Recent advances in the epidemiology, prevention, diagnosis, and Melanie W. Pound

Transcription

Recent advances in the epidemiology, prevention, diagnosis, and
treatment of fungal pneumonia
Melanie W. Pounda,c, Richard H. Drewb and John R. Perfectc
Although pneumonia caused by fungi is not a common
occurrence in the general population, disease in an enlarging
immunocompromized population is encountered with increasing
frequency. Fungal pneumonias are most frequently caused by
Aspergillus spp., dimorphic fungi and Cryptococcus
neoformans. Recent studies have identified risk factors of
thrombocytopenia, environmental events (such as construction
or renovation) and immunosuppressive drug therapies as being
specific risk factors for invasive fungal disease in select patient
populations. Diagnostic strategies to detect circulating antigens
and polymerase chain reaction based detection systems have
been explored to improve identification prior to the progressive
advanced disease. Advances in prophylactic strategies include
increased use of aerosolized formulations of amphotericin B,
usually in conjunction with new and old systemic antifungal
agents. Despite recent published guidelines for treatment of
fungal pneumonia based on etiology, mortality remains high in
some infections with advanced disease. Caspofungin, a new
echinocandin antifungal, has recently been approved by the US
Food and Drug Administration for the treatment of invasive
Aspergillus infections in patients unresponsive to or unable to
receive amphotericin B. A triazole antifungal, voriconazole, has
shown promise in phase III clinical trials in patients with
refractory fungal infections and is expected to be available in
early 2002. Other echinocandin and triazole antifungals are
under development in attempts to provide improved effective
therapy for fungal pneumonia. Curr Opin Infect Dis 15:183±194. # 2002
Lippincott Williams & Wilkins.
a
Internal Medicine/Infectious Diseases/Academia, bCampbell University School of
Pharmacy, Buies Creek and cDivision of Infectious Diseases, Duke University Medical
Center, Durham, North Carolina, USA
Correspondence to Melanie W. Pound PharmD, P.O. Box 3089, Duke University
Medical Center, Durham, NC 27710, USA
Tel: +1 919 684 6364; fax: +1 919 681 2741; e-mail: [email protected]
Current Opinion in Infectious Diseases 2002, 15:183±194
Abbreviations
ELISA
FDA
IPA
enzyme-linked immunosorbent assay
US Food and Drug Administration
invasive pulmonary aspergillosis
# 2002 Lippincott Williams & Wilkins
0951-7375
Introduction
Fungi rarely cause lower respiratory tract infections in
the general population. Only one of three recent studies
reported fungi as an etiology in this clinical setting [1±3].
In contrast, directed epidemiological studies have
described the growing incidence of fungal pneumonia
in high-risk patient populations (such as those with
AIDS or those who have undergone hematopoietic stem
cell replacement or solid organ transplantation) ranging
from 3±56% (Table 1) [4±20]. Speci®c risk factors in
these patients include poor allograft function and
fulminant hepatic failure before transplantation (in liver
transplant recipients), increased immunosuppression,
cytomegalovirus infection, airway colonization with
Aspergillus (in lung transplant recipients), history of
coccidioidal pulmonary infections, thrombocytopenia,
dialysis dependency and use of OKT3 monoclonal
antibodies [21].
Lower respiratory tract infections can either be the
primary presentation of the disease, such as in the case of
invasive aspergillosis or coccidioidomycosis, or be a
manifestation of a disseminated fungal infection such as
cryptococcosis. A recent study of infectious complications in heart transplant recipients reported invasive
fungal infections in 10.2% of patients [18]. Of these
infections, 37.6% were limited to pulmonary infections
whereas 27% were disseminated disease. The most
common pathogens causing pulmonary fungal infections
in a retrospective study of 140 patients from 1988 to
1997 were Aspergillus (57%), Cryptococcus (21%) and
Candida (14%) [22 . .].
Comprehensive reviews have been previously published
summarizing diagnostic and treatment strategies for
fungal pneumonia [20,23 . .,24 . .,25]. The purpose of this
review is to provide a summary of recent (year 2000 to
present) advances in information regarding the epidemiology, risk factors, prevention, diagnosis and treatment
of fungal pneumonia. In addition, data regarding
potential new treatments undergoing evaluations will
be summarized.
Epidemiology and risk factors
While fungal pneumonia is rare in the general population, it is increasing in incidence in immunocompromised populations. Certain fungal species can be
especially problematic for these individuals; these are
discussed below.
183
184 Respiratory infections
Table 1. Incidence of fungal pneumonia in special patient populations
Population
Incidence of fungal pneumonia
Fungal pathogens
HIV-infected patients
Unavailable (30±45% Cryptococcus)
[4,5]
Bone marrow transplant patients
Allogeneic
Cryptococcus neoformans, Aspergillus spp.,
Coccidioides immitus, Histoplasma capsulatum,
Blastomyces dermatitidis
12±56%
Aspergillus spp, Scedosporium spp.,
Fusarium spp., Candida spp.
