Cryptococcal lung disease

Rhett M. Shirleya and John W. Baddleya,b

a
Department of Medicine, Division of Infectious
Diseases, University of Alabama at Birmingham and
b
Birmingham Veterans Affairs Medical Center,
Birmingham, Alabama, USA
Correspondence to John W. Baddley, MD, MSPH,
Department of Medicine, Division of Infectious
Diseases, University of Alabama at Birmingham, 1900
University Boulevard, 229 Tinsley Harrison Tower,
Birmingham, AL 35294-0006, USA
Tel: +1 205 934 5191; fax: +1 205 934 5155;
e-mail: jbaddley@uab.edu
Current Opinion in Pulmonary Medicine 2009,
15:254–260
Purpose of review
Cryptococcosis is an important opportunistic fungal infection, especially in the
immunocompromised patient. Meningitis is the most common manifestation of
cryptococcosis; however, cryptococcal lung disease is probably underdiagnosed, and
knowledge of epidemiology, diagnosis, and treatment is necessary.
Recent findings
Cryptococcal lung disease ranges from asymptomatic colonization or infection to
severe pneumonia with respiratory failure. Clinical presentation of pulmonary
cryptococcosis is highly variable and often is related to the immune status of the patient.
There have been many important clinical trials outlining treatment of cryptococcal
meningitis in patients with AIDS, but there is a lack of treatment data available for
patients with cryptococcal lung disease. Treatment recommendations for cryptococcal
lung disease are made on the basis of host immune status and severity of clinical illness.
For less severe disease, fluconazole therapy is recommended. In immunocompromised
patients, or those with severe disease, induction therapy with an amphotericin B
preparation and flucytosine, followed by fluconazole as consolidation and maintenance
therapy, is recommended.
Summary
Cryptococcal lung disease is an important and probably underdiagnosed infection.
Knowledge of the epidemiology, diagnostic methodologies, and treatment is needed to
ensure good patient outcomes.

Keywords
amphotericin B, cryptococcosis, Cryptococcus neoformans, fluconazole, pneumonia

Curr Opin Pulm Med 15:254–260

ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins
1070-5287

contaminated by pigeon droppings. Pulmonary infection

Introduction
Cryptococcosis is an important opportunistic infection
that presents most frequently as meningitis or menin-
goencephalitis, particularly in HIV-infected patients.
Pulmonary disease is less common, but is probably under-
diagnosed due to the nonspecific nature of symptoms or
increased frequency of other pulmonary opportunistic
infections. Treatment of cryptococcal lung disease has
not been adequately studied in clinical trials; however,
treatment recommendations have been adapted from
studies of AIDS patients with cryptococcal meningitis
and other observational studies [1–7]. This review will
outline the epidemiology, diagnosis, and treatment of
cryptococcal lung disease.
Epidemiology and pathogenesis
Cryptococcosis describes infection by the encapsulated,
nonmycelial budding yeasts Cryptococcus neoformans var.
grubii (serotype A), C. neoformans var. neoformans (sero-
type D), or C. gattii. These saprophytic fungi are dis-
tributed worldwide and are particularly abundant in soil
1070-5287 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins
results from inhalation of the organism from an environ-
mental source, and because the organism has a propensity
to metastasize to the central nervous system (CNS),
meningitis or meningoencephalitis is the most common
recognized disease manifestation.
The large majority of AIDS-related cryptococcosis is
caused by C. grubii with a significant minority attributable
to C. neoformans [8]. AIDS-related C. gattii infection is
relatively uncommon, as this species is more apt to cause
clinical disease in the immunocompetent host. C. gattii
infection has been described throughout the world, but
endemnicity has primarily been limited to tropical and
subtropical regions. A notable exception is the emer-
gence of C. gattii in Vancouver, Canada, and the Pacific
Northwest United States since 1999 [9,10]. The majority
of the 59 cases that were originally described occurred in
immunocompetent patients. Seventy-five per cent of
cases were isolated to the lung and 25% involved the
CNS. Of the patients with pulmonary involvement, 68%
had a single or multiple pulmonary nodules [10,11].
DOI:10.1097/MCP.0b013e328329268d

