Cryptococcal lung infections

Cryptococcal Lung
Infections
Kate Skolnik, MDa
, Shaunna Huston, PhDb
, Christopher H. Mody, MDc,d,
*
INTRODUCTION
Cryptococcus remains one of the leading causes of
acquired immunodeficiency syndrome (AIDS)-
related deaths, and is among the most common
fungal pathogens worldwide.1
Cryptococcus de-
mands global attention because of the high mortal-
ity, unique geographic distribution, and its
propensity to cause severe and rapidly progressive
disease in both healthy and immunosuppressed in-
dividuals.1,2
Cryptococcus neoformans, which
mainly infects immunosuppressed individuals,
and Cryptococcus gattii, which has a high propen-
sity to infect healthy individuals, are the 2 major
species of Cryptococcus that are associated with
mortality.1
Arguably, the greatest virulence factor
for both species is the cryptococcal polysaccha-
ride capsule, which helps evade immune detec-
tion.3
The organism often leads to respiratory
infection but can also disseminate to other organs,
in particular to the meninges causing meningoen-
cephalitis, which is associated with poor clinical
outcomes.2,4
Current diagnostics are based on
detection of antigen and culture techniques, and
treatment recommendations are tailored based
on fungal susceptibility, location, and severity of
disease. Research is advancing technologies to
enable more effective and efficient diagnostics for
early detection along with improved prophylactic
and therapeutic regimes.
Disclosure Statement: The authors have nothing to disclose.
a
Division of Respirology, Department of Internal Medicine, Rockyview General Hospital, University of Calgary,
Respirology Offices, 7007 14th Street Southwest, Calgary, Alberta T2V 1P9, Canada; b
Department of Physi-
ology and Pharmacology, Health Research Innovation Centre, University of Calgary, Room 4AA08, 3330 Hospi-
tal Drive Northwest, Calgary, Alberta T2N 4N1, Canada; c
Department of Microbiology and Infectious Diseases,
Health Research Innovation Centre, University of Calgary, Room 4AA14, 3330 Hospital Drive Northwest, Cal-
gary, Alberta T2N 4N1, Canada; d
Department of Internal Medicine, Health Research Innovation Centre, Uni-
versity of Calgary, Room 4AA14, 3330 Hospital Drive Northwest, Calgary, Alberta T2N 4N1, Canada
* Corresponding author. Health Research Innovation Centre, Room 4AA14, 3330 Hospital Drive Northwest,
Calgary, Alberta T2N 4N1, Canada.
E-mail address: cmody@ucalgary.ca
KEYWORDS
Cryptococcus Cryptococcosis Fungal lung infection Endemic mycoses Treatment
KEY POINTS
Cryptococcus infections have high morbidity and mortality rates worldwide, particularly in the
context of immune suppression and central nervous system involvement.
Cryptococcus neoformans can be found globally and predominantly affects the immune-
suppressed individual, whereas Cryptococcus gattii is endemic to certain regions and often affects
immune-competent individuals.
Most individuals with cryptococcal pulmonary infection present with symptoms; however, they may
be mild and nonspecific, making timely diagnosis challenging.
Pulmonary nodules or focal consolidation is the most common radiographic finding with
Cryptococcus.
Azoles (specifically fluconazole) and amphotericin B (in severe disease) are key cryptococcal ther-
apies. There is no role for echinocandins.
Clin Chest Med 38 (2017) 451–464
http://dx.doi.org/10.1016/j.ccm.2017.04.007
0272-5231/17/Ó 2017 Elsevier Inc. All rights reserved.
