Epidemiology, management and outcomes of Cryptococcus gattii infections: A 22-year cohort.

Background: Cryptococcus gattii is a globally endemic pathogen causing disease in apparently immune-competent hosts. We describe a 22-year cohort study from Australia's Northern Territory to evaluate trends in epidemiology and management, and outcome predictors. Methods: A retrospective cohort study of all C. gattii infections at the northern Australian referral hospital 1996–2018 was conducted. Cases were defined as confirmed (culture-positive) or probable. Demographic, clinical and outcome data were extracted from medical records. Results: 45 individuals with C. gattii infection were included: 44 Aboriginal Australians; 35 with confirmed infection; none HIV positive out of 38 tested. Multifocal disease (pulmonary and central nervous system) occurred in 20/45 (44%). Nine people (20%) died within 12 months of diagnosis, five attributed directly to C. gattii. Significant residual disability was evident in 4/36 (11%) survivors. Predictors of mortality included: treatment before the year 2002 (4/11 versus 1/34); interruption to induction therapy (2/8 versus 3/37) and end-stage kidney disease (2/5 versus 3/40). Prolonged antifungal therapy was the standard approach in this cohort, with median treatment duration being 425 days (IQR 166–715). Ten individuals had adjunctive lung resection surgery for large pulmonary cryptococcomas (median diameter 6cm [range 2.2-10cm], versus 2.8cm [1.2-9cm] in those managed non-operatively). One died post-operatively, and 7 had thoracic surgical complications, but ultimately 9/10 (90%) treated surgically were cured compared with 10/15 (67%) who did not have lung surgery. Four patients were diagnosed with immune reconstitution inflammatory syndrome which was associated with age <40 years, brain cryptococcomas, high cerebrospinal fluid pressure, and serum cryptococcal antigen titre >1:512. Conclusion: C. gattii infection remains a challenging condition but treatment outcomes have significantly improved over 2 decades, with eradication of infection the norm. Adjunctive surgery for the management of bulky pulmonary C. gattii infection appears to increase the likelihood of durable cure and likely reduces the required duration of antifungal therapy. Author summary: Cryptococcus gattii is an environmental fungus responsible for invasive infection, predominately in the central nervous system (CNS) and lungs. There is little evidence to guide its management. We have found First Nations Australians in this region have one of the highest incidences of Cryptococcus gattii infection in the world, with rates possibly increasing. Mortality was associated with end stage kidney disease, diagnosis in earlier years of the study, and unplanned interruptions to intravenous treatment. Whilst mortality improved through the study, neurological disability such as visual or hearing impairment following cure continues to be seen and is associated with brain cryptococcomas and high cerebral spinal fluid (CSF) pressure at diagnosis or during treatment. Blocked CSF shunts are uncommon and concerns of such potential complications should not preclude necessary surgical intervention for persisting increased CSF opening pressures or hydrocephalus which has been associated with poor outcome. Infection recurrence or persistence was associated with large pulmonary cryptococcomas (over 3cm diameter) not undergoing pulmonary surgery and we recommend that surgery be considered for any pulmonary cryptococcoma with a diameter over 2 to 3cm. Eradication of infection can be expected provided there is adequate therapy but may require very prolonged antifungal treatment. [ABSTRACT FROM AUTHOR]