ABSTRACT
Cryptococcosis is an invasive fungal infection (IFI), caused predominantly by Cryptococcus neoformans or Cryptococcus gattii, that affects both immunocompromised (IC) and non-IC patients. Although the most
serious disease manifestation is meningoencephalitis, cryptococcal pneumonia is underdiagnosed
and may disseminate to the central nervous system (CNS) and other sites depending
upon host defenses and administration of appropriate antifungal therapy. The clinical
presentation of pulmonary cryptococcosis varies along a spectrum from asymptomatic
infection to severe pneumonia and respiratory failure, and the radiological presentation
can be characterized by an array of findings, including nodules, consolidation, cavitary
lesions, and a diffuse interstitial pattern. Diagnosis most often relies upon isolation
of Cryptococcus from a pulmonary specimen in the appropriate clinical and radiological context. Treatment
recommendations include induction therapy with an amphotericin B preparation and flucytosine
for IC patients and those with severe disease and fluconazole for mild-to-moderate,
localized disease. Knowledge of the pathophysiology, epidemiology, clinical presentation,
and treatment of pulmonary cryptococcosis may lead to greater recognition of this
underdiagnosed IFI and improved outcomes.
KEYWORDS
Cryptococcus
- pulmonary - cryptococcosis - cryptococcal - pneumonia
REFERENCES
- 1
Park B J, Wannemuehler K A, Marston B J, Govender N, Pappas P G, Chiller T M.
Estimation of the current global burden of cryptococcal meningitis among persons living
with HIV/AIDS.
AIDS.
2009;
23
(4)
525-530
- 2
Chang W C, Tzao C, Hsu H H et al..
Pulmonary cryptococcosis: comparison of clinical and radiographic characteristics
in immunocompetent and immunocompromised patients.
Chest.
2006;
129
(2)
333-340
- 3
Aberg J A, Mundy L M, Powderly W G.
Pulmonary cryptococcosis in patients without HIV infection.
Chest.
1999;
115
(3)
734-740
- 4
Hage C A, Wood K L, Winer-Muram H T, Wilson S J, Sarosi G, Knox K S.
Pulmonary cryptococcosis after initiation of anti-tumor necrosis factor-alpha therapy.
Chest.
2003;
124
(6)
2395-2397
- 5
Pappas P G, Perfect J R, Cloud G A et al..
Cryptococcosis in human immunodeficiency virus-negative patients in the era of effective
azole therapy.
Clin Infect Dis.
2001;
33
(5)
690-699
- 6
Vilchez R A, Irish W, Lacomis J, Costello P, Fung J, Kusne S.
The clinical epidemiology of pulmonary cryptococcosis in non-AIDS patients at a tertiary
care medical center.
Medicine (Baltimore).
2001;
80
(5)
308-312
- 7
Lui G, Lee N, Ip M et al..
Cryptococcosis in apparently immunocompetent patients.
QJM.
2006;
99
(3)
143-151
- 8
Nadrous H F, Antonios V S, Terrell C L, Ryu J H.
Pulmonary cryptococcosis in nonimmunocompromised patients.
Chest.
2003;
124
(6)
2143-2147
- 9
Chambers C, MacDougall L, Li M, Galanis E.
Tourism and specific risk areas for Cryptococcus gattii, Vancouver Island, Canada.
Emerg Infect Dis.
2008;
14
(11)
1781-1783
- 10
Khawcharoenporn T, Apisarnthanarak A, Mundy L M.
Non-neoformans cryptococcal infections: a systematic review.
Infection.
2007;
35
(2)
51-58
- 11
Jenney A, Pandithage K, Fisher D A, Currie B J.
Cryptococcus infection in tropical Australia.
J Clin Microbiol.
2004;
42
(8)
3865-3868
- 12
Goldman D L, Khine H, Abadi J et al..
Serologic evidence for Cryptococcus neoformans infection in early childhood.
Pediatrics.
2001;
107
(5)
E66-E71
- 13
Velagapudi R, Hsueh Y P, Geunes-Boyer S, Wright J R, Heitman J.
Spores as infectious propagules of Cryptococcus neoformans.
Infect Immun.
2009;
77
(10)
4345-4355
- 14
Giles S S, Dagenais T R, Botts M R, Keller N P, Hull C M.
Elucidating the pathogenesis of spores from the human fungal pathogen Cryptococcus
neoformans.
Infect Immun.
2009;
77
(8)
3491-3500
- 15
Botts M R, Hull C M.
Dueling in the lung: how Cryptococcus spores race the host for survival.
