Infect Dis Clin N Am 16 (2002) 875–894

Aspergillosis
Pathogenesis, clinical manifestations,
and therapy
Kieren A. Marr, MDa,*, Thomas Patterson, MDb,
David Denning, MB, BSc
a
Program in Infectious Diseases, Fred Hutchinson Cancer Research Center,
1100 Fairview Avenue, N. D3-100, Seattle, WA 98109, USA
b
Department of Medicine, The University of Texas Health Sciences Center at San Antonio,
Mail Code 7881, 7703 Floyd Curl Drive, San Antonio, TX 78229–3900, USA
c
Department of Infectious Diseases and Tropical Medicine, North Manchester
General Hospital, Crumpsall, Manchester M8 6RR, United Kingdom

Diseases caused by Aspergillus species are numerous, ranging from aller-

gic manifestations, to pulmonary saprophytic or locally destructive disease,
to the almost uniformly fatal infection that disseminates from the lungs to
distal organs in severely immunocompromised persons. Within the last few
decades, several events have increased the importance of diseases caused by
Aspergillus species. First, an increase in overall incidence has been noted,
largely attributed to an increased at-risk population. Also, the introduction
of new antifungals with variable activity against molds emphasizes new
requirements that clinicians become aware of therapeutic alternatives other
than amphotericin B. This article focuses on the epidemiology and pathogen-
esis of diseases caused by Aspergillus species, and diagnosis and therapy of the
most morbid manifestation, invasive aspergillosis.

Mycology, pathogenesis, and host defense

More than 180 species within the genus Aspergillus have been described to
date. These organisms are ascomycetes within the subdivision Deuteromyco-
tina, because most do not undergo sexual reproduction [1]. The typical

* Corresponding author.
E-mail address: kmarr@fhcrc.org (K.A. Marr).
Program in Infectious Diseases, Fred Hutchinson Cancer Research Center, 1100 Fairview
Avenue, N. D3-100, Seattle, WA 98109.

0891-5520/02/$ - see front matter Ó 2002, Elsevier Science (USA). All rights reserved.
PII: S 0 8 9 1 - 5 5 2 0 ( 0 2 ) 0 0 0 3 5 - 1
876 K.A. Marr et al / Infect Dis Clin N Am 16 (2002) 875–894

asexual growth stage and cellular forms of Aspergillus species are shown in
Fig. 1. The saprophytic, environmental state of the organism is that which
most people recognize as mold; formation of aerial hyphal stalks with asex-
ual reproduction of conidia creates the fluffy consistency and color that is
characteristic of each Aspergillus species. Conidia, which are readily aerosoli-
zed, represent the mechanism by which these organisms spread within the
environment and cause pulmonary infection after inhalation. Growth into
angioinvasive filamentous forms results in local pulmonary inflammation,
destruction, and potentially, hematogenous dissemination.
Although the infective form of the organism is conidia, usually acquired
through a respiratory route, hyphal growth results in disease in tissue, and
extrapulmonary dissemination. The incubation period of invasive infection
is highly variable, extending from 2 days to more than 3 months. The clin-
ical manifestations of aspergillosis are both the result of the degree to which
the organism invades and destroys tissues, and the manifestation of the
hosts’ (appropriate or inappropriate) immune response. Conidia encounter
multiple lines of defense brought forth by the pulmonary environment.
Physical barriers and entrapment by bronchial mucous are probably more ef-
ficacious against species with larger conidia, and less effective against Asper-
gillus fumigatus, the most common cause of disease, because this organism
has very small conidia, with diameters approximating 2 to 3 lm. Multi-
ple investigators have noted antifungal activity of antimicrobial peptides,
but the first line of cellular defense against conidia are macrophages, which
ingest conidia, kill germinating cells, and secrete cytokines and chemokines

Fig. 1. Cellular morphology of Aspergillus species during environmental and in vivo growth.
Conidia, infectious forms, are aerosolized by aerial hyphae growing in the environment.
Organisms acquired through the respiratory tract germinate into filamentous forms, which may
invade pulmonary vasculature and disseminate hematogenously. (Adapted from images
acquired through the Aspergillus web site [www.aspergillus.man.ac.uk]; with permission).
 K.A. Marr et al / Infect Dis Clin N Am 16 (2002) 875–894 877