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The frequency of antibodies to C. neoformans developing
at an early age suggests that asymptomatic infection is
common in hosts with adequate immunity [12]. Crypto-
coccus species have long been known to cause disease in
normal hosts, but the majority of patients have significant
underlying immune defects. Indeed, prior to 1955, only
approximately 300 cases had been reported in the
medical literature. Important predisposing conditions
for cryptococcosis include HIV infection, diabetes melli-
tus, hepatic cirrhosis, hematologic malignancies, solid
organ, and, to a lesser extent, stem cell transplantation,
corticosteroid therapy, sarcoidosis, connective tissue
disorders, and other immunosuppressive medications
including tumor necrosis factor (TNF)-a inhibitors
[6,13–18].
Worsening of the incidence and severity of cryptococcosis
mirrored the rise of the HIV epidemic, as Cryptococcus
became one of the most common causes of fungal pul-
monary infections in AIDS patients [19–23]. Expectedly,
cryptococcosis in AIDS patients has met a dramatic
decline in incidence with the advent of highly active
antiretroviral therapy (HAART) as the standard of care
for HIV patients [17]. Pulmonary involvement in AIDS
patients with cryptococcal meningitis is present in 25–
55% of cases, and generally occurs in patients with CD4
cell count less than 100 cells/ml [6]. Among solid organ
transplant (SOT) recipients, Singh et al. [24] reported
pulmonary disease to be present in 54% of all patients
with cryptococcosis, with 33% having only lung disease. It
is difficult to ascertain the incidence of cryptococcal lung
disease in HIV-negative patients because surveillance
data are limited. A population-based study [25] in four
United States areas reported an annual cryptococcosis
incidence of 0.2–0.9 per 100 000 population. Although
the vast majority of cryptococcal infections are identified
in the lungs and CNS, cryptococcosis can affect any organ
system, resulting in a wide range of clinically apparent
disease.
The primary portal of entry of Cryptococcus is through the
inhalation of the encapsulated yeast leading to pulmonary
and disseminated infection. An identifiable environmen-
tal exposure is not typically apparent, and human-to-
human transmission does not occur. Once inhaled into
the alveoli, contact with alveolar macrophages elicits a T
helper cell type 1 (Th1) response prompting granulom-
atous inflammation. An effective immune response can
eliminate the yeast or result in the formation of dormant
living yeast within a pulmonary lymph node complex
[26,27]. Thus, the expected histopathologic finding in the
normal host is granuloma formation associated with a
monocytic infiltrate and multinucleated giant cells
accompanied by abundant yeast [28,29]. In contrast,
compromised cell-mediated immunity allows more
severe, disseminated primary disease in addition to the
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Cryptococcal lung disease Shirley and Baddley 255
reactivation of dormant yeast. The limited inflammatory
response results in a range of histopathologic findings
from interstitial mononuclear infiltration to yeast visual-
ized within normal appearing lung parenchyma [30].
Virulence is augmented by the polysaccharide capsule,
which blocks phagocytosis, among other protective
effects.
Clinical manifestations
Cryptococcal pulmonary involvement ranges from
asymptomatic colonization or infection to severe pneu-
monia with respiratory failure. Clinical presentation of
pulmonary cryptococcosis is highly variable and often is
related to the immune status of the patient. In the
immunocompetent patient, clinical symptoms are pre-
sent weeks to months before diagnosis; however, patients
may be totally asymptomatic [18,31,32]. The onset of
symptoms in immunocompromised patients is generally
subacute, but rapidly progressive pulmonary disease in
this population may occur [19,22,33].
The typical constellation of symptoms of pulmonary
cryptococcosis includes cough, fever, malaise, chest pain,
weight loss, dyspnea, night sweats, and hemoptysis
[6,18,34]. These nonspecific symptoms may be similar
to those in other pulmonary infections, perhaps leading to
delayed diagnosis. A significantly lower prevalence of
symptoms has been described in immunocompetent
versus immunocompromised patients, with as many as
25% of HIV-negative patients with pulmonary involve-
ment lacking respiratory symptoms [6,18]. The increased