chestmed.theclinics.com

EPIDEMIOLOGY
General Cryptococcal Epidemiology
Among the 37 species of Cryptococcus, only a
few are human pathogens.5
C neoformans is
characterized as an opportunistic pathogen
because it commonly causes infections in individ-
uals with impaired immunity. C neoformans
causes more than 1 million infections in AIDS pa-
tients annually, and, unfortunately, most of these
patients will die within a few months of diag-
nosis.2
By contrast, C gattii has a more distinct
geographic range and is more likely to affect
healthy individuals leading to its characterization
as an endemic mycosis.6,7
C gattii is classically
located in tropical and subtropical areas of the
world such as Australia and Papua New Guinea,
but more recently it has emerged as an endemic
mycosis on the west coast of Canada and the
United States.7
Rarely, Cryptococcus laurentii
causes infection in individuals with compromised
immunity8–10
and even less often in patients who
are immune competent.11,12
Immunosuppression
is a significant risk factor, and the prevalence of
cryptococcal infection significantly increased dur-
ing the emergence of AIDS.13
Currently, in devel-
oped countries with effective antiretroviral
therapies, the prevalence of opportunistic crypto-
coccal infections has decreased, but Crypto-
coccus continues to affect those with other
defects in cell-mediated immunity. Infections
also occur in healthy individuals, especially if
exposed in endemic areas.14,15
Although Cryptococcus causes both endemic
and opportunistic mycosis, transmission of Crypto-
coccus occurs directly from the environment rather
than from human to human.16–18
Although Crypto-
coccus can cause infection in animals such as
cats, dogs, ferrets, cockatiels, parrots, llamas, hors-
es, and marine mammals,19,20
direct transmission
from these species is exceptionally rare. The pri-
mary environmental sources of C gattii are trees,
such as eucalyptus, Douglas-fir, red cedar, and
Garry oak, among others,16,17,21
but it can also be
foundin the soil, water, and air in endemic regions.22
C gattii has been isolated from the environment
mainlyinAustralia,NewZealand,PapaNewGuinea,
Central America, parts of South America, and the
Pacific Northwest of North America including Van-
couver Island.18,21,23–25
Interestingly, C gattii has
also been identified in the Mediterranean basin on
various trees, including olive and eucalyptus, which
marks the first detection of the species in Europe.26
In contrast, C neoformans is found worldwide, with
the primary source being pigeon excrement,
although certain subtypes are more common in
particular regions of the world.16,18
C neoformans
has also been linked to other bird species such as
magpies and cockatiels.27,28
Additionally, there
seems to be a seasonality to C gattii infections in
some regions, which has not been noted with C
neoformans.29
Cryptococcal Subtypes
It is important to differentiate between subtypes of
C neoformans and C gattii for clinical purposes. C
neoformans is divided into 2 major groups known
as C neoformans var grubii (serotype A) and C
neoformans var neoformans (serotype D).30
Addi-
tionally, a hybrid serotype, AD, has also been iden-
tified as a clinically significant subtype.30
C
neoformans and C gattii have also more recently
been subdivided into 4 molecular types, termed
VNI, VNII, VNIII, VNIV and VGI, VGII, VGIII, VGIV,
respectively, which may lead to further species
distinctions.30,31
C neoformans var grubii and C
neoformans var neoformans have important differ-
ences in their genomes and replication methods,30
which have clinical implications, as certain sero-
types and molecular types may be more likely to
respond to treatment.31
STRUCTURE AND LIFE CYCLE
Cryptococci are eukaryotic organisms that belong
to the phylum Basidiomycota of filamentous fungi.32
The cryptococcal cell is enveloped by a cell
membrane, cell wall, and a characteristic polysac-
charide capsule.4
The capsule is unique to Crypto-
coccus and sets it apart from other pathogenic
fungi.33
It is composed of glucuronoxylomannan
(GXM), which is the predominant polysaccharide,
GalXM (galactoxylomannan), and mannopro-
teins.34,35
Structural differences in GXM allow for
the identification of Cryptococcus based on sero-
type.36
The fungal cell wall consists of chitin and
b-glucans (which provide structural integrity), pores
(which allow for the movement of important mole-
cules and transport vesicles), melanin (which pro-
tects the cell from oxidative stress), and proteins
that serve a variety of cellular functions.37–39
Crypto-
coccal cells can be identified by light microscopy
but require special stains such as mucicarmine or
Periodic-acid Schiff to identify the capsule or silver
stains to identify the cell wall.40
Cryptococcus is
also readily identified with India ink staining, in which
exclusion of the stain in the perimeter of the fungal
cell is indicative of the fungal capsule (Fig. 1).41,42
Cryptococcus species are able to reproduce
asexually through simple budding, and sexually,
through the mating of a- and a-mating types.43,44
Asexual reproduction is more common and oc-
curs in the human host.43,45
Sexual reproduction
Skolnik et al
452

provides greater genetic diversity and, with this,
the potential for increased virulence.46