[6±8]
Autologous
Solid organ transplant patients
Liver
Kidney
Rare
37%
Unavailable
Lung
Unavailable
Heart
3±10.2%
Aspergillosis
Aspergillus spp. were found to be the primary cause of
fungal pneumonia in a recent review examining pulmonary infections in cancer patients [24 . .]. Up to 90% of
invasive aspergillosis cases start in or are con®ned to the
lungs [26]. In one series, the incidence of invasive
aspergillosis in patients undergoing hematopoietic stem
cell transplantation increased from 7.3% in 1992 to 16.9%
in 1998 [27]. While allogeneic recipients continued to
show the greatest risk of infection, increases were also
observed in those receiving autologous transplantation.
Differences in the onset of invasive fungal infections
relative to transplantation type have been reported.
While the highest period of risk for invasive fungal
infections in liver transplant recipients (including the
risk of aspergillosis) is within 4 weeks of transplantation,
invasive fungal infections in lung transplant recipients
may present several months after transplantation [21].
The median time of presentation of invasive aspergillosis in lung transplantation was 120 days, with 49% of
infections occurring within 3 months, 68% within 6
months, and 79% within 9 months of transplantation
[21]. The highest risk of Aspergillus infections in patients
undergoing bone marrow transplantation is thought to be
during the period of neutropenia. However, recent
reports have cited Aspergillus infections occurring after
engraftment and are associated with graft-versus-host
disease and administration of high doses of steroids. The
risk for bone marrow transplant patients may extend over
the entire year after transplantation [27]. Aspergillus
infections in heart transplant recipients may also have a
variable time course, including late infection. The
®ndings of a recent study by Montoya et al. [18] describe
the median onset of Aspergillus infection as 52 days after
transplantation.
Although A. fumigatus is the predominant species causing
invasive disease, an increase in the incidence of nonfumigatus aspergillosis has been noted in several studies
Aspergillus spp., Cryptococcus neoformans
Cryptococcus neoformans, Aspergillus spp.,
Mucor spp.
Aspergillus spp., Cryptococcus neoformans,
Candida spp.
Aspergillus spp., Candida spp.
Reference
[9,10]
[11±13]
[14,15]
[16,17]
[18,19]
[28 .,29,30 .,31 .]. Of 12 allogeneic bone marrow transplant patients with Aspergillus infection, seven infections
were caused by A. fumigatus and the rest by A. terreus
(n = 3), A. versicolor (n = 1) and A. ustus (n = 1) [30 .]. Other
studies have reported the rate of non-fumigatus aspergillosis to be as high as 25% [31 .]. This has a signi®cant
impact on treatment, since infections due to A. terreus are
usually poorly responsive to amphotericin B therapy
[32,33].
Pulmonary aspergillosis has been associated with the use
of other immunosuppressive therapies besides corticosteroids, such as in¯iximab therapy, desferrioxamine,
cyclosporin A and even high-dose inhaled ¯uticasone
use, although these ®ndings are rare and have only been
noted in case reports [34±36,37 .]. Among other risk
factors for aspergillosis are coinfection with or treatment
for cytomegalovirus infection. For example, bone
marrow recipients receiving more than 4 weeks of
ganciclovir preemptive therapy for cytomegalovirus
infections had an increased risk of invasive aspergillosis
[38]. Each week of ganciclovir treatment beyond 4
weeks increased the risk of invasive fungal infection by
1.4. The association of cytomegalovirus with aspergillosis
was also observed in other recent studies [18,39 .].
Recent associations have been made with thrombocytopenia and the risk of Aspergillus infections in patients
undergoing liver transplantation. One report describes
preinfection thrombocytopenia (platelet counts below
306103/cmm) in all 21 liver transplant patients with
fungal infections [40].
A recent study found those at high-risk for invasive
aspergillosis after culture isolation of Aspergillus from a
nonsterile body site to include groups such as allogeneic
bone marrow transplant patients, hematologic cancer
patients, and those with signs such as neutropenia and
malnutrition [31 .]. The ability to interpret a positive
Aspergillus culture from a sterile body site is directly
related to underlying disease. While above-high-risk
Fungal pneumonia Pound et al. 185
patients are likely to have infection, others like patients
with cystic ®brosis and connective tissue diseases are
more likely to be colonized. There is an intermediate
risk group, which includes AIDS patients, solid organ
transplant patients, and those receiving corticosteroids,
in whom there needs to be more clinical information to
help in prediction of disease [31 .].
Environmental risk factors, such as Aspergillus spores
secondary to hospital construction or renovation and
water supplies, have previously been identi®ed [26]. A
recent retrospective study found 72 cases of invasive
aspergillosis compared with 433 patients colonized with
Aspergillus [29]. Of these cases, 25% were nosocomially
acquired, 62.5% were acquired in the community, and
only 12.5% were from unknown sites or geography [29].
Other investigators have reported the role of environmental control (in combination with the use of
itraconazole prophylaxis) in reducing the rate of Aspergillus infection from 42% to 22.5% in lung transplant
patients, while the absolute reduction in nosocomial
Aspergillus infection was 5.8% [41].