prevalence of symptoms among immunocompromised
patients may be explained in part by the frequent pre-
sence of concomitant CNS or disseminated cryptococcal
disease.
The natural history of pulmonary cryptococcosis is also
highly dependent on the degree of immunosuppression,
as isolated pulmonary disease in the immunocompro-
mised host is more likely to disseminate, suggesting
the need for early antifungal therapy. Kerkering et al.
[34] described a series of patients with pulmonary cryp-
tococcosis prior to the HIV epidemic and found that only
1/7 immunocompetent patients developed disseminated
cryptococcosis. In contrast, 28/34 immunocompromised
patients developed disseminated disease, despite a
higher rate of treatment with systemic antifungal therapy
[34]. Nonimmunocompromised hosts may have self-lim-
ited disease that resolves over a period of weeks to
months without directed antifungal therapy [34]. How-
ever, progression from isolated pulmonary infection to
disseminated cryptococcosis does occur in a minority of
normal hosts. Among AIDS patients, although pulmonary
manifestations are common, rapid dissemination is the
expected natural history [22]. Untreated infection in the
 256 Infectious diseases
presence of persistent cell-mediated immune dysfunc-
tion is highly fatal [35–37].
A unique clinical circumstance is encountered in pro-
foundly immunosuppressed HIV patients as they initiate
HAART and begin the process of immune reconstitution,
or in SOT patients who withdraw or reduce immunosup-
pression. As cell-mediated immune responses are
restored, there is the potential of a directed immune
response to an underlying antigen. This results in clinical
deterioration known as immune reconstitution inflamma-
tory syndrome (IRIS). An underlying subclinical crypto-
coccal infection or killed yeast from a prior treated
infection may evoke IRIS. The more common scenario
is seen with cryptococcal meningitis; however, interstitial
pneumonia, pulmonary nodules, and mediastinal lym-
phadenopathy have all been described in this context
[38–40].
Radiography
The radiographic features of pulmonary cryptococcosis
are varied and are influenced by the degree of immuno-
suppression of the patient. Findings can be broadly
categorized into pulmonary nodules or masses (Fig. 1);
segmental or lobar consolidation; reticulonodular (diffuse
interstitial) infiltrates (Fig. 2); mediastinal or hilar adeno-
pathy; or less commonly, pleural effusions [18,33,41].
In HIV-negative patients, solitary or multiple pulmonary
nodules are seen on approximately 60–80% of chest
radiographs [18,42–44]. Pulmonary nodules are varied
in size, ranging up to more than 30 mm, and appearance
may range from smooth to spiculated [45]. Focal or
multifocal airspace consolidation is the next most com-
Figure 1 Chest radiograph showing nodular infiltrates
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Figure 2 Chest radiograph showing diffuse interstitial infil-
trates
Reproduced by courtesy of James McKinnell, MD.
mon radiographic pattern among HIV-negative patients
and is present in 10–30% of patients [18,43].
In patients with AIDS, the most common radiographic
abnormalities are diffuse, interstitial infiltrates and lobar,
often mass-like, infiltrates occurring in 70–75% of infec-
tions [46–48]. Pulmonary nodules are expected in 30%,
but are more likely to cavitate than nodules in patients
without immune compromise [18,46]. The presence of
interstitial infiltrates or pleural effusions is often associ-
ated with disseminated disease. Occasionally, cryptococ-
cal pneumonia will progress rapidly to acute respiratory
distress syndrome (ARDS) [49]. Other less commonly
associated radiographic findings include ground glass
attenuation, lymphadenopathy, and pulmonary mass-like
lesions as large as 50 mm [44].
Radiographically, C. gattii infection manifests as focal
pulmonary disease, almost exclusively, and is frequently
mistaken as a malignancy [50,51].
Laboratory diagnosis
Diagnosis of cryptococcal lung disease can be achieved
using several methods. In addition to consistent clinical
history and radiographic features, a definitive diagnosis of
cryptococcosis is made by culture and identification of
the organism from a nonsterile site. Sputum samples are
easily obtained for testing, but are limited by decreased
sensitivity of diagnosis. Better yields will occur if more
invasive procedures such as bronchoscopy with bronch-
oalveolar lavage (BAL), transbronchial biopsy, or open
lung biopsy are performed. C. neoformans can grow on