Both mat-
ing strategies have the potential to increase ge-
netic diversity.45,46
The reproductive strategy is
also influenced by Cryptococcus variety. For
example, less than half of C neoformans var grubii
are fertile, whereas most C neoformans var neofor-
mans are capable of sexual reproduction.30,47
Interestingly, the highly virulent C gattii subtype
VGIIa, which is responsible for the outbreak on
Vancouver Island, seems to have emerged specif-
ically from same-sex reproduction, suggesting
that different types of reproduction may provide
environmental adaptation and virulence.45
PATHOGENESIS
The primary risk factor for C gattii infection is expo-
sure from environmental sources in endemic re-
gions. It is unclear why most C gattii infections
occur in healthy individuals.48
By contrast, C neo-
formans infection is more common in immunosup-
pressed patients, in particular, those with defective
cell-mediated immunity such as those with human
immunodeficiency virus (HIV), idiopathic CD4 lym-
phopenia, organ transplant, hematologic malig-
nancies or those receiving immune-suppressive
medications (including systemic steroids, biolo-
gic agents, chemotherapy, and other cytotoxic
therapies).16,49
Although it is much less common,
individuals with a milder degree of immune sup-
pression (such as splenectomy, cirrhosis, diabetes
mellitus, systemic lupus erythematosus, and preg-
nancy) have an increased risk of getting C neofor-
mans infections.50–53
Independent of the type of cryptococcal infec-
tion or the primary organ involved, the fungus typi-
cally enters the body through the lungs.54
After
entering, the organism undergoes changes to a
phenotype that facilitates invasive infection of the
host.54
Although C neoformans takes advantage
of natural weak points in the immune system, C
gattii is postulated to have additional unique viru-
lence factors that allow it to evade the immune
system.3,55–57
C neoformans infections may also occur owing
to the reactivation of latent infection, similar to
tuberculosis.57–60
In one study, antibodies to Cryp-
tococcus were found in most individuals in the
borough of the Bronx, New York, independent of
prior exposure or HIV status, suggesting that
exposure is surprisingly common.61
Additionally,
years after emigrants from Africa moved to France,
infections developed with organisms of an African
phenotype rather than a French phenotype, sug-
gesting that organisms were dormant in these
hosts for years.58
There is evidence that anti-
cryptococcal antibodies (and Cryptococcus) can
persist in the body for years without symptom
development.58,61
However, when impairment in
immunity occurs, as with solid-organ transplanta-
tion or AIDS, dormant Cryptococcus may reacti-
vate and develop into an active fungal
infection.58,60
By contrast, C gattii infections
seem to occur de novo,62
although it must be
noted that clinical disease may occur months or
years after exposure.63,64
VIRULENCE FACTORS
The distinctive polysaccharide capsule of Crypto-
coccus spp. acts as a key virulence factor.4,37
The polysaccharide capsule prevents phagocy-
tosis, allowing the organism to bypass the host
innate immune response.65
In addition, GXM is
known to directly interfere with T lymphocyte
function,66
whereas GalXM has been shown to
induce cytokine dysregulation and T lymphocyte
apoptosis,67
and both GXM and GalXM are
capable of stimulating macrophage apoptosis.68
In addition to the polysaccharide capsule, Cryp-
tococcus has several virulence factors that act as
antioxidants, neutralizing host innate immune mol-
ecules and preventing oxidative damage to the
cell.69
These antioxidants include mannitol,70
superoxide dismutase,71
thioredoxin reductase,72
and pigments such as melanin.69
Melanin also
binds to antibiotics, which may confer antifungal
resistance.73
Additional virulence factors target
the host by various mechanisms including destabi-
lization of the cell membrane (as with b1 phospho-
lipase),74
degradation of host proteins (as with
metalloproteinases),75
and altering pH (via ure-
ase).76
The a-mating type of C gattii is also a viru-
lence factor.77
C gattii likely has additional
virulence factors that allow it to cause invasive
infection in hosts with intact immune systems;
Fig. 1. Cryptococcus species as visualized by India ink
staining. Arrows indicate the fungal cell capsule.
Cryptococcal Lung Infections 453

however, the exact nature of these factors is yet to
be discovered.
CLINICAL OUTCOMES OF CRYPTOCOCCAL
PULMONARY INFECTION
Clinical Manifestations of Cryptococcal
Pulmonary Infection
Cryptococcal infection can produce a range of
manifestations from minimal symptoms to severe
life-threatening disease.78
Cryptococcus most
often leads to pulmonary75,76
and central nervous
system (CNS) disease,79,80
the latter being a ma-
jor source of morbidity and mortality. However,
Cryptococcus can also present as infection in
the bone,78
skin,81
eyes,82
and prostate83,84
and
may even cause disseminated disease and cryp-
tococcemia.85,86
These findings may occur in
isolation or in association with pulmonary Crypto-
coccus infection. Interestingly, these presenta-
tions can occur in both immune-suppressed
and immune-competent individuals, although
cryptococcemia is rare in those with intact
immunity.