A signi®cant contribution to describing the epidemiology of Aspergillus infections and its treatment
outcomes is the establishment of standard de®nitions
of disease, as well as responses to therapy, based on
patient risk factors, and histopathologic and culture
evidence [31 .]. The diagnosis of invasive aspergillosis
is considered de®nite if there are both positive tissue
sample and culture from that site or if there is a
positive sample from a sterile site regardless of the
tissue results. Probable invasive aspergillosis is de®ned
as having an immunocompromised host with positive
sputum cultures or another organ system meeting
de®nite invasive aspergillosis criteria. The diagnosis of
possible invasive aspergillosis is based on a variety of
criteria including symptoms, chest radiograph and
inability to make a de®nitive diagnosis [31 .]. These
de®nition criteria are necessary due to a high
incidence of Aspergillus colonization in lung transplant
recipients (23%) and tracheobronchitis (4%) when
compared with invasive disease (6%) [21]. Criteria
for disease and uniform criteria for treatment outcome
have helped make comparisons between treatment
modalities more robust.
Despite potent antifungal agents, the prognosis of
patients with invasive aspergillosis remains grim
[41,42 .]. In one series, the overall mortality of patients
with invasive aspergillosis was 58%, and was highest for
bone marrow transplant recipients (86.7%) and for
patients with central nervous system or disseminated
aspergillosis (88.1%) [42 .]. Other investigators describe
3-month survival to be as low as 38% [31 .]. Despite
treatment with amphotericin B deoxycholate and lipid
formulations of amphotericin B, one-half to two-thirds of
patients died as a result of infection.
Other forms of Aspergillus pulmonary disease besides
invasive aspergillosis can be confusing in their management and outcome. According to a recent study, chronic
necrotizing aspergillosis, aspergilloma and allergic
bronchopulmonary aspergillosis were reported at 2%,
4% and 3% respectively from patients with positive
Aspergillus cultures (n = 1209) [31 .]. Of the chronic
necrotizing aspergillosis patients, 16% died within 3
months of positive culture and this group received a
variety of treatments or no treatment. Only one patient
died in a 3 month follow-up among the aspergilloma
patients. Treatment for these patients included amphotericin B, itraconazole and ¯uconazole, but only one case
of surgical resection which probably re¯ects poor
pulmonary functions in this group. As for the allergic
bronchopulmonary aspergillosis patients, only 17%
received itraconazole therapy, but a recent study
suggested bene®t from this azole [43]. There were no
deaths in this group [31 .].
Candidiasis
While most fungal infections are due to Candida spp.,
pneumonia due to Candida spp. is quite rare and is
usually associated with severely ill, immunocompromised individuals or those with septic pulmonary emboli
[44 . .]. In contrast to infection, Candida colonization is
common, and is found in the respiratory tract of up
to 12% of mechanically ventilated patients without
evidence of disease [45].
A recent prospective study examined Candida infections
among predominately cancer patients and found C.
albicans to account for 67.3% (n = 349) [46]. Only 5% of
C. albicans were resistant to the azoles. However, 114
patients were infected with other Candida species,
including C. glabrata (45.6%), C. tropicalis (18.4%), C.
parapsilosis (16.6%) and C. krusei (9.6%). The presence of
non-albicans Candida in up to one-half of patients with
invasive candidiasis raises concerns over the empiric use
of ¯uconazole therapy for these patients, since nonalbicans Candida are less predictably susceptible to
¯uconazole, and C. krusei is considered resistant. The
overall Candida species resistance rate to ¯uconazole was
9.4%. Prior use of an azole antifungal led to a signi®cant
association with C. albicans resistance to ¯uconazole [46].
However, in fungal pneumonias, Candida is a minor
cause.
Cryptococcus
Infections due to Cryptococcus neoformans are usually
manifested as meningitis; in fact, prior to highly active
antiretroviral therapy, as many as 5±15% of HIV patients
were diagnosed with this fungal meningitis [47]. Even in
non-HIV infected patients, the overall mortality rate for
disseminated infection may be as high as 30% [48 . .].
This infection is usually contracted through inhalation of
small yeasts or basidiospores directly into the pulmonary
tract. Pulmonary symptoms, if they occur, are often
similar to other bacterial pneumonia although infection
can progress to acute respiratory failure, even in nonHIV patients [49]. However, this respiratory failure is
most often described in those patients with disseminated
disease [49]. On the other hand, Pappas et al. reported
that as many as 25% of patients with cryptococcal
pulmonary involvement lack respiratory symptoms
[48 . .]. While most patients in the study received
antifungal therapy for isolation of Cryptococcus neoformans
from the lung or airways and ¯uconazole appears to be
the drug of choice for uncomplicated pulmonary infection, only 10% were considered treatment failures [48 . .].
Coccidioidomycosis
Pulmonary manifestations of coccidioidomycosis are
caused by infection with Coccidioides immitis arthrospores
and account for approximately 100 000 fungal infections
per year [50 . .]. Areas endemic for Coccidioides infections
(the southwestern portion of the US, particularly areas of
Arizona, New Mexico, Texas and California, and parts of
Central and South America) often have an increased
infection rate during dust storms, construction and high
winds. Infections have become more frequent as
increased populations move into these areas [50 . .,51].
