Prevention, diagnosis, and treatment of invasive fungal infections in patients with cancer and neutropenia

455
Original Article

Prevention, Diagnosis, and Treatment of
Invasive Fungal Infections in Patients with
Cancer and Neutropenia
Thomas A. Cumbo, MD, and Brahm H. Segal, MD, Buffalo, New York

Key Words
Neutropenia, fever, Candida, Aspergillus, fungal infection

Abstract
Invasive fungal infections are a major cause of morbidity and mortality in patients with prolonged neutropenia and in allogeneic
hematopoietic stem cell transplant recipients. The degree and duration of neutropenia influence the risk of opportunistic fungal infections. Because Candida and Aspergillus species are the major
causes of invasive fungal infections in neutropenic patients, the fungal section of the NCCN guidelines focus on these two pathogens.
Effective prevention and therapy of invasive fungal pathogens is a
priority in highly immunocompromised patients with cancer. Three
strategies in preventing and treating patients at high risk for fungal infection will be considered: (1) prophylaxis; (2) empirical therapy; and (3) treatment for probable or proven fungal infection. In
addition to more effective antifungal agents, growing interest has
been noted in novel non-culture detection methods to facilitate
early diagnosis of invasive fungal infections. (JNCCN 2004;2:455–469)

Invasive fungal infections are a major cause of morbidity
and mortality in patients with prolonged neutropenia
and in allogeneic hematopoietic stem cell transplant recipients (HSCT). The deficits in host defense that render patients susceptible to fungal infections are complex,
but can be broadly divided into the following categories:
(1) neutropenia; (2) qualitative deficits in phagocyte

From the Division of Infectious Diseases, Department of Medicine,
School of Medicine and Biomedical Sciences, SUNY at Buffalo,
Buffalo, New York.

Received May 19, 2004; accepted for publication July 12, 2004.
Dr. Cumbo has no relevant financial disclosures. Dr. Segal receives
financial support in the form of laboratory funding, speaker
honoraria, or consulting fees from Fujisawa Healthcare, Merck Inc.,
Pfizer, and Schering-Plough.
Correspondence: Brahm H. Segal, MD, Division of Infectious
Diseases, Roswell Park Cancer Institute, Buffalo, NY 14263.
E-mail:

function; (3) deficits in mucosal immunity; and (4) deficits
in adaptive (cell-mediated and humoral) immunity.
Because Candida and Aspergillus species are the major causes of invasive fungal infections in neutropenic
patients, the fungal section of the NCCN guidelines focuses on these two pathogens. Effective prevention and
therapy of invasive fungal pathogens is a priority in highly
immunocompromised patients with cancer. Three strategies in preventing and treating patients at high risk for
fungal infection will be considered: (1) prophylaxis, (2)
empirical therapy, and (3) treatment for probable or
proven fungal infection. These strategies correspond to
different levels of risk of fungal infection. Although these
terms are useful operational definitions, the distinction
between these modes is often not easily made in clinical
practice. In addition to more effective antifungal agents,
growing interest has been seen in novel non-culture detection methods to facilitate early diagnosis of invasive
fungal infections. The current NCCN guidelines have
been significantly modified compared with last year, reflecting important new data from clinical trials. Table 1
summarizes the major antifungal agents used in patients
with prolonged neutropenia and HSCT recipients.

Invasive Candidiasis
The opportunistic yeasts cause a spectrum of clinical disease that ranges from superficial and mucosal infections

such as mucosal candidiasis to disseminated disease involving visceral sites. Candida species are endogenous
flora that gain access to the bloodstream through a breach
in an anatomic barrier. The bowel is the principal portal
of entry in patients with acute leukemia receiving highly
mucotoxic regimens.1 Candida species are the fourth most
common nosocomial blood culture isolates in the United

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Table 1 Antifungal Agents
Antifungal agents

Comments

Azoles
Fluconazole

Itraconazole

2nd Generation Azoles

Voriconazole

Posaconazolea

Ravuconazolea

Acceptable alternative to amphotericin B for candidemia at dose of 400 to 800 mg/d;
broad range of MICs to C. glabrata; C. krusei is resistant; prophylaxis in high-risk
patients (e.g., acute leukemia during neutropenia, hematopoietic transplantation);
maintenance therapy for cryptococcal meningitis; inactive against filamentous fungi.
Active against Candida sp., Aspergillus sp., dimorphic fungi, dark-walled molds.
Cyclodextrin formulation has ↑bioavailability compared with capsules and can be
administered parenterally. Itraconazole solution approved for empirical therapy for
neutropenic fever.
2nd generation antifungal triazoles (voriconazole, posaconazole, and ravuconazole)
have broad spectrum of activity, including Candida sp. (including most, but not all,
fluconazole-resistant isolates), Aspergillus sp., dimorphic fungi, C. neoformans,
Trichosporon sp., Fusarium sp., Scedosporium sp., and dark-walled molds.
New standard of care as initial therapy for invasive aspergillosis; treatment of other
filamentous fungi resistant to amphotericin B (Fusarium sp., Scedosporium sp., and
dark-walled molds); poor activity against zygomycetes; acceptable alternative to
amphotericin B formulations as empirical therapy for neutropenic fever.
Similar spectrum of activity to voriconazole, but active against zygomycetes; growing clinical database from compassionate use protocols for treatment of Aspergillus
sp. and other refractory filamentous fungi (Fusarium sp., Scedosporium sp., and
dark-walled molds).
Phase II study in progress.

