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

Abstract

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.

Fig 1. Northern Territory Top End^a regional incidence based on available data.

The Northern Territory Top End is defined for for this study to include those regions shaded in blue with exception to Barkly. These regions all feed to Royal Darwin Hospital as their major hospital. (Central Desert, Alice Springs and MacDonnell are not part of this region. Barkly feeds both to RDH and to Alice Springs and subsequently Fig 1 may underestimate the true incidence for that region.) Figure developed using geographic boundary data from the Australian Bureau of Statistics available: https://www.abs.gov.au/AUSSTATS/abs@.nsf/DetailsPage/1259.0.30.0012007.

Fig 2. Study diagram.

Note 12 patients not managed at study hospital–these are cases diagnosed at a hospital outside the Top End Region that refers some microbiological specimens to RDH for processing.

Fig 3. Timeline.

New diagnoses, management and outcomes of patients infected with C. gattii managed at RDH over the 22 years of the study. Death 2ry to CG Death attributed to C. gattii Death Other Death within 12 months or before completion of treatment attributed to other cause Neuro sq Infection cured with significant neurological sequelae IRIS immune reconstitution syndrome CNS central nervous system VP VP shunt inserted AR Access reservoir inserted Itra itraconazole Vori voriconazole.

Fig 4. Surgical or conservative management vs diameter of largest pulmonary cryptococcoma and outcome^a.