Professional Documents
Culture Documents
Cryptococcal Lung Mycoses
Cryptococcal Lung Mycoses
Cryptococcal Lung Mycoses
Infections
Kate Skolnik, MDa, Shaunna Huston, PhDb, Christopher H. Mody, MDc,d,*
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.
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
tests are nondiagnostic, but clinical suspicion for 400 mg once daily for 6 to 12 months (longer dura-
Cryptococcus remains high because of exposure tion preferred).48,121 In the setting of severe cryp-
history, further diagnostic testing may be required. tococcal lung infection or milder lung disease
In some situations, a video-assisted thoraco- with concurrent disseminated or CNS infection,
scopic biopsy or a surgical wedge resection may more aggressive therapy is warranted.48,121 In
be considered if a pulmonary nodule is growing these cases, the induction treatment consists of
and cannot be accessed by bronchoscopy or intravenous amphotericin B deoxycholate (AmB;
percutaneous biopsy.93 Surgical intervention may 0.7–1 mg/kg/d) with intravenous or oral flucytosine
be important in individuals with risk factors for (100 mg/kg/d) for 2 weeks followed by fluconazole,
lung cancer or immune suppression. These biopsy 400 mg once daily (OD) for a minimum of
and surgical specimens should be sent for fungal 8 weeks.48,121–124 Alternative induction regimens
cultures in addition to histopathology. that can be considered in the absence of flucyto-
sine (if it is not available or not tolerated) include
TREATMENT a longer duration of AmB or increasing the dose
Treatment Indications and duration of fluconazole (see Table 2).48,121
Liposomal AmB should be used in place of the
Antifungal treatment may not be required for usual deoxycholate formulation in those at risk of
everyone with Cryptococcus that is isolated from renal dysfunction, which is often the case for trans-
the lungs. In some individuals, Cryptococcus plant patients. Of note, fluconazole has superior
may simply be colonizing the airways, and patients efficacy against Cryptococcus compared with
remain asymptomatic. Occasionally, cryptococcal other azoles. Doses as high as 1200 mg daily
pulmonary nodules may also not require treatment have been used with minimal toxicity, and it has
if involvement is minimal and patients have no excellent CNS penetration.48,121 Consequently,
symptoms.48 However, immune-suppressed indi- alternate azoles are reserved for resistant isolates
viduals with pulmonary Cryptococcus should be or rare patients with fluconazole intolerance.121 Af-
offered antifungal therapy.48,121 Therapy is partic- ter induction, maintenance therapy (or secondary
ularly important in those with impaired cell- prophylaxis) should be continued with fluconazole,
mediated immunity, such as those receiving 200 mg/d, in organ transplants or other forms of
immunosuppressive therapy after organ trans- severe immunosuppression for 6 to 12 months.121
plant, those with hematologic malignancies, those In contrast, secondary prophylaxis should be
receiving chemotherapy or biologic agents, and continued until a CD4 count of 200 or greater is
those with long-term prednisone use. There is sustained for at least 3 months in HIV patients on
also a lower threshold to treat asymptomatic indi- antiretroviral therapy.48,121 In those with HIV, anti-
viduals with mild immune impairment, such as retroviral therapy should commence 5 weeks after
diabetes or severe renal failure. In addition, initiation of cryptococcal treatment to reduce the
immune-competent individuals with mild to severe risk of immune reconstitution inflammatory syn-
symptomatic pulmonary cryptococcal infection drome, which can be particularly severe and detri-
should be treated.48,121 One must be mindful that mental with CNS cryptococcal infection.121,122,125
some immune-competent individuals may have The evidence behind what has now become
impaired immunity in the future; therefore, it is standard therapy is derived from a few key
essential that those with previously identified studies. A landmark treatment trial for crypto-
Cryptococcus be followed up carefully for signs coccal meningitis in AIDS patients found that
of reactivation and active infection. combined AmB (0.7 mg/kg/d) and flucytosine
(100 mg/kg/d) for 2 weeks had a higher likelihood
Treatment of Cryptococcus neoformans
of achieving negative cryptococcal cultures
Pulmonary Disease
compared with AmB alone.123 Furthermore, pa-
Recommended treatment regimens for crypto- tients who were placed on fluconazole for the
coccal pulmonary infection are summarized following 8 weeks had a statistically significant
in Table 2. Immune-suppressed individuals (spe- lower fungal burden than those on itraconazole
cifically, those infected with HIV or have had organ (regardless of flucytosine use).123 Additional
transplant) with mild cryptococcal pulmonary dis- studies have validated these findings124,126 and
ease or asymptomatic colonization (Cryptococcus also demonstrated lower risk of relapse with flucy-
isolated from respiratory specimens in the tosine use,126 although there was no correspond-
absence of symptoms or radiographic findings) ing difference in mortality.127
can be treated with fluconazole alone. However, In immunocompetent individuals with mild-to-
CNS or disseminated disease must be first ruled moderate pulmonary disease (based on combina-
out.48,121 The standard dose of fluconazole is tion of symptoms and radiographic findings) the
457
Table 2
Summary of treatment regimens for pulmonary cryptococcal infection
mainstay of therapy is daily fluconazole for meningitis.128 Adjunctive interferon-g may also
6 months (see Table 2).48,121 Treatment for severe be considered in those with severe C neoformans
pulmonary cryptococcal disease or milder lung infection.48,121 Finally, it is important to monitor
disease with disseminated or extrapulmonary complications from therapy in the form of renal
infection is similar to immunocompromised pa- toxicity (with AmB) or hepatotoxicity (with azoles,
tients, where parenteral AmB should be used for including high dose fluconazole).