Polyenes
Nystatin
Amphotericin B desoxycholate (Amb-D)
Lipid formulations of amphotericin B
Liposomal amphotericin B (LAMB)

Amphotericin B lipid complex (ABLC)

Amphotericin B colloidal dispersion
5-flucytosine (5-FC)

Echinocandins

Caspofungin

Micafungina
Anidulafungina

Topical agent useful for mucosal candidiasis; parenteral liposomal nystatin is
experimental.
Broad spectrum of antifungal activity, but with significant infusion-related adverse
events and nephrotoxicity
Equal to or superior efficacy and ↓toxicity compared with Amb-D; ↑↑pharmacy
acquisition cost.
↓proven breakthrough fungal infections and ↓infusion- and nephrotoxicity vs.
Amb-D as empirical therapy for persistent neutropenic fever; ↓infusion- nephrotoxicity vs. amphotericin B lipid complex as empirical therapy.
Extensive compassionate use database for patients with refractory invasive fungal
infections or intolerance to Amb-D; sucessfully used in hepatosplenic candidiasis in
pediatric patients; ↑↑levels in reticuloendothelial system.
Similar efficacy vs. Amb-D as therapy for invasive aspergillosis; ↓nephrotoxicity, but
↑infusion toxicity vs. Amb-D.
Randomized studies support combination Amb-D and 5-flucytosine for cryptococcal
meningitis; pyrimidine analogue with dose- and duration-dependent myelotoxicity
and gastrointestinal toxicity; monitoring of serum levels and adjustment of dosing
for azotemia required.

Class of antifungal peptides that inhibit synthesis of glucan, a fungal cell wall
constituent; potently cidal against Candida sp., including fluconazole-resistant;
fungistatic against Aspergillus sp., principally acting at growing hyphal tips;
infrequent infusion-related events and not nephrotoxic.
Compassionate use study of patients with refractory invasive aspergillosis or intolerance to licensed antifungal agents showed 41% successful responses (superior to
carefully-matched historical controls) led to approval for this indication; favorable
rate of successful outcome and ↓ toxicity vs. Amb-D for invasive candidiasis; comparable efficacy and ↓ toxicity vs. LAMB as empirical therapy for neutropenic fever.
Trend toward ↓ invasive aspergillosis and reduced frequency of empirical antifungal
therapy compared with fluconazole in HSCT recipients
Similar efficacy to fluconazole in AIDS-associated Candida esophagitis; phase III
candidemia trial in progress.

Non-licensed compounds

a

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Prevention, Diagnosis, and Treatment of Invasive Fungal Infections

States.2-4 The crude mortality rate varies in different
series, but is generally between 30% to 60%.5
In a European surveillance study of candidemia in
cancer patients, the overall 30-day mortality was 39%,
with increased mortality occurring in older patients, in
patients with poorly controlled malignancy, and in cases
in which Candida (Torulopsis) glabrata was isolated.6

However, blood stream infection by non-C. albicans
species was associated with neutropenia in solid tumor
patients and acute leukemia and antifungal prophylaxis in hematology patients. Among hematology patients, additional factors associated with mortality were
allogeneic bone marrow transplantation, septic shock,
and lack of antifungal prophylaxis. In a retrospective
study of 476 cases of candidemia at M. D. Anderson
Cancer Center, the mortality rate was 52%.
Neutropenia, a high APACHE score, and disseminated
candidiasis were associated with poorer outcomes.7
Chronic disseminated candidiasis (also termed hepatosplenic candidiasis) is a complication of highly
mucotoxic chemotherapy, such as anthracycline-containing regimens for acute leukemia. During neutropenia, the liver and spleen as well as kidneys, lungs,
skin, bone, and other sites, become seeded by Candida
in the blood stream (which may be undetected by blood
culture).8 The only symptom may be persistent fever after neutrophil recovery. Usually after resolution of neutropenia, numerous target lesions in the liver and spleen
become apparent by radiologic imaging, such as computed tomography (CT) scan, ultrasonography, or magnetic resonance imaging. Serial ultrasound analysis in
patients in whom a high clinical suspicion exists may
further enhance the likelihood of detecting new or
evolving lesions.9 A liver biopsy is required for a definitive diagnosis, but because the lesions are discrete,
a blind percutaneous biopsy may be falsely negative. An
open or laporoscopic-guided liver biopsy should be
considered if a percutaneous biopsy is non-diagnostic.
Alternatively, a trial of systemic antifungal therapy
(amphotericin B formulation, fluconazole, or caspofungin) may be considered without a definitive tissue
diagnosis; resolution of fever and improvement radiographically in response to antifungal therapy would
be considered presumptive evidence of candidiasis.
Chronic disseminated candidiasis per se is not a contraindication for subsequent cytotoxic chemotherapy
or hematopoietic transplantation.10,11 Patients in whom
fever and lesions have resolved with antifungal therapy can undergo further episodes of neutropenia with-

out progression of the fungal infection if antifungal

therapy is reinitiated during the neutropenic periods.11
Therapy for Invasive Candidiasis

All candidemic patients should be treated with systemic antifungal therapy. The NCCN panel’s recommendations on therapy for invasive candidiasis are in
general agreement with recently published guidelines
from the Infectious Diseases Society of America.12
Fluconazole has been shown to be a highly acceptable
alternative to conventional amphotericin B in nonneutropenic patients with principally catheter-associated candidemia.13,14 High-dose fluconazole (800 mg
daily) was recently compared with fluconazole (800 mg
daily) plus conventional amphotericin B in non-neutropenic patients with primarily catheter-associated
candidemia in a randomized, blinded trial.15 Failure of
blood culture clearance was more common in fluconazole versus combination recipients (17% and 6%, respectively), and the combination regimen trended
toward more rapid blood culture clearance. However,
overall survival was similar (despite fluconazole alone
recipients having a poorer physiologic score at randomization), and the combination arm had more frequent infusion-related nephrotoxicity. This study was
not designed to address whether fluconazole plus amphotericin B was more effective than amphotericin B
alone. Among neutropenic patients, fluconazole was
as effective as amphotericin B in a matched cohort16
and in a randomized prospective study.17 To our knowledge, randomized trials evaluating lipid formulations
of amphotericin B as initial therapy of invasive candidiasis have not been published.
Recently, a phase III, randomized, prospective,
double-blinded study compared the echinocandin
caspofungin with conventional amphotericin B in
adults with invasive candidiasis.18 A total of 239 patients were enrolled. In the modified intent-to-treat
analysis, the favorable response rates were 73.4% and
61.7% in the caspofungin and amphotericin B arms,
respectively (P = NS). Among patients who received
at least 5 days of study drug, which was a prespecified
criterion for the “evaluable patients analysis,” caspofungin was statistically superior to amphotericin B
(81% vs. 65% successful outcome, respectively; P <