most bacterial and fungal culture media and can be
detected after 2–7 days of growth. The use of concana-
vine–glycine bromothymol blue agar will help to
differentiate C. gattii from C. neoformans [52]. Because
Cryptococcus species are not considered as normal respir-
atory flora, isolation from a respiratory sample is
considered significant, especially among immunocom-
promised patients.
Presumptive diagnosis of cryptococcosis can also be made
by examination of preparations from clinical samples or
tissues. On routine hematoxylin and eosin staining, C.
neoformans is difficult to identify. However, Gomori
methenamine silver or periodic acid–Schiff staining
allows for identification. Cryptococcus can be recognized
by its oval shape and narrow-based budding. With use of
the mucicarmine stain, the cryptococcal capsule will stain
rose to burgundy in color and help differentiate C. neofor-
mans from other yeast organisms such as Blastomyces
dermatiditis and Histoplasma capsulatum.
Serum cryptococcal antigen (CrAg) detection is highly
accurate for the diagnosis of disseminated cryptococcosis.
A titer of at least 1 : 4 strongly suggests cryptococcal
infection, particularly in the immunocompromised
patient. CrAg is found in cerebrospinal fluid (CSF) in
more than 90% and in serum in more than 80% of patients
with cryptococcal meningitis [53]. However, the utility of
this test is much more limited in patients with crypto-
coccal lung disease. In HIV-negative patients with pul-
monary cryptococcosis, serum CrAg will be positive in
25–56% of patients [6,7]. Patients with extrapulmonary
and pulmonary cryptococcosis are more likely to have
higher antigen titers when compared with patients with
only cryptococcal lung disease [43,54]. Although serum
CrAg titers will typically decline with treatment, they are
not a reliable marker of treatment response. Evaluation of
CrAg testing of sputum or BAL specimens has revealed
inconsistent results and is not routinely available [55,56].
Treatment
The goals and expectations of the treatment of crypto-
coccal lung disease are to control the signs and symptoms
of pneumonia, prevent dissemination, sterilize infected
tissue, and prevent recurrence [57]. Because the risks of
dissemination and recurrence are related to host immu-
nity, treatment approaches for cryptococcal pneumonia
should be categorized on the basis of patient immune
function. A common clinical dilemma is how extensively
to pursue a diagnosis of dissemination, including CNS
involvement, in a patient with documented or suspected
pulmonary cryptococcosis. Because dissemination is
expected or often present in immunosuppressed patients,
this population should be evaluated with blood and CSF
cultures and serum and CSF CrAg titers [35]. Practice
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Cryptococcal lung disease Shirley and Baddley 257
management guidelines recommend pursuing a similar
evaluation in immunocompetent patients [57]. However,
recently elucidated predictors of extrapulmonary disease,
including neurologic symptoms, fever, weight loss, hepa-
tic cirrhosis, high-dose corticosteroids, and serum CrAg
ratio of more than 1 : 64 may be helpful in determining
the need for a more aggressive diagnostic evaluation in
patients presenting with cryptococcal lung disease [43].
Immunosuppressed patients
The principles of treatment of disseminated or CNS
cryptococcosis center around the concept of induction
(initial therapy), consolidation (clearance), and mainten-
ance (suppression) therapy [2,3]. This strategy has been
adopted for most immunocompromised patients with
pulmonary disease, as dissemination is likely to occur
in patients presenting with cryptococcal pneumonia. To
date, randomized clinical trials evaluating cryptococcosis
in HIV patients have focused on CNS infections [2,3]. If
infection is confined to the lungs, then specific treatment
is dependent on the severity of disease (Table 1).
When cryptococcal pneumonia is accompanied by dis-
seminated disease in the immunocompromised host,
then aggressive systemic antifungal therapy is warranted.
The recently published Infectious Diseases Society of
America (IDSA) guidelines for cryptococcal disease
recommend induction with amphotericin B deoxycholate
(0.7–1.0 mg/kg per day) or liposomal amphotericin B
(6 mg/kg per day) and flucytosine 100 mg/kg per day
orally for 2 weeks. This is followed by consolidation with
fluconazole 400 mg/day orally for a minimum of 8 weeks.
Maintenance therapy with fluconazole 200 mg/day
should be continued for 6–12 months, but may be dis-
continued safely in HIV patients with a CD4 cell count of
more than 100 cells/ml for at least 3 months after having
received at least 12 months of antifungal therapy. For
other non-HIV immunocompromised patients, especially
SOT patients, limited data exist to guide the discontinu-
ation of maintenance fluconazole. Singh et al. [58] pro-
spectively evaluated a cohort of consecutive organ trans-
plant recipients with C. neoformans infection. Fifty-four
patients received maintenance therapy for a median
duration of 183 days. Follow-up was continued for a
median of 2.1 years, and only one patient developed a
recurrence [58]. In many instances, maintenance fluco-
nazole can be safely discontinued after 6–12 months of
therapy. The decision to discontinue maintenance
therapy should be individualized and should consider
host immune recovery or improvement and clinical and
radiographic findings.
When cryptococcal infection is isolated to the lungs,
immunocompromised patients should receive treat-
ment based on disease severity. Severe clinical disease,
 258 Infectious diseases

