Cryptococcus gattii: Infectious substances pathogen safety data sheet

Section I – Infectious agent

Name

Cryptococcus gattii

Agent type

Fungi

Taxonomy

Family

Cryptococcaceae

Genus

Cryptococcus

Species

gattii

Synonym or cross-reference

Previously referred to as Cryptococcus neoformans var. gattii and Cryptococcus neoformans serotypes B and C^Footnote1; proposed taxonomy of C. gattii includes C. gattii sensu stricto (VGI), C. deuterogattii (VGII), C. bacillisporus (VGIII), C. tetragattii (VGIV), and C. decagattii (VGIV/VGIIIc), collectively to be referred to as C. gattii species complex^Footnote2; and also known as cryptococcosis^Footnote2.

Characteristics

Brief description

C. gattii is a dimorphic basidiomycete that occurs mainly in a yeast-like form but can transform into a filamentous hyphal form during sexual development. The teleomorph form of C. gattii is Filobasidiella gattii^Footnote2. The hyphae form mycelia and produce basidospores^Footnote2. Haploid yeast cells are encapsulated, round or oval-shaped and measure approximately 5 to 20 μm in diameter^Footnote3. The genome is organized into 14 chromosomes with a total size of approximately 18.4 Mb^Footnote4.

Properties

C. gattii cells are able to replicate within host macrophage phagosomes and can evade phagocytosis from other innate immune cells^{Footnote5Footnote6}. The polysaccharide capsule plays a role in evading and suppressing the host immune response; melanin provides protection against oxidative stress; enzymes, such as invasins, phospholipase B, urease, superoxide dismutase, and trehalose, play a role in the dissemination of the fungal pathogen in the host and transport across the blood-brain barrier^{Footnote2Footnote7Footnote8Footnote9}.

Some C. gattii genotypes (e.g., VGI, VGII, VGIII) are more commonly isolated from infections in immunocompetent hosts, while other genotypes tend to affect mainly immunocompromised hosts^{Footnote2Footnote10Footnote11}. Clinical characteristics and disease progression differ among members of C. gattii species complex^{Footnote2Footnote12}; for example, VGII is considered to be a highly virulent genotype^{Footnote2Footnote12}.

C. gattii can reproduce both sexually (basidiospores) and asexually (yeast budding). There are two mating types: MATa and MATα^Footnote2. Cells of the opposite or same mating types can sexually reproduce^Footnote2.

Section II – Hazard identification

Pathogenicity and toxicity

C. gattii infections commonly affect the respiratory and/or the central nervous system (CNS), but other parts of the body (e.g., skin, bone, lymph nodes, soft tissues) can also be involved^{Footnote2Footnote13Footnote14Footnote15}. The proportion of cases with CNS involvement presenting with meningitis or cerebral infection varies among strains from 18% to 85%^{Footnote2Footnote11Footnote16}.

Pulmonary disease symptoms include cough, chest pain, and hemoptysis^{Footnote2Footnote11}. Individuals can be asymptomatic with presence of mass lesions (cryptococcomas) at infected sites^{Footnote2Footnote11}. Neurological disease symptoms include headache, fever, nausea, confusion, visual disturbances, and neck stiffness^{Footnote2Footnote7Footnote11Footnote17Footnote18}. Meningitis is the most frequent clinical presentation in children and HIV patients^{Footnote2Footnote18}.

Complications associated with CNS infections include hydrocephalus (17-50%), raised intracranial pressure, papilledema, visual impairment or blindness (18-53%), and deafness^Footnote2. Immune reconstitution inflammatory syndrome (9-17%), which is associated with worsening of disease symptoms weeks to months after beginning treatment with antifungal drugs, has been described^{Footnote16Footnote19Footnote20}. Neurological sequelae, such as visual impairment, have been reported following the completion of treatment^Footnote2. Relapses are uncommon (4.4%)^Footnote20, but there have been rare reports in which suspected latent infections re-emerged in individuals^Footnote21.

Mortality rates of C. gattii infections vary according to many factors including access to health resources, C. gattii genotype, and host immune status^{Footnote2Footnote7}. Case fatality for immunocompetent individuals with CNS involvement varies from 9-42%^Footnote7.