An individual’s underlying risk factors may affect
the manifestations of cryptococcal disease. For
example, those with pre-existing lung disease
are more likely to have significant pulmonary infec-
tion,78
whereas those with HIV or organ transplant
and healthy subjects are more likely to have CNS
infection.78,87–89
Lung involvement occurs in 28%
to 64% of HIV-negative individuals infected with
Cryptococcus52,90
compared with less than 5%
of those co-infected with Cryptococcus and
HIV.90
By contrast, C gattii tends to cause more
pulmonary disease and is generally seen in
immune-competent individuals.91
Furthermore,
the prevalence of pulmonary cryptococcal infec-
tion may be underestimated, as individuals can
have asymptomatic pulmonary nodules that never
come to medical attention.92
Cryptococcal pulmonary infection can cause
vague symptoms and a wide spectrum of disease
severity including minimal or no symptoms in a
subset of individuals.93
Consequently, early diag-
nosis may be challenging, and cryptococcal dis-
ease may be overlooked in the setting of subtle
symptoms. Most patients with cryptococcal lung
infection are clinically symptomatic.94–96
When
present, pulmonary symptoms can include dry
cough, dyspnea, chest tightness, and fever,
with cough and fever being the most common (Ta-
ble 1).4,48,95
Mediastinal or hilar lymphadenopathy
may occur in both immune-competent and
immune-suppressed individuals, which may be a
solitary finding or associated with other pulmonary
manifestations.97,98
Those with lymphadenopathy
may present with symptoms secondary to
compression of adjacent structures if the adenop-
athy is severe. Cryptococcoma, a granulomatous
mass harboring the fungus, may be mistaken for
lung cancer on imaging94,99–102
and has been
described more frequently in infections caused
by C gattii in immune-competent patients99,100
but can also occur with C neoformans.52
Rarely,
endobronchial infection can occur.101,102
In some
cases, severe pulmonary disease leading to respi-
ratory failure can be seen, and acute respiratory
distress syndrome has occurred in immune-
compromised individuals with pulmonary crypto-
coccosis.103,104
A miliary tuberculosislike presen-
tation with Cryptococcus in an AIDS patient has
also been reported but is exceedingly rare.105,106
Importantly, although immune-compromised indi-
viduals, such as those with HIV, are less likely to
manifest with pulmonary symptoms, when pre-
sent, the manifestations can be very severe.
Radiographic Findings of Cryptococcal
Pulmonary Infection
Radiographic findings can include pulmonary nod-
ules (single or multiple), lobar or segmental consol-
idation, nodular or reticulonodular interstitial
pattern, ground glass opacities, masses, hilar/
mediastinal lymphadenopathy, and even pleural
effusions.52,85,93,94,97,98,105
Cryptococcal pleural
effusions are typically limited to severely immune-
suppressed individuals, as is seen with AIDS or
ideopathic CD4 lymphopenia (Fig. 2). Reticular
or reticulonodular interstitial changes are the
most frequent radiographic presentation in HIV,
whereas dense nodules, consolidation, or intersti-
tial changes seem to be the most common findings
in the immune-competent population.52,85,107,108
Table 1
Potential manifestations of pulmonary
cryptococcal infection
Symptoms Radiographic Findings
None
Fevera
Dry cougha
Dyspnea
Chest pain/
discomfort
Malaise
Single or multiple pulmo-
nary nodulesa
Consolidation (lobar or
segmental)a
Nodular interstitial pattern
Reticular interstitial pattern
Ground glass opacities
Mass
Mediastinal/hilar
lymphadenopathy
Pleural effusions
a
Most common.
Skolnik et al
454

Overall, about half of all cryptococcal infections
present with chest radiograph findings, with some
variability depending on cryptococcal subtype and
host immune status (see Table 1). In one study of
predominantly C neoformans–affected individuals,
66% of those without HIV had an abnormal chest
radiograph, compared with 40% of those with
HIV.96
In those with HIV and pulmonary C neofor-
mans infection, infiltrates or several small nodules
were most commonly seen.96
Cryptococcal pul-
monary involvement was confirmed in only 58%
and 14%, respectively.96
In comparison, a Colom-
bian study focusing on C gattii (with a minority of
individuals having concurrent HIV) found abnormal
chest radiographs in 15% of individuals with
known C gattii and only half of them had pulmo-
nary involvement.109
However, these numbers
are likely an underestimate, as only 40% of sub-
jects underwent chest imaging. A separate study
of HIV-negative individuals had findings that fell
between those of the aforementioned studies,
with 36% having pulmonary involvement.78
Computed tomography scanning would likely
improve the sensitivity for detecting crypto-
coccal-related changes and should be pursued
when radiographs are not helpful, but clinical sus-
picion for Cryptococcus persists.
