Management of Cryptococcus gattii meningoencephalitis

Summary

Cryptococcosis is a fungal disease caused by Cryptococcus neoformans and Cryptococcus gattii. By inhalation and subsequent pulmonary infection, it may disseminate to the CNS and cause meningitis or meningoencephalitis. Most cases occur in immunosuppressed hosts, including patients with HIV/AIDS, patients receiving immunosuppressing drugs, and solid organ transplant recipients. However, cryptococcosis also occurs in individuals with apparently healthy immune systems. A growing number of cases are caused by C gattii, with infections occurring in both immunosuppressed and immunocompetent individuals. In the majority of documented cases, treatment of C gattii infection of the CNS requires aggressive management of raised intracranial pressure along with standard antifungal therapy. Early cerebrospinal fluid evacuation is often needed through placement of a percutaneous lumbar drain or ventriculostomy. Furthermore, pharmacological immunosuppression with a high dose of dexamethasone is sometimes needed to ameliorate a persistently increased inflammatory response and to reduce intracranial pressure. In this Grand Round, we present the case of an otherwise healthy adolescent female patient, who, despite aggressive management, succumbed to C gattii meningoencephalitis. We also present a review of the existing literature and discuss optimum clinical management of meningoencephalitis caused by C gattii.

Introduction

Cryptococcosis is one of the most common invasive fungal diseases in human beings, with more than 1 million cases per year and around 650 000 deaths in sub-Saharan Africa.1, 2 Of the more than 30 species of the genus Cryptococcus, Cryptococcus neoformans and Cryptococcus gattii are the only species that are commonly pathogenic because of their ability to grow at 37°C and the presence of other virulence factors such as production of melanin and a protective capsule.³ The epidemiology and clinical features of infections caused by C neoformans have been previously described. Infections occur worldwide, affecting predominantly patients with HIV/AIDS or other immunocompromising conditions, although infections do occur among apparently immmunocompetent individuals.1, 4, 5, 6, 7, 8

Many aspects of the epidemiology and clinical features of infections caused by C gattii are relatively less well defined.9, 10 C gattii is a fungal pathogen that grows preferentially in soil around various kinds of trees.7, 11 Similar to C neoformans, it causes pulmonary and CNS disease in people.8, 12, 13 The initial recognition of C gattii as a pathogen was reported in a patient with a lumbar tumour by pathologist Ferdinand Curtis in 1896.¹¹ Historically, most cases due to C gattii have been seen in tropical and subtropical regions, but it is now regarded as an emerging fungal pathogen in other geographical settings.⁹ Cases of C gattii meningoencephalitis occurring among otherwise healthy, immunocompetent individuals have predominated in the literature.14, 15, 16 However, recent reports from the USA have shown that those infected frequently have some underlying condition that could potentially be associated with immunosuppression.12, 17, 18 C gattii tend to produce severe CNS manifestations, including meningitis, encephalitis, or, more frequently, meningoencephalitis. These manifestations might lead to excessive neurological morbidity due to the associated intracranial hypertension.8, 12, 13

C gattii was previously thought to be a subtype of C neoformans (subtype B and C, referring to capsular antigens), but is now recognised as a unique species.¹⁹ The species is divided into four unique molecular types (variety gattii; VGI-IV).5, 9 There is endemicity of VGI and VGII strains in Australia, VGII and VGIII strains in South America, VGI strains in India, and VGIV strains in Africa.9, 10, 20 In the USA, cases of C gattii have been noted in southern California and Hawaii. Typing of isolates recovered from human beings and animals in those regions suggested similarity to other strains arising in more tropical regions, specifically VGI and VGIII.9, 10, 20 Since 2004, an outbreak of infection has been identified in the Pacific northwest region in North America, involving primarily clonal VGII strains (clonal VGIIa and VGIIb in Canada, and clonal VGIIc in the USA).21, 22, 23, 24, 25 These isolates, first recognised on Vancouver Island, have now been documented to have expanded onto western mainland Canada as well as several Pacific northwestern states in the USA.²² Many of these cases have presented predominantly with respiratory symptoms and have occurred in immunocompromised hosts (38% of British Columbia cases and 59% of the USA cases; table).⁹ Moreover, since 2009, more than 25 autochthonous (non-outbreak) cases of C gattii have been documented in other parts of the USA, the most common molecular types being VGI or VGIII.34, 35, 36, 37

Much of our knowledge on cryptococcosis has been derived from studies focused on C neoformans infection in people with HIV. We now appreciate several unique features of CNS disease caused by C gattii. Herein, we present an illustrative case and review the existing medical literature to address the optimum medical management of meningoencephalitis caused by C gattii.