Curr Opin Microbiol.
2010;
13
(4)
437-442
- 16
Feldmesser M, Kress Y, Casadevall A.
Dynamic changes in the morphology of Cryptococcus neoformans during murine pulmonary
infection.
Microbiology.
2001;
147
(Pt 8)
2355-2365
- 17
Zaragoza O, García-Rodas R, Nosanchuk J D, Cuenca-Estrella M, Rodríguez-Tudela J L,
Casadevall A.
Fungal cell gigantism during mammalian infection.
PLoS Pathog.
2010;
6
(6)
e1000945
- 18
Okagaki L H, Strain A K, Nielsen J N et al..
Cryptococcal cell morphology affects host cell interactions and pathogenicity.
PLoS Pathog.
2010;
6
(6)
e1000953
- 19
Sionov E, Lee H, Chang Y C, Kwon-Chung K J.
Cryptococcus neoformans overcomes stress of azole drugs by formation of disomy in
specific multiple chromosomes.
PLoS Pathog.
2010;
6
(4)
e1000848
- 20
Herring A C, Lee J, McDonald R A, Toews G B, Huffnagle G B.
Induction of interleukin-12 and gamma interferon requires tumor necrosis factor alpha
for protective T1-cell-mediated immunity to pulmonary Cryptococcus neoformans infection.
Infect Immun.
2002;
70
(6)
2959-2964
- 21
Baker R D.
The primary pulmonary lymph node complex of crytptococcosis.
Am J Clin Pathol.
1976;
65
(1)
83-92
- 22
Feigin D S.
Pulmonary cryptococcosis: radiologic-pathologic correlates of its three forms.
AJR Am J Roentgenol.
1983;
141
(6)
1262-1272
- 23
Zinck S E, Leung A N, Frost M, Berry G J, Müller N L.
Pulmonary cryptococcosis: CT and pathologic findings.
J Comput Assist Tomogr.
2002;
26
(3)
330-334
- 24
Chechani V, Kamholz S L.
Pulmonary manifestations of disseminated cryptococcosis in patients with AIDS.
Chest.
1990;
98
(5)
1060-1066
- 25
Newberry Jr W M, Walter J E, Chandler Jr J W, Tosh F E.
Epidemiologic study of Cryptococcus neoformans.
Ann Intern Med.
1967;
67
(4)
724-732
- 26
Zuger A, Louie E, Holzman R S, Simberkoff M S, Rahal J J.
Cryptococcal disease in patients with the acquired immunodeficiency syndrome. Diagnostic
features and outcome of treatment.
Ann Intern Med.
1986;
104
(2)
234-240
- 27
Dismukes W E.
Cryptococcal meningitis in patients with AIDS.
J Infect Dis.
1988;
157
(4)
624-628
- 28
Chuck S L, Sande M A.
Infections with Cryptococcus neoformans in the acquired immunodeficiency syndrome.
N Engl J Med.
1989;
321
(12)
794-799
- 29
Clark R A, Greer D, Atkinson W, Valainis G T, Hyslop N.
Spectrum of Cryptococcus neoformans infection in 68 patients infected with human immunodeficiency
virus.
Rev Infect Dis.
1990;
12
(5)
768-777
- 30
Cameron M L, Bartlett J A, Gallis H A, Waskin H A.
Manifestations of pulmonary cryptococcosis in patients with acquired immunodeficiency
syndrome.
Rev Infect Dis.
1991;
13
(1)
64-67
- 31
Meyohas M C, Roux P, Bollens D et al..
Pulmonary cryptococcosis: localized and disseminated infections in 27 patients with
AIDS.
Clin Infect Dis.
1995;
21
(3)
628-633
- 32
Wong M L, Back P, Candy G, Nelson G, Murray J.
Cryptococcal pneumonia in African miners at autopsy.
Int J Tuberc Lung Dis.
2007;
11
(5)
528-533
- 33
Deok-jong Yoo S, Worodria W, Davis J L et al..
The prevalence and clinical course of HIV-associated pulmonary cryptococcosis in Uganda.
J Acquir Immune Defic Syndr.
2010;
54
(3)
269-274
- 34
Hajjeh R A, Conn L A, Stephens D S Cryptococcal Active Surveillance Group et al.
Cryptococcosis: population-based multistate active surveillance and risk factors in
human immunodeficiency virus-infected persons.
J Infect Dis.
1999;
179
(2)
449-454
- 35
Pappas P G, Alexander B D, Andes D R et al..