DIAGNOSIS
Testing for Cryptococcus should be considered in
anyone with risk factors or exposure history and
persistent pulmonary symptoms or radiographic
findings despite treatment of common bacterial
pathogens. Diagnosis of cryptococcal pulmonary
infections usually requires a combination of micro-
biologic and radiographic investigations. Although
microbiologic tests are the key to diagnosis,
pulmonary imaging may bring subclinical infection
to the clinicians’ attention and suggest Crypto-
coccus as part of a differential diagnosis
(see Table 1). As part of the diagnostic process,
there should be an assessment for possible
extrapulmonary complications of disease; in
particular, neurologic involvement should be
considered and investigated.49
Cryptococcus can be identified by various
methods, including fungal culture, special stains,
and immunohistochemical tests that identify
cryptococcal antigen.6,110
Fungal culture may be
obtained by plating respiratory samples on selec-
tive media. Cryptococcus grows best in tem-
peratures between 30
C and 35
C,111
and
environmental concentrations decrease with hott-
er weather.112
Cryptococcus can be identified by
exclusion of India ink stain in the immediate cell
perimeter; however, this method cannot differen-
tiate between viable and dead fungal cells (see
Fig. 1).6
Alternatively, the diagnosis may be
made by detection of cryptococcal polysaccha-
ride antigen in body fluids by various immunologic
techniques.113,114
In respiratory secretions, the la-
tex agglutination assay has a sensitivity between
93% and 100% and specificity of 93% to
98%,113
whereas enzyme-linked immunosorbent
assay has a sensitivity of 99% and specificity of
97% for Cryptococcus.114
These results are
similar to assays performed on cerebrospinal fluid
samples.115,116
However, the latex agglutination
assay was found to be slightly more sensitive
than enzyme-linked immunosorbent assay for
blood and cerebrospinal fluid samples from a
larger study.116
The lateral flow assay is the new-
est test for cryptococcal antigen with good yield
and has been adopted at most centers because
it is easier to use.115,117
An important downfall of
these assays is suboptimal sensitivity in detecting
C gattii. In one study, 40% of C gattii were missed
despite the application of all 3 tests.118
Neverthe-
less, lateral flow assay seems to have the best
sensitivity for C gattii and has largely replaced
other methods.119
Furthermore, although the
enzyme-linked immunosorbent assay, latex agglu-
tination assay, and lateral flow assay are generally
highly sensitive and specific, none of the tests can
differentiate viable from dead fungal cells.6
In addi-
tion, DNA amplification has largely replaced
canavanine-glycine-bromothymol blue selective
media for further identification and confirmation of
the presence of C gattii.120
If the aforementioned
Fig. 2. Computed tomography scan of drowned lung
in an adult with idiopathic CD4 lymphopenia second-
ary to invasive cryptococcal pneumonia and associ-
ated pleural effusion.

tests are nondiagnostic, but clinical suspicion for
Cryptococcus remains high because of exposure
history, further diagnostic testing may be required.
In some situations, a video-assisted thoraco-
scopic biopsy or a surgical wedge resection may
be considered if a pulmonary nodule is growing
and cannot be accessed by bronchoscopy or
percutaneous biopsy.93
Surgical intervention may
be important in individuals with risk factors for
lung cancer or immune suppression. These biopsy
and surgical specimens should be sent for fungal
cultures in addition to histopathology.
TREATMENT
Treatment Indications
Antifungal treatment may not be required for
everyone with Cryptococcus that is isolated from
the lungs. In some individuals, Cryptococcus
may simply be colonizing the airways, and patients
remain asymptomatic. Occasionally, cryptococcal
pulmonary nodules may also not require treatment
if involvement is minimal and patients have no
symptoms.48
However, immune-suppressed indi-
viduals with pulmonary Cryptococcus should be
offered antifungal therapy.48,121
Therapy is partic-
ularly important in those with impaired cell-
mediated immunity, such as those receiving
immunosuppressive therapy after organ trans-
plant, those with hematologic malignancies, those
receiving chemotherapy or biologic agents, and
those with long-term prednisone use. There is
also a lower threshold to treat asymptomatic indi-
viduals with mild immune impairment, such as
diabetes or severe renal failure. In addition,
immune-competent individuals with mild to severe
symptomatic pulmonary cryptococcal infection
should be treated.48,121
One must be mindful that
some immune-competent individuals may have
impaired immunity in the future; therefore, it is
essential that those with previously identified
Cryptococcus be followed up carefully for signs
of reactivation and active infection.