However, a recent case series reported coccidioidomycosis occurring in non-endemic areas [52]. Therefore,
this disease should be considered in the differential
diagnosis regardless of the geographic area, especially
with immunosuppressed patients and those with a
history of recent travel to endemic areas [52]. Manifestations include primary pulmonary coccidioidomycosis,
chronic progressive pulmonary coccidioidomycosis and
pulmonary manifestations of disseminated coccidioidomycosis. A recent study examined the risk factors
associated with development of coccidioidomycosis and
found a statistically signi®cant association for this fungal
infection with diabetic patients, cigarette smokers, and
those having undergone previous antifungal therapy
[53].
Blastomycosis
The dimorphic fungus, Blastomyces dermatitidis, causes
pulmonary manifestations of blastomycosis. Like Coccidioides, it is also found in certain geographic regions such
as the southeast and central US (in particular the
Mississippi and Ohio River valleys). While this type of
fungal pneumonia is usually infrequent in these endemic
areas, there have been several outbreaks of disease
reported [54]. Acute infection is usually mild and very
seldom is it diagnosed, or therapy given, in the
immunocompetent individual. However, as with any
patient, there is always the potential for dissemination to
occur and patients can develop severe infection (acute
respiratory distress syndrome) or chronic pulmonary
lesions.
Histoplasmosis
Histoplasmosis is caused by Histoplasma capsulatum and
is a frequent respiratory pathogen in endemic areas. This
fungus is found worldwide, including North and Latin
America, and parts of Europe and Asia. In the US, it is
commonly found in the Ohio and Mississippi River
valleys. Like other dimorphic pulmonary fungal infections, histoplasmosis also presents clinically in several
different ways, including acute pulmonary pneumonitis,
mediastinal granulomatous in¯ammation and ®brosis,
chronic pulmonary, cavitary and disseminated disease.
Other fungal pathogens
Paracoccidioidomycosis, penicillinosis and zygomycosis
can also cause pneumonia. Paracoccidioidomycosis is
problematic in Central and South America within
subtropical areas. Penicillinosis is found solely in Southeast Asia and has the potential to disseminate from the
respiratory tract to other organs like the skin in HIVinfected patients.
Zygomycosis includes fungi from the Absidia, Mucor and
Rhizomucor classes. While these fungal pneumonias are
rare, they can be fatal if untreated. A recent report
summarized the experience of four patients with
Cunninghamella bertholletiae pulmonary infection [55]. Of
these patients, all four were treated with amphotericin B
or liposomal amphotericin B and three patients died [55].
Zygomycosis among solid organ transplant patients is
also associated with a high mortality rate (up to 60%),
emphasizing the critical importance of treatment [56].
We generally recommend medical treatment with lipid
products of amphotericin B and surgical debulking or
removal of infarcted lung tissue.
Diagnostic advances
Because the symptoms of fungal pneumonia are often
nonspeci®c, a de®nitive clinical diagnosis based on
presentation is usually impossible and diagnosis is only
helped by risk factors of patients. While histopathologic
and culture methods have become the standard diagnostic tools, these often require invasive procedures to
obtain suf®cient pathologic evidence of invasive disease,
and the airway cultures are from nonsterile sites with
frequent fungal colonization. In addition, cultures from
bone marrow, cerebrospinal ¯uid and blood infrequently
yield Aspergillus growth, and Aspergillus hyphae can be
indistinguishable from certain other hyalohyphomycetes
such as Fusarium or Scedosporium species [57 . .]. Since
respiratory tract cultures may simply be the result of
fungal colonization, the culture isolates from these sites,
which are not sterile, do not necessarily correspond to
disease [31 .,57 . .]. However, risk-strati®cation may help
predict disease. For example, in one study the risk of
invasive aspergillosis was 50±70% in high-risk patients
such as bone marrow transplant patients with a positive
culture for Aspergillus, but in cystic ®brosis patients a
positive sputum culture was rarely associated with
invasive aspergillosis [31 .]. Because of the high mortality
rate associated with these pulmonary fungal infections,
especially invasive pulmonary aspergillosis (IPA), early
diagnosis is likely essential to survival.
In addition to the radiologic diagnosis of IPA by
characteristic ®ndings seen on chest computed tomography (halo sign and cavitary lesions), detection of
circulating fungal antigens would be useful in the
establishment of a diagnosis in immunocompromised
hosts. Enzyme-linked immunosorbent assay (ELISA)
and latex agglutination tests can detect circulating
galactomannan in cases of aspergillosis. In addition,
detection of plasma (1?3)-b-D-glucan may also be
useful in screening for invasive mycoses. While the
ELISA and b-glucan tests are highly speci®c (97% and
84%, respectively in one study of invasive aspergillosis
[58 .]), they may detect disease only in the advanced
stages in some patients. One study reported a mean of
25.8 days and 25.6 days for positive results in latex
agglutination and b-glucan evaluations, respectively [59],
and both of these assays were preceded by a computed
tomography diagnosis of infection by an average of 10.3±
11.3 days. Furthermore, given the species-speci®city of
the galactomannan assay, some emerging non-Aspergillus
mycoses will not be detected [60]. In addition, falsepositive reactions occurred at a rate of 14% in one study
[60]. It is likely that these tests will perform best with
serial screening of high-risk patients and must be
accompanied by other diagnostic strategies (such as
cultures, histopathology, and appropriate radiographic
imaging techniques).
