Invasive fungal infections (IFIs) result in significant mortality in immunosuppressed individuals. Of these, invasive pulmonary aspergillosis (IPA), caused by the opportunistic mold Aspergillus fumigatus , is the most lethal.
Disseminated disease following invasive pulmonary aspergillosis (IPA) remains a significant contributor to mortality amongst patients with hematologic malignancies (HMs). At the highest risk of mortality are those with disseminated disease to the central nervous system, known as cerebral aspergillosis (CA). However, little is known about the risk factors contributing to disease amongst HM patients. A systematic review using PRISMA guidelines was undertaken to define HM patient subgroups, preventative measures, therapeutic interventions, and outcomes of patients with disseminated CA following IPA. The review resulted in the identification of 761 records, of which 596 articles were screened, with the final inclusion of 47 studies and 76 total patients. From included articles, the proportion of CA was assessed amongst HM patient subgroups. Further, pre-and post-infection characteristics, fungal species, and mortality were evaluated for the total population included and HM patient subgroups. Patients with acute myeloid leukemia and acute lymphoid lymphoma, patients receiving corticosteroids as a part of their HM therapeutic regimen, and anti-fungal prophylaxis constitute the top identified patient populations at risk for disseminated CA. Overall, information presented here indicates that measures for the prevention of IPA should be taken in higher-risk HM patient subgroups. Specifically, the type of anti-fungal therapy used should be carefully considered for those patients with IPA and increased risk for cerebral dissemination. Additional reports detailing patient characteristics are needed to define further the risk of developing disseminated CA from IPA in patients with HMs.
Invasive pulmonary aspergillosis (IPA), a leading cause of death in immunosuppressed patients, is an infection most often attributed to the opportunistic fungi Aspergillus fumigatus (AF). The most common site of primary infection with this invasive disease is the lung, and the most prevalent site of secondary infection following hematological dissemination is the central nervous system (CNS). Dissemination of AF to the CNS, termed cerebral aspergillosis (CA), occurs in up to 40% of immunocompromised patients with IPA and has a mortality rate approaching 90%. While the experimental murine model of IPA and the resulting immune response have been extensively characterized, the current models available for CA are inconsistent and physiologically irrelevant. The lack of relevant models results in a considerable gap in knowledge for the neurological pathogenicity of infection. To address this gap, we infected wild‐type male and female C57BL/6 immunocompetent, or immunosuppressed (via high‐dose corticosteroid) mice using a one‐ (intranasal) or two‐hit (intranasal plus intravenous) method of inoculation with AF. Following immunosuppression and infection, mice were monitored for severe weight loss (>20%), neurological symptoms (e.g., altered‐gate, severe head‐tilt, and/or spinning in cage), and mortality daily for 10 days. At day 4 post‐inoculation, both brain and lung were assessed for fungal burden, and the immunological response to AF was evaluated in the brain. We observed significant weight loss, worse disease severity, and increased fungal burden in the brain in immunosuppressed mice infected via the two‐hit method. Further, in these mice, we found a significant disruption in cytokine and chemokine response in the brain as well as immune cell trafficking to the brain. In conclusion, we have developed a well‐defined, physiologically relevant, model of disseminated CA in immunosuppressed mice with primary pulmonary infection. This model will serve to advance understanding of the disease mechanism, identify immunopathogenic processes, and aid in defining the neuroinflammatory response to CA.
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