.05). In candidemic patients, the time to sterilization
of blood was similar between the two arms, but caspofungin showed less toxicity. The small number of enrolled neutropenic patients precluded a comparison
between study arms with adequate power. The overall

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survival was similar between the two groups. This
study strongly supports caspofungin as an option for initial therapy for invasive candidiasis in adults.
Based on these studies, the NCCN panel recommends either caspofungin or fluconazole (400 to 800
mg daily in patients with normal renal function) as initial therapy for candidiasis. Because caspofungin is
fungicidal against virtually all clinical isolates of
Candida species, including azole-resistant strains, the
NCCN panel specifically recommends caspofungin as
therapy for candidemia in the following settings: clinical instability, isolation of C. glabrata or C. krusei, or
breakthrough candidemia in patients receiving azole
prophylaxis. A phase III randomized study comparing
voriconazole with conventional amphotericin B in
patients with invasive candidiasis has completed enrollment, but the results have not yet been presented
publicly.
Amphotericin B formulations are not recommended as initial therapy because of increased toxicity and lack of demonstration of benefit over less
toxic alternatives. Amphotericin B lipid complex

was safe and effective in adult and pediatric patients
with disseminated candidiasis refractory to standard
therapy and in patients intolerant to standard
agents.19–21 In specific rare cases of complicated candidiasis, an amphotericin B formulation (often paired
with 5-flucytosine) should be considered as initial
therapy for invasive candidiasis, such as endocarditis, meningitis, or retinitis with macular involvement. An infectious diseases consultation is strongly
advised.
Early catheter removal may reduce the likelihood
of late complications by eliminating a potential nidus
of ongoing candidemia and should therefore be considered in all patients with candidemia. Removal of intravenous catheters in candidemic patients has been
shown to reduce the time to sterilization of the blood
in non-neutropenic patients in which the catheter
was the likely portal of entry.14,22 In patients who receive chemotherapy with significant mucotoxicity,
candidemia was likely to arise from defects in the gut
mucosa rather than the catheter.1,23,24 In a recent review
of studies of candidemia, Nucci and Anaissie25 noted
the lack of association between early central venous
catheter removal and improved survival, and questioned the routine practice of catheter removal in all
candidemic patients. If the catheter is not removed as
part of the initial management of candidemia, we ad-

vise that it be removed in the setting of lack of resolution of fever within 2 to 3 days or persistent candidemia after 2 days of appropriate antifungal therapy.

Invasive Aspergillosis
Filamentous fungi (molds) are ubiquitous soil inhabitants whose conidia we inhale on a regular basis.
Following inhalation, the respiratory mucosa and alveolar macrophages constitute the first line of host defense
against conidia. At the hyphal stage, neutrophils are
most important in controlling infection. Thus, prolonged neutropenia is a critical risk factor for invasive
aspergillosis.26 Repeated cycles of prolonged neutropenia and concomitant corticosteroid therapy further increase the risk of filamentous fungal infection. Most
filamentous fungal infections are caused by Aspergillus

species. In addition, the frequency of rare but emerging pathogenic fungi commonly resistant to amphotericin B (Scedosporium species, Fusarium species, and
dark-walled molds) has significantly increased over the
past several years among patients with hematologic
malignancies and in HSCT recipients.27
Prolonged and persistent neutropenia is a critical
risk factor for aspergillosis.26 More recent studies have
reported the predominance of aspergillosis cases occurring in the post-engraftment rather than the neutropenic period in allogeneic HSCT recipients, with
immunosuppressive therapy for graft-versus-host disease (GVHD) being a principal risk factor.28–34 There
are three likely reasons for the increased proportion of
invasive filamentous fungal infections in the postengraftment period: (1) shortening of the duration of
neutropenia as a result of infusion of larger numbers
of myeloid progenitors and treatment with colony
stimulating factors; (2) increased proportion of unrelated donors and HLA-mismatched transplants, which
predispose to GVHD; and (3) increased proportion
of patients surviving beyond the early transplant
period.
Aspergillosis can involve virtually any organ in
the immunocompromised host, but sinopulmonary
disease is the most common. In addition to air, hospital water systems may be a source of nosocomial aspergillosis.35 Invasive aspergillosis in the neutropenic
host may present as fever, sinus pain, or congestion,
cough, pleuritic chest pain, and hempotysis. Erosion
through a large central blood vessel wall can lead
to massive pulmonary hemorrhage. The radiographic

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Prevention, Diagnosis, and Treatment of Invasive Fungal Infections

appearance of pulmonary aspergillosis includes bronchopneumonia, lobar consolidation, segmental pneumonia, nodular lesions resembling septic emboli,
and cavitary lesions. The central nervous system is
a common target for hematogenous aspergillosis.
Gastrointestinal aspergillosis usually coexists with
pulmonary disease, but in rare instances, a sole organ is involved. Other sites of disseminated aspergillosis include the skin, heart, eye, bone, kidney,
liver, and thyroid.
Diagnosis

