C. gattii in Pacific Northwest, USA | CDC EID

Volume 15, Number 8–August 2009
Synopsis
Spread of Cryptococcus gattii into Pacific Northwest Region of the United States
Kausik Datta, Karen H. Bartlett, Rebecca Baer, Edmond Byrnes, Eleni Galanis, Joseph Heitman, Linda Hoang, Mira J. Leslie, Laura MacDougall, Shelley S. Magill, Muhammad G. Morshed, and Kieren A. Marr, for the Cryptococcus gattii Working Group of the Pacific Northwest1
Author affiliations: Johns Hopkins University School of Medicine, Baltimore, Maryland, USA (K. Datta, K.A. Marr); University of British Columbia, Vancouver, British Columbia, Canada (K.H. Bartlett); Washington State Department of Health, Shoreline, Washington, USA (R. Baer); Duke University Medical Center, Durham, North Carolina, USA (E. Byrnes, J. Heitman); British Columbia Centre for Disease Control, Vancouver (E. Galanis, L. Hoang, L. MacDougall, M.G. Morshed); British Columbia Ministry of Agriculture and Lands, Abbotsford, British Columbia, Canada (M.J. Leslie); and Centers for Disease Control and Prevention, Atlanta, Georgia, USA (S.S. Magill)

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Abstract
Cryptococcus gattii has emerged as a human and animal pathogen in the Pacific Northwest. First recognized on Vancouver Island, British Columbia, Canada, it now involves mainland British Columbia, and Washington and Oregon in the United States. In Canada, the incidence of disease has been one of the highest worldwide. In the United States, lack of cryptococcal species identification and case surveillance limit our knowledge of C. gattii epidemiology. Infections in the Pacific Northwest are caused by multiple genotypes, but the major strain is genetically novel and may have emerged recently in association with unique mating or environmental changes. C. gattii disease affects immunocompromised and immunocompetent persons, causing substantial illness and death. Successful management requires an aggressive medical and surgical approach and consideration of potentially variable antifungal drug susceptibilities. We summarize the study results of a group of investigators and review current knowledge with the goal of increasing awareness and highlighting areas where further knowledge is required.

Cryptococcus gattii (formerly C. neoformans var. gattii) (1) is a basidiomycotic yeast acquired by inhalation. In a susceptible host, the disease (cryptococcosis), caused by C. gattii and the congeneric pathogen C. neoformans, usually results in pneumonia or dissemination to distant tissues, especially to the central nervous system. Some studies have shown that C. gattii appears to differ from other cryptococcal pathogens in phenotypic characteristics, natural habitat, epidemiology, clinical disease manifestations and response to antifungal drugs. We briefly summarize these features before discussing the emergence of C. gattii in the Pacific Northwest region of Canada and the United States.

Based on the distribution of specific antigenic determinants on the polysaccharide capsule, pathogenic cryptococci have been divided into capsular serotypes B and C (both C. gattii), A (C. neoformans var. grubii), D (C. neoformans var. neoformans), and the hybrid diploid AD (1). Clinical and environmental C. gattii isolates obtained from most parts of the world belong to serotype B (2), the serotype also responsible for cryptococcal disease in the Pacific Northwest. The global distribution of C. gattii serotype C appears relatively more geographically restricted (2–4).

C. gattii causes disease in healthy, immunocompetent persons and in persons with immunosuppressive conditions, including those with HIV infection, organ transplant recipients, and patients with hematologic malignancies (2,3,5,6). However, because clinical cryptococcal isolates are not routinely subtyped to the serotype or species level, the actual incidence of C. gattii infection in HIV-negative persons is not known. In a US population-based surveillance study, 2 of 27 cryptococcal isolates obtained from HIV-negative persons were C. gattii (7). Although C. neoformans serotype A has been the most common cause of human disease worldwide since the HIV pandemic began, C. gattii may have previously caused proportionally more disease. For example, in Thailand in the pre-AIDS era, C. gattii comprised 66% of cryptococcal isolates, which decreased to ≈4% during the AIDS epidemic (8).

In general, cryptococcal disease can occur in 1 of 2 ways: a primary disease progression in the context of immunosuppression, or reactivation of a subclinical, latent infection. Progression from infection or colonization to disease likely depends upon a complex interplay of factors associated with the host and the organism.

The natural history of C. gattii infection is not well understood, but some studies suggest subtle differences in disease caused by C. gattii and C. neoformans. C. gattii causes cryptococcomas in the lung and brain (often large, multifocal lesions) more commonly than C. neoformans, and C. gattii disease is more often associated with neurologic sequelae, frequently requiring aggressive neurosurgical management (9,10). Differences in clinical manifestations and outcome suggested by some studies may in part be explained by differences in host immune status (9), although not all studies have demonstrated these differences (4).

