Outcomes of central nervous system cryptococcosis vary with host immune function: Results from a multi-center, prospective study

Summary

Background

Central nervous system (CNS) cryptococcosis is most commonly encountered among HIV-infected and other immunosuppressed hosts but is less well-characterized among non-immunosuppressed patients.

Methods

We conducted a three year, prospective, observational study to compare the clinical manifestations and outcome of CNS cryptococcosis in three patient populations: HIV-infected patients (n = 54), HIV-negative immunosuppressed patients (n = 21), and non-immunosuppressed patients (n = 11).

Results

Time from initial symptoms to presentation did not differ between the groups. HIV-infected patients were significantly more likely to present with fevers (p < 0.0001), but were less likely to have abnormal mental status, CNS mass lesions and pulmonary involvement (p = 0.001, 0.01 and 0.03, respectively). The clinical manifestations among HIV-negative immunosuppressed patients were generally intermediate to the other groups. Overall, acuity of illness was worse among non-immunosuppressed patients, as measured by APACHE II scores (p = 0.02). Intracranial pressure was higher in HIV-infected and non-immunosuppressed patients than immunosuppressed patients (p = 0.008 and 0.01, respectively). Repeated lumbar punctures were more common among HIV-infected patients (p = 0.01). There was a trend toward more frequent placement of permanent CNS shunts among non-HIV patients (p = 0.05). The mortality rate was greatest for non-immunosuppressed patients (p = 0.04).

Conclusion

CNS cryptococcosis in non-immunosuppressed patients was associated with poorer prognosis. Our findings suggest that host immune responses may contribute to pathogenesis of CNS cryptococcosis, with more intact immune function associated with increased CNS-related morbidity and overall mortality.

Introduction

Cryptococcus spp. are encapsulated yeasts that are major causes of invasive fungal diseases. Initial cryptococcal infection is by inhalation into the lungs, but clinically apparent pulmonary disease is less common than central nervous system (CNS) cryptococcosis, in particular meningo-encephalitis. Before the HIV epidemic, cryptococcosis was an uncommon disease predominantly seen among immunosuppressed individuals, including those with hematologic malignancies, solid organ transplant (SOT) recipients, and individuals receiving corticosteroids or other immunosuppressive drugs.1, 2 Cryptococcosis emerged as an important opportunistic infection (OI) in the early years of the HIV epidemic, affecting approximately 12% of patients with AIDS. After the introduction of highly active antiretroviral therapy (HAART), the incidence of cryptococcosis, as with other OIs, dropped significantly among AIDS patients in the developed world. The disease remains prevalent, however, in the developing world and among persons with limited access to HAART. Outside of the HIV-infected population, the incidence of cryptococcosis has likely not changed,³ but there is an increasing recognition of the importance of the disease.4, 5, 6, 7, 8, 9, 10, 11, 12, 13 In part, this reflects the lengthened survival of at-risk persons, such as SOT recipients and other profoundly immunosuppressed hosts, and the introduction of potent new immunosuppressive agents like anti-TNFα monoclonal antibodies.¹⁴ Appreciation of the impact of cryptococcosis among immunocompetent hosts has also increased due to the Vancouver Cryptococcus gattii outbreak,15, 16, 17 in which persons with no apparent defects in immune function were disproportionately involved, and as a consequence of a recent series of Cryptococcus neoformans var. grubii infections that highlighted adverse outcomes.¹²

To date, relatively few studies have compared cryptococcosis in HIV-infected and HIV-uninfected patients.¹¹ The objectives of the present study were to describe the clinical manifestations and outcome of CNS cryptococcosis among HIV-infected, HIV-negative immunosuppressed, and non-immunosuppressed patients.