Background
Cryptococcus neoformans is an encapsulated yeast. In 1894, Busse, a pathologist, first described the yeast in a paper he presented to the Greifswald Medical Society. Busse isolated the yeast from the tibia of a 31-year-old woman, noted its resistance to sodium hydroxide, and published the case report that same year.[1] The following year, a surgeon named Buschke reported the same isolate from the same patient, thus establishing the early eponym of Busse-Buschke disease.[2] This single case served to identify a new yeast and to prove its pathogenic potential.
Since the initial reports, researchers have identified the diverse spectrum of host responses to cryptococcal infection. The responses range from a harmless colonization of the airways and asymptomatic infection in laboratory workers (resulting in only a positive skin test finding) to meningitis or disseminated disease. Although virulence in animals and, possibly, humans varies among strains of cryptococci, virulence probably plays a relatively small role in the outcome of an infection. The crucial factor is the immune status of the host.
The most serious infections usually develop in patients with defective cell-mediated immunity. For example, patients with AIDS, patients undergoing organ transplantation, patients with reticuloendothelial malignancy, patients undergoing corticosteroid treatment (but not those with neutropenia or immunoglobulin deficiency), and patients with sarcoidosis develop the most serious cryptococcal infections.
With the global emergence of AIDS, the incidence of cryptococcosis is increasing and now represents a major life-threatening fungal infection in these patients.
Mycology
Although the genus Cryptococcus contains more than 50 species, only C neoformans and Cryptococcus gattii are considered principal pathogens in humans. Previously, C neoformans was defined as having two varieties—var neoformans and var gattii. However, based on the elucidation of the genomic sequences, C neoformans and C gattii are now considered two distinct species. These two species have 5 serotypes based on antigenic specificity of the capsular polysaccharide; these include serotypes A, D, and AD (C neoformans) and serotypes B and C (C gattii).
C neoformans is the most common species in the United States and other temperate climates throughout the world and is found in aged pigeon droppings. Until recently, C gattii was found principally in tropical and subtropical climates. C gattii is not associated with birds but grows in the litter around certain species of eucalyptus trees (ie, Eucalyptus camaldulensis, Eucalyptus tereticornis).
Worldwide, C neoformans serotype A causes most cryptococcal infections in immunocompromised patients, including patients infected with HIV. For unknown reasons, Cgattii rarely infects persons with HIV infection and other immunosuppressed patients. Patients infected with C gattii are usually immunocompetent, respond slowly to treatment, and are at risk for developing intracerebral mass lesions (eg, cryptococcomas).
C neoformans reproduces by budding and forms round yeastlike cells that are 3-6 µm in diameter. Within the host and in certain culture media, a large polysaccharide capsule surrounds each cell. C neoformans forms smooth, convex, yellow or tan colonies on solid media at 20-37°C (68-98.6°F). This fungus is identified based on its microscopic appearance, biochemical test results, and ability to grow at 37°C (98.6°F); most nonpathogenic Cryptococcus strains do not grow at this temperature. In addition, C neoformans does not assimilate lactose and nitrates or produce pseudomycelia on cornmeal or rice-Tween agar.
Most strains of C neoformans can use creatinine as a nitrogen source, which may partially explain the growth of the organism in creatinine-rich avian feces. Another useful biochemical characteristic of C neoformans, which distinguishes it from nonpathogenic strains, is its ability to produce melanin. The fungal enzyme phenol oxidase acts on certain substrates (eg, dihydroxyphenylalanine, caffeic acid) to produce melanin.
C gattii contains genotypes VGI and the more commonly identified VGIIa and VDIIb. Cryptococcus species can reproduce via same-sex mating, and VGIIa may have arisen from the same-sex mating of VGIIb and another strain that has yet to be identified.
In 1976, Kwon-Chung described the perfect (ie, sexual, teleomorphic) form of C neoformans, which was named Filobasidiella neoformans. Prior to the identification of F neoformans, which is mycelial, C neoformans was considered a monomorphic yeast. F neoformans results from the mating of suitable strains of serotypes A and D. The perfect state of C gattii is Filobasidiella bacillispora and results from the mating of serotypes B and C. Some strains of A and D can mate with strains of B and C.
