Cryptococcus gattii infection: Clinical features and diagnosis
- Sharon Chen, PhD, MBBS, FRACP, FRCPA
Sharon Chen, PhD, MBBS, FRACP, FRCPA
- Clinical Associate Professor
- Sydney Medical School, University of Sydney
- Kieren A Marr, MD
Kieren A Marr, MD
- Section Editor — Compromised Host Infections; Fungal Infections
- Professor of Medicine and Oncology
- Johns Hopkins University School of Medicine
- Tania C Sorrell, MD
Tania C Sorrell, MD
- Professor of Clinical Infectious Diseases and Director of the Centre for Infectious Diseases and Microbiology
- Sydney Medical School, University of Sydney
Cryptococcus gattii has emerged as an important fungal pathogen. Infection manifests most often as potentially fatal meningoencephalitis and/or pulmonary disease. The emergence of clusters of cryptococcosis due to C. gattii in British Columbia, Canada in 1999, with subsequent spread to the United States Pacific Northwest, challenged our understanding of this disease [1,2]. With more robust microbial testing, we now appreciate its presence as an important pathogen in North America, especially in western regions. C. gattii infection had previously been detected infrequently and was thought to be largely restricted to tropical and subtropical regions, including Australia and Papua New Guinea. It is now clear that sporadic cases occur in various regions around the world.
The clinical manifestations, complications, and diagnosis of C. gattii infection will be reviewed here. The microbiology, epidemiology, pathogenesis, and treatment of C. gattii infection are discussed separately; C. neoformans infection is also reviewed elsewhere. (See "Cryptococcus gattii infection: Microbiology, epidemiology, and pathogenesis" and "Cryptococcus gattii infection: Treatment" and "Microbiology and epidemiology of Cryptococcus neoformans infection" and "Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in HIV-infected patients" and "Clinical manifestations and diagnosis of Cryptococcus neoformans meningoencephalitis in HIV-seronegative patients" and "Cryptococcus neoformans infection outside the central nervous system" and "Cryptococcus neoformans: Treatment of meningoencephalitis and disseminated infection in HIV seronegative patients".)
Incubation period — The incubation period of C. gattii infection in humans is uncertain. A study of seven travelers to Vancouver Island, British Columbia, revealed a median time to clinical presentation of six to seven months (range 2 to 11 months) . A subsequent report of a traveler to British Columbia suggested a shorter incubation of six weeks , whereas other reports have described patients who developed infection 13 months and 36 months after exposure, respectively [5,6]. The proportion of C. gattii disease representing acute infection versus reactivation of latent infection remains unknown; however, most reported cases of C. gattii infection appear to be primary infections.
Clinical features — C. gattii infection often presents as an indolent illness and most commonly involves the central nervous system (CNS), the lungs, or both. Neurologic infection is more common in cases of C. gattii infection that occur in endemic areas (eg, Australia), compared with the Vancouver outbreak setting, where pulmonary manifestations were more frequent. As with C. neoformans, HIV-infected patients with C. gattii infection overwhelmingly present with meningoencephalitis (up to 97 percent of cases) [7,8]. Systemic features including fever, chills, and weight loss were reported in 17 to 47 percent of patients in the North American Pacific Northwest outbreak [9-11]. Fever was reported in 54 percent of HIV-infected patients with C. gattii infection in South Africa  and in 37 percent of patients in Columbia , but was uncommon (10 percent) in patients with C. gattii infection in Australia .
Neurologic features — Headache and neck stiffness are common neurologic symptoms at diagnosis. Other neurologic deficits that may be present, or evolve during the course of illness, include seizures, cranial nerve deficits, cerebellar abnormalities, focal limb weakness, and abnormal mentation (eg, confusion and personality change) [12-16].To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Chaturvedi V, Chaturvedi S. Cryptococcus gattii: a resurgent fungal pathogen. Trends Microbiol 2011; 19:564.
- Harris J, Lockhart S, Chiller T. Cryptococcus gattii: where do we go from here? Med Mycol 2012; 50:113.
- MacDougall L, Fyfe M. Emergence of Cryptococcus gattii in a novel environment provides clues to its incubation period. J Clin Microbiol 2006; 44:1851.
- Lindberg J, Hagen F, Laursen A, et al. Cryptococcus gattii risk for tourists visiting Vancouver Island, Canada. Emerg Infect Dis 2007; 13:178.