to coordinate secondary cellular defenses [2–6]. Efficacy may be enhanced by

conidial opsonization with complement or collectins, such as mannose-
binding lectin and surfactant proteins [7,8]. Germinating conidia and hyphae
that escape macrophage surveillance are destroyed primarily by neutrophils
and monocytes [9,10]. A role for T lymphocytes has been demonstrated, espe-
cially in resolving the more chronic forms of infection. Administration of cyto-
kines that stimulate a Th1-type of response has been associated with both
decreased mortality after infection and protection against infection in murine
models [11–13]. T cells may mediate the effector function of macrophages [2].
Multiple lines of defense work coordinately against the different cellular
states of the organism to decrease microbial burden and prevent invasive
infection. Other clinical manifestations arise because of aberrant inflamma-
tory responses, or an incomplete resolution of appropriate responses. At one
end of the spectrum, the purely inflammatory syndrome allergic broncho-
pulmonary aspergillosis (ABPA) is characterized by exuberant Th2-type
CD4+ T-cell responses to Aspergillus antigens [14]. At the other end of the
spectrum is invasive aspergillosis, in which hyphae invade tissue. Even in
this context, however, there is additional evidence that exuberant, or dysre-
gulated inflammation can characterize the clinical manifestations and much
of the pathology of invasive aspergillosis. The histologic course of disease,
as described in animal models, is characterized by the rapid development
of a neutrophilic infiltrate, followed by inflammation that is composed of
primarily mononuclear cells [3]. The latter component, which may be impor-
tant in coordinating resolution of inflammation or ‘‘clean-up,’’ is delayed
and sustained in animals administered corticosteroids [3,15]. Studies per-
formed in rabbits demonstrated that neutropenic animals develop infection
disseminated to extrapulmonary tissues, and histopathology of pulmonary
sections shows prominent fungal elements and hemorrhagic necrosis. Ani-
mals at risk for aspergillosis after administration of cyclosporine A and
corticosteroids die at equivalent rates, but pulmonary histopathology is
characterized predominantly by mononuclear inflammation [15]. These
studies emphasize that the clinical manifestations of diseases caused by
Aspergillus species may be attributed both to tissue invasion by the fungus,
and to the physiologic effects of the host response.
Aspergillus fumigatus is the most common species to cause disease, impli-
cated in approximately 90% of invasive cases in the literature. Although few
specific virulence factors of this organism have fulfilled Koch’s postulates,
studies have shown that some of the important factors involved in its
increased pathogenicity include conidial characteristics, such as size, adhe-
sins [16–18], and hydrophobicity [19], and the presence of cell wall pigments
with antioxidant activity [20,21]. Hyphal factors thought to be important in
conferring pathogenicity include antioxidant defenses, such as mannitol
(hydroxyl scavenger), catalases (H2O2 scavenger) [22,23], and superoxide
dismutases [24], and enzymes, such as phospholipases [25] and proteases
[26–29], that function to suppress immune function and destroy tissues. For
878 K.A. Marr et al / Infect Dis Clin N Am 16 (2002) 875–894

an extensive discussion of virulence factors and host defense against A. fumi-

gatus, readers are referred to a recent comprehensive review [30].
Other Aspergillus species do cause disease, and recent data suggest that the
role of these other organisms as pathogens may be increasing [31]. Differen-
ces in both disease patterns and antifungal susceptibilities have recently been
described. For instance, Aspergillus flavus has been implicated as the cause of
a disproportionate number of infections limited to the paranasal sinuses [31].
Although Aspergillus terreus is an uncommon cause of invasive disease, it is
resistant to amphotericin B, and infection has been associated with very high
mortality [32–34]. Aspergillus nidulans is a common cause of infection in peo-
ple with chronic granulomatous disease [35], although it remains an uncom-
mon cause of infection in patients with hematologic malignancies. Finally,
there is indication that some of these organisms may be acquired through dif-
ferent environmental (or nosocomial) sources. For instance, Aspergillus
niger, which is an infrequent pathogen but a frequent colonizing isolate in the
gastrointestinal tract [31,36], was recovered in the largest amounts in and
around hospital water distribution systems, which may serve as a potential
source of infection [37,38]. Other investigators noted that A. terreus might
be acquired through nosocomial exposure to plants [39].
Variable epidemiology, pathogenicity, and even antifungal susceptibility
patterns may dictate important differences in clinical manifestations, ther-
apy, and outcome of diseases caused by Aspergillus species. Although iden-
tification of hyphal forms characteristic of Aspergillus species in tissue
biopsies constitutes one common method of diagnosis, other agents of hya-
lohyphomycosis, such as Fusarium spp. and Pseudallescheria spp., may be
indistinguishable on tissues samples. In addition, because Aspergillus species
are identified based on morphologic characteristics of conidial and conidio-
phore morphology, laboratory growth of the organism is necessary to deter-
mine the species. Because variable antifungal susceptibilities exist among
Aspergillus species, the importance of mycologic identification for therapeu-
tic decision making cannot be overemphasized.