Invasive fungal infections among organ transplant recipients: results of the Transplant-Associated
Infection Surveillance Network (TRANSNET).
Clin Infect Dis.
2010;
50
(8)
1101-1111
- 36
Dromer F, Mathoulin S, Dupont B, Laporte A. French Cryptococcosis Study Group .
Epidemiology of cryptococcosis in France: a 9-year survey (1985-1993).
Clin Infect Dis.
1996;
23
(1)
82-90
- 37
Chen S, Sorrell T, Nimmo G Australasian Cryptococcal Study Group et al.
Epidemiology and host- and variety-dependent characteristics of infection due to Cryptococcus
neoformans in Australia and New Zealand.
Clin Infect Dis.
2000;
31
(2)
499-508
- 38
Galanis E, Macdougall L.
Epidemiology of Cryptococcus gattii, British Columbia, Canada, 1999–2007.
Emerg Infect Dis.
2010;
16
(2)
251-257
- 39
Rozenbaum R, Gonçalves A J.
Clinical epidemiological study of 171 cases of cryptococcosis.
Clin Infect Dis.
1994;
18
(3)
369-380
- 40
Visnegarwala F, Graviss E A, Lacke C E et al..
Acute respiratory failure associated with cryptococcosis in patients with AIDS: analysis
of predictive factors.
Clin Infect Dis.
1998;
27
(5)
1231-1237
- 41
Lee K H, Chang U I, Kim H W et al..
Acute respiratory failure associated with cryptococcal pneumonia and disseminated
cryptococcosis in an AIDS patient.
Korean J Intern Med.
2006;
21
(1)
39-42
- 42
Trevenzoli M, Cattelan A M, Rea F et al..
Mediastinitis due to cryptococcal infection: a new clinical entity in the HAART era.
J Infect.
2002;
45
(3)
173-179
- 43
Jenny-Avital E R, Abadi M.
Immune reconstitution cryptococcosis after initiation of successful highly active
antiretroviral therapy.
Clin Infect Dis.
2002;
35
(12)
e128-e133
- 44
Emmons III W W, Luchsinger S, Miller L.
Progressive pulmonary cryptococcosis in a patient who is immunocompetent.
South Med J.
1995;
88
(6)
657-660
- 45
Chang W C, Tzao C, Hsu H H, Chang H, Lo C P, Chen C Y.
Isolated cryptococcal thoracic empyema with osteomyelitis of the rib in an immunocompetent
host.
J Infect.
2005;
51
(3)
e117-e119
- 46
Yang C J, Hwang J J, Wang T H et al..
Clinical and radiographic presentations of pulmonary cryptococcosis in immunocompetent
patients.
Scand J Infect Dis.
2006;
38
(9)
788-793
- 47
Lindell R M, Hartman T E, Nadrous H F, Ryu J H.
Pulmonary cryptococcosis: CT findings in immunocompetent patients.
Radiology.
2005;
236
(1)
326-331
- 48
Gordonson J, Birnbaum W, Jacobson G, Sargent E N.
Pulmonary cryptococcosis.
Radiology.
1974;
112
(3)
557-561
- 49
Lacomis J M, Costello P, Vilchez R, Kusne S.
The radiology of pulmonary cryptococcosis in a tertiary medical center.
J Thorac Imaging.
2001;
16
(3)
139-148
- 50
Sider L, Westcott M A.
Pulmonary manifestations of cryptococcosis in patients with AIDS: CT features.
J Thorac Imaging.
1994;
9
(2)
78-84
- 51
Woodring J H, Ciporkin G, Lee C, Worm B, Woolley S.
Pulmonary cryptococcosis.
Semin Roentgenol.
1996;
31
(1)
67-75
- 52
Baddley J W, Perfect J R, Oster R A et al..
Pulmonary cryptococcosis in patients without HIV infection: factors associated with
disseminated disease.
Eur J Clin Microbiol Infect Dis.
2008;
27
(10)
937-943
- 53
Malabonga V M, Basti J, Kamholz S L.
Utility of bronchoscopic sampling techniques for cryptococcal disease in AIDS.
Chest.
1991;
99
(2)
370-372
- 54
Baughman R P, Rhodes J C, Dohn M N, Henderson H, Frame P T.
Detection of cryptococcal antigen in bronchoalveolar lavage fluid: a prospective study
of diagnostic utility.
Am Rev Respir Dis.
1992;
145
(5)
1226-1229
- 55
Bottone E J, Sindone M, Caraballo V.
