Cryptococcus gattii: the tip of the iceberg.

TO THE EDITOR—Our historical understanding of Cryptococcus gattii depicts a fungus that is geographically restricted to tropical and subtropical regions, where it has a propensity to cause central nervous system (CNS) disease in persons with normal immune systems. This fungus, which only recently has been appreciated as a species distinct from its more well-known and cosmopolitan sibling, Cryptococcus neoformans, has been described as particularly prevalent in areas that contain eucalypts, especially in northern Australia, South America, and parts of Africa and Asia. Although C. gattii was recognized some time ago to cause disease in North America, particularly southern California, the infection did not become particularly concerning until its emergence on Vancouver Island, British Columbia, during the late 1990s. Subsequently, there were reports emphasizing its presence as a significant human and veterinary pathogen in the broader Pacific Northwest (PNW), especially in the US states of Washington and Oregon [1, 2]. Most recently, detailed analyses of the genetics of organisms isolated from multiple locations in the United States emphasize 2 important conclusions: emergence of a notable outbreak of genetically similar strains in the PNW and increasing recognition of other strains as a cause of disease across a larger area in the United States (Figure 1). The article in this issue by Harris et al summarizes efforts by the Centers for Disease Control and Prevention (CDC) to describe the unique clinical features of infection with outbreak and nonoutbreak C. gattii strains in the United States [3]. The authors are to be congratulated for herculean efforts performed in compiling recognized cases, efforts dependent on extensive communication and follow-up with referring clinicians in geographically dispersed regions. Despite limitations in methodology, some important clinical observations are introduced, with controversies raised. Methods used in this study separate recognized cases as those caused by outbreak and nonoutbreak C. gattii strains. Although the intent of this separation is well founded—to evaluate the clinical features of infections caused by the unique organism arising in the PNW—the logic justifying this separation seems to be somewhat convoluted and arbitrary, yielding, at best, interesting hypotheses from these data rather than firm conclusions. Investigators state that the case patients infected with outbreak strains were defined as having likely acquired infection from the PNW or British Columbia, contingent on exposure within 1 year of clinical presentation. Isolates were then considered to be outbreak strain if identified as one of the genotypes that have been described from the area (VGIIa, VGIIb, and VGIIc). Isolates in the CDC collection are largely separated by region of endemicity, with VGII isolates arising in the PNW and others (VGI and VGIII) arising in different regions. However, attention is drawn to the recognized case caused by a VGII strain that arose in a patient with only geographic exposure on Hawaii; this case was considered to be caused by a nonoutbreak strain because of the exposure. Perhaps this is justified, because of the unpublished findings, through use of multilocus sequence typing, that this VGII strain appears to be genetically dissimilar (E. Byrnes, unpublished communication, July 2011). However, the distribution of VGII in the United States may, in fact, be more broad; an isolate recovered from the environment in California in the 1990s was subsequently found to be VGIIa–very similar to the recently recovered VGIIa isolates from the PNW [2]. These issues outline a problem inherent in the definition used in this study: overlaps, including the presence of VGII genotypes in areas not in the PNW and the presence of VGI and VGIII isolates in the PNW [2, 4], make the separation between outbreak and nonoutbreak somewhat arbitrary. Received 26 August 2011; accepted 30 August 2011. Correspondence: Kieren A. Marr, MD, Division of Infectious Diseases, Johns Hopkins University School of Medicine, 720 Rutland Ave, Ross 1064, Baltimore, MD 21205 (kmarr4@ jhmi.edu). Clinical Infectious Diseases The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. permissions@oup.com. 1058-4838/2011/5312-0004$14.00 DOI: 10.1093/cid/cir738