Clinical manifestations, epidemiology, diagnosis, and management

The spectrum of clinical manifestations includes primary allergic manifes-
tations, saprophytic involvement, and invasive infection, largely dictated by
the degree or specific type of immune deficit (Fig. 2). Risks, clinical manifes-
tations, diagnosis, therapy, and outcomes of each differ.

Allergic disease
Aspergillus species are one of the many fungal genera capable of produc-
ing allergens that elicit allergic reaction in the sinuses or airways, potentially
causing asthma, allergic sinusitis, alveolitis, and ABPA. Although these
 K.A. Marr et al / Infect Dis Clin N Am 16 (2002) 875–894 879

Fig. 2. The spectrum of clinical manifestations (right) relative to degree (or type) of immune
suppression. The risk of invasive disease increases concomitant with the degree of immune
suppression. Not shown on this spectrum is the concept that the specific immune deficit may
lead to clinical manifestations (ie, chronic CD4+ T-cell depletion may predispose for
tracheobronchitis, whereas granulocytopenia is a risk for invasive pulmonary aspergillosis).

ubiquitous organisms can be potent aeroallergens, the relative importance of

Aspergillus species in the pathogenesis of allergic inhalant diseases, such as
asthma or rhinitis, is not well understood. More attention has been paid to
ABPA, which is a type I and type III hypersensitivity to A. fumigatus grow-
ing in airway mucous. This most severe form of fungal allergy may be
underdiagnosed, but is known to occur frequently in people with cystic fib-
rosis and bronchial asthma [30,40,41]. Clinically, this syndrome manifests as
asthma with fleeting pulmonary infiltrates representing recurrent inflamma-
tion that can eventually lead to proximal bronchiectasis and lung fibrosis.
Diagnostic criteria for ABPA include clinical factors, such as a history of
asthma, recurrent pulmonary infiltrates, and productive sputum containing
mucous plugs or brown specks, and laboratory findings, such as isolation of
Aspergillus species in sputum, eosinophilia, findings of central bronchiecta-
sis on CT scan, and immunologic responses (skin reactivity, precipitating
antibodies, and Aspergillus-specific IgE) [30,42,43]. Although the presence
of all primary diagnostic criteria are considered confirmatory, identification
of fewer may be suggestive of ABPA, which can be particularly helpful in
establishing a diagnosis during the spectrum of disease that exists before
fibrotic lung destruction [42,44,45].
The pathogenesis of ABPA has been an active field of study, with inves-
tigations revealing that patients with ABPA demonstrate a prominent Th2-
type CD4+ response to A. fumigatus allergens [46–48]. Genotypic analyses
suggest increased susceptibility in association with specific HLA-DR mole-
cules (DR2 and DR5) [49,50]. Multiple A. fumigatus allergens have been
described [51]. The predominance of allergens associated with the hyphal
stage of A. fumigatus demonstrates that late-stage growth, as opposed to
bronchial exposure to conidia, may be important in the pathogenesis.
880 K.A. Marr et al / Infect Dis Clin N Am 16 (2002) 875–894

Therapy of allergic disease relies on effective control of inflammatory

responses. Because ABPA is the most severe manifestation, this is the con-
dition that requires the most aggressive management, with corticosteroids
and antifungal drugs. Management with corticosteroids has long been the
mainstay of therapy. More recently, Stevens et al [52] demonstrated in a
randomized trial that itraconazole (200 to 400 mg/d), administered for 16
to 32 weeks, results in reduction in corticosteroid dependence, circulating
IgE, and improvement in pulmonary function.