Table 1 Treatment of cryptococcal lung disease

Immunocompromised Asymptomatic or mild-to-moderate disease
patient Fluconazole 400 mg daily for a minimum of 6–12 months
Alternatives: itraconazole 400 mg/day
Severe, progressive disease, or suspected or proven dissemination
Induction: amphotericin B (0.5–0.7 mg/kg per day) or lipid preparations of amphotericin B with or with
out flucytosine (100 mg/kg per day) for 2–4 weeks
Consolidation: fluconazole 400 mg/day for 8–10 weeks, then fluconazole 200 mg/day for a minimum of 6–12 months
Alternatives: itraconazole may be substituted for fluconazole
Maintenance therapy: fluconazole 200 mg/day as lifelong therapy or until immune reconstitution is attaineda
Alternatives: amphotericin B (1 mg/kg per week)
Itraconazole 200–400 mg/day

Immunocompetent Colonizationb
patient Observation
Asymptomatic or minimally symptomatic disease
Fluconazole 400 mg/day for 3–6 monthsc
Mild-to-moderate disease
Fluconazole 400 mg/day for 6–12 months
Alternative: itraconazole 200–400 mg/day for 6–12 months
Severe or progressive disease
Induction: amphotericin B (0.5–0.7 mg/kg per day) or lipid preparations of amphotericin B with or without
flucytosine (100 mg/kg per day) for 2–4 weeks
Consolidation: fluconazole 400 mg/day for 8–10 weeks, then fluconazole 200 mg/day for a minimum of 6–12 months
Alternatives: itraconazole may be substituted for fluconazole
a
Discontinuation may be considered for HIV patients with a CD4 cell count >100 cells/ml for at least 3 months after having received at least 12 months
of antifungal therapy.
b
Colonization is defined as a positive respiratory tract culture without signs or symptoms of pulmonary disease or radiographic abnormalities.
c
Although patients with asymptomatic infection have been successfully treated with observation alone, the authors recommend treatment.

including ARDS, should be treated as disseminated
infection with induction, consolidation, and maintenance
therapy. Pneumonia with mild-to-moderate symp-
toms can be approached more conservatively, with
fluconazole 400 mg/day for 6–12 months followed by
maintenance fluconazole until immune reconstitution
is attained (Table 1).
Immunocompetent patients
It is far less likely for pulmonary cryptococcosis to dis-
seminate in an immunocompetent patient. Prior to the
US Food and Drug Administration (FDA) approval of
fluconazole, isolated cryptococcal pneumonia in the
asymptomatic or mildly symptomatic patient was not
treated routinely [34,47,59,60]. Spontaneous resolution
was common, and the few available therapeutic options
(amphotericin B and flucytosine) were highly toxic and
required prolonged therapy. The availability of flucona-
zole provided a well tolerated, easily administrated
option for this patient population. Pappas et al. [6]
described an 84% success rate in treatment of isolated
pulmonary cryptococcosis with an average duration of
treatment of 3 months among HIV-negative patients with
cryptococcosis. Unfortunately, prospective trials compar-
ing fluconazole with placebo are not available, but fluco-
nazole has gained favor due to its ease of use and effec-
tiveness [6]. C. gattii infections, although rare, occur
disproportionately more in immunocompetent hosts. Pul-
monary infections largely resemble C. neoformans infec-
tions, with the noteworthy addendum that they have a
propensity to more frequently cause pulmonary crypto-
coccomas and may be more aggressive. Management of C.
gattii infections with antifungal therapy is similar to that
of C. neoformans. However, extrapolating from the
delayed response of cerebral cryptococcomas to antifun-
gal therapy, the presence of multiple or large pulmonary
cryptococcomas may necessitate an induction course of
amphotericin B and flucytosine, a longer course of anti-
fungal therapy, or surgical resection of large lesions in
some cases [50,61].
For patients with asymptomatic or minimally symptomatic
disease, fluconazole at a dose of 400 mg/day for 3–6 months
is recommended. For those with mild-to-moderate dis-
ease, recommended treatment is fluconazole 400 mg/day
for 6–12 months. As mentioned previously, immunocom-
petent patients with severe disease should be treated
similarly to immunocompromised patients, with induction
amphotericin B and flucytosine, followed by fluconazole
(Table 1). Itraconazole at a dose of 200–400 mg/day may
be used as an alternative therapy to fluconazole [62]. In the
past several years, newer azole agents such as voriconazole
and posaconazole have become available for use. These
agents have good in-vitro activity against Cryptococcus
species [63]. However, treatment of C. neoformans with
these drugs is limited to small case series or salvage studies
[64–66]. Until more treatment data are available, it is likely
that these agents will be reserved for refractory infections
or cases of medication intolerance.

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Conclusion
Cryptococcal lung disease is an important opportunistic
infection that is uncommon, but probably underdiag-
nosed. Pulmonary involvement ranges from asympto-
matic colonization or infection to severe pneumonia with
respiratory failure, often mimicking other opportunistic
pneumonias. Treatment recommendations have been
adapted from studies of AIDS patients with cryptococcal
meningitis and other observational studies and are based
on severity of disease and underlying immune status of
the patient. Knowledge of epidemiology, diagnosis, and
treatment is valuable to ensure appropriate patient care.
Acknowledgements
Dr Baddley has received research support from Pfizer, Astellas Pharma,
and Merck and Co.
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