Cryptococcus gattii infections in China: extent of the problem?

Approximately 70 species are accepted in the genus Cryptococcus;1 however, only two species, Cryptococcus neoformans (C. neoformans, serotypes A, AD and D) and C. gattii (serotypes B and C) are responsible for almost all human cryptococcal infections,2,3 and resulted in over 1 million new cases of cryptococcosis in the world each year with over 600-000 casualties.4 It is generally assumed that cryptococcal infections are acquired by inhalation of fungal spores, desiccated cells, or poorly encapsulated yeasts from environmental niches, such as decayed wood debris of certain tree species or bird droppings.5 Epidemiological surveys have shown that C. neoformans caused about 80% of cryptococcosis cases globally each year, particularly in immunocompromised persons, such as human immunodeficiency virus (HIV)-infected people and acquired immunodeficiency syndrome (AIDS) patients,2,3 while C. gattii primarily infects apparently immunocompetent hosts, and is mainly responsible for the remaining cases of cryptococcosis.6,7 Thus C. gattii is also an encapsulated basidiomycetous yeast that causes life-threatening infections in humans and animals. The species was firstly described in a case of cryptococcosis in a seven-year-old child in Congo in 1970.2 The first documented C. gattii infection in China was reported in 1980, and involved a 43-year-old male industrial worker infected by the VGI C. gattii strain S8012, and the patient was cured by treatment with amphotericin B.8 According to the current classification, C. gattii can be further subdivided into four different molecular types: VGI/AFLP4, VGII/AFLP6, VGIII/AFLP5A/5B/5C, and VGIV/AFLP7, among which molecular type VGI/AFLP4 C. gattii strain is prevalent in the world.9,10 Until rather recently, studies on C. gattii infections worldwide lagged behind those on C. neoformans that causes nearly 99% of cryptococcosis cases in HIV-infected people and AIDS patients in the world.3 Relatively few early studies informed us that C. gattii infections were before an endemic disease of immunocompetent persons living in tropical or subtropical regions of the world. 2,6,7 However, a highly virulent C. gattii, belonging to genotype VGIIa/AFLP6a, unprecedentedly emerged since 1999 as a resurgent fungal pathogen in still ongoing outbreaks in the temperate climates of British Columbia (BC), Canada, and the Pacific Northwest of the USA (USPNW).11,12 Since then, new risk factors and new environmental niches of C. gattii infections have been identified, and includes AIDS, cancer, smoking and occurrence on other species of trees, since these outbreaks.13 Thus the outbreaks have profoundly changed our views on the pathogen character of C. gattii.6,7 Thus, C. gattii and C. neoformans differ in ecology, biochemistry, genetics, their ability to cause disease, and clinical characteristics.14–16 Both species tend to infect the central nervous system, but C. gattii causes more frequently respiratory disease, nerve functional obstruction, and higher median cerebrospinal fluid (CSF) pressure compared with C. neoformans.14–16 For example, a previous analysis performed by us based on 88 cryptococcosis patients in China (C. gattii-infected patients: C. neoformans-infected patients = 12:76) revealed that C. gattii predominantly affected the central nervous system of HIV-negative patients without identifiable underlying diseases. The median CSF pressure of C. gattii-infected patients was higher ((349±47) mmH2O) than the median CSF pressure of C. neoformans-infected patients ((300±56) mmH2O, P=0.007).17 Moreover, abnormal neurology, especially optic nerve functional obstruction, was more frequently observed among C. gattii-infected patients (33%, 4/12) during induction antifungal therapy than in C. neoformans-infected patients (5.6%, 4/72) (P <0.05),17 which was in agreement with previous observations.14–16 Currently, C. gattii is considered a primary fungal pathogen that mainly infects otherwise healthy individuals, whereas C. neoformans is seen as a secondary pathogen because it primarily infects immunocompromised people.2 In clinical mycology laboratories in China, C. gattii is rarely reported. A recent overview on cryptococcosis in China covering data from 1985 to 2010 indicated the occurrence of approximately 8770 cases of cryptococcosis during that time.18 However, this study still failed to reveal the profile of C. gattii infections in China during that period. Several molecular epidemiological studies suggested that C. gattii infections accounted for approximate 8% of cryptococcal infections in China, mainly affecting immunocompetent hosts, and with the molecular type VGI/AFLP4 being the most common in China,17,19,20 with VGIIb/AFLP6b being less common. For instance, Chen et al19 analyzed 129 clinical isolates of the C. neoformans species complex strains obtained from 1980 to 2006, which revealed that this species accounted for 6.9% (9/129) of cryptococcosis cases in the mainland of China, and all of nine patients were infected by molecular type VGI/AFLP4. Up to now, there are no reports on the epidemiology of C. gattii infections in China including their environmental niches, which considerably limits our understanding of the genetic population structure and ecology profile of C. gattii. This hampers preventive treatment of possible introductions and expansions of highly virulent genotypes of C. gattii from overseas into China. Notably, the number of cryptococcosis cases per year increased steadily in a Chinese university hospital over 10 years, 21 and over 70% of C. gattii infections in China were observed since 1999,17,19,20 which may indicate that the incidence of the species is increasing. A clinical C. gattii strain isolated in 2007 in Japan was found to be identical to strain R265 with molecular type VGIIa/AFLP6a, which belongs to the major Vancouver Island outbreak molecular type, and importantly the patient had no history of overseas travels except visits to Guam in 1990 and Saipan in 1999.22 In Europe, 60% of the C. gattii cases may be due to import from other continents.23 Phylogenetic analysis of clinical C. gattii isolates from China also suggested that molecular type VGI isolates have a close genetic relationship with C. gattii isolates from Australia.24 It indeed remains to be seen how many cases in China are related to immigration or to transfer from rural to urban regions. We should be aware of these dispersal mechanisms as emerging fungal pathogens have been increasingly recognized as major threats to human health during the past decades.25 As a result, clinicians, veterinarians, mycologists and Public Health officials should be aware of an emerging C. gattii among Chinese patients and maintain alertness to diagnose this fatal mycosis, particularly in the subtropical Southeast regions of the mainland of China where comparatively more C. gattii-infected patients were diagnosed. This is also a region with a major trade in foreign woods, and where proper environmental niches exist, such as the growth of various Eucalyptus species. In summary, C. gattii infections may be more common that is presently known in China, especially in its Southeastern part. Thus, a comprehensive environmental and clinical surveillance of C. gattii infections is urgently needed to investigate the presence, abundance and genotypic diversity of the pathogen in order to understand its spread and pathogenicity in this part of the world, and to predict and prevent potential future outbreaks of this significant pathogen.

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