Saprophytic to invasive disease

Although the first case of aspergilloma occurred in 1848, the syndrome
was described as a saprophytic condition in the 1950s. Aspergillomas, or
‘‘fungus balls,’’ occur when pre-existing lung lesions become secondarily
infected with Aspergillus species. Common pre-existing conditions classically
include tuberculosis, sarcoidosis, bullous emphysema, or other pulmonary
diseases associated with cavitary lung lesions [53–57], but aspergillomas can
also occur in areas of bronchiectatic involvement as a consequence of ABPA
[58]. Aspergillomas consist of a mass of hyphae protected within a matrix of
fibrin and cellular debris. Because they develop as a complication of exist-
ing cavitary lesions, they are typically unilateral, and located in the upper
lobes (consistent with the upper lobe predominance of bullous lung disease)
but bilateral involvement has been reported to occur in up to 5% to 10% of
cases [59].
In addition to occurring within pre-existing cavities, fungal balls may
appear in previously normal lung. These are not referred to as aspergillo-
mas, because they represent a progressive infection and require systemic
antifungal therapy. These lesions, which occur in people with mild to mod-
erate degrees of immune suppression, such as in the setting of diabetes,
chronic obstructive lung disease, or after resolution of neutropenia, have
been termed chronic necrotizing aspergillosis, or semi-invasive aspergillosis
[60,61]. Some of these patients have subacute invasive aspergillosis (espe-
cially patients on corticosteroids and those with AIDS), whereas others have
a truly chronic infection that evolves over many months to years. Recently,
a deficiency in mannose binding protein has been associated with the devel-
opment of chronic infection in otherwise healthy hosts [8]. In subacute inva-
sive aspergillosis, progression to hemorrhagic necrosis surrounded by a
peripheral fibrinous capsule is typical, ultimately appearing characteristic
of a cavitated aspergilloma (Fig. 3) [62]. Alternatively, thin- or thick-walled
cavities appear. In those with chronic disease, paracavitary infiltrates,
expansion of the cavity over time, and lack of pleural thickening or fungus
ball is typical [60].
Although definitive therapy of aspergilloma has been classically consid-
ered to be surgical resection, postsurgical complications can be numerous,
especially for lesions located close to pleura [63]. In this setting, disruption
 K.A. Marr et al / Infect Dis Clin N Am 16 (2002) 875–894 881

Fig. 3. A thick-walled, cavitated lesion (subacute aspergillosis).

of the cavity can lead to empyema and fistula formation, and loss of lung
volume can be particularly problematic in people with pre-existing lung dis-
ease. It is also particularly important to distinguish the noninvasive form of
aspergilloma from the semi-invasive form, because the latter might be
accompanied by more extensive, perhaps extrapulmonary extension, neces-
sitating antifungal therapy. Therapy of invasive aspergillosis is discussed in
greater depth in the following sections.

Sinusitis
Fungal sinusitis can be allergic, saprophytic, or invasive in nature. Aller-
gic sinusitis typically occurs in people who have a history of atopy, with
manifestations including allergic rhinitis, nasal polyposis, recurrent sinusitis,
and sometimes asthma. In the immunocompetent host, disease is character-
ized by allergic inflammation to a live mold within the sinus cavity, resulting
in edema, obstruction, and occasionally polyposis [64]. Inflammation can be
chronic, progressing to extensive tissue destruction, but pathology demon-
strates allergic mucin and inflammation, without signs of fungal hyphal
invasion into bone [65,66]. A retrospective study of patients with allergic
fungal sinusitis documented bony erosion in 20% of patients, most fre-
quently with erosion of the ethmoid sinuses, and orbital and anterior cranial
bones [67]. Effective treatment is focused on drainage and alleviation of
allergic symptoms, through nasal corticosteroids and saline douches.
882 K.A. Marr et al / Infect Dis Clin N Am 16 (2002) 875–894

Although a definitive role for systemic therapy has not been established, sev-
eral authors have suggested that antifungal therapy or systemic corticoste-
roids may decrease recurrence in the setting of adequate drainage [63,
64,68–70].
Sinus involvement can be limited to a tangled mat of hyphae within the
maxillary sinus cavity, with little or no invasive or allergic component. Sur-
gical or endoscopic removal of localized fungal balls is usually sufficient
therapy, although clearing of the ethmoid sinuses can be important to pre-
vent recurrence. There does not seem to be a role for antifungal therapy,
except in settings concerning for potential invasion, such as sphenoid sinus-
itis [71,72].
The most serious manifestation of sinus infection is invasive sinusitis,
which typically occurs in people who have compromised immunity, espe-
cially in the setting of hematopoietic stem cell transplantation (HSCT) and
neutropenia [73,74]. Hyphae can invade mucous and bone, leading to hem-
orrhagic infarction and spread into adjacent critical structures, such as the
orbit and brain. Because the clinical presentation can be variable, a high
index of suspicion is required, along with aggressive radiographic and surgi-
cal intervention to establish diagnosis. Biopsy with culture is important,
because organisms with variable antifungal susceptibilities, including
amphotericin B–resistant species, are known to cause acute sinusitis. Effec-
tive therapy is dependent on adequate surgical drainage and resection of tis-
sues and bone (if indicated by necrosis or extensive infection), combined
with antifungal therapy and withdrawal of immunosuppression, if possible.
Because pulmonary infection may be present concomitantly, radiographic
evaluation of the lungs with CT scan is indicated in immunosuppressed
patients with documented fungal sinusitis. Despite therapy, mortality is
high, ranging from 20% to 100%, depending on the state of the host’s under-
lying disease [75,76]. Apparent successful therapy followed by relapse during
another course of myeloablative chemotherapy is common.
A more indolent form of invasive sinusitis has been described in patients
who have chronic infection, particularly in geographic areas that have high
or persistent levels of exposure to environmental molds. In such areas as
Saudi Arabia, Sudan, and other dry or tropical climates, this clinical man-
ifestation appears in people with apparently normal immunity. Retrospec-
tive review of cases in Saudi Arabia documented A. flavus as the most
frequent implicated pathogen, with complete surgical evacuation and pro-
longed antifungal therapy associated with relapse-free survival [77].