- Georgi A, Schneemann M, Tintelnot K, et al. Cryptococcus gattii meningoencephalitis in an immunocompetent person 13 months after exposure. Infection 2009; 37:370.
- Johannson KA, Huston SM, Mody CH, Davidson W. Cryptococcus gattii pneumonia. CMAJ 2012; 184:1387.
- Morgan J, McCarthy KM, Gould S, et al. Cryptococcus gattii infection: characteristics and epidemiology of cases identified in a South African province with high HIV seroprevalence, 2002-2004. Clin Infect Dis 2006; 43:1077.
- Steele KT, Thakur R, Nthobatsang R, et al. In-hospital mortality of HIV-infected cryptococcal meningitis patients with C. gattii and C. neoformans infection in Gaborone, Botswana. Med Mycol 2010; 48:1112.
- Centers for Disease Control and Prevention (CDC). Emergence of Cryptococcus gattii-- Pacific Northwest, 2004-2010. MMWR Morb Mortal Wkly Rep 2010; 59:865.
- Harris JR, Lockhart SR, Debess E, et al. Cryptococcus gattii in the United States: clinical aspects of infection with an emerging pathogen. Clin Infect Dis 2011; 53:1188.
- Phillips P, Galanis E, MacDougall L, et al. Longitudinal clinical findings and outcome among patients with Cryptococcus gattii infection in British Columbia. Clin Infect Dis 2015; 60:1368.
- Lizarazo J, Escandón P, Agudelo CI, et al. Retrospective study of the epidemiology and clinical manifestations of Cryptococcus gattii infections in Colombia from 1997-2011. PLoS Negl Trop Dis 2014; 8:e3272.
- Chen SC, Slavin MA, Heath CH, et al. Clinical manifestations of Cryptococcus gattii infection: determinants of neurological sequelae and death. Clin Infect Dis 2012; 55:789.
- Sorrell TC, Chen SC-A, Phillips P, Marr KA. Clinical perspectives on Cryptococcus neoformans and Cryptococcus gattii: implications for diagnosis and management. In: Cryptococcus, Heitman J, Kozel TR, Kwon-Chung KJ, et al (Eds), ASM Press, Washington DC 2011. p.595.
- Mitchell DH, Sorrell TC, Allworth AM, et al. Cryptococcal disease of the CNS in immunocompetent hosts: influence of cryptococcal variety on clinical manifestations and outcome. Clin Infect Dis 1995; 20:611.
- Lalloo D, Fisher D, Naraqi S, et al. Cryptococcal meningitis (C. neoformans var. gattii) leading to blindness in previously healthy Melanesian adults in Papua New Guinea. Q J Med 1994; 87:343.
- Chen S, Sorrell T, Nimmo G, et al. Epidemiology and host- and variety-dependent characteristics of infection due to Cryptococcus neoformans in Australia and New Zealand. Australasian Cryptococcal Study Group. Clin Infect Dis 2000; 31:499.
- Jenney A, Pandithage K, Fisher DA, Currie BJ. Cryptococcus infection in tropical Australia. J Clin Microbiol 2004; 42:3865.
- Galanis E, Macdougall L, Kidd S, et al. Epidemiology of Cryptococcus gattii, British Columbia, Canada, 1999-2007. Emerg Infect Dis 2010; 16:251.
- Galanis E, Hoang L, Kibsey P, et al. Clinical presentation, diagnosis and management of Cryptococcus gattii cases: Lessons learned from British Columbia. Can J Infect Dis Med Microbiol 2009; 20:23.
- Garrett L, Marr K, West S, Allada G. 74-year-old man from the pacific northwest with fever and a lung mass. Chest 2011; 140:814.
- Mitchell DH, Sorrell TC. Pancoast's syndrome due to pulmonary infection with Cryptococcus neoformans variety gattii. Clin Infect Dis 1992; 14:1142.
- Speed B, Dunt D. Clinical and host differences between infections with the two varieties of Cryptococcus neoformans. Clin Infect Dis 1995; 21:28.
- Dora JM, Kelbert S, Deutschendorf C, et al. Cutaneous cryptococccosis due to Cryptococcus gattii in immunocompetent hosts: case report and review. Mycopathologia 2006; 161:235.
- Mistry N, Tan K, Shokravi M, Hoang L. Cryptococcus gattii infections with cutaneous involvement. J Cutan Med Surg 2011; 15:236.
