Management, outcomes and predictors of mortality of Cryptococcus infection in patients without HIV: a multicentre study in 46 hospitals from Australia and New Zealand

Julien Coussement; Christopher H Heath; Matthew B Roberts; Rebekah J Lane; Tim Spelman; Olivia C Smibert; Anthony Longhitano; C Orla Morrissey; Blake Nield; Monica Tripathy; Joshua S Davis; Karina J Kennedy; Sarah A Lynar; Lucy C Crawford; Simeon J Crawford; Benjamin J Smith; Andrew P Gador-Whyte; Rose Haywood; Andrew A Mahony; Julia C Howard; Genevieve B Walls; Gabrielle M O'Kane; Matthew T Broom; Caitlin L Keighley; Olivia Bupha-Intr; Louise Cooley; Jennifer A O'Hern; Justin D Jackson; Arthur J Morris; Caroline Bartolo; Adrian R Tramontana; Katherine C Grimwade; Victor Au Yeung; Roy Chean; Emily Woolnough; Benjamin W Teh; Monica A Slavin; Sharon C-A Chen

doi:10.1093/cid/ciae630

Management, outcomes and predictors of mortality of Cryptococcus infection in patients without HIV: a multicentre study in 46 hospitals from Australia and New Zealand

Clin Infect Dis. 2024 Dec 18:ciae630. doi: 10.1093/cid/ciae630. Online ahead of print.

Authors

Julien Coussement^{1

2}, Christopher H Heath^{3

4}, Matthew B Roberts^{5

6}, Rebekah J Lane⁷, Tim Spelman^{8

9

10

11}, Olivia C Smibert¹², Anthony Longhitano¹³, C Orla Morrissey^{14

15}, Blake Nield¹⁶, Monica Tripathy¹⁷, Joshua S Davis¹⁸, Karina J Kennedy¹⁹, Sarah A Lynar^{20

21}, Lucy C Crawford²⁰, Simeon J Crawford²², Benjamin J Smith²³, Andrew P Gador-Whyte²⁴, Rose Haywood²⁵, Andrew A Mahony²⁶, Julia C Howard²⁷, Genevieve B Walls²⁸, Gabrielle M O'Kane^{29

30}, Matthew T Broom^{31

32}, Caitlin L Keighley³³, Olivia Bupha-Intr³⁴, Louise Cooley³⁵, Jennifer A O'Hern^{20

36}, Justin D Jackson³⁷, Arthur J Morris⁷, Caroline Bartolo³⁸, Adrian R Tramontana^{39

40}, Katherine C Grimwade^{41

42}, Victor Au Yeung⁴³, Roy Chean⁴⁴, Emily Woolnough⁴⁵, Benjamin W Teh¹, Monica A Slavin^{1

46}, Sharon C-A Chen⁴⁷

Affiliations

¹ Department of Infectious Diseases, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
² Department of Infectious Diseases, Guadeloupe University Hospital, Pointe-a-Pitre, Guadeloupe.
³ Department of Microbiology, PathWest Laboratory Medicine, and Department of Infectious Diseases, Fiona Stanley Hospital, Murdoch, WA, Australia.
⁴ Department of Infectious Diseases, Royal Perth Hospital, Perth, WA, Australia.
⁵ Royal Adelaide Hospital, Adelaide, SA, Australia.
⁶ Flinders Medical Centre, Bedford Park, SA, Australia.
⁷ Auckland City Hospital, Te Toka Tumai, New Zealand.
⁸ Department of Health Services Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
⁹ Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
¹⁰ Burnet Institute, Melbourne, VIC, Australia.
¹¹ The University of Melbourne Department of Surgery, St. Vincent's Hospital Melbourne, Fitzroy, VIC, Australia.
¹² Austin Health, Heidelberg, VIC, Australia.
¹³ Monash Health, Clayton, VIC, Australia.
¹⁴ Department of Infectious Diseases, Alfred Health, Melbourne, VIC, Australia.
¹⁵ Department of Infectious Diseases, School of Translational Medicine, Monash University, Melbourne, VIC, Australia.
¹⁶ Royal Prince Alfred Hospital, Camperdown, NSW, Australia.
¹⁷ Gold Coast Hospital and Health Service, Southport, QLD, Australia.
¹⁸ John Hunter Hospital, Newcastle, NSW, Australia.
¹⁹ ACT Pathology, Canberra Health Services, Canberra, ACT, Australia.
²⁰ Royal Darwin and Palmerston Hospitals, Darwin, NT, Australia.
²¹ Menzies School of Health Research, Darwin, NT, Australia.
²² Wollongong Hospital, Wollongong, NSW, Australia.
²³ Eastern Health, Box Hill, VIC, Australia.
²⁴ St Vincent's Hospital Melbourne, Melbourne, VIC, Australia.
²⁵ The Prince of Wales Hospital, Sydney, NSW, Australia.
²⁶ Bendigo Health, Bendigo, VIC, Australia.
²⁷ Te Whatu Ora Waikato, Hamilton, New Zealand.
²⁸ Middlemore Hospital, Te Whatu Ora Counties Manukau, Auckland, New Zealand.
²⁹ Gosford Hospital, Gosford, NSW, Australia.
³⁰ Wyong Hospital, Hamlyn Terrace, NSW, Australia.
³¹ North Shore Hospital, Te Whatu Ora Waitemata, Auckland, New Zealand.
³² Waitakere Hospital, Te Whatu Ora Waitemata, Auckland, New Zealand.
³³ Southern IML Pathology, Wollongong, NSW, Australia.
³⁴ Capital, Coast and Hutt Valley District, Wellington, New Zealand.
³⁵ Royal Hobart Hospital, Hobart, TAS, Australia.
³⁶ Launceston General Hospital, Launceston, TAS, Australia.
³⁷ Albury Wodonga Health, Albury, VIC, Australia.
³⁸ Barwon Health, Geelong, VIC, Australia.
³⁹ Western Health, Footscray, VIC, Australia.
⁴⁰ Western Clinical School, Melbourne Medical School, the University of Melbourne, St Albans, VIC, Australia.
⁴¹ Tauranga Hospital, Hauora a Toi Bay of Plenty, Tauranga, New Zealand.
⁴² Whakatane Hospital, Hauora a Toi Bay of Plenty, Whakatane, New Zealand.
⁴³ Ballarat Health Services, Ballarat, VIC, Australia.
⁴⁴ Latrobe Regional Hospital, Traralgon, VIC, Australia.
⁴⁵ St John of God Midland Public and Private Hospital, Midland, WA, Australia.
⁴⁶ Victorian Infectious Diseases Service, Royal Melbourne Hospital, Melbourne, VIC, Australia.
⁴⁷ Centre for Infectious Diseases and Microbiology Laboratory Services, Institute of Clinical Pathology and Medical Research, New South Wales Health Pathology, Westmead Hospital, The University of Sydney, Sydney, NSW, Australia.

PMID: 39692570
DOI: 10.1093/cid/ciae630

Abstract

Background: Limited data exist regarding outcomes of cryptococcosis in patients without HIV with few studies having compared outcomes of Cryptococcus gattii, versus C. neoformans, infection.

Methods: We conducted a retrospective study in 46 Australian and New Zealand hospitals to determine the outcomes of cryptococcosis in patients without HIV diagnosed between 2015 and 2019, and compared outcomes of C. gattii versus C. neoformans infections. Multivariable analysis identified predictors of mortality within one year.

Results: Of 426 patients, one-year all-cause mortality was 21%. C. gattii infection was associated with a lower mortality than C. neoformans (adjusted odds ratio [OR]: 0.47, 95% confidence interval [CI]: 0.23-0.95), whilst severe neurological symptoms at presentation was the strongest predictor of death (adjusted OR: 8.46, 95% CI: 2.99-23.98). Almost all (99.5%) patients with central nervous system (CNS) infection received induction antifungal therapy versus 27.7% of isolated pulmonary cryptococcosis. The commonest regimen in CNS disease was liposomal amphotericin B with flucytosine (93.8%, mean duration 31 ± 13 days). Among patients with CNS cryptococcosis, C. gattii infection was associated with higher risk of immune reconstitution inflammatory response (C-IRIS) than C. neoformans (21% versus 3%, p<0.001). Nineteen patients received amphotericin B-based re-induction therapy for suspected relapse but none had microbiological relapse. Serum cryptococcal antigen positivity and lung imaging abnormalities resolved slowly (resolution at one year in 25% and 34% of patients, respectively).

Conclusion: Compared with C. neoformans, C. gattii infection demonstrated lower mortality but higher C-IRIS risk in CNS infection. Severe neurological symptoms were the strongest predictor of mortality.

Keywords: Cryptococcus gattii; Cryptococcus neoformans; antifungal therapy; cryptococcosis; prognosis.

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