Treatment of Cryptococcus neoformans
Pulmonary Disease
Recommended treatment regimens for crypto-
coccal pulmonary infection are summarized
in Table 2. Immune-suppressed individuals (spe-
cifically, those infected with HIV or have had organ
transplant) with mild cryptococcal pulmonary dis-
ease or asymptomatic colonization (Cryptococcus
isolated from respiratory specimens in the
absence of symptoms or radiographic findings)
can be treated with fluconazole alone. However,
CNS or disseminated disease must be first ruled
out.48,121
The standard dose of fluconazole is
400 mg once daily for 6 to 12 months (longer dura-
tion preferred).48,121
In the setting of severe cryp-
tococcal lung infection or milder lung disease
with concurrent disseminated or CNS infection,
more aggressive therapy is warranted.48,121
In
these cases, the induction treatment consists of
intravenous amphotericin B deoxycholate (AmB;
0.7–1 mg/kg/d) with intravenous or oral flucytosine
(100 mg/kg/d) for 2 weeks followed by fluconazole,
400 mg once daily (OD) for a minimum of
8 weeks.48,121–124
Alternative induction regimens
that can be considered in the absence of flucyto-
sine (if it is not available or not tolerated) include
a longer duration of AmB or increasing the dose
and duration of fluconazole (see Table 2).48,121
Liposomal AmB should be used in place of the
usual deoxycholate formulation in those at risk of
renal dysfunction, which is often the case for trans-
plant patients. Of note, fluconazole has superior
efficacy against Cryptococcus compared with
other azoles. Doses as high as 1200 mg daily
have been used with minimal toxicity, and it has
excellent CNS penetration.48,121
Consequently,
alternate azoles are reserved for resistant isolates
or rare patients with fluconazole intolerance.121
Af-
ter induction, maintenance therapy (or secondary
prophylaxis) should be continued with fluconazole,
200 mg/d, in organ transplants or other forms of
severe immunosuppression for 6 to 12 months.121
In contrast, secondary prophylaxis should be
continued until a CD4 count of 200 or greater is
sustained for at least 3 months in HIV patients on
antiretroviral therapy.48,121
In those with HIV, anti-
retroviral therapy should commence 5 weeks after
initiation of cryptococcal treatment to reduce the
risk of immune reconstitution inflammatory syn-
drome, which can be particularly severe and detri-
mental with CNS cryptococcal infection.121,122,125
The evidence behind what has now become
standard therapy is derived from a few key
studies. A landmark treatment trial for crypto-
coccal meningitis in AIDS patients found that
combined AmB (0.7 mg/kg/d) and flucytosine
(100 mg/kg/d) for 2 weeks had a higher likelihood
of achieving negative cryptococcal cultures
compared with AmB alone.123
Furthermore, pa-
tients who were placed on fluconazole for the
following 8 weeks had a statistically significant
lower fungal burden than those on itraconazole
(regardless of flucytosine use).123
Additional
studies have validated these findings124,126
and
also demonstrated lower risk of relapse with flucy-
tosine use,126
although there was no correspond-
ing difference in mortality.127
In immunocompetent individuals with mild-to-
moderate pulmonary disease (based on combina-
tion of symptoms and radiographic findings) the
Skolnik et al
456

Table 2
Summary of treatment regimens for pulmonary cryptococcal infection
Form of Disease Treatment Comments
Immune suppressedd
1
mild/moderate lung
infection
Fluconazolea
400 mg po OD for 6–12 mo Secondary prophylaxis
required; fluconazole
200 mg po OD
Immunosuppressed (HIV1
and CD4100/mm3
)
1 positive cryptococcal
serum antigen
Fluconazole 800 mg/d for 2 weeks, followed by
400 mg/d for 8 weeks
Secondary prophylaxis
required
Immune suppressed 1
severe lung infection
and/or extrapulmonary
infection
AmB 0.7–1.0 mg/kg/d IV 1 flucytosineb
100 mg/kg/d for 2 wk followed by fluconazole
400 mg po OD for 8 wk
Alternatives
1. Liposomal Amphotericin B (3–6 mg/kg IV
daily) or amphotericin B lipid complex
(5 mg/kg IV daily)1 flucytosineb
100 mg/kg/d
for 2 wk in those with renal failure or chronic
kidney disease followed by fluconazole
2. AmB 0.7–1.0 mg/kg/d IV 1 flucytosine
100 mg/kg/d for 6–10 wk
3. AmB 0.7–1.0 mg/kg/d IV for 6–10 wk
4. AmB 0.7–1.0 mg/kg/d IV and
fluconazole 800 mg OD for 2 wk then
fluconazole 800 mg OD for 8 wk
5. Fluconazole 1200 mg OD 1 flucytosine
100 mg/kg OD for 6 wk
6. Fluconazole 1200–2000 mg OD for 10–12 wk
Secondary prophylaxis
required; fluconazole
200 mg po OD
Immune competent 1
mild/moderate lung
infection
Fluconazolea
400 mg po OD for 6 mo
Alternatives
1. Itraconazole 200 mg po bid for 6 mo
2. Voriconazole 200 mg po bid for 6 mo
3. Posaconazole delayed release (DR) 300 mg po
bid once then 300 mg OD for 6 mo (guided by
drug levels)
4. Fluconazole 400 mg po bid for 6 moc
No secondary
prophylaxis
Immune competent 1
severe lung infection
and/or extrapulmonary
infection
AmB 0.7–1.0 mg/kg/d IV flucytosine
100 mg/kg/d for 2 wk followed by fluconazole
Alternatives
Same as C neoformans treatment in severe
lung or disseminated disease in the immune
suppressed
No secondary
prophylaxis
C gattii 1 mild/moderate
lung infection
Same as C neoformans treatment in mild lung
disease in immune suppressed but may require
longer duration of therapy
No secondary
prophylaxis
C gattii 1 severe lung
infection and/or
extrapulmonary
infection
Same as C neoformans treatment in severe lung
or disseminated disease in immune suppressed
but may require longer duration of therapy
No secondary
prophylaxis
Abbreviations: bid, twice a day; IV, intravenous; po, orally.