Some reports have observed variable-to-decreased in vitro antifungal drug susceptibilities in clinical and environmental C. gattii isolates (11,12); other studies have shown no differences (4). Clinical significance of in vitro susceptibility of cryptococcal isolates is unclear because testing methods are not standardized and MIC breakpoints have not been defined.

C. gattii is found typically in the tropics and subtropics (2). Accordingly, although detected in many regions, C. gattii has been found to be endemic to Australia and New Zealand, Papua New Guinea, South and Southeast Asia (Cambodia, Malaysia, Thailand, Vietnam, People's Republic of China, Taiwan, Singapore, Nepal, and the Indian subcontinent), parts of Latin America (Argentina, Brazil, Colombia, Uruguay, Paraguay, Peru, and Venezuela), southern California, Mexico, Hawaii, Central and South Africa, and certain parts of Europe (Austria, Germany, France, Italy, Greece, and Spain) (2,13).

Our understanding of the epidemiology of cryptococcosis is limited by our currently used diagnostic methods. Diagnosis of cryptococcosis frequently relies on direct microscopy, culture of clinical samples, or detection of cryptococcal antigen in body fluids. However, the organism is not identified to species level in many clinical microbiology laboratories. One biochemical characteristic that distinguishes C. gattii from C. neoformans is its ability to produce blue coloration on l-canavanine-glycine-bromothymol blue (CGB) medium (14), although, occasionally, some isolates identified as C. gattii by molecular typing may be CGB negative (L. Hoang, unpub. data).

Molecular typing studies, which are essential in tracking C. gattii epidemiology, have used the techniques of PCR fingerprinting (15), restriction fragment length polymorphism (RFLP) analysis (16), intergenic spacer sequencing (17), amplified fragment length polymorphism analysis (18), and more recently, multilocus sequence typing (MLST) (19,20). Molecular typing has identified distinct haploid C. gattii lineages among clinical, veterinary, and environmental isolates, such as VGI, VGII, VGIII, and VGIV (19,21,22), which appear to have distinct biogeoclimatic distribution zones. For example, most clinical isolates from Australia and eucalyptus-associated C. gattii isolates belong to molecular type VGI; VGII isolates have been found in domestic animals in Australia and in Aboriginal persons in the Northern Territory (2). On Vancouver Island and mainland British Columbia, most human, veterinary, and environmental C. gattii isolates belong to the genotype VGII, with its 2 molecular subtypes VGIIa (predominant genotype, ≈90% of VGII) and VGIIb (≈10%), representing 2 independent clonal populations (20,22,23).

Emergence on Vancouver Island and in Mainland British Columbia
Isolated cases of C. gattii disease were identified in the animal population of British Columbia in 2000 (24). C. gattii disease was recognized as an epidemic on Vancouver Island and lower mainland British Columbia (23,25) and retrospectively found to have been affecting residents and travelers to the island, as well as the domestic and wild animal population, since 1999 (24).

In 2003, cryptococcal infection became a reportable disease in British Columbia, which strengthened surveillance efforts. The British Columbia Centre for Disease Control reported a cumulative incidence of 218 C. gattii cases in humans during 1999–2007, with an average of 24.2 cases per year (26). The average annual incidence rate of C. gattii infection was 5.8 cases per million on mainland British Columbia and 25.1 cases per million on Vancouver Island; this rate is higher than those reported in other C. gattii–endemic areas of the world (27). During this same period, 19 deaths from C. gattii disease were documented, for a case-fatality rate of 8.7% (26). Of these 218 cases, 55% were in men; the mean age at diagnosis was 58.7 years. Possible risk factors included smoking, cancer, and HIV infection (26). Annual incidence, after reaching a plateau during 2000–2005, increased in 2006. Although most C. gattii cases have occurred among residents of Vancouver Island the numbers of cases have steadily increased among residents of lower mainland British Columbia, likely caused by an active expansion of the epidemic zone since 2004 from Vancouver Island to mainland British Columbia and the northwestern United States (Washington and Oregon) (27). The exact mode of transmission of C. gattii from Vancouver Island to lower mainland British Columbia is not known. However, studies of possible dispersal mechanisms have indicated an association of C. gattii cases with high-traffic locations, and evidence of anthropogenic dispersal through vehicle wheel wells, footwear, construction and forestry activity (leading to aerial dispersal), and water (23). A few domestic and international travelers to the disease-endemic zone on Vancouver Island have subsequently contracted cryptococcal disease caused by C. gattii VGIIa, the molecular subtype most commonly associated with the Vancouver Island emergence (28,29).

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