients with lung aspergilloma with headache and sinusitis. Prompt biopsy and antifungal treatment are important due to the high mortality rate of the infection.

The Muddied Waters of Ibrutinib Therapy.

A 37-year-old male was admitted with an atypical presentation of central nervous system (CNS) aspergillosis while on ibrutinib therapy for a CNS relapse of mantle cell lymphoma. This case highlights the importance of a high clinical suspicion of opportunistic infections in patients receiving small-molecule kinase inhibitors. This report includes a review of reported cases of Aspergillus infections in patients receiving ibrutinib and the shared features of these cases.

Gliotoxin as putative virulence factor and immunotherapeutic target in a cell culture model of cerebral aspergillosis.

The mycotoxin gliotoxin is an important metabolite produced by Aspergillus fumigatus, but its precise role in the pathogenesis of cerebral aspergillosis is not yet determined. We could demonstrate that growth in cerebrospinal fluid (CSF) induced the production and secretion of significant amounts of gliotoxin by A. fumigatus. These concentrations of 590-720nM were sufficient to reduce the viability of astrocytes and neurons, as well as of primary microglia, already after few hours of incubation. Annexin staining and electron microscopy revealed the induction of apoptosis rather than necrosis as the relevant mode of gliotoxin action in the brain. Furthermore, even a low gliotoxin concentration of 100nM, which was subtoxic for astrocytes, was able to significantly down-modulate the phagocytic capacity of astrocytes. In order to improve the current antimycotic therapy of cerebral aspergillosis by supporting innate immunity in the fight against Aspergillus, we aimed to neutralize the toxic potency of gliotoxin towards different brain cell types. Compounds such as dithiothreitol (DTT) or glutathione that reduce the internal disulfide bond of gliotoxin were shown here to be able to interfere with the gliotoxin-induced decrease of cell viability and to save the cells from induction of apoptosis. Thus, exploration of these substances may lead to novel approaches for adjunctive treatment of cerebral aspergillosis.

Secretion of a fungal protease represents a complement evasion mechanism in cerebral aspergillosis.

Complement represents a central immune weapon in the brain, but the high lethality of cerebral aspergillosis indicates a low efficacy of the antifungal complement attack. Studies with cerebrospinal fluid (CSF) samples derived from a patient with cerebral aspergillosis showed a degradation of complement proteins, implying that Aspergillus might produce proteases to evade their antimicrobial potency. Further investigations of this hypothesis showed that Aspergillus, when cultured in CSF to simulate growth conditions in the brain, secreted a protease that can cleave various complement proteins. Aspergillus fumigatus, the most frequent cause of cerebral aspergillosis, destroyed complement activity more efficiently than other Aspergillus species. The degradation of complement in CSF resulted in a drastic reduction of the capacity to opsonize fungal hyphae. Furthermore, the Aspergillus-derived protease could diminish the amount of complement receptor CR3, a surface molecule to mediate eradication of opsonized pathogens, on granulocytes and microglia. The lack of these prerequisites caused a significant decrease in phagocytosis of primary microglia. Additional studies implied that the complement-degrading activity shares many characteristics with the previously described alkaline protease Alp1. To improve the current therapy for cerebral aspergillosis, we tried to regain the antifungal effects of complement by repressing the secretion of this degrading activity. Supplementation of CSF with nitrogen sources rescued the complement proteins and abolished any cleavage. Glutamine or arginine are of special interest for this purpose since they represent endogenous substances in the CNS and might be included in a future supportive therapy to reduce the high lethality of cerebral aspergillosis.

Inhibition of voriconazole metabolism by chloramphenicol in an adolescent with central nervous system aspergillosis.

For an adolescent with bacterial meningitis and subsequent cerebral aspergillosis, intravenous voriconazole dose requirements substantially decreased during coadministration with intravenous chloramphenicol and considerably rose after discontinuation of the antibiotic. In agreement with in vitro evidence, these data suggest that chloramphenicol is a rather significant inhibitor of hepatic CYP3A4 and/or CYP2C19.

Voriconazole brain tissue levels in rhinocerebral aspergillosis in a successfully treated young woman.

Invasive aspergillosis of the central nervous system has a mortality rate exceeding 90%. We describe a 29-year-old woman with a medical history of chronic polyarthritis who developed a proven rhinocerebral Aspergillus fumigatus infection refractory to first-line treatment with liposomal amphotericin B. The patient responded successfully to salvage combination treatment with voriconazole and caspofungin. Furthermore, for the first time, voriconazole levels in an intracerebral abscess were measured in this patient undergoing voriconazole oral therapy.