C. gattii is mainly associated with nasal and lower respiratory infection in koalas, horses, sheep, and goats, but disseminated disease and CNS involvement have been reported^{Footnote2Footnote3Footnote22Footnote23}. Asymptomatic infections have been found in koalas^{Footnote24Footnote25}. Cats commonly present with infections of the nasal and paranasal cavity^Footnote2. Other infection sites include the skin, lymph nodes, brain, meninges, and eyes^Footnote2. In dogs, infections are usually disseminated involving nasal cavity, CNS, skin, kidney, and the gastrointestinal tract^Footnote2. Symptoms of respiratory infection include sneezing, nasal discharge and lethargy. Neurological symptoms include stumbling, paralysis, and in some cases blindness^Footnote2. Generally, nasal and pulmonary cases are treatable^{Footnote26Footnote27}, while CNS involvement is associated with increased likelihood of serious disease and mortality^{Footnote28Footnote29Footnote30}.

Epidemiology

Members of the C. gattii species complex are found worldwide; each C. gattii genotype has a different geographical distribution^{Footnote2Footnote7}. C. gattii is endemic in some regions including Australia (0.61 cases per million people per year)^Footnote2; British Columbia, Canada^Footnote11; Pacific Northwest, United States^Footnote31; Papua New Guinea (42.8 cases per million people per year)^Footnote7; Brazil^Footnote32; and parts of Africa^Footnote2. The average annual incidence of cryptococcosis in British Columbia, Canada during the 1999-2007 outbreak was 5.8 cases per million people per year^Footnote11 and the mortality rate during the outbreak was 23%^Footnote20. This cryptococcosis outbreak subsequently spread to the Pacific Northwest United States^Footnote33.

Estimates of global incidence of cryptococcosis and deaths attributable to C. gattii are uncertain. Less than 20% of human cryptococcosis of the CNS is attributable to C. gattii^{Footnote17Footnote34Footnote35}. Cryptococcosis is generally uncommon in children^Footnote2.

Outbreaks of cryptococcosis in goats and horses have been reported^{Footnote22Footnote23}. A cryptococcosis outbreak affecting dogs, cats, ferrets, and a bird was reported in 2003 in British Columbia, Canada^Footnote36.

Presence of anti-granulocyte-macrophage colony-stimulating factor autoantibodies is associated with CNS cryptococcosis in apparently immunocompetent individuals^{Footnote37Footnote38}. Conditions associated with an increased risk of C. gattii infection include HIV infection, invasive cancer, solid organ transplant, immunosuppressive drugs, and smoking^Footnote2. An immunocompromised status is also associated with a higher mortality rate^Footnote16.

Host range

Natural host(s)

Humans, sheep^Footnote23, llamas^Footnote33, deer^Footnote29, goats^Footnote22, horses^{Footnote23Footnote27Footnote28}, ferrets^{Footnote39Footnote40}, cats^{Footnote2Footnote26}, dogs^{Footnote2Footnote41}, koalas^Footnote42, porpoises^{Footnote43Footnote44}, seals^Footnote30, and avian species^{Footnote45Footnote46}.

Other host(s)

Rats^Footnote47, mice^Footnote48, and zebrafish^Footnote49 have been experimentally infected.

Infectious dose

Unknown.

Incubation period

Approximately 2 to 13 months but can be up to several years^{Footnote2Footnote50}.

Communicability

The primary transmission route is inhalation of airborne infectious propagules (i.e., desiccated yeast cells, basidospores) into the respiratory tract^{Footnote2Footnote51}. C. gattii transmission via direct inoculation has been reported^{Footnote52Footnote53}.

Section III – Dissemination

Reservoir

C. gattii can inhabit the nasal cavity and lower respiratory tract of humans and animals, in some cases without causing clinical symptoms^{Footnote11Footnote42}. Exposure to environmental sources of C. gattii associated with trees or soil is likely the main source of human and animal infection^Footnote2.

Zoonosis

None.

Vectors

None.