Infection of the trachea and bronchi

Aspergillus species cause localized infection in the trachea or bronchi,
resulting in a spectrum of diseases in the bronchial airways. Obstruct-
ing bronchial aspergillosis is characterized by large mucoid Aspergillus-con-
taining casts that obstruct the airways, causing atelectasis, and appearing
 K.A. Marr et al / Infect Dis Clin N Am 16 (2002) 875–894 883

clinically as bilateral lower-lobe infiltration [78]. Progression to a more

inflammatory, potentially invasive condition results in bronchial membranes
and plaques in the upper airways, or pseudomembranous tracheobronchitis
[79]. Obstructing bronchial aspergillosis appears particularly common in
people with AIDS [78,80–83]. Airways aspergillosis also occurs in patients
who have relatively severe immunosuppression (neutropenia and HSCT)
[84–86], and in people with apparently normal immune status [81,87–90].
Another patient population at particularly high risk for bronchial mani-
festations of Aspergillus infection is lung allograft recipients, who as a result
of prolonged, potent immunosuppression and abnormal lung architecture
develop both invasive aspergillosis and a disproportionate amount of ulcer-
ative and pseudomembranous tracheobronchitis [91]. The incidence of
Aspergillus isolation from the airways of lung transplant recipients ranges
from 20% to 40%, with a high proportion of cases occurring during the first
6 months after transplantation [92]. Clinical manifestations can be variable,
ranging from isolated tracheobronchitis, to anastomotic infection, to inva-
sive aspergillosis, which may occur in 5% to 10% of transplant recipients
[92,93].
Clinical manifestations of bronchial infection result from bronchial
obstruction and potentially invasive infection, and can include wheezing
(sometimes unilateral); cough; hypoxia; fever; and hemoptysis. Diagnosis
requires bronchoscopy, which can also be therapeutic if removal of mucous
plugging is possible. Therapy requires systemically administered antifungal
therapy. Although case reports of topical, or aerosolized formulations of
amphotericin B have noted clinical response to therapy [94], and effective
prevention in lung transplant recipients [93,95], no large controlled studies
have been performed. Despite antifungal therapy, many cases progress to
transmural necrosis of the airway, and either tracheal perforation or inva-
sive pulmonary aspergillosis (IPA), especially in immunocompromised
individuals.

Invasive pulmonary aspergillosis

The incidence of invasive aspergillosis has increased during the last de-
cade. In an autopsy study performed in a university hospital in Germany,
the prevalence of invasive fungal infections increased between 1978 and
1992, principally because of an increase in invasive infections caused by
Aspergillus species [96]. In the late 1970s 1% to 2% of unselected autopsies
had a systemic fungal infection, most candidiasis, whereas in the early
1990s, 7% had a systemic fungal infection, 60% of which were invasive
aspergillosis. This increase is thought to be associated with increasing num-
bers of people at risk because of HIV infection, solid organ transplantation,
HSCT, and intensified chemotherapeutic regimens. The incidence of infec-
tion has also increased within risk categories, as documented in HSCT recip-
ients. One transplant center reported that the incidence of invasive
884 K.A. Marr et al / Infect Dis Clin N Am 16 (2002) 875–894