Early diagnosis of aspergillosis in highly immunocompromised patients remains difficult. Blood cultures are rarely positive; sputum and bronchoalveolar
cultures have approximately 50% sensitivity in focal
pulmonary lesions, and definitive diagnosis often requires an invasive procedure and is usually only made
when the disease is advanced. In a patient with neutropenia and a pulmonary infiltrate, isolation of an
Aspergillus species from a sputum or bronchoalveolar
lavage specimen should be presumed to represent invasive disease.36
Chest CT scans facilitate detection of pulmonary
aspergillosis in patients with persistent neutropenic
fever leading to earlier initiation of therapy, which in
turn may be associated with an improved outcome.37
A CT scan may show peripheral or subpleural nodules
inapparent on plain chest radiographs. The “halo sign”
is a characteristic chest CT feature of angioinvasive
organisms.38 The hazy alveolar infiltrates appear to
correspond to regions of ischemia and are highly suggestive of invasive aspergillosis.38
A sensitive double-sandwich enzyme-linked immunosorbent assay (ELISA) for detection of the fungal cell wall constituent galactomannan has been
developed.39 Maertens et al.40 obtained serial serum
galactomannan levels from neutropenic and HSCT
patients at high risk for aspergillosis. The positive and
negative predictive values for predicting invasive aspergillosis were 87.5% and 98.4%, respectively. All
proven cases of invasive aspergillosis, including 23

cases confirmed after autopsy only, had been detected
before death, although serial sampling was necessary
to maximize detection. Prospective serial monitoring
of galactomannan antigenemia in allogeneic HSCT
recipients yielded positive and negative predictive values of 94.4% and 98.8%, respectively, and antigenemia preceded radiographic findings by more than a
week in 80% of cases of invasive aspergillosis.41

Herbrecht et al.42 evaluated the galactomannan
antigenemia assay in 4 groups of patients: neutropenic
fever of unknown etiology, suspected pulmonary infection, suspected extrapulmonary aspergillosis, and
surveillance in HSCT recipients. Among cases of neutropenic fever (n = 261), only 1 possible case of invasive aspergillosis occurred. The positive predictive
value of the antigenemia assay was 7.1% (1 true positive, 13 false positives) and the negative predictive
value was 100% (247 true negatives and no false negatives). Patients received prophylactic or empiric antifungal agents according to the judgment of the
treating physician.
The galactomannan assay was evaluated using
1,890 blood samples from 170 patients at high risk for
invasive mold infection from 3 major cancer centers
in North America. Using a lower cut-off (0.5 units)
than in the European studies, this study found that
the galactomannan assay identified 25 of 31 patients
with invasive aspergillosis (81% sensitivity), and had
a specificity of 89%.43 The FDA recently approved the
Platelia Aspergillus enzyme immunoassay (Bio-Rad
Laboratories, Redmond, WA).
These prospective studies showed significant differences in the sensitivity and positive predictive value
of the antigenemia assay. In the study by Herbrecht et
al.,42 the very low incidence of invasive aspergillosis in
patients with neutropenic fever would be expected to
reduce the positive predictive value of the assay. In
addition, the sensitivity of the assay may be reduced

by concomitant use of antifungal agents with activity
against molds. Serial galactomannan sampling will increase sensitivity. False-positive results may be more
common in children and allogeneic HSCT recipients42 and in persons receiving concomitant
piperacillin tazobactam.44 The variable sensitivity between studies even in cases of definite aspergillosis
highlights the limitation of this assay as the sole diagnostic tool for detecting early Aspergillus infection.
The NCCN panel recommends a chest CT scan
in patients with prolonged neutropenia (≥10 days)
and persistent or recurrent fever of unknown origin and
unresponsive to empirical antibacterial agents. A chest
CT scan may be considered earlier in patients with
multiple prior cycles of potently cytotoxic chemotherapy and in those receiving systemic corticosteroid
therapy. In patients at high risk for invasive mold infection with a pulmonary infiltrate, a positive galactomannan assay establishes the diagnosis of “probable

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aspergillosis,”45 and in general obviates an invasive diagnostic procedure. Insufficient data are available to
recommend routine serial galactomannan monitoring
in patients with persistent neutropenic fever without
physical examination findings suggestive of fungal infection or a lesion on chest CT scan.
Therapy

Important new developments in the antifungal armamentarium have occurred. Lipid formulations of amphotericin B have allowed for greater amounts of drug
delivery with reduced toxicity.21,46,47 Amphotericin B
colloidal dispersion had similar efficacy and survival,
reduced nephrotoxicity, and increased infusional toxicity compared with conventional amphotericin B in
a randomized study of patients with invasive aspergillosis.46 Liposomal amphotericin B48,49 and amphotericin B lipid complex19,21 have been evaluated in
open-label non-randomized studies in invasive aspergillosis. These lipid formulations are safer than conventional amphotericin B, but such studies do not
permit definitive conclusions as to whether they are
more efficacious.
Voriconazole, posaconazole (SCH 56592), and
ravuconazole (BMS 207147) are second-generation
triazoles with a broad spectrum of activity against opportunistic yeasts and molds. Currently, only voriconazole is licensed. Voriconazole was compared with
conventional amphotericin B (1.0 to 1.5 mg/kg daily)
as initial therapy in an open-label, randomized trial of
patients with invasive aspergillosis.50 Voriconazole was
more effective than amphotericin B (51% vs. 32% of
subjects had a complete or partial response) and was
associated with improved survival at 12 weeks (71%
vs. 58%, respectively). Among neutropenic patients,
the success rate in the voriconazole arm was 51%,
which was superior to the amphotericin B arm.50 In a
non-comparative study of 116 patients with invasive
aspergillosis in which voriconazole was given either as
initial (52%) or salvage (48%) therapy, a complete or
partial response occurred in 48% of patients, with a
more favorable prognosis in the initial therapy group.51
In both the randomized and non-comparative studies, the poorest prognosis was seen in extrapulmonary
aspergillosis and in allogeneic HSCT recipients. In a
retrospective analysis of 86 patients with central nervous system (CNS) aspergillosis treated with voriconazole either as primary or salvage therapy, 34% had a
complete or partial response.52 This success rate compares very favorably to previous series in which the