Section IV – Stability and viability

Drug susceptibility/resistance

Susceptibility to antifungals varies slightly among members of the C. gattii species complex^Footnote54. Amphotericin B, 5-flucytosine, and azoles (e.g., fluconazole, voriconazole, posaconazole, itraconazole) have been used to treat C. gattii infections^{Footnote2Footnote55}.

APX001 is effective against C. gattii in vivo and is in clinical development^Footnote56. Arylamidine T-2307 is effective against C. gattii in vivo^Footnote48.

Low frequency of fluconazole resistance has been reported in some regions^{Footnote2Footnote54}.

Susceptibility to disinfectants

Iodine polyvinylpyrrolidone (10%), sodium laurylsulfate (2%), chlorhexidine (0.5%), ethanol (70%), sodium hypochlorite (1%), and quaternary ammonium compounds are effective against Cryptococcus spp.^{Footnote57Footnote58Footnote59}.

Physical inactivation

Cryptococcus spp. are moderately susceptible to inactivation by UV radiation (20,000 μJ/cm²)^Footnote60, and completely inactivated by moist heat treatment (121 °C for at least 15 min)^Footnote59.

Survival outside host

Members of the C. gattii species complex have been recovered from samples of decaying wood stored at room temperature for 10 years, suggesting that C. gattii can survive for prolonged periods on naturally colonized materials^{Footnote61Footnote62}. C. gattii can survive for over a year in freshwater and seawater, and for months on fomites (e.g., footwear)^Footnote62.

Section V – First aid/medical

Surveillance

Imaging technology can be used to visualize cryptococcomas in the lungs, brain, and other sites in the body^Footnote2. Clinical specimens, such as cerebrospinal fluid or serum, can be analyzed using cryptococcal antigen tests (e.g., latex agglutination, enzyme-linked immunoassay, lateral flow assay), which provide rapid results and are commercially available but do not provide species-level identification^{Footnote2Footnote63}. C. gattii can be cultured on various types of nutrient agar^Footnote2. Polymerase chain reaction (PCR)-based tests and internal transcribed spacer (ITS) sequencing are used for species-level identification^{Footnote2Footnote7}. Strains of C. gattii can be typed using multi-locus sequence typing (MLST) or whole-genome sequencing^Footnote2. Species identification by matrix-assisted laser desorption ionization- time of flight (MALDI-TOF) mass spectrometry has also been applied in some diagnostic labs^Footnote7.

Note: The specific recommendations for surveillance in the laboratory should come from the medical surveillance program, which is based on a local risk assessment of the pathogens and activities being undertaken, as well as an overarching risk assessment of the biosafety program as a whole. More information on medical surveillance is available in the Canadian Biosafety Handbook (CBH).

First aid/treatment

Treatment usually involves consolidation therapy with antifungal drugs for approximately 6 weeks, followed by maintenance therapy as required^Footnote64. Approximate durations of treatment for lung and CNS infections are 6 to 12 months and 12 to 18 months respectively^Footnote2. Surgery may be required to remove mass lesions.

Treatment of C. gattii infections in animals also involves administration of antifungal drugs^{Footnote2Footnote65}.

Note: The specific recommendations for first aid/treatment in the laboratory should come from the post-exposure response plan, which is developed as part of the medical surveillance program. More information on the post-exposure response plan can be found in the CBH.

Immunization

No vaccine is currently available^Footnote66.

Note: More information on the medical surveillance program can be found in the CBH, and by consulting the Canadian Immunization Guide.

Prophylaxis

None.

Note: More information on prophylaxis as part of the medical surveillance program can be found in the CBH.

Section VI – Laboratory hazard

Laboratory-acquired infections

None reported to date.

Note: Please consult the Canadian Biosafety Standard (CBS) and CBH for additional details on requirements for reporting exposure incidents. A Canadian biosafety guideline describing notification and reporting procedures is also available.

Sources/specimens

Biopsy specimens (e.g., lung, brain), blood, cerebrospinal fluid, bronchoalveolar lavage fluid, sputum^{Footnote2Footnote7}.

Primary hazards

Primary exposure hazard is inhalation of airborne or aerosolized infectious material.

Special hazards

None.