Molecular diagnostic techniques are being evaluated to
quickly and accurately identify certain fungal species. A
recent study revealed polymerase chain reaction technology to be a useful tool in identifying Aspergillus
species. While maintaining high speci®city for IPA
(92%), polymerase chain reaction techniques improved
sensitivity to 79% (compared with 58% and 68% seen
with ELISA and b-glucan, respectively) [58 .]. This same
assay was also shown to be useful for other fungal
species, including Candida and Cryptococcus [61].
The role of antifungal susceptibility testing has recently
been reviewed [62] The US National Committee for
Clinical Laboratory Standards has approved a reference
in-vitro method for testing selected antifungal agents
(¯uconazole, itraconazole and ¯ucytosine) against Candi-
da spp. and Cryptococcus neoformans. The majority of the
data on outcomes of patients with candidiasis represented patients with oropharyngeal disease and not
invasive infections. Therefore, it is more likely that such
susceptibility testing will identify patients who will fail
with a certain therapy, rather than predict those that will
respond. Methods for testing moulds (including Aspergillus spp., Fusarium spp., Rhizopus spp., Pseudallescheria
boydii and Sporothrix schenckii) have also been published
[62]. However, these techniques are often time-consuming and require consistent standards. Also, further
validation of their clinical applications is needed.
Prophylactic strategies
A recent metaanalysis describes the use of oral
¯uconazole as prophylaxis in neutropenic patients
(predominantly cancer patients) and failed to demonstrate a reduction in mortality or systemic fungal
infections [63]. In contrast to this general population,
guidelines have recently been published which discuss
appropriate prophylaxis against opportunistic infections
in high-risk stem cell transplant recipients [64 . .]. As a
primary fungal infection in this population is candidiasis,
and ¯uconazole has been shown to reduce infections and
mortality in this group, the drug is recommended for
allogeneic stem cell transplant patients. Because the rate
of fungal infections is low in autologous bone marrow
transplant patients, antifungal prophylaxis is not generally required [64 . .]. However, the increasing population of stem cell transplants with aspergillosis makes the
evaluation of measures to prevent aspergillosis critical.
Prophylactic strategies against invasive fungal infections
in patients undergoing solid organ transplantation has
also been recently reviewed [21]. While ¯uconazole has
proven to be an effective option in prevention of
Candida infections in liver transplant patients, in certain
high-risk patients, this option is inadequate to provide
effective prophylaxis against Aspergillus infections [65].
Since lung transplant patients are at very high risk for
developing invasive aspergillosis, directed antifungal
prophylaxis is supported [66].
Although not a new strategy, the application of
aerosolized amphotericin B as a prophylactic strategy
(with or without additional systemic prophylaxis) has
received recent attention. The data regarding aerosolized amphotericin B as a prophylactic strategy have
been previously reviewed [21]. Because of its lack of
signi®cant systemic toxicity, ease of administration, low
expense, lack of drug interactions, and ease of monitoring, aerosolized amphotericin B may be an attractive
prophylactic strategy in the prevention of fungal infections. It has been administered to a variety of
immunocompromised patient populations with variable
results [18,67]. A statistically signi®cant decrease
(P50.005) in the incidence of fungal infections was
observed in patients with lung, heart-lung and heart
transplants following prophylactic administration of
aerosolized amphotericin B [68]. A more recent randomized study examined aerosolized amphotericin B to
prevent invasive aspergillosis in patients with prolonged
neutropenia [67]. These patients were predominantly
leukemia and autologous bone marrow transplant patients. The results of this study revealed a lower, but not
statistically signi®cant incidence of invasive aspergillosis,
although the overall incidence of aspergillosis was low
[67].
While experience with the use of intravenous lipidbased formulations of amphotericin B (such as amphotericin B lipid complex and liposomal amphotericin B)
for treatment of known or suspected invasive infection is
growing, there is limited published experience with
these preparations administered prophylactically as an
aerosol [39 .,69]. Experience in the use of the aerosolized
lipid complex in 51 patients undergoing lung transplantation has been recently published [69]. Administration
of 100 mg (ventilated patients) or 50 mg (nonventilated
patients) was well tolerated in the majority of patients
studied (98%). Only two patients had either proven or
probable pulmonary fungal infections due to Candida
during the study. However, extrapulmonary fungal
infection was reported in 8% of the participants,
indicating the potential need for adjunctive systemic
antifungal prophylaxis. Thus, amphotericin B lipid
complex in the aerosol form may be a safe alternative
to traditional aerosolized amphotericin B therapy [69].
Controversies surrounding environmental control for
prevention of aspergillosis have been recently addressed.