Epidemiology
C neoformans is distributed worldwide. Most cases of cryptococcosis involve serotypes A and D. Serotypes B and C, C gattii, are most common in tropical and subtropical areas and can be isolated from certain species of eucalyptus trees and the air beneath them. C neoformans, which is recovered from aged pigeon feces, bird nests, and guano, is invariably serotype A or D. Although serotypes A and D exist in high concentrations in the pigeon feces, the fungus does not infect the birds. In moist or desiccated pigeon excreta, C neoformans may remain viable for 2 years or longer. In saprobic environments, C neoformans grows unencapsulated; however, unencapsulated strains regain their virulence following reacquisition of their polysaccharide capsule. C gattii usually causes disease in patients with intact cell-mediated immunity.
Naturally occurring cryptococcosis occurs in both animals and humans, but neither animal-to-human transmission nor person-to-person respiratory transmission via the respiratory route has been documented. Transmission via organ transplantation has been reported when infected donor organs were used. C neoformans causes the vast majority of cryptococcal infections in immunosuppressed hosts, including patients with AIDS, whereas C gattii causes 70%-80% of cryptococcal infections among immunocompetent hosts.
Although C neoformans is found worldwide, C gattii is usually identified in subtropical areas such as Australia, South America, Southeast Asia, and Central and sub-Saharan Africa. In the United States, C gattii is found in Southern California and more recently in the states of Washington and Oregon.
As noted above, C gattii may be found in association with several different trees, such as river red gum trees (E camaldulensis) and forest red gum trees (E tereticornis). Infection is acquired by inhalation of air-borne propagules that infect the lungs and may result in fungemia, leading to CNS involvement.
In 1999, C gattii emerged on Vancouver Island, British Columbia, Canada. Infections were reported among residents and visitors to the island, as well as among domesticated and wild animals. Disease has been most often identified in cats, dogs and ferrets. Marine mammals have also been infected. Vectors can disperse the spores from an endemic area to a previously unaffected area. This may have been the route of spread in the case of Vancouver Island. Since 2003, cryptococcal disease has become a provincially notifiable infection in British Columbia. Isolates have been identified in coastal Douglas fir and coastal western hemlock bioclimatic zones. C gattii has been identified subsequently in the states of Washington and Oregon.
The incidence of infection related to age, race, or occupation does not significantly differ. Healthy persons with a history of exposure to pigeons or bird feces and laboratory workers exposed to an aerosol of the organism have a higher rate of positive delayed hypersensitivity skin reactions to cryptococcal antigen or cryptococci. Occasionally, laboratory accidents result in transmission of C neoformans, but pulmonary and disseminated disease is rare in this setting. Accidental cutaneous inoculation with C neoformans causes localized cutaneous disease.
A report from British Columbia, Canada indicates that risk factors for infection by C gattii include steroid use and underlying pulmonary disease.[3] The authors also report a predilection for individuals older than 50 years, current smokers, and those with immunosuppression due to HIV or invasive malignancy.
Pathophysiology
Of the more than 50 species that comprise the genus Cryptococcus, human disease is primarily associated with C neoformans and C gattii. Animal models provide much of the understanding of the pathogenesis and the host defense mechanisms involved in cryptococcal infections. The organism is primarily transmitted via the respiratory route, but not directly from human to human.
Following inhalation, the yeast spores are deposited into the pulmonary alveoli, where they must survive the neutral-to-alkaline pH and physiologic concentrations of carbon dioxide before they are phagocytized by alveolar macrophages. Glucosylceramide synthase (GCS) has been identified as an essential factor in the survival of C neoformans in this extracellular environment.[4] Although GCS is a critical factor in extracellular survival of the yeast, the yeast no longer requires GCS to survive the intracellular, more acidic, environment within the macrophage once it is phagocytized by alveolar macrophages.
Unencapsulated yeast are readily phagocytosed and destroyed, whereas encapsulated organisms are more resistant to phagocytosis. The cryptococcal polysaccharide capsule has antiphagocytic properties and may be immunosuppressive. The antiphagocytic properties of the capsule block recognition of the yeast by phagocytes and inhibit leukocyte migration into the area of fungal replication.