frequency of successful responses to amphotericin B was
almost nil.53 Voriconazole appears to have comparable
safety and efficacy in children with invasive mold infections compared with adults.54 Based on the strength
of this database, the NCCN panel recommends
voriconazole as first-line therapy for invasive aspergillosis.
Aspergillus fumigatus and Aspergillus flavus are the
most common species causing invasive disease in neutropenic patients and after HSCT. Aspergillus terreus
is seen with increasing frequency at several cancer
centers and is notable for being resistant to amphotericin B. Treatment of A. terreus with voriconazole was
associated with improved survival compared with amphotericin B.55
Caspofungin has been evaluated as salvage therapy in patients with invasive aspergillosis refractory to
standard antifungal therapy and in patients intolerant of standard therapy. The frequency of a successful
outcome ranged between 40% to 45%, which compares favorably with carefully matched historical controls.56,57 However, echinocandins have not been
evaluated as initial therapy for invasive aspergillosis.
Significant interest has been noted in combination antifungal therapy pairing an echinocandin with
either an amphotericin B preparation or a secondgeneration azole with activity against Aspergillus
species. The rationale is that echinocandins target a
unique site (the B-glucan constituent of the fungal
cell wall) distinct from that of amphotericin B and
azoles, which target the fungal cell membrane. Studies
in vitro have shown neutral to synergistic activity (but
no antagonism) involving the combination of an
echinocandin with an azole or amphotericin B preparation, and combination therapy has been effective
in animal models of aspergillosis. The published clinical experience involving combination regimens is
limited to small series from single centers.58,59
Randomized studies are required to define the role of
combination therapy as primary therapy for invasive
aspergillosis.
Several centers reasonably use combination regimens as salvage therapy for refractory aspergillosis.
The combination of caspofungin and liposomal amphotericin B as salvage therapy led to a favorable outcome in approximately 40% to 60% patients with

either proven or possible invasive aspergillosis.59,60 In
47 patients with invasive aspergillosis refractory to
amphotericin B preparations, the combination of

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voriconazole and caspofungin was associated with increased survival compared with voriconazole alone
(Kieren Marr, personal communication). Although
these results are promising compared with the historic
success rate of salvage regimens for invasive aspergillosis, these studies are retrospective. Therefore,
other host- and infection-related factors may have influenced the outcome. In cases of invasive aspergillosis refractory to voriconazole, salvage therapy with
caspofungin plus a lipid formulation of amphotericin
B (≥ 5 mg/kg/d) is reasonable.
Patients who recover from an episode of invasive
aspergillosis are at risk for recurrence of infection during subsequent immunosuppression. In a multicenter
European series of 48 patients with aspergillosis who
subsequently underwent HSCT (77% allogeneic), 12
of 41 (29%) receiving secondary prophylaxis had recurrence of infection, compared with 4 of 7 (57%)
who did not.61 Fourteen of 16 (88%) patients with relapsed infection died. Smaller series showed that systemic antifungal therapy (with or without surgical
resection) of primary fungal infection followed by secondary prophylaxis suppressed reactivation in the majority of patients undergoing additional cycles of
cytotoxic chemotherapy or HSCT.
Surgical excision of locally invasive disease, such
as sinusitis, primary cutaneous lesions, intravitreal disease, or bone lesions should be performed when feasible. In neutropenic patients and in allogeneic HSCT
recipients, combined surgery and systemic antifungal
therapy should be considered in cases of apparent localized disease because of the risk of subclinical dissemination.

Antifungal Prophylaxis
The rationale for prophylaxis is to prevent fungal infections in a targeted group of high-risk patients. In
HSCT recipients, two double-blinded, placebo-controlled trials have shown that prophylactic fluconazole
controlled yeast colonization and reduced the rate of
mucosal candidiasis and invasive Candida infections.62,63
The use of empirical amphotericin B for prolonged
neutropenic fever also was delayed. A reduction in
mortality was noted in the study by Slavin et al.,63 in
which most of the patients were allograft recipients.
This effect of fluconazole was found to confer significant long-term improvement in survival, possibly by
reducing Candida antigen-induced gut GVHD.64

In a meta-analysis, antifungal prophylaxis with
either azoles or low-dose amphotericin B reduced the
frequency of superficial and invasive fungal infection
and fungal infection-related mortality in HSCT recipients and in non-transplant patients with acute
leukemia and prolonged neutropenia.65 Viscoli et al.66
noted an association between antifungal prophylaxis
and an increased risk of bacteremia based on a retrospective analysis of clinical trials. This possible association merits evaluation in a prospective study.
Fluconazole prophylaxis reduced fungal colonization, invasive infection, and fungal infection-related
mortality in non-transplant patients with leukemia
and in autologous transplant recipients in a placebocontrolled trial.67 The benefit of fluconazole prophylaxis was greatest in autologous transplant recipients
not receiving colony growth factor support and in patients receiving mucotoxic regimens consisting of cytarabine plus anthracyclines. This finding is consistent
with the bowel being a principal portal of entry for
Candida bloodstream infections. Other studies of nontransplant patients with acute leukemia showed no
significant benefit of fluconazole.68,69 Fluconazole prophylaxis in this population is associated with colonization by azole-resistant Candida strains, which may
be less intrinsically virulent than azole-sensitive C.
albicans based on the low frequency of candidemia,
invasive candidiasis, and attributable mortality.70