Hajjeh and Warnock [26] suggested that invasive
aspergillosis cases are often sporadic in nature and seem
to occur from both the hospital setting as well as the
community. While control measures can be taken to
prevent nosocomial infections, protecting patients once
they leave the hospital is more dif®cult [26]. However,
the introduction of high-ef®ciency particulate air ®lters at
one center dramatically reduced the incidence of IPA in
leukemia patients in the hospital setting with a
statistically signi®cant difference in the rates of IPA
before and after installation of the ®lters (P50.0003)
[70 .]. There has also been concern about the water
supply as a vehicle for transmission of moulds in the
hospital setting, and this potential environmental contamination needs to be checked in each high-risk area
for patient management [71].
Advances in treatment options
The current therapy for treating fungal pneumonia may
be effective for some cases, but limitations of treatment
still exist. Newer agents, however, have been researched
and offer promise in the treatment of fungal infections.
Such new agents are discussed below.
Caspofungin
Echinocandins are a new class of antifungals which
inhibit fungal cell wall synthesis by interfering with
glucan synthesis. Caspofungin is the ®rst echinocandin
to be approved by the US Food and Drug Administration (FDA) for treatment [72,73 . .]. It demonstrates
activity in vitro against a broad spectrum of fungal
pathogens, including A. fumigatus, A. ¯avus, A. terreus and
A. niger and Candida species, including azoleresistant isolates [74]. In contrast, caspofungin lacks
reliable activity against Cryptococcus, other moulds, and
endemic dimorphic fungi [75].
In-vitro and animal studies regarding caspofungin were
recently summarized [73 . .]. An equal or increased
survival rate associated with caspofungin-treated mice
was demonstrated when compared with either placebo or
amphotericin B-treated mice models for disseminated
and pulmonary aspergillosis. In a clinical trial for IPA
(de®nite or probable) refractory or intolerant to conventional therapy, approximately 40% of patients showed a
complete or partial response to caspofungin when
treated for up to 162 days (mean 31.1 days) [76].
Caspofungin is currently FDA-approved as therapy for
IPA refractory to other ®rst-line agents. An intravenous
loading dose of 70 mg on day one is followed by 50 mg
per day on subsequent days, infused over 1 h. While no
adjustment is necessary for patients with renal dysfunction, reductions are recommended for patients with
moderate hepatic insuf®ciency. Caspofungin is not
metabolized by, nor does it induce or inhibit, cytochrome
P450 enzymes frequently responsible for drug interactions. However, increases in alanine aminotransferase
concentrations have occurred in normal subjects during
coadministration with cyclosporin A. Therefore, the
concomitant use of these medications must be justi®ed
by clinical bene®t. Decreases have been observed in the
tacrolimus area under the time±concentration curve by
20%, thereby necessitating close monitoring of tacrolimus
concentrations if coadministered with caspofungin. The
most commonly associated side-effects include fever,
nausea, vomiting and infusion-related venous effects [76].
Several questions remain regarding the application of
caspofungin in clinical practice. While it demonstrates
activity in vitro against Candida spp., published human
experience for Candida infections is limited to esophageal candidiasis [77 .]. Data are lacking in humans
regarding its ef®cacy in invasive candidiasis but should
be available soon, and it is likely that this class of agents
will become part of the routine management of
candidiasis [78±80]. It is also not clear as to the use of
caspofungin in combination with other antifungal agents,
but its mechanism of action would suggest that bene®t
would be increased if the drug was administered early in
infection. Dif®culties in establishing reliable in-vitro
susceptibility testing methodologies for caspofungin
against Aspergillus and Candida may limit use of the
predictive role of this test in patients undergoing
caspofungin therapy.
Amphotericin B aerosol
The role of aerosolized amphotericin B deoxycholate as
an adjunct to systemic therapy for the treatment of
refractory invasive pulmonary fungal infections is not
well de®ned. Previously published case reports have
described its use in combination with systemic therapy
for infections such as tracheobronchial aspergillosis [81].
However, data are lacking from randomized, controlled
trials to adequately describe its role in therapy.
Intravenous itraconazole
Erratic absorption of oral itraconazole capsules has
limited its use in the treatment of severe, invasive
fungal infections [82]. While the oral cyclodextrin
solution has improved bioavailability, it is still recommended to monitor serum concentrations of itraconazole
following oral administration in patients with invasive
fungal infections [83 . .]. The introduction of the
intravenous formulation of itraconazole was intended to
produce a faster and more consistent serum concentration. Caillot et al. [84] evaluated 14 days of intravenous
itraconazole followed by 12 weeks of oral itraconazole
therapy in 31 patients with IPA. The results showed a
48% complete or partial response without severe sideeffects. Intravenous itraconazole has been FDAapproved for the treatment of blastomycosis (pulmonary
and extrapulmonary), histoplasmosis (including chronic
cavitary pulmonary disease and disseminated disease),
nonmeningeal histoplasmosis, and aspergillosis (pulmonary and extrapulmonary) in patients who are intolerant of
or who are refractory to amphotericin B therapy [82,85].