a
Fluconazole may be replaced with one of the following if it is unavailable or contraindicated: itraconazole, 200 mg po
bid; voriconazole, 200 mg po bid; or posaconazole delayed release (DR) 300 mg po bid once then 300 mg OD for 6 mo
(guided by drug levels) (but fluconazole is preferred as first line).
b
Flucytosine is given in 4 divided doses.
c
If not responding to standard dosing fluconazole.
d
Immune-suppressed individualsinclude those with HIV, organ transplant,hematologicmalignancy, andonimmunesup-
pressing medications. Treatment regimen may require extension if inadequate response with standard duration.
Data from Limper AH, Knox KS, Sarosi GA, et al. An official American Thoracic Society statement: treatment of fungal
infections in adult pulmonary and critical care patients. Am J Respir Crit Care Med 2011;183(1):96–128; and 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(3):291–322.
457

mainstay of therapy is daily fluconazole for
6 months (see Table 2).48,121
Treatment for severe
pulmonary cryptococcal disease or milder lung
disease with disseminated or extrapulmonary
infection is similar to immunocompromised pa-
tients, where parenteral AmB should be used for
at least the first 2 weeks of treatment, and flucyto-
sine is strongly recommended (see Table 2).48,121
The remainder of treatment may be completed
using 8 to 10 weeks of a daily azole or 6 to 10 addi-
tional weeks of AmB.48,121
As with immune-
suppressed patients, maintenance therapy is
advised.
Treatment of Cryptococcus gattii Pulmonary
Disease
The treatment for mild C gattii pulmonary disease,
such as a single pulmonary cryptococcoma
(nodule) is the same as for C neoformans.121
How-
ever, for severe C gattii pulmonary infection,
a longer induction regimen is recommended (4–
6 weeks of AmB and flucytosine) and longer main-
tenance therapy (up to 18 months of fluconazole
therapy). The longer regimen is thought to be
necessary because C gattii tends to form multiple
or large cryptococcomas, which may be more
difficult to penetrate with antifungal agents.121
There is also a recommendation against the use
of interferon therapy in C gattii lung infections but
greater use of thoracic surgery compared with C
neoformans.121
Treatment Challenges and Complications
Clinicians must maintain a high index of suspicion
for CNS infection regardless of the patient’s im-
mune status, as symptoms may be subtle. Conse-
quently, a lumbar puncture is usually performed in
immunosuppressed individuals and in many
immunocompetent individuals with cryptococcal
lung infection, unless the extent of disease is
limited, such as a nodule with negative serum
cryptococcal antigen.120
Surgical intervention
may also be required if there are complications
caused by compression of vital structures or
persistent focal infection despite optimal medical
therapy, which tends to occur more frequently
with C gattii.
Occasionally, severe cryptococcal infection can
be associated with a profound inflammatory
response and potentially life threatening acute res-
piratory distress syndrome. In these circum-
stances, a short (approximately 1 week) course
of oral corticosteroids is suggested, despite mini-
mal evidence to support this practice.48,121
Notably, dexamethasone was recently found to
have no benefit in patients with cryptococcal
meningitis.128
Adjunctive interferon-g may also
be considered in those with severe C neoformans
infection.48,121
Finally, it is important to monitor
complications from therapy in the form of renal
toxicity (with AmB) or hepatotoxicity (with azoles,
including high dose fluconazole).
Treatment Failure and Resistant Cryptococcal
Infection
The therapeutic goal is resolution of clinical symp-
toms and radiographic findings with eradication of
viable organisms. Residual radiographic abnor-
malities may be present despite microbiologic
cure and persistent positive cryptococcal antigen.
However, this should not necessarily be deemed a
treatment failure if the patient exhibits resolution of
clinical symptoms. Reasons for treatment failure
may include drug intolerance, drug resistance,
inaccessibility to key drugs (as with flucytosine in
developing countries), suboptimal drug concen-
trations, and surgical complications.