Fluconazole is not active against filamentous fungi.
The erratic bioavailability of itraconazole capsules
limits its usefulness as prophylaxis in neutropenic patients, particularly those receiving mucotoxic regimens. The cyclodextrin solution formulation of
itraconazole is a more viable option as prophylaxis in
patients with prolonged neutropenia because intravenous administration leads to therapeutic levels by
3 days,71 and oral absorption is significantly improved
over the capsule form. In a double-blind, placebo-controlled study of 405 patients with hematologic malignancy and prolonged neutropenia, prophylactic oral
solution of itraconazole (2.5 mg/kg twice a day) initiated at the time of chemotherapy resulted in fewer
suspected and proven fungal infections compared
with the control group (24% vs. 33%, respectively;
P < .05).72
A lower incidence of candidemia (1 vs. 8 cases)
and a reduction in use of empirical amphotericin B
was also noted in the itraconazole group. Four cases of
aspergillosis occurred in the itraconazole arm and 1

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case in the placebo arm; the overall low incidence of
mold infection precluded a comparative analysis.
Additional studies have shown that the oral

cyclodextrin formulation of itraconazole is, in general, safe and effective as prophylaxis during prolonged
neutropenia as long as adequate serum levels are maintained.73–77
Winston et al.78 compared itraconazole solution
with fluconazole as prophylaxis in allogeneic HSCT
recipients in an open-label, multicenter, randomized
trial. Antifungal prophylaxis was administered from
day 1 until day 100 after transplant. Proven invasive
fungal infections (mostly Candida and Aspergillus
species) occurred in 6 of 71 itraconazole recipients
(9%) and in 17 of 67 fluconazole recipients (25%)
during the first 180 days of transplantation (P = .01).
Although the researchers noted a trend toward reduction in fungal infection-related mortality in itraconazole recipients, overall 180-day mortality was
similar.
In another randomized study, itraconazole (solution) or fluconazole prophylaxis was administered to
allogeneic HSCT recipients (n = 304) for the first 180
days of transplant and until 4 weeks after therapy for
GVHD was stopped.79 Fewer invasive mold infections
were seen in itraconazole (5%) versus fluconazole
(12%) recipients, and the rates of invasive candidiasis were similar (3% and 2%, respectively). Hepatic
toxicity and discontinuation because of gastrointestinal intolerance were more common in itraconazole
recipients. No difference in survival or fungal-infection free survival occurred. Itraconazole, led to an increase in cyclophosphamide metabolites, which in
turn correlated with hyperbilirubinemia and nephrotoxicity during the early transplant period.80 This finding reinforces a note of caution about itraconazole and
newer second-generation triazoles, which are potent
inhibitors of cytochrome P450 isoenzymes, with regard to the potential for drug-drug interactions. It also
highlights the need for well-designed randomized trials that evaluate safety and efficacy to guide decisions
about use of antifungal agents in specific settings.
Low-dose amphotericin B has been used as prophylaxis in patients receiving chemotherapy for acute
leukemia. Conventional amphotericin B has not been
shown to be more effective than azoles; however, it
does have significantly greater nephrotoxicity,81 and in

our opinion should not be used as primary prophylaxis. Low-dose amphotericin B lipid complex and li-

posomal amphotericin B appear to have similar efficacy and were tolerated well as prophylaxis in patients
with acute myeloid leukemia and myelodysplastic syndrome undergoing induction chemotherapy.82
Prophylaxis with aerosolized amphotericin B (conventional or lipid formulations) merits further evaluation in clinical trials.
The NCCN panel recommends either fluconazole or itraconazole (solution) as prophylaxis in allogeneic HSCT recipients. Prophylaxis should be
administered until at least day 100 after transplantation. Prophylaxis continuation should be considered
in patients with GVHD requiring corticosteroid therapy. Fluconazole or itraconazole should be considered
in patients without transplantation patients with acute
leukemia and in autologous HSCT recipients receiving mucotoxic regimens; prophylaxis should be administered until neutrophil recovery. Itraconazole,
voriconazole, and, to a lesser degree fluconazole are potent inhibitors of specific cytochrome p450 isoenzymes, requiring close monitoring for drug-drug
interactions and appropriate dosing modifications of
agents metabolized via this pathway. Itraconazole is
contraindicated in persons with significant cardiac
dysfunction based on its negative inotropic properties. Intravenous (but not oral) itraconazole should
be avoided in patients with preexisting azotemia based
on the potential for the cyclodextrin vehicle to accumulate systemically and worsen kidney function. A
multicenter randomized trial comparing fluconazole
with voriconazole as prophylaxis in allogeneic HSCT
recipients has begun; at this point, no data are available to support voriconazole as prophylaxis. If an amphotericin B product is used as primary prophylaxis,
a lipid formulation is preferred over conventional amphotericin B because of reduced toxicity. The
echinocandin, micafungin, appears to be highly promising as prophylaxis in HSCT recipients,83 but has not
yet been approved by the FDA. Secondary prophylaxis with an appropriate antifungal agent is advised
in patients with prior chronic disseminated candidiasis11 or invasive filamentous fungal infection61 during
subsequent cycles of cytotoxic chemotherapy or HSCT.