The current dosing recommendations for intravenous
itraconazole include 200 mg (infused over 1 h) twice a
day for a total of four doses, followed by 200 mg per day
for a maximum of 14 days. At this point the patient
should be placed on oral itraconazole. Patients with renal
dysfunction (creatinine clearance 530 ml/min) should
not be placed on intravenous itraconazole because of the
reduced clearance of hydroxypropyl-b-cyclodextrin, a
side-chain moiety. Drug interactions can be problematic
(as with the oral formulation) and certain drugs are
contraindicated with intravenous itraconazole (e.g. cisapride, pimozide, quinidine and dofetilide). It also
interacts with 3-hydroxy-3-methyl-glutaryl coenzyme A
reductase inhibitors metabolized by cytochrome P3A4
[85]. Commonly occurring adverse events include
diarrhea, abdominal pain and nausea and vomiting.
Liver function tests should also be monitored especially
in those patients with liver disease [85].
Lipid-based formulations of amphotericin B
Amphotericin B lipid complex (Abelcet; Elan Pharmaceuticals, San Francisco, California, USA), liposomal
amphotericin B (Ambisome; Fujisawa, Deer®eld, Illinois, USA) and amphotericin B colloidal dispersion
(Amphotec; Intermune Pharmaceuticals, Brisbane, California, USA) are lipid-based formulations of amphotericin B that have demonstrated reductions in the
incidence of nephrotoxicity when compared with
amphotericin B deoxycholate. In addition, liposomal
amphotericin B has demonstrated a reduction in infusion-related reactions when compared with the deoxycholate, but the acquisition cost of these agents is
several-fold higher. In addition, data are lacking to
demonstrate their superiority in the treatment of
invasive pulmonary fungal infections despite the high
concentrations of amphotericin B delivered to the lungs
of those receiving the lipid complex formulation.
According to the Infectious Diseases Society of America
guidelines, these agents are rarely used as ®rst-line
agents and primarily play a role when the patient
experiences worsening renal function with the traditional
treatments [44 . .,50 . .,57 . .,83 . .,86 . .,87]. However, practically they become attractive agents to use when
nephrotoxicity is an issue and high doses of drug need
to be delivered rapidly. This translates into frequent use
of these agents in transplant patients and those with
renal dysfunction.
Voriconazole
Newer triazole antifungal agents have recently been
investigated in attempts to improve upon the activity of
existing agents such as ¯uconazole against Aspergillus
spp. and non-albicans Candida. Voriconazole exhibits
fungistatic activity in vitro against the Candida spp., and
fungicidal activity against the Aspergillus species [88±93].
Voriconazole has been studied in solid organ and bone
marrow transplant patients with histoplasmosis and
invasive pulmonary disease (C. glabrata) [94]. Early data
suggest that voriconazole may be useful in the treatment
of these diseases when patients are unable to take ®rstline therapy. Data from a recent randomized study were
presented which compared initial therapy with amphotericin B to voriconazole in 392 patients with invasive
aspergillosis [95]. Pulmonary invasive aspergillosis was
seen in 84% and 83% of patients, respectively. Patients
in this study were randomized to initial therapy with
either amphotericin B deoxycholate 1 mg/kg (n = 133) or
voriconazole 6 mg/kg62, then 4 mg/kg every 12 h
followed by 200 mg twice daily (n = 144). Therapy could
then continue with alternate agents. The mean length of
therapy for the initial randomized treatment was 11 days
for amphotericin B deoxycholate and 77 days for
voriconazole. A complete or partial response at week
12 was seen in 31.6% and 52.8% of amphotericin B
deoxycholate- and voriconazole-treated patients, respectively (95% con®dence interval for difference 10.4±
32.9%). Survival was 57.9% and 70.8%, respectively
(hazard ratio 0.59, 95% con®dence interval 0.40±0.88).
This study is the ®rst to indicate a signi®cant advance in
the treatment of invasive aspergillosis over standard
amphotericin B deoxycholate.
Voriconazole was recently reviewed by the Advisory
Committee of the FDA [96]. The most common sideeffects observed in the investigational trials included
hepatotoxicity and visual adverse events. Hepatotoxicity
was demonstrated through liver function tests abnormalities, while the visual effects were predominantly
enhanced or altered visual perception with an incidence
as high as 46% [96]. Animal studies suggest that
voriconazole may also prolong QT intervals. Drug
interactions may also be problematic, because it is
metabolized via cytochrome P450. Coadministration of
rifampin and sirolimus with voriconazole is contraindicated. Other drugs that may need to be adjusted or
carefully monitored when coadministered with voriconazole include (but are not limited to) phenytoin,
warfarin, tacrolimus and cyclosporin. While an exact
dosing regimen is unknown at this time, it appears that it
may need to be given twice daily [96].
Cytokine therapy
Available data suggest that cytokines or chemokines may
play a role in assisting in the eradication of fungi
[97 . .,98,99 .]. Interferon-g and granulocyte±macrophage
colony-stimulating factor have been demonstrated to
augment hyphal destruction when used independently
against Aspergillus and Fusarium spp. [98]. Recent
publications have reviewed the potential role of leukocyte transfusions, colony-stimulating factors, and interleukin therapy in the treatment of invasive fungal
infections [97 . .,99 .]. However, more data are needed
in this area before these modalities could be considered
for routine clinical practice. In fact, there is concern that
occasionally cytokines such as granulocyte±macrophage
colony-stimulating factor or granulocyte colony-stimulating factor may bring back a cellular reaction so intense
that it can cause acute respiratory distress syndrome as
neutrophils migrate and degranulate in the site of a
fungal pulmonary infection. It makes a clinician consider
some down regulation of this cytokine cascade with
corticosteroids. However, precise management of the
patient is not clear and needs to be individualized.