Section VII – Exposure controls/personal protection

Risk group classification

C. gattii is a Risk Group 3 human pathogen and Risk Group 3 animal pathogen^{Footnote67Footnote68}.

Containment requirements

Containment Level 3 facilities, equipment, and operational practices outlined in the CBS for work involving infectious or potentially infectious materials, animals, or cultures.

Protective clothing

The applicable Containment Level 3 requirements for personal protective equipment and clothing outlined in the CBS to be followed. At minimum, use of full body coverage dedicated protective clothing, dedicated protective footwear and/or additional protective footwear, gloves when handling infectious materials or animals, face protection when there is a known or potential risk of exposure to splashes or flying objects, respirators when there is a risk of exposure to infectious aerosols, and an additional layer of protective clothing prior to work with infectious materials or animals.

Note: A local risk assessment will identify the appropriate hand, foot, head, body, eye/face, and respiratory protection, and the personal protective equipment requirements for the containment zone must be documented.

Other precautions

All activities involving open vessels of infectious material are to be performed in a certified biological safety cabinet (BSC) or other appropriate primary containment device. The use of needles, syringes, and other sharp objects to be strictly limited. Additional precautions must be considered with work involving animals or large-scale activities.

Section VIII – Handling and storage

Spills

Allow aerosols to settle. Wearing protective clothing, gently cover the spill with absorbent paper towel and apply suitable disinfectant, starting at the perimeter and working towards the centre. Allow sufficient contact time with the disinfectant before clean up (CBH).

Disposal

Regulated materials, as well as all items and waste to be decontaminated at the containment barrier prior to removal from the containment zone, animal room, animal cubicle, or post mortem room. This can be achieved by using decontamination technologies and processes that have been demonstrated to be effective against the infectious material, such as chemical disinfectants, autoclaving, irradiation, incineration, an effluent treatment system, or gaseous decontamination (CBH).

Storage

The applicable Containment Level 3 requirements for storage outlined in the CBS are to be followed. Primary containers of regulated materials removed from the containment zone to be stored in a labelled, leak-proof, impact-resistant secondary container, and kept either in locked storage equipment or within an area with limited access.

SSBA: Containers of security sensitive biological agents (SSBA) stored outside the containment zone must be labelled, leakproof, impact resistant, and kept in locked storage equipment that is fixed in place (i.e., non-movable) and within an area with limited access.

An inventory of RG3 and RG4 pathogens, and SSBA toxins in long-term storage, to be maintained and to include:

1. specific identification of the regulated materials; and
2. a mechanism that allows for the detection of a missing or stolen sample in a timely manner.

Section IX – Regulatory and other information

Canadian regulatory information

Controlled activities with C. gattii require a Human Pathogens and Toxins Licence, issued by the Public Health Agency of Canada^Footnote68.

The following is a non-exhaustive list of applicable designations, regulation, or legislation:

• Human Pathogen and Toxins Act and Human Pathogens and Toxins Regulations
• Health of Animals Act and Health of Animals Regulations
• Transportation of Dangerous Goods Regulations

Last file update

October, 2019

Prepared by

Centre for Biosecurity, Public Health Agency of Canada.

Disclaimer

The scientific information, opinions, and recommendations contained in this Pathogen Safety Data Sheet have been developed based on or compiled from trusted sources available at the time of publication. Newly discovered hazards are frequent and this information may not be completely up to date. The Government of Canada accepts no responsibility for the accuracy, sufficiency, or reliability or for any loss or injury resulting from the use of the information.

Persons in Canada are responsible for complying with the relevant laws, including regulations, guidelines and standards applicable to the import, transport, and use of pathogens in Canada set by relevant regulatory authorities, including the Public Health Agency of Canada, Health Canada, Canadian Food Inspection Agency, Environment and Climate Change Canada, and Transport Canada. The risk classification and related regulatory requirements referenced in this Pathogen Safety Data Sheet, such as those found in the Canadian Biosafety Standard, may be incomplete and are specific to the Canadian context. Other jurisdictions will have their own requirements.

Copyright ^© Public Health Agency of Canada, 2023, Canada