Protected Environments
The Centers for Disease Control (CDC) have proposed detailed guidelines related to infection control
procedures to minimize opportunistic infections after

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Prevention, Diagnosis, and Treatment of Invasive Fungal Infections

HSCT.84 The guidelines related to invasive mold infections can reasonably be extrapolated to other
patients with cancer at high risk for mold infection
(such as those with prolonged neutropenia). Although
well-designed clinical trials have not validated the
use of high-efficiency particulate air (HEPA) filtration, we agree with the CDC recommendation that
HEPA filters be used in rooms of allogeneic HSCT
recipients. The principal benefit of HEPA filtration is
probably related to prevention of mold infections. In
a retrospective analysis, HEPA filters were protective
in highly immunocompromised patients with hematologic malignancies in the setting of an outbreak of
aspergillosis.85 The value of laminar air flow in preventing infections is unclear and is not generally recommended. Routine air sampling to quantify fungal
spore concentrations is also not advised.
Hospital policies vary with regard to patients at
high risk for mold infections using masks when outside of a protected environment. The value of using
masks is unproven. N95 respirators are likely to provide
the best protection; however, fit-testing and training
are required for optimal benefit. They are also uncomfortable and may not be tolerated by patients for
prolonged periods. Routine surgical masks may not
provide any protection from inhalation of fungal spores.
Guidelines related to minimizing patient exposure to
fungal spores during hospital construction have been
previously described in authoritative reviews.84,86

Empirical Antifungal Therapy in
Persistent Neutropenic Fever
The rationale for empirical antifungal therapy for persistent febrile neutropenia is that clinical examination and collection of cultures are not sufficiently
sensitive for early detection of fungal infections. Before
standard implementation of empirical antifungal therapy, there was a correlation between prolonged neutropenic fever and mortality in patients with cancer,
and fungal infection was frequently found at autopsy.87
Two randomized prospective studies showed that
empiric amphotericin B was associated with a trend toward fewer serious fungal infections in antibiotictreated neutropenic patients with persistent fever.87,88
Because fungal infections are uncommonly encountered in the first 7 days of neutropenic fever, empirical antifungal therapy is typically begun between days

4 to 7 of neutropenic fever. We suggest that empiric
antifungal therapy be continued for the duration of
neutropenia.
In a randomized study of patients with neutropenic
fever unresponsive to standard antibacterial agents,
liposomal amphotericin B (LAMB) was associated
with fewer proven breakthrough fungal infections and
less infusion-related and renal toxicity compared with
conventional desoxycholate amphotericin B.46 Using
decision analysis models in which both drug cost and
risk of nephrotoxicity were considered, break-even
points for the cost of LAMB were derived.89 This analysis is valuable in highlighting overall cost of care rather
than solely pharmacy acquisition prices. In another
randomized study of empiric antifungal therapy for
neutropenic fever, LAMB reduced infusion-related
toxicity and nephrotoxicity compared with amphotericin B lipid complex.90
Intravenous followed by oral itraconazole solution (cyclodextrin formulation) was as effective as,
but less toxic than conventional amphotericin B as
empirical therapy for neutropenic fever in an open,
randomized study,91 leading to FDA approval of itraconazole solution for this indication. Prior use of prophylactic fluconazole was similar in both groups. This

is an important consideration given the potential for
cross-resistance of fungal pathogens to different classes
of azoles. Fluconazole also has been used successfully
as empirical therapy for neutropenic fever.92,93 However,
its lack of activity against molds makes fluconazole
unsuitable as empirical antifungal therapy in patients
at high risk for mold infection.
Newer generation azoles and echinocandins are attractive candidates for antifungal prophylaxis and empirical therapy for neutropenic fever. Voriconazole was
compared with LAMB in a non-blinded, randomized
study of empirical antifungal therapy in patients with
persistent neutropenic fever (n = 837 patients, 72%
with hematologic malignancies) unresponsive to antibacterial agents.94 Treatment success was stringently
defined and required fulfillment of all criteria grouped
into a composite outcome. Based on the composite
analysis, the overall success rates were 26% with
voriconazole and 31% with LAMB. Empirical
voriconazole was associated with fewer breakthrough
fungal infections (1.9% vs. 5.0%), with the greatest
protective benefit occurring in the protocol-defined
high-risk patients (relapsed acute leukemia and allogeneic HSCT).

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Although patients were stratified according risk
of fungal infection at the time of enrollment and the
study was prospectively powered to evaluate differences
in breakthrough fungal infections, this endpoint was
not by itself a protocol-defined determinant for successful outcome. Infusion-related and nephrotoxicity
were more common in the LAMB arm, whereas transient visual changes and visual hallucinations were
more common in the voriconazole arm. Because of the
lack of proof of non-inferiority of voriconazole compared with LAMB based on pre-specified endpoints
for a successful outcome, voriconazole was not approved
by the FDA for use as empirical therapy. Voriconazole
has poor in vitro activity against zygomycetes (agents
of mucormycosis), and recent case reports note breakthrough zygomycosis in allogeneic HSCT recipients
receiving voriconazole as prophylaxis and empirical
antifungal therapy.95
Caspofungin was recently compared with LAMB
as empiric therapy for persistent neutropenic fever in
a randomized double-blind study.96 The overall success rate, as defined by a pre-specified composite analysis, was 34% in both arms. The frequency rates of
breakthrough fungal infections were similar in caspofungin (5.2%) and LAMB (4.5%) recipients. Drugrelated toxicities and premature withdrawals because
of drug-related adverse events were significantly lower
in caspofungin recipients. A trend to improved 7-day
post-therapy survival was seen in caspofungin as compared with LAMB recipients (92.6% vs. 89.2%, respectively; P = .051). In patients with a baseline fungal
infection, mortality was 11% in caspofungin and 44%
in LAMB recipients, respectively (P < .01). The results of this study have been published in abstract form
only.
The selection of an empirical antifungal agent
should be tailored to the individual patient and should
broadly consider risk of breakthrough fungal infection, toxicity, and a pharmacoeconomic analysis as
opposed to solely the pharmacy acquisition costs. The

NCCN panel considers the following agents to be acceptable as empirical therapy for neutropenic fever:
amphotericin B (conventional and lipid formulations);
fluconazole; itraconazole (solution); voriconazole; and
caspofungin. Of the amphotericin B formulations, the
committee believes LAMB to be preferable based on
reduced nephrotoxicity. Because fluconazole is not active against filamentous fungi, we believe fluconazole
to be more suitable as prophylaxis during neutropenia

rather than as empirical therapy in patients at high risk
for invasive filamentous fungal infection (acute
leukemia and allogeneic HSCT). In our opinion,
voriconazole and LAMB are equally appropriate options as empirical antifungal therapy, despite the lack
of FDA approval of voriconazole for this indication
(see previous sections). Caspofungin had equal efficacy
and superior tolerability compared with LAMB in a
recently analyzed randomized study presented in
abstract form.96 Assuming these results are confirmed
after publication in a peer-reviewed journal, the
NCCN panel would consider caspofungin to be preferable to amphotericin B formulations as empirical antifungal therapy.