Of particular concern, Cryptococcus strains
resistant to key antifungals have emerged in recent
years and require adjustment of standard thera-
peutic regimens. In the setting of fluconazole resis-
tance or intolerance, an alternative azole121
can be
trialed. Itraconazole is one option, although it sac-
rifices the superior CNS penetration and lower
toxicity of fluconazole.121
Similar outcomes have
been observed with voriconazole and AmB/high-
dose fluconazole induction for cryptococcal
meningitis.129
In the setting of AmB resistance/
intolerance, flucytosine and high-dose fluconazole
(800 mg/d to 1200 mg/d) have been used for in-
duction.121
Flucytosine-resistant strains may be
managed with AmB and high-dose fluconazole.
Antifungal susceptibility testing should be consid-
ered treatment failure or when relapse occurs in
the patient. Drug level monitoring (specifically
azoles) may also be helpful in cases slow to
respond to treatment.
Prophylaxis
Primary cryptococcal prophylaxis should be initi-
ated in those with HIV and continued until
the CD4 count is 200 or greater for at least
3 months.48,121
In contrast, guidelines do not
routinely recommend primary cryptococcal pro-
phylaxis in transplant patients; however, screening
for cryptococcal antigen may be considered in
areas with a high incidence of cryptococcal infec-
tion and with primary prophylaxis in those who are
positive for cryptococcal antigen.121
Nevertheless,
most lung transplant centers have some form
of antifungal prophylaxis directly after trans-
plant (although not necessarily cryptococcal
Skolnik et al
458

specific).130
Secondary cryptococcal prophylaxis
with daily fluconazole should be initiated at the
time of completion of induction therapy as dis-
cussed above.48,121
PROGNOSIS
Despite improved diagnostic techniques and treat-
ment options, cryptococcal mortality remains high
even in developed countries (25% to 35%), with a
range between 7% and 65%.52,73,85,89,90,131,132
Mortality with invasive cryptococcal infections is
substantial regardless of immune status, type of
organ involvement, or species (C neoformans vs
C gattii).52,85,90
However, certain modifying factors
seem to increase mortality risk, such as CNS
involvement2,132
and cryptococcemia.132,133
The
presence of organ failure or hematologic malig-
nancy has variable effects on cryptococcal mortal-
ity.132,133
Interestingly, investigators found that
there was no statistically significant difference in
deaths between HIV-positive and HIV-negative pa-
tients with C neoformans infection in one study.48
NEW DEVELOPMENTS AND FUTURE
DIRECTIONS
Research priorities in Cryptococcus include devel-
oping antifungal treatment regimens with lower
toxicity and better efficacy. Recent advances
include the development of novel conjugates or
delivery methods for AmB to improve drug delivery
and efficacy, and lower toxicity. A preparation has
been described that combines AmB with polyeth-
ylene glycol, which resulted in a compound that
had comparable in vitro efficacy against C neofor-
mans but 2 times less toxicity than AmB.134
A
novel delivery method through encapsulated
AmB in a biodegradable fibrin microsphere has
been described.135
This AmB-fibrin microsphere
not only led to sustained drug release but was
also significantly more efficacious at reducing
cryptococcal burden and survival in mice
compared with AmB alone.135
Additionally, adjuncts have been developed to
augment standard anticryptococcal therapy.
Because iron is required for microbial growth, inhi-
bition of iron uptake has been examined in Crypto-
coccus.136
Lai and colleagues136
found that
several iron chelators such as lactoferrin signifi-
cantly improved AmB efficacy in vitro. However,
some chelators interfered with azole therapy indi-
cating that further work will be needed.136
Novel
compounds, such as quercetin and rutin, have
also been investigated as adjuncts to AmB.137
Both agents improved in vitro AmB efficacy, but
only quercetin reduced AmB-related cell toxicity.
There continues to be much interest in devel-
oping a cryptococcal vaccine. Approaches include
cryptococcal proteins, polysaccharide, and whole
avirulent or genetically modified organisms.138–140
Eliciting antibody-mediated immunity and cell-
mediated immunity has shown promise and we
await clinical trials.141,142
Finally, novel antifungal agents and cryptococcal
molecular targets are also under investiga-
tion.143,144
Interestingly, sertraline had comparable
efficacy to fluconazole against Cryptococcus
in vitro and in murine models.143
Highly effective
non–flucytosine-containing regimens are also of
interest, as this drug is not available in many coun-
tries. The combination of terbinafine with flucona-
zole is one such example with excellent in vitro
activity against C neoformans compared with other
regimens.31
Invasive cryptococcal infections contribute to a
high global burden of morbidity and mortality.
Although diagnosis and therapy has improved
over the years, there is still much work to be
done to optimize Cryptococcus management
and improve mortality. Ongoing research is essen-
tial to tackle these important problems.
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