- Byrnes EJ 3rd, Li W, Lewit Y, et al. First reported case of Cryptococcus gattii in the Southeastern USA: implications for travel-associated acquisition of an emerging pathogen. PLoS One 2009; 4:e5851.
- Araújo BS, Bay M, Reichert R, Goldani LZ. Intra-abdominal cryptococcosis by Cryptococcus gattii: case report and review. Mycopathologia 2012; 174:81.
- Dall Bello AG, Severo CB, Schio S, Severo LC. First reported case of cellulitis due to Cryptococcus gattii in lung transplantation recipient: a case report. Dermatol Online J 2013; 19:20395.
- Lindell RM, Hartman TE, Nadrous HF, Ryu JH. Pulmonary cryptococcosis: CT findings in immunocompetent patients. Radiology 2005; 236:326.
- Yang CJ, Hwang JJ, Wang TH, et al. Clinical and radiographic presentations of pulmonary cryptococcosis in immunocompetent patients. Scand J Infect Dis 2006; 38:788.
- Graybill JR, Sobel J, Saag M, et al. Diagnosis and management of increased intracranial pressure in patients with AIDS and cryptococcal meningitis. The NIAID Mycoses Study Group and AIDS Cooperative Treatment Groups. Clin Infect Dis 2000; 30:47.
- Saag MS, Graybill RJ, Larsen RA, et al. Practice guidelines for the management of cryptococcal disease. Infectious Diseases Society of America. Clin Infect Dis 2000; 30:710.
- Seaton RA, Verma N, Naraqi S, et al. The effect of corticosteroids on visual loss in Cryptococcus neoformans var. gattii meningitis. Trans R Soc Trop Med Hyg 1997; 91:50.
- Chen SC, Korman TM, Slavin MA, et al. Antifungal therapy and management of complications of cryptococcosis due to Cryptococcus gattii. Clin Infect Dis 2013; 57:543.
- Franco-Paredes C, Womack T, Bohlmeyer T, et al. Management of Cryptococcus gattii meningoencephalitis. Lancet Infect Dis 2015; 15:348.
- Park MK, Hospenthal DR, Bennett JE. Treatment of hydrocephalus secondary to cryptococcal meningitis by use of shunting. Clin Infect Dis 1999; 28:629.
- Rex JH, Larsen RA, Dismukes WE, et al. Catastrophic visual loss due to Cryptococcus neoformans meningitis. Medicine (Baltimore) 1993; 72:207.
- Andreola C, Ribeiro MP, de Carli CR, et al. Multifocal choroiditis in disseminated Cryptococcus neoformans infection. Am J Ophthalmol 2006; 142:346.
- Phillips P, Chapman K, Sharp M, et al. Dexamethasone in Cryptococcus gattii central nervous system infection. Clin Infect Dis 2009; 49:591.
- Lane M, McBride J, Archer J. Steroid responsive late deterioration in Cryptococcus neoformans variety gattii meningitis. Neurology 2004; 63:713.
- Bicanic T, Meintjes G, Rebe K, et al. Immune reconstitution inflammatory syndrome in HIV-associated cryptococcal meningitis: a prospective study. J Acquir Immune Defic Syndr 2009; 51:130.
- Einsiedel L, Gordon DL, Dyer JR. Paradoxical inflammatory reaction during treatment of Cryptococcus neoformans var. gattii meningitis in an HIV-seronegative woman. Clin Infect Dis 2004; 39:e78.
- Panackal AA, Wuest SC, Lin YC, et al. Paradoxical Immune Responses in Non-HIV Cryptococcal Meningitis. PLoS Pathog 2015; 11:e1004884.
- Panackal AA, Komori M, Kosa P, et al. Spinal Arachnoiditis as a Complication of Cryptococcal Meningoencephalitis in Non-HIV Previously Healthy Adults. Clin Infect Dis 2017; 64:275.
- Xie LX, Chen YS, Liu SY, Shi YX. Pulmonary cryptococcosis: comparison of CT findings in immunocompetent and immunocompromised patients. Acta Radiol 2015; 56:447.
- Roebuck DJ, Fisher DA, Currie BJ. Cryptococcosis in HIV negative patients: findings on chest radiography. Thorax 1998; 53:554.