Immune Augmentation
Colony-Stimulating Factors

A corner stone in controlling invasive fungal infections
relates to immune reconstitution. In neutropenic
patients, rapid recovery from neutropenia is of key
importance in resolving an established infection,
particularly invasive fungal infections. Whenever
feasible, discontinuation of immunosuppressive medications (such as corticosteroids) is advised in the setting of serious fungal infections.
Primary administration of colony-stimulating factors (CSF) has reduced the incidence of febrile neutropenia by approximately 50% in randomized trials

in adults in whom the incidence of neutropenic fever
was greater than 40% in the control group. In patients
with acute myelogenous leukemia, CSFs produce a
modest decrease in the duration of neutropenia, which
in some studies has translated into a reduction in the
duration of fever, use of antibiotics, and hospitalization.97,98 This benefit has mainly been shown in patients 55 years of age or older and after consolidation
chemotherapy. With the exception of one placebocontrolled study in which granulocyte-macrophage
(GM)-CSF was associated with a lower frequency of
fatal fungal infections and early mortality in acute
myelogenous leukemia,99 CSFs have not produced a
survival advantage.
The American Society of Clinical Oncology
(ASCO) has recommended that prophylactic CSFs
(G-CSF and GM-CSF) be used only in populations in
which the frequency of febrile neutropenia is likely to
exceed 40%.100 The ASCO guidelines also suggested
that certain patients receiving a relatively non-myelo-

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Prevention, Diagnosis, and Treatment of Invasive Fungal Infections

suppressive regimen might benefit from CSFs if they
are at high risk for infectious complications. In our
opinion, patients with prior serious or life-threatening
infection such as invasive fungal infection should also
be considered for CSF treatment during subsequent

chemotherapy.
The rationale for CSFs for established infections
(as opposed to prophylaxis) stems from both the quantitative and qualitative effects of these agents on
phagocytic cells. In neutropenic patients with lifethreatening infections, survival is strongly influenced
by the rapidity of neutrophil recovery. Randomized
trials have not shown a benefit for CSFs as adjunct
therapy for uncomplicated neutropenic fever. Although the benefit of a CSF for established infections
is unproven, it may be considered in the setting of
profound neutropenia (ANC < 100/mcL) and in serious infections, including invasive fungal infection
(Category 2B).

in cases of documented infections that are likely to
respond to conventional therapy. In some highly alloimmunized patients, transfused granulocytes are rapidly consumed and are likely to have more toxicity
than benefit. In allogeneic transplants in which the
donor and recipient are cytomegalovirus (CMV)
seronegative, using CMV seronegative granulocyte
donors is advised.102

Granulocyte Transfusions

Invasive fungal infections are a major cause of morbidity and mortality in patients with prolonged neutropenia and in allogeneic HSCT recipients. Seminal
advances in the antifungal armamentarium have been
made, leading to new standards of care. In addition,
newer non-culture–based diagnostic assays permit earlier diagnosis of invasive aspergillosis and may obviate an invasive procedure in specific settings. We have
stressed an evidence-based approach to guide the use
of these new treatment and diagnostic modalities.
New areas of research will focus on modeling combination antifungal agents, drug discovery (facilitated
by identification of promising drug targets using A. fumigatus genomics data), and immune augmentation.

The rationale for granulocyte transfusions is to provide

supportive therapy for the neutropenic patient with a
life-threatening infection by augmenting the number
of circulating neutrophils until myeloid regeneration
occurs. Today, the impetus to reexamine the role of
granulocyte transfusions stems largely from improvements in donor mobilization methods. Price et al.101
conducted a phase I to II study of granulocyte transfusions derived from unrelated, non-HLA-matched
community donors, after G-CSF and dexamethasone
mobilization. Chills, fever, and oxygen desaturation of
3% or more occurred in association with 7% of transfusions, but did not limit therapy. Eight of 11 patients
with bacterial infections or candidemia survived, but
all 8 patients with invasive mold infection died. This
study showed the safety and feasibility of using community donors for granulocytapheresis donations.
In the absence of modern, prospective, randomized studies, the NCCN panel recommends that granulocyte transfusions should be reserved for patients
with prolonged neutropenia and life-threatening infections refractory to conventional therapy (Category
2B). Filamentous fungi are likely to constitute the majority of such refractory infections. Given the potential toxicity and unproven benefit of granulocyte
transfusions, it is also acceptable to not use granulocyte transfusions as adjunctive therapy. Currently,
there is no justification (outside of a clinical trial) to
use granulocyte transfusions either as prophylaxis or

Other Immune Augmentation Strategies

Other immune augmentation strategies have been
used in refractory invasive fungal infections, which
include infusions of donor lymphocytes in allogeneic
HSCT recipients and use of recombinant interferongamma (IFN-␥). Data are limited to case studies, and
the NCCN panel is therefore unable to make any recommendations about these adjunctive therapies.

Conclusions

Acknowledgment

The authors are grateful to Nikolaus Almyroudis, MD,
for his expert review and helpful comments.

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