Value of assessing cryptococcal antigen in bronchoalveolar lavage and sputum specimens
from patients with AIDS.
Mt Sinai J Med.
1998;
65
(5-6)
422-425
- 56
Kralovic S M, Rhodes J C.
Utility of routine testing of bronchoalveolar lavage fluid for cryptococcal antigen.
J Clin Microbiol.
1998;
36
(10)
3088-3089
- 57
Perfect J R, Dismukes W E, 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
(3)
291-322
- 58
Tanner D C, Weinstein M P, Fedorciw B, Joho K L, Thorpe J J, Reller L.
Comparison of commercial kits for detection of cryptococcal antigen.
J Clin Microbiol.
1994;
32
(7)
1680-1684
- 59
Aberg J A, Watson J, Segal M, Chang L W.
Clinical utility of monitoring serum cryptococcal antigen (sCRAG) titers in patients
with AIDS-related cryptococcal disease.
HIV Clin Trials.
2000;
1
(1)
1-6
- 60
Lindsley M D, Mekha N, Baggett H C et al..
Evaluation of a newly developed lateral flow immunoassay for the diagnosis of cryptococcosis.
Clin Infect Dis.
2011;
53
(4)
321-325
- 61
Mussini C, Pezzotti P, Miró J M International Working Group on Cryptococcosis et al.
Discontinuation of maintenance therapy for cryptococcal meningitis in patients with
AIDS treated with highly active antiretroviral therapy: an international observational
study.
Clin Infect Dis.
2004;
38
(4)
565-571
- 62
Vibhagool A, Sungkanuparph S, Mootsikapun P et al..
Discontinuation of secondary prophylaxis for cryptococcal meningitis in human immunodeficiency
virus-infected patients treated with highly active antiretroviral therapy: a prospective,
multicenter, randomized study.
Clin Infect Dis.
2003;
36
(10)
1329-1331
- 63
Singh N, Lortholary O, Alexander B D et al..
Antifungal management practices and evolution of infection in organ transplant recipients
with cryptococcus neoformans infection.
Transplantation.
2005;
80
(8)
1033-1039
- 64
Meyohas M C, Meynard J L, Bollens D et al..
Treatment of non-meningeal cryptococcosis in patients with AIDS. Centre d’Informations
et de Soins de l’Immunodéficience Humaine de l’Est Parisien.
J Infect.
1996;
33
(1)
7-10
- 65
Dromer F, Mathoulin S, Dupont B, Brugiere O, Letenneur L. French Cryptococcosis Study
Group .
Comparison of the efficacy of amphotericin B and fluconazole in the treatment of cryptococcosis
in human immunodeficiency virus-negative patients: retrospective analysis of 83 cases.
Clin Infect Dis.
1996;
22
(Suppl 2)
S154-S160
- 66
Saag M S, Cloud G A, Graybill J R National Institute of Allergy and Infectious Diseases
Mycoses Study Group et al.
A comparison of itraconazole versus fluconazole as maintenance therapy for AIDS-associated
cryptococcal meningitis.
Clin Infect Dis.
1999;
28
(2)
291-296
- 67
Esposito V, Viglietti R, Gargiulo M et al..
Successful treatment of Cryptococcal meningitis with a combination of liposomal amphotericin
B, flucytosine and posaconazole: two case reports.
In Vivo.
2009;
23
(3)
465-468
- 68
Alexander B D, Perfect J R, Daly J S et al..
Posaconazole as salvage therapy in patients with invasive fungal infections after
solid organ transplant.
Transplantation.
2008;
86
(6)
791-796
- 69
Raad I I, Graybill J R, Bustamante A B et al..
Safety of long-term oral posaconazole use in the treatment of refractory invasive
fungal infections.
Clin Infect Dis.
2006;
42
(12)
1726-1734
- 70
Perfect J R, Marr K A, Walsh T J et al..
Voriconazole treatment for less-common, emerging, or refractory fungal infections.
Clin Infect Dis.
2003;
36
(9)
1122-1131
- 71
Sabbatani S, Manfredi R, Pavoni M, Consales A, Chiodo F.
Voriconazole proves effective in long-term treatment of a cerebral cryptococcoma in
a chronic nephropathic HIV-negative patient, after fluconazole failure.
Mycopathologia.
2004;
158
(2)
165-171
Peter G. PappasM.D.
Department of Medicine, Division of Infectious Diseases, University of Alabama at
Birmingham, Tinsley Harrison Tower 229
1530 3rd Ave. S, Birmingham, AL 35294
Email: pappas@uab.edu