- Baddley JW, Perfect JR, Oster RA, et al. Pulmonary cryptococcosis in patients without HIV infection: factors associated with disseminated disease. Eur J Clin Microbiol Infect Dis 2008; 27:937.
- Choi HW, Chong S, Kim MK, Park IW. Pulmonary cryptococcosis manifesting as diffuse air-space consolidations in an immunocompetent patient. J Thorac Dis 2017; 9:E138.
- Charlier C, Dromer F, Lévêque C, et al. Cryptococcal neuroradiological lesions correlate with severity during cryptococcal meningoencephalitis in HIV-positive patients in the HAART era. PLoS One 2008; 3:e1950.
- MacDougall L, Fyfe M, Romney M, et al. Risk factors for Cryptococcus gattii infection, British Columbia, Canada. Emerg Infect Dis 2011; 17:193.
- Browne SK, Burbelo PD, Chetchotisakd P, et al. Adult-onset immunodeficiency in Thailand and Taiwan. N Engl J Med 2012; 367:725.
- Rosen LB, Freeman AF, Yang LM, et al. Anti-GM-CSF autoantibodies in patients with cryptococcal meningitis. J Immunol 2013; 190:3959.
- Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of america. Clin Infect Dis 2010; 50:291.
- Chen SC, Meyer W, Sorrell TC. Cryptococcus gattii infections. Clin Microbiol Rev 2014; 27:980.
- Lazcano O, Speights VO Jr, Strickler JG, et al. Combined histochemical stains in the differential diagnosis of Cryptococcus neoformans. Mod Pathol 1993; 6:80.
- Diaz MR, Nguyen MH. Diagnostic approach based on capsular antigen, capsule detection, β-glucan and DNA analysis. In: Cryptococcus: From human pathogen to model yeast, Heitman J, Kozel TR, Kwon-Chung KJ, et al (Eds), ASM Press, Washington DC 2011. p.547.
- Hazen KC, Howell SA. Candida, Cryptococcus, and other yeasts of medical importance. In: Manual of Clinical Microbiology, Murray PR, Barron EJ, Jorgensen JH, et al (Eds), ASM Press, Washington DC 2007. p.762.
- Sidrim JJ, Costa AK, Cordeiro RA, et al. Molecular methods for the diagnosis and characterization of Cryptococcus: a review. Can J Microbiol 2010; 56:445.
- Lindsley MD, Mekha N, Baggett HC, et al. Evaluation of a newly developed lateral flow immunoassay for the diagnosis of cryptococcosis. Clin Infect Dis 2011; 53:321.
- Jarvis JN, Percival A, Bauman S, et al. Evaluation of a novel point-of-care cryptococcal antigen test on serum, plasma, and urine from patients with HIV-associated cryptococcal meningitis. Clin Infect Dis 2011; 53:1019.
- IMMY CrAg lateral flow assay for the detection of cryptococcal antigen. http://www.immy.com/wp-content/uploads/2012/05/CR2003-CrAg-LFA-PI-US.pdf (Accessed on September 10, 2013).
- McMullan BJ, Halliday C, Sorrell TC, et al. Clinical utility of the cryptococcal antigen lateral flow assay in a diagnostic mycology laboratory. PLoS One 2012; 7:e49541.
- Tintelnot K, Hagen F, Han CO, et al. Pitfalls in Serological Diagnosis of Cryptococcus gattii Infections. Med Mycol 2015; 53:874.
- Feng X, Fu X, Ling B, et al. Development of a singleplex PCR assay for rapid identification and differentiation of Cryptococcus neoformans var. grubii, Cryptococcus neoformans var. neoformans, Cryptococcus gattii, and hybrids. J Clin Microbiol 2013; 51:1920.
- Feng X, Fu X, Ling B, et al. Rapid differentiation of cryptic species within Cryptococcus gattii by a duplex PCR assay. J Clin Microbiol 2013; 51:3110.
- CLINICAL MANIFESTATIONS
- Incubation period
- Clinical features
- - Neurologic features
- - Papilledema
- - Pulmonary features
- - Other features
- Comparison of C. gattii and C. neoformans infection
- - IRIS-like syndrome
- Chest imaging
- Brain imaging
- Approach to diagnosis
- Diagnostic tests
- - Culture and histopathology
- - Cryptococcal antigen
- Lateral flow assay
- - Molecular tests
- DIFFERENTIAL DIAGNOSIS