aspergillosis increased during the early 1990s in recipients of both autolo-

gous and allogeneic grafts [31,36]. Currently, aspergillosis is a prominent
cause of infectious morbidity and mortality in patients with hematologic
malignancies, and in recipients of stem cell and solid organ transplants.
Risks for invasive aspergillosis include any underlying disease or medical
intervention that impairs neutrophil function or quantity. This most fre-
quently involves patients who have received myeloablative chemotherapy
or HSCT, have an underlying disease that results in neutrophil dysfunction,
or have received long courses of corticosteroids. The epidemiology of
aspergillosis after allogeneic HSCT emphasizes the importance of the
post-enlargement risk period [36,97,98]. Results of these studies indicate a
bimodal incidence, with two peaks associated with neutropenia and graft-
versus-host disease (GVHD) [36]. More recent studies indicate that risks
persist greater than 6 months after HSCT in patients who have severe
chronic GVHD and cytomegalovirus disease [99]. The underlying disease
of the recipient, HLA-match of the graft, and stem cell source all impact the
risk and the timing of Aspergillus infection after transplant [31,36]. Recipi-
ents of cord blood, who classically have a long pre-engraftment period, have
a high risk for aspergillosis early after HSCT, whereas recipients of mis-
matched or HLA-unrelated peripheral blood stem cells have a high risk for
aspergillosis late, during GVHD.
The clinical presentation of IPA is variable, typically involving fever,
hemoptysis, cough, or pleuritic chest pain. Symptoms are neither sensitive
nor specific, and many patients, especially those maintained on corticoste-
roids during GVHD, are recognized as having aspergillosis relatively late
after infection, with radiographs demonstrating pulmonary nodules or infil-
trates, or after the onset of neurologic symptoms caused by disseminated
infection. A review of 22 cases of IPA in allogeneic bone marrow transplant
recipients found that 50% of cases presented with respiratory symptoms;
32% presented with fever; and 27% of cases presented with neurologic symp-
toms indicating dissemination (seizures, hemiparesis, and stupor) [98]. Fever
may be more common in neutropenic patients, but about 20% of these
patients do not have fever or cough for the first several days of infection.
The radiographic presentation is also variable, with abnormalities ranging
from classic nodular or cavitating lesions to diffuse infiltrates on chest radio-
graph and CT scan [98,100]. Because progression of pulmonary infection is
characterized by invasion of small vessels and hemorrhage, lesions may be
surrounded by a low-attenuation halo or may even present as areas of hem-
orrhagic infarction [62,101]. Although detection of the halo sign is helpful in
raising suspicion for IPA, one must not rely on this finding to establish diag-
noses. Limitations arise from the fact that other organisms, most frequently
other molds, such as Fusarium spp. and Zygomycetes, or even bacteria, such
as Pseudomonas aeruginosa, may initiate similar hemorrhagic processes in
the lung, and halo signs may not appear in nonneutropenic hosts or during
more progressive stages of a pneumonic presentation.
 K.A. Marr et al / Infect Dis Clin N Am 16 (2002) 875–894 885

Early diagnosis of aspergillosis remains a challenge. Caillot et al [101]

demonstrated that the use of screening CT scans in febrile neutropenic
patients may allow for earlier diagnoses of unilateral lesions, which if
treated aggressively may lead to improved outcome. Cultures of the respira-
tory tract are critically important, especially in patients at high risk for infec-
tion in the setting of undefined pulmonary abnormalities. Fungal media
have a higher yield than bacteriologic media. Although these cultures have
a high specificity in high-risk (leukemic, HSCT) patients, sensitivity is low
(approximating 30%) [102]. The utility of screening cultures has not been
determined, although studies have found a high positive predictive value
(>60%) of respiratory tract colonization in high-risk (HSCT) patients [36].
More recent studies have indicated a promising role for circulating markers
of infection, using either a double-sandwich (ds) ELISA (Sanofi Diagnostics
Pasteur, Marnes-la-Coquette, France) that detects galactomannan, or poly-
merase chain reaction. Although previous investigators reported that the sen-
sitivity of ELISA-based assays is variable, ranging from 60% to 100%, more
recent, controlled studies report that biweekly screening with the dsELISA
yields positive and negative predictive values greater than 90% [103,104]. It
is most likely that reported variability results from differences in study design,
patient populations, and antifungal use patterns. Other investigators have
reported that polymerase chain reaction detection of circulating nucleic acids
(19S rRNA) is useful to establish diagnosis, with high sensitivities and speci-
ficities [105–107]. It seems reasonable that the best diagnostic approach uses
both screening and radiographic modalities, with culture and histology
obtained from lower respiratory tract tissue to confirm the diