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). Geographic distribution of recognized Cryptococcus gattii infections in the United States. Data and figure were provided by Dr Edmond Byrnes (Johns Hopkins University), summarized by personal communications with the Centers for Disease Control and Prevention (Dr J. Harris), referring physicians, and literature review. 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. Perhaps a larger question here is what is the outbreak? Given the accepted definition—an occurrence of disease greater than would be expected at a particular time and place—we might conclude that all of these US cases may constitute a larger outbreak of C. gattii infection in the United States. Only the future will tell how this outbreak will evolve, now that the infection itself is recognized in multiple regions. However, for the purposes of this study, it might have been more accurate to say that the study focused on defining clinical differences in infections caused by VGIIa–c isolates, compared with others recently recognized in the United States. Even with that separation, there are differences in hosts, diagnostic methods, and recognition bias between endemic and nonendemic regions that make conclusions based on isolate type difficult to fully accept. Data presented indicate a unique propensity for outbreak strains to cause pulmonary disease, with nonoutbreak strains recognized more frequently as a cause of CNS infection. In addition, a large number of patients who had infection in the outbreak region developed disease in the presence of some type of underlying disease, ranging from lung disease to fully immunocompromising conditions, such as human immunodeficiency virus infection or AIDS or receipt of transplant. Outcomes were worse in older persons and in those who received corticosteroids within 1 year of diagnosis (for any reason). These observations are important, and they describe important features of C. gattii infection emerging in the PNW; it is an infection that can present as both CNS and isolated pulmonary disease, in both immunocompetent and relatively immunosuppressed patients. As noted by the authors, this challenges the historical teaching that this organism typically causes CNS infection in immunocompetent persons. A very curious observation was that, in this model, CNS disease was associated with a decreased risk of death. This observation seems counterintuitive, given what we know about CNS infections; explanations proposed, that the host group is less immunosuppressed or that disease is recognized earlier in progression, do not make sense when considering our current understanding of the biology and pathogenesis, in which the route of infection is through the lungs. With this consideration, CNS disease would likely be a later, more advanced manifestation than pulmonary disease, arising in persons who are more immunologically suppressed. Is this truly a difference based on the biology of the organism, the host, or all those vague (but real) differences in clinical care? In my opinion, the differences described between outbreak and nonoutbreak infections are weakly supported, with only 12 persons sampled in the nonoutbreak group and multiple biases introduced by different geography, including differences in diagnostics and therapies and the variability of hosts that reside in different geographic regions. When this outbreak was recognized in British Columbia, clinicians in Washington and Oregon became alerted to its potential presence, compelled in part by news media, driving application of diagnostic tests to identify species and enabling more advanced case identification and aggressive therapies. We simply started looking for the infection and found it in all stages, both early (in the lungs) and late (in the brain), and in many different types of hosts. In most other regions in the United States, these cases have become apparent largely by communications with astute clinicians who felt compelled to draw attention to unusual Cryptococcus infections in normal hosts, usually those who had outcomes that were bad enough to emphasize. I do not know whether the differences reported reflect the organism, the hosts, or the way in which we have recognized and reported the infections. In part, the emphasis on comparing outbreak and nonoutbreak infections in this study somewhat detracts from what might be the larger issue, which is that infection with C. gattii may be considered a different syndrome than the more commonly recognized infection with C. neoformans, with more pulmonary disease, and both lung and CNS disease arising in a mixture of hosts. One could effectively argue in favor of routinely identifying this organism to the species level in all geographic locations, especially in light of recent noted differences in azole drug susceptibilities, prominent largely in VGII types [5–8]. The CDC group has described what can be considered the “tip of the iceberg” of infections caused by C. gattii in the United States, making important distinctions pertaining to clinical presentation and noting poor outcomes of documented disease. The PNW region, with Canadian neighbors, can be considered the host region to the newest endemic mycosis in North America. However, there are other US regions where this organism is apparent, although having a different genetic make-up. Whether the clinical presentation and outcomes of C. gattii infections are truly different in this region, which perhaps defines an endemic outbreak, is a controversial conclusion, but many of the observations described show important differences with the disease typically caused by C. neoformans. It is time to initiate more systematic, prospective efforts to uncover the rest of the iceberg. Critical questions that still linger include the following: (1) How many persons are infected in regions of endemicity? (2) What is the contemporary geographic distribution of C. gattii and C. neoformans in the United States? (3) What immunologic variables determine risk for disease in immunologically normal and suppressed hosts? (4) What is the natural history of the infection, and how can we better treat and prevent it? Now, we are breaking the ice. Dr Marr has served on advisory boards for Astellas, Merck, and Pfizer and has received grant funding from Astellas, Enzon, Merck, Pfizer, and Sigma Tau. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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