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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]

Background: Patients without human immunodeficiency virus (HIV) are increasingly recognized as being at risk for cryptococcosis. Knowledge of characteristics of cryptococcosis in these patients remains incomplete., Methods: We conducted a retrospective study of cryptococcosis in 46 Australian and New Zealand hospitals to compare its frequency in patients with and without HIV and describe its characteristics in patients without HIV. Patients with cryptococcosis between January 2015 and December 2019 were included., Results: Of 475 patients with cryptococcosis, 90% were without HIV (426 of 475) with marked predominance in both Cryptococcus neoformans (88.7%) and Cryptococcus gattii cases (94.3%). Most patients without HIV (60.8%) had a known immunocompromising condition: cancer (n = 91), organ transplantation (n = 81), or other immunocompromising condition (n = 97). Cryptococcosis presented as incidental imaging findings in 16.4% of patients (70 of 426). The serum cryptococcal antigen test was positive in 85.1% of tested patients (319 of 375); high titers independently predicted risk of central nervous system involvement. Lumbar puncture was performed in 167 patients to screen for asymptomatic meningitis, with a positivity rate of 13.2% where meningitis could have been predicted by a high serum cryptococcal antigen titer and/or fungemia in 95% of evaluable cases. One-year all-cause mortality was 20.9% in patients without HIV and 21.7% in patients with HIV (P = .89)., Conclusions: Ninety percent of cryptococcosis cases occurred in patients without HIV (89% and 94% for C. neoformans and C. gattii, respectively). Emerging patient risk groups were evident. A high level of awareness is warranted to diagnose cryptococcosis in patients without HIV., Competing Interests: Potential conflicts of interest . T. S. has received consulting fees for serving on advisory boards and steering committees from Biogen. O. M. has received grants from Gilead Sciences and Merck, Sharp and Dohme Australia and honoraria from Gilead Sciences; support for attending meetings from F2G; and participated on data and safety monitoring boards (DSMB) or advisory boards for Gilead Sciences and Merck, Sharp and Dohme Australia. K. J. K. has received payment for expert testimony at the 46th Society of Hospital Pharmacists of Australia National Conference. A. R. T. has received honoraria from the Medical Journal of Australia, paid to institution, and reports grants or contracts from CTRA with the University of Melbourne (reimbursement of costs paid to institution). B. W. T. is supported by a Medical Research Future Fund Investigator Fellowship; has received grants from MSD and Seqirus; has received honoraria from Pfizer, Alexion, and Janssen; and participated on DSMBs or advisory boards for CSL­Behring, Takeda, and Moderna. S. C. A. C. has received educational grants from F2G and MSD Australia; reports untied educational grants from MSD Australia and F2G Pty Ltd; and reports a role as editor-in-chief for Medical Mycology (journal of ISHAM). M. A. S. has received grants from Gilead Sciences, Merck, and F2G; has received honoraria from F2G; and participated on DSMBs or advisory boards for Pfizer, Cidara, and Roche. R. J. L. reports paid participation on a GSK advisory board. S. A. L. reports grants or contracts as principal investigator on 3 projects funded through a Hot North fund grant and a UK Government Fleming Fund Grant (as part of broader funding for the Menzies School of Health Research; no salary, project costs remunerated only); unpaid participation on a DSMB or advisory board for the Australian Academy of Science and the Australian Academy of Health and Medical Sciences roundtable of experts for the House of Representatives Committee on Health and Ageing; and an unpaid role as a National Tuberculosis Advisory Committee member. M. T. B. reports an unpaid role as an Advanced Training Committee member for General Medicine for the Royal Australasian College of Physicians and an unpaid member of the Vocational Training Committee for Medical Registrars in the Auckland region for the Northern Region Alliance. C. L. K. reports an unpaid role on the Australian Society of Infectious Diseases Board of Directors. E. W. reports a role as a committee member of the Australasian Society for Infectious Diseases Equity and Diversity Committee (unpaid). K. C. G. reports a role as a member of the New Zealand Committee of the Australasian Society for Infectious Diseases. All other authors report no potential conflicts. All authors have submitted the International Committee of Medical Journal Editors Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)