at least the first 2 weeks of treatment, and flucyto-
sine is strongly recommended (see Table 2).48,121 Treatment Failure and Resistant Cryptococcal
The remainder of treatment may be completed Infection
using 8 to 10 weeks of a daily azole or 6 to 10 addi-
The therapeutic goal is resolution of clinical symp-
tional weeks of AmB.48,121 As with immune-
toms and radiographic findings with eradication of
suppressed patients, maintenance therapy is
viable organisms. Residual radiographic abnor-
advised.
malities may be present despite microbiologic
cure and persistent positive cryptococcal antigen.
Treatment of Cryptococcus gattii Pulmonary
However, this should not necessarily be deemed a
Disease
treatment failure if the patient exhibits resolution of
The treatment for mild C gattii pulmonary disease, clinical symptoms. Reasons for treatment failure
such as a single pulmonary cryptococcoma may include drug intolerance, drug resistance,
(nodule) is the same as for C neoformans.121 How- inaccessibility to key drugs (as with flucytosine in
ever, for severe C gattii pulmonary infection, developing countries), suboptimal drug concen-
a longer induction regimen is recommended (4– trations, and surgical complications.
6 weeks of AmB and flucytosine) and longer main- Of particular concern, Cryptococcus strains
tenance therapy (up to 18 months of fluconazole resistant to key antifungals have emerged in recent
therapy). The longer regimen is thought to be years and require adjustment of standard thera-
necessary because C gattii tends to form multiple peutic regimens. In the setting of fluconazole resis-
or large cryptococcomas, which may be more tance or intolerance, an alternative azole121 can be
difficult to penetrate with antifungal agents.121 trialed. Itraconazole is one option, although it sac-
There is also a recommendation against the use rifices the superior CNS penetration and lower
of interferon therapy in C gattii lung infections but toxicity of fluconazole.121 Similar outcomes have
greater use of thoracic surgery compared with C been observed with voriconazole and AmB/high-
neoformans.121 dose fluconazole induction for cryptococcal
meningitis.129 In the setting of AmB resistance/
Treatment Challenges and Complications intolerance, flucytosine and high-dose fluconazole
(800 mg/d to 1200 mg/d) have been used for in-
Clinicians must maintain a high index of suspicion
duction.121 Flucytosine-resistant strains may be
for CNS infection regardless of the patient’s im-
managed with AmB and high-dose fluconazole.
mune status, as symptoms may be subtle. Conse-
Antifungal susceptibility testing should be consid-
quently, a lumbar puncture is usually performed in
ered treatment failure or when relapse occurs in
immunosuppressed individuals and in many
the patient. Drug level monitoring (specifically
immunocompetent individuals with cryptococcal
azoles) may also be helpful in cases slow to
lung infection, unless the extent of disease is
respond to treatment.
limited, such as a nodule with negative serum
cryptococcal antigen.120 Surgical intervention
Prophylaxis
may also be required if there are complications
caused by compression of vital structures or Primary cryptococcal prophylaxis should be initi-
persistent focal infection despite optimal medical ated in those with HIV and continued until
therapy, which tends to occur more frequently the CD4 count is 200 or greater for at least
with C gattii. 3 months.48,121 In contrast, guidelines do not
Occasionally, severe cryptococcal infection can routinely recommend primary cryptococcal pro-
be associated with a profound inflammatory phylaxis in transplant patients; however, screening
response and potentially life threatening acute res- for cryptococcal antigen may be considered in
piratory distress syndrome. In these circum- areas with a high incidence of cryptococcal infec-
stances, a short (approximately 1 week) course tion and with primary prophylaxis in those who are
of oral corticosteroids is suggested, despite mini- positive for cryptococcal antigen.121 Nevertheless,
mal evidence to support this practice.48,121 most lung transplant centers have some form
Notably, dexamethasone was recently found to of antifungal prophylaxis directly after trans-
have no benefit in patients with cryptococcal plant (although not necessarily cryptococcal
Cryptococcal Lung Infections 459
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