The host response to cryptococcal infection includes both cellular and humoral components. Animal models demonstrate that natural killer cells participate in the early killing of cryptococci and, possibly, antibody-dependent cell-mediated killing. In vitro monocyte-derived macrophages, natural killer cells, and T lymphocytes can inhibit or kill cryptococci. A successful host response includes an increase in helper T-cell activity, skin test conversion, and a reduction in the number of viable organisms in the tissues. In addition to cellular mechanisms, anticryptococcal antibodies and soluble anticryptococcal factors have been described. Antibodies to cryptococcal antigens play a critical role in enhancing the macrophage- and lymphocyte-mediated immune response to the organism. Researchers have used monoclonal antibodies to capsular polysaccharide to passively immunize mice against C neoformans.
C neoformans infection is usually characterized by little or no necrosis or organ dysfunction until late in the disease. Organ damage may be accelerated in persons with heavy infections. The lack of identifiable endotoxins or exotoxins may be partly responsible for the absence of extensive necrosis early in cryptococcal infections. Organ damage is primarily due to tissue distortion secondary to the expanding fungal burden. Extensive inflammation or fibrosis is rare. The characteristic lesion of C neoformans consists of a cystic cluster of yeast with no well-defined inflammatory response. Well-formed granulomas are generally absent.
C neoformans can cause an asymptomatic pulmonary infection followed later by the development of meningitis, which is often the first indication of disease. If limited to the lungs, C neoformans infection may cause pneumonia, poorly defined mass lesions, pulmonary nodules, and, rarely, pleural effusion. Although immune defects are common in patients with meningitis or disseminated infection, patients with disease that is confined to the lungs are usually immunocompetent.
Epidemiology
Frequency
United States
Prior to 1946, only 200 patients with cryptococcal disease had been reported in the medical literature. The development and use of corticosteroids and improvement in patient survival with some malignancies increased the reported incidence of cryptococcal disease. Since the mid 1980s, most cryptococcal disease has occurred in patients with AIDS. A study published in March 2005 that reviewed data from 1981-2000, the first 2 decades of the AIDS epidemic, showed that the annual incidence per million person-years was 19 cases in men and 2.6 cases in women. The highest incidence occurred from 1981-1992; afterward, the incidence began to decline. In women, the peak incidence occurred in 1997. The overall incidence in cryptococcal disease decreased and preceded the availability of highly active antiretroviral therapy for AIDS.
Approximately 7%-15% of patients with AIDS develop cryptococcal infections. In 1993, the US Centers for Disease Control and Prevention reported that 6% of 274,150 patients with AIDS developed cryptococcal disease. Furthermore, patients with AIDS-associated cryptococcal infections now account for 80%-90% of all patients with cryptococcosis.
International
C neoformans has a worldwide distribution and, similar to in the United States, preferentially infects immunosuppressed individuals, especially those with AIDS. In sub-Saharan Africa, 15%-30% of all patients with AIDS develop cryptococcal disease. However, in some areas, such as Zimbabwe, 88% of patients with AIDS have cryptococcal infection as their AIDS-defining illness. Most case reports of C gattii have been from Australia, with a few case reports from the southern California coast and tropical regions of Central and South America. As mentioned above, some recent cases have been reported from Vancouver, British Columbia, Canada and the states of Washington and Oregon, United States.
Mortality/Morbidity
Prior to the use of amphotericin B (Throughout this article, the term amphotericin B refers to amphotericin B desoxycholate.), cryptococcal meningitis and disseminated disease were invariably fatal; however, with the availability of amphotericin B, lipid preparations of amphotericin B, flucytosine, fluconazole, and other azoles, the mortality rate of cryptococcal disease dramatically decreased. In 1995, Speed and Dunt reported a 14% mortality rate among patients with cryptococcal disease who were treated with amphotericin B plus flucytosine and a 28% mortality rate among patients treated with other regimens.[5]
Race
No clear racial predilection has been reported for either cryptococcal infection or disease. No occupational predilection has been defined.
Sex
In most studies, cryptococcal disease is reportedly more common in men than in women.
Age
In a 1972 review, Lewis and Rabinovich reported that almost two thirds of patients with cryptococcal disease were older than 40 years[6] ; furthermore, in patients aged 50 years and older, cryptococcal disease was more than 3 times as common in men as in women. However, the pandemic of AIDS has led to a simultaneous and dramatic rise in the incidence of cryptococcal disease and a reduction in the average age of affected patients.
Busse O. Ueber parasitare zelleninschlusse und ihre zuchtung. Zentralbl. Bakterial. 1894;16:175-80.
Buschke A. Ueber eine durch Coccidien Hervergerufene Krankheit des menschen. Deutsche Med. Wochenschr. 1895;21 (3):14.
Macdougall L, Fyfe M, Romney M, Starr M, Galanis E. Risk Factors for Cryptococcus gattii Infection, British Columbia, Canada. Emerg Infect Dis. Feb 2011;17(2):193-9. [Medline].
Rittershaus PC, Kechichian TB, Allegood JC, Merrill AH Jr, Hennig M, Luberto C. Glucosylceramide synthase is an essential regulator of pathogenicity of Cryptococcus neoformans. J Clin Invest. Jun 2006;116(6):1651-9. [Medline]. [Full Text].
Speed B, Dunt D. Clinical and host differences between infections with the two varieties of Cryptococcus neoformans. Clin Infect Dis. Jul 1995;21(1):28-34; discussion 35-6. [Medline].
Lewis JL, Rabinovich S. The wide spectrum of cryptococcal infections. Am J Med. Sep 1972;53(3):315-22. [Medline].
Sun HY, Alexander BD, Lortholary O, et al. Unrecognized pretransplant and donor-derived cryptococcal disease in organ transplant recipients. Clin Infect Dis. Nov 1 2010;51(9):1062-9. [Medline].
Lindsley MD, Mekha N, Baggett HC, Surinthong Y, Autthateinchai R, Sawatwong P, et al. Evaluation of a newly developed lateral flow immunoassay for the diagnosis of cryptococcosis. Clin Infect Dis. Aug 2011;53(4):321-5. [Medline]. [Full Text].
[Guideline] Kaplan JE, Masur H, Holmes KK. Guidelines for preventing opportunistic infections among HIV-infected persons--2002. Recommendations of the U.S. Public Health Service and the Infectious Diseases Society of America. MMWR Recomm Rep. Jun 14 2002;51:1-52. [Medline].
[Guideline] Saag MS, Graybill RJ, Larsen RA, Pappas PG, Perfect JR, Powderly WG, et al. Practice guidelines for the management of cryptococcal disease. Infectious Diseases Society of America. Clin Infect Dis. Apr 2000;30(4):710-8. [Medline].
Pappas PG, Perfect J, Larsen RA, et al. Cryptococcus in HIV-negative patients: analysis of 306 cases [abstract 101]. In: 36th Annual Meeting of the Infectious Diseases Society of America (Denver, CO). Alexandria, VA: Infectious Diseases Society of America; 1998.
Lortholary O, Fontanet A, Mémain N, Martin A, Sitbon K, Dromer F. Incidence and risk factors of immune reconstitution inflammatory syndrome complicating HIV-associated cryptococcosis in France. AIDS. Jul 1 2005;19(10):1043-9. [Medline].
Sungkanuparph S, Filler SG, Chetchotisakd P, Pappas PG, Nolen TL, Manosuthi W, et al. Cryptococcal immune reconstitution inflammatory syndrome after antiretroviral therapy in AIDS patients with cryptococcal meningitis: a prospective multicenter study. Clin Infect Dis. Sep 15 2009;49(6):931-4. [Medline].
Eriksson U, Seifert B, Schaffner A. Comparison of effects of amphotericin B deoxycholate infused over 4 or 24 hours: randomised controlled trial. BMJ. Mar 10 2001;322(7286):579-82. [Medline].
Imhof A, Walter RB, Schaffner A. Continuous infusion of escalated doses of amphotericin B deoxycholate: an open-label observational study. Clin Infect Dis. Apr 15 2003;36(8):943-51. [Medline].
Anderson DJ, Schmidt C, Goodman J, Pomeroy C. Cryptococcal disease presenting as cellulitis. Clin Infect Dis. Mar 1992;14(3):666-72. [Medline].
Baddley JW, Perfect JR, Oster RA, Larsen RA, Pankey GA, Henderson H, et al. Pulmonary cryptococcosis in patients without HIV infection: factors associated with disseminated disease. Eur J Clin Microbiol Infect Dis. Oct 2008;27(10):937-43. [Medline].
Bassetti M, Repetto E, Mikulska M, Miglino M, Clavio M, Gobbi M, et al. Cryptococcus neoformans fatal sepsis in a chronic lymphocytic leukemia patient treated with alemtuzumab: case report and review of the literature. J Chemother. Apr 2009;21(2):211-4. [Medline].
Benson CA, Kaplan JE, Masur H. Treating Opportunistic Infections Among HIV-Infected Adults and Adolescents: Recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association/Infectious Diseases Society of America. [Full Text].
Chuck SL, Sande MA. Infections with Cryptococcus neoformans in the acquired immunodeficiency syndrome. N Engl J Med. Sep 21 1989;321(12):794-9. [Medline].
Dromer F, Bernede-Bauduin C, Guillemot D, Lortholary O. Major role for amphotericin B-flucytosine combination in severe cryptococcosis. PLoS One. Aug 6 2008;3(8):e2870. [Medline].
Dykstra MA, Friedman L, Murphy JW. Capsule size of Cryptococcus neoformans: control and relationship to virulence. Infect Immun. Apr 1977;16(1):129-35. [Medline].
Ellis DH, Pfeiffer TJ. Natural habitat of Cryptococcus neoformans var. gattii. J Clin Microbiol. Jul 1990;28(7):1642-4. [Medline].
Eric Searls D, Sico JJ, Bulent Omay S, Bannykh S, Kuohung V, Baehring J. Unusual presentations of nervous system infection by Cryptococcus neoformans. Clin Neurol Neurosurg. Sep 2009;111(7):638-42. [Medline].
Friedman GD, Jeffrey Fessel W, Udaltsova NV, Hurley LB. Cryptococcosis: the 1981-2000 epidemic. Mycoses. Mar 2005;48(2):122-5. [Medline].
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. Jan 2000;30(1):47-54. [Medline].
Hayashi Y, Ito G, Takeyama S. [Clinical study on fluconazole (FLCZ) in the treatment of primary pulmonary cryptococcosis]. Kansenshogaku Zasshi. Dec 1998;72(12):1261-8. [Medline].
Hoban DJ, Zhanel GG, Karlowsky JA. In vitro susceptibilities of Candida and Cryptococcus neoformans isolates from blood cultures of neutropenic patients. Antimicrob Agents Chemother. Jun 1999;43(6):1463-4. [Medline].
Klepser ME, Wolfe EJ, Pfaller MA. Antifungal pharmacodynamic characteristics of fluconazole and amphotericin B against Cryptococcus neoformans. Journal of Antimicrobial Chemotherapy. 1998;41(3):397-401. [Medline].
Kralovic SM, Rhodes JC. Utility of routine testing of bronchoalveolar lavage fluid for cryptococcal antigen. Journal of Clinical Microbiology. 1998;36(10):3088-9. [Medline].
Levitz SM. The ecology of Cryptococcus neoformans and the epidemiology of cryptococcosis. Rev Infect Dis. Nov-Dec 1991;13(6):1163-9. [Medline].
Ma AL, Fong NC, Leung CW. Cryptococcal meningitis in an immunocompetent adolescent. Ann Trop Paediatr. Sep 2008;28(3):231-4. [Medline].
Mitchell AP. Cryptococcal virulence: beyond the usual suspects. J Clin Invest. Jun 2006;116(6):1481-3. [Medline]. [Full Text].
Mitchell TG, Perfect JR. Cryptococcosis in the era of AIDS--100 years after the discovery of Cryptococcus neoformans. Clin Microbiol Rev. Oct 1995;8(4):515-48. [Medline].
