Cryptococcosis-a systematic review to inform the World Health Organization Fungal Priority Pathogens List

Aiken Dao^{1

2

3}, Hannah Yejin Kim^{1

4

5}, Katherine Garnham^{1

6}, Sarah Kidd⁷, Hatim Sati⁸, John Perfect⁹, Tania C Sorrell^{1

2

3}, Thomas Harrison^{10

11}, Volker Rickerts¹², Valeria Gigante⁸, Ana Alastruey-Izquierdo¹³, Jan-Willem Alffenaar^{1

3

4}, C Orla Morrissey^{14

15}, Sharon C-A Chen¹⁶, Justin Beardsley^{1

2

3}

Affiliations

¹ Sydney Infectious Diseases Institute, The University of Sydney, Sydney, Australia.
² Westmead Institute for Medical Research, Westmead, Sydney, Australia.
³ Westmead Clinical School, Westmead Hospital, Sydney, Australia.
⁴ Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, Camperdown, Australia.
⁵ Department of Pharmacy, Westmead Hospital, Westmead, Australia.
⁶ Sunshine Coast University Hospital, Birtinya, Qld 4575, Australia.
⁷ National Mycology Reference Centre, Microbiology and Infectious Diseases, SA Pathology, Adelaide, Australia.
⁸ AMR Division, World Health Organization, Geneva, Switzerland.
⁹ Duke University Medical Center, Durham, NC, USA.
¹⁰ Institute of Infection and Immunity, St George's University London, London, UK.
¹¹ Medical Research Council Centre for Medical Mycology, University of Exeter, Exeter, UK.
¹² Robert Koch Institute, Berlin, Germany.
¹³ Mycology Reference Laboratory, National Centre for Microbiology, Instituto de Salud Carlos III, Madrid, Spain.
¹⁴ Department of Infectious Diseases, Alfred Health, Melbourne, Australia.
¹⁵ Monash University, Department of Infectious Diseases, Melbourne, Victoria, Australia.
¹⁶ Centre for Infectious Diseases and Microbiology Laboratory Services, Institute of Clinical Pathology and Medical Research, New South Wales Health Pathology, Westmead Hospital, Westmead, Sydney, Australia.

PMID: 38935902
PMCID: PMC11210623
DOI: 10.1093/mmy/myae043

Cryptococcosis-a systematic review to inform the World Health Organization Fungal Priority Pathogens List

Aiken Dao et al. Med Mycol. 2024.

. 2024 Jun 27;62(6):myae043.

doi: 10.1093/mmy/myae043.

Authors

Affiliations

¹ Sydney Infectious Diseases Institute, The University of Sydney, Sydney, Australia.
² Westmead Institute for Medical Research, Westmead, Sydney, Australia.
³ Westmead Clinical School, Westmead Hospital, Sydney, Australia.
⁴ Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, Camperdown, Australia.
⁵ Department of Pharmacy, Westmead Hospital, Westmead, Australia.
⁶ Sunshine Coast University Hospital, Birtinya, Qld 4575, Australia.
⁷ National Mycology Reference Centre, Microbiology and Infectious Diseases, SA Pathology, Adelaide, Australia.
⁸ AMR Division, World Health Organization, Geneva, Switzerland.
⁹ Duke University Medical Center, Durham, NC, USA.
¹⁰ Institute of Infection and Immunity, St George's University London, London, UK.
¹¹ Medical Research Council Centre for Medical Mycology, University of Exeter, Exeter, UK.
¹² Robert Koch Institute, Berlin, Germany.
¹³ Mycology Reference Laboratory, National Centre for Microbiology, Instituto de Salud Carlos III, Madrid, Spain.
¹⁴ Department of Infectious Diseases, Alfred Health, Melbourne, Australia.
¹⁵ Monash University, Department of Infectious Diseases, Melbourne, Victoria, Australia.
¹⁶ Centre for Infectious Diseases and Microbiology Laboratory Services, Institute of Clinical Pathology and Medical Research, New South Wales Health Pathology, Westmead Hospital, Westmead, Sydney, Australia.

PMID: 38935902
PMCID: PMC11210623
DOI: 10.1093/mmy/myae043

Abstract

Cryptococcosis causes a high burden of disease worldwide. This systematic review summarizes the literature on Cryptococcus neoformans and C. gattii infections to inform the World Health Organization's first Fungal Priority Pathogen List. PubMed and Web of Science were used to identify studies reporting on annual incidence, mortality, morbidity, antifungal resistance, preventability, and distribution/emergence in the past 10 years. Mortality rates due to C. neoformans were 41%-61%. Complications included acute renal impairment, raised intracranial pressure needing shunts, and blindness. There was moderate evidence of reduced susceptibility (MIC range 16-32 mg/l) of C. neoformans to fluconazole, itraconazole, ketoconazole, voriconazole, and amphotericin B. Cryptococcus gattii infections comprised 11%-33% of all cases of invasive cryptococcosis globally. The mortality rates were 10%-23% for central nervous system (CNS) and pulmonary infections, and ∼43% for bloodstream infections. Complications described included neurological sequelae (17%-27% in C. gattii infections) and immune reconstitution inflammatory syndrome. MICs were generally low for amphotericin B (MICs: 0.25-0.5 mg/l), 5-flucytosine (MIC range: 0.5-2 mg/l), itraconazole, posaconazole, and voriconazole (MIC range: 0.06-0.5 mg/l). There is a need for increased surveillance of disease phenotype and outcome, long-term disability, and drug susceptibility to inform robust estimates of disease burden.

Keywords: Cryptococcus gattii; Cryptococcus neoformans; cryptococcal meningitis; cryptococcosis; invasive fungal infection.

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Conflict of interest statement

AA-I has received personal fees for educational talks on behalf of Gilead and Pfizer.

None.

Figures

**Figure 1.**
Flow diagram for selection of studies included in the systematic review for *C. neoformans*.

**Figure 2.**
Flow diagram for selection of studies included in the systematic review for *C. gattii*.

See this image and copyright information in PMC

References

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1. Byrnes EJ III, Li W, Lewit Y et al. Emergence and pathogenicity of highly virulent Cryptococcus gattii genotypes in the Northwest United States. PLoS Pathog. 2010; 6(4): e1000850. - PMC - PubMed
1. Chen S, Sorrell T, Nimmo G et al. Epidemiology and host- and variety-dependent characteristics of infection due to Cryptococcus neoformans in Australia and New Zealand. Australasian Cryptococcal Study Group. Clin Infect Dis. 2000; 31(2): 499–508. - PubMed
1. Kidd SE, Hagen F, Tscharke RL et al. A rare genotype of Cryptococcus gattii caused the cryptococcosis outbreak on Vancouver Island (British Columbia, Canada). Proc Natl Acad Sci USA. 2004; 101(49): 17258–17263. - PMC - PubMed

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Cryptococcosis-a systematic review to inform the World Health Organization Fungal Priority Pathogens List

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Cryptococcosis-a systematic review to inform the World Health Organization Fungal Priority Pathogens List

Authors

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Conflict of interest statement

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