Cryptococcus gattii Infection in Healthy Hosts: A Sentinel for Subclinical Immunodeficiency?

TO THE EDITOR—Discordant risks for infection caused by different Cryptococcus species have been described, with Cryptococcus gattii causing disease in healthy hosts. This organism was restricted to tropical regions until recently, with the emergence of an outbreak on Vancouver Island, Canada, and expansion to involve a broader geography in western North America [1, 2]. In 2007, a 38-year-old white woman presented to her local emergency room in Oregon with headache, neck stiffness, and nausea. Cerebrospinal fluid (CSF) was notable for pleocytosis, for which she received ceftriaxone and dexamethasone. Her persistent headache prompted repeat CSF evaluation; the cryptococcal antigen titer was 1:100 000, and cultures revealed Cryptococcus species, later identified as C. gattii (VGIIa). Despite treatment with liposomal amphotericin B and 5-flucytosine, symptoms persisted, with development of cranial nerve 6 and 8 palsies and persistently elevated CSF pressure. Serial lumbar punctures, a shunt, and corticosteroid administration eventually led to resolution of symptoms. Antifungal therapy was discontinued 2 years later, and the patient is healthy today. The patient had never traveled to Vancouver Island and related no unusual exposures. Her history included scoliosis and polycystic ovaries. Her T-cell counts and ratios were normal; however, she had a low total immunoglobulin (Ig) G level (<500 mg/mL). Her organism-specific subtype response was measured in separate sera obtained 4 months after presentation, and 1 year later by antigen-capture enzyme-linked immunosorbent assay with C. gattii, heat-killed after growth at 30°C and 37°C (to stimulate capsule production). The presence of capsule-specific IgG3 increased between the times of serum collection, with the IgG2 level remaining low (Table 1). Cryptococcus gattii Antibody Levelsa,b Abbreviation: Ig, immunoglobulin. Different measures on same serum. Very few capsule-specific IgG1 or IgG4 levels were measured (not shown). Cryptococcus gattii Antibody Levelsa,b Abbreviation: Ig, immunoglobulin. Different measures on same serum. Very few capsule-specific IgG1 or IgG4 levels were measured (not shown). C. gattii has emerged in western North America. The population at risk differs from that in the rural, tropical regions to which the organism was previously restricted, with regard to both race and prevalence of medical immunosuppression (eg, transplants). This case was among the first to occur in Oregon, and it illustrates the typical presentation and clinical course, characterized by a robust central nervous system inflammatory response and pressure-related neurologic complications. Antibody measurements suggest that the patient mounted primarily an IgG3 response to C. gattii, not an IgG2 response; some degree of risk thus may be mediated by an inability to mount a protective IgG2 response to capsular polysaccharide [3]. We hypothesize that a subset of immunologically healthy hosts harbor subclinical antibody deficiencies that predispose them to disease, with risks compounded in the setting of additional exogenous immunosuppression. Research is warranted to determine the prevalence of infection caused by C. gattii in new regions of endemicity, to describe immunologic protectors and risks, and to define appropriate therapies. All authors: No reported conflicts. All authors have 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.