Morris MI, Villmann M. Echinocandins in the management of invasive fungal infections, Part 2. Am J Health Syst Pharm. Oct 1 2006;63(19):1813-20. [Medline]. [Full Text].
National Institute of Allergy and Infectious Diseases, National Institutes of Health. Study Shows Promise of Fluconazole for Treatment of AIDS-Related Cryptococcal Meningitis. Available at: http://www.aegis.com/pubs/Cdc_Fact_Sheets/1993/CDC93043.html. Atlanta, Ga: Centers for Disease Control and Prevention; 1992. [Full Text].
Nielsen K, Cox GM, Wang P, et al. Sexual cycle of Cryptococcus neoformans var. grubii and virulence of congenic a and alpha isolates. Infect Immun. Sep 2003;71(9):4831-41. [Medline].
Orsini J, Nowakowski J, Delaney V, Sakoulas G, Wormser GP. Cryptococcal infection presenting as cellulitis in a renal transplant recipient. Transpl Infect Dis. Feb 2009;11(1):68-71. [Medline].
Powderly WG, Saag MS, Cloud GA, et al. A controlled trial of fluconazole or amphotericin B to prevent relapse of cryptococcal meningitis in patients with the acquired immunodeficiency syndrome. The NIAID AIDS Clinical Trials Group and Mycoses Study Group. N Engl J Med. Mar 19 1992;326(12):793-8. [Medline].
Robinson PA, Bauer M, Leal MA, et al. Early mycological treatment failure in AIDS-associated cryptococcal meningitis. Clinical Infectious Diseases. 1999;28(1):82-92. [Medline].
[Guideline] Saag MS, Graybill RJ, Larsen RA, Pappas PG, Perfect JR, Powderly WG. Practice guidelines for the management of cryptococcal disease. Infectious Diseases Society of America. Clin Infect Dis. Apr 2000;30(4):710-8. [Medline].
Saag MS, Powderly WG, Cloud GA, et al. Comparison of amphotericin B with fluconazole in the treatment of acute AIDS-associated cryptococcal meningitis. The NIAID Mycoses Study Group and the AIDS Clinical Trials Group. N Engl J Med. Jan 9 1992;326(2):83-9. [Medline].
Selik RM, Chu SY, Ward JW. Trends in infectious diseases and cancers among persons dying of HIV infection in the United States from 1987 to 1992. Ann Intern Med. Dec 15 1995;123(12):933-6. [Medline].
[Guideline] Shoham S, Cover C, Donegan N, Fulnecky E, Kumar P. Cryptococcus neoformans meningitis at 2 hospitals in Washington, D.C.: adherence of health care providers to published practice guidelines for the management of cryptococcal disease. Clin Infect Dis. Feb 1 2005;40(3):477-9. [Medline].
Singh N, Alexander BD, Lortholary O, Dromer F, Gupta KL, John GT, et al. Cryptococcus neoformans in Organ Transplant recipients: Impact of Calcineurin-Inhibitor Agents on Mortality. Journal of Infectious Diseases. March/2007;195:756-764. [Medline].
Sundstrom JB, Cherniak R. T-cell-dependent and T-cell-independent mechanisms of tolerance to glucuronoxylomannan of Cryptococcus neoformans serotype A. Infect Immun. Apr 1993;61(4):1340-5. [Medline].
Torres HA, Prieto VG, Raad II, Kontoyiannis DP. Proven pulmonary cryptococcosis due to capsule-deficient Cryptococcus neoformans does not differ clinically from proven pulmonary cryptococcosis due to capsule-intact Cr. neoformans. Mycoses. Jan 2005;48(1):21-4. [Medline].
van der Horst CM, Saag MS, Cloud GA, et al. Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. National Institute of Allergy and Infectious Diseases Mycoses Study Group and AIDS Clinical Trials Group. N Engl J Med. Jul 3 1997;337(1):15-21. [Medline].
Voss A, de Pauw BE. High-dose fluconazole therapy in patients with severe fungal infections. Eur J Clin Microbiol Infect Dis. Mar 1999;18(3):165-74. [Medline].
Print