Future therapies
In addition to voriconazole, newer triazoles are being
investigated with increased activity in vitro against
Aspergillus and non-albicans Candida. Ravuconazole (formerly known as BMS-207147) demonstrates in-vitro
activity against A. fumigatus and Cryptococcus neoformans
[100,101]. Animal models suggest favorable penetration
of drug into lung tissue [102]. However, clinical studies
are needed to assess ravuconazole's ef®cacy in pulmonary infections. Posaconazole (formerly known as SCH56592) exhibits in-vitro and in-vivo activity against
Cryptococcus neoformans, Candida spp., Aspergillus spp.,
Fusarium solani, Blastomyces dermatitidis, Coccidioides
immitis and Zygomycetes [103±110]. It has demonstrated
ef®cacy in animal models of invasive aspergillosis [111],
and has shown effectiveness against zygomycosis (Mucor
spp.) [112], and coccidioidomycosis [113]. In addition,
activity was demonstrated against disseminated histoplasmosis in CD4, CD8 depleted mice, with ef®cacy
equivalent to amphotericin B and superior to itraconazole [114]. Posaconazole has also been studied in
combination therapy [103]. Posaconazole in combination
with ¯ucytosine, was signi®cantly more effective
(P50.01) than when ¯ucytosine was used alone in the
treatment of cryptococcal meningitis in mice [103].
However, the combination was not more effective than
posaconazole alone. The most common side-effects
associated with posaconazole administration include
diarrhea, ¯atulence, muscle weakness and ocular discomfort [104]. Further evaluations are needed in the
pulmonary setting to fully assess its utility in fungal
pneumonia, but our preliminary experience suggests that
it should effectively treat fungal pneumonias.
In addition to caspofungin, other echinocandins are
being investigated for their potential role in the
treatment of invasive fungal infections. Micafungin
(formerly FK 463) is an echinocandin-like antifungal
agent demonstrating in-vitro activity against Candida,
Aspergillus and Penicillium [115,116]. A recent study
showed that clearance of C. albicans in disseminated
disease was dose-dependent [117]. However this was not
the case in IPA with A. fumigatus [117]. In addition,
combination therapy with amphotericin B has demonstrated synergism in treating pulmonary aspergillosis in
mice [118,119].
Another echinocandin, anidulafungin (formerly LY303366) has also shown in-vitro activity against Candida
spp. and in-vitro and in-vivo activity (animal models)
against invasive aspergillosis [100,120±122]. Clinical
trials are currently evaluating anidulafungin's ef®cacy.
Conclusion
Because of the signi®cant morbidity and mortality
associated with fungal pneumonia, improvements in
prevention, diagnosis and treatment are essential to the
survival of these patients. Prophylactic strategies in highrisk patient populations (such as those undergoing bone
Table 2. Summary of Infectious Diseases Society of America guidelines on the management of primary pulmonary fungal disease
Pathogen
Diagnosis
Treatment
Aspergillus
Invasive pulmonary aspergillosis
Aspergilloma
Allergic bronchopulmonary aspergillosis
Mild±moderate pulmonary symptoms or culture-positive
from respiratory tract
Severe symptoms and immunocompromised hosts
Pneumonia
Primary respiratory
uncomplicated
diffuse pneumonia
Pulmonary nodule, asymptomatic
Pulmonary cavity
asymptomatic
symptomatic
ruptured
Chronic fibrocavitary pneumonia
Life-threatening
Mild to moderate
Acute pulmonary
Chronic pulmonary
AmB (initially), Itra
Surgical resection
Itra, corticosteroids
FLU, Itra, AmB
Cryptococcus
Candida
Coccidioidomyces
Blastomyces
Histoplasma
AmB+5-FC, FLU, Itraa
AmB or FLU
AmB or FLUb
AmB, then oral azole
Surgical resection
No antifungal therapy recommended
Oral azoles if complicationsc
Surgery and AmB
Oral azoles, AmB or surgery if needed
AmB
Itra
AmB + corticosteroids, then Itra
AmB, then Itra
Reference
[57 . .]
[86 . .]
[44 . .]
[50 . .]
[87]
[83 . .]
a
Treatment choice based on phase of therapy: induction, consolidation or maintenance. bTreatment recommended if symptomatic. cComplications
include local discomfort, fungal or bacterial superinfection, hemoptysis. AmB, amphotericin B; Itra, itraconazole; FLU, fluconazole; 5-FC, 5-flucytosine.
marrow transplantation, solid organ transplantation or
certain immunosuppressive cancer chemotherapy) often
require systemic antifungal agents. This may be
augmented with aerosolized amphotericin B to protect
the lung entry of invasive fungi. Advances in diagnostic
laboratory tests may aid in the early detection of disease
if properly studied. Recently published treatment guidelines aid in the selection of treatment for fungal
pneumonias (Table 2), while recent advances in drug
discovery will allow for additional treatment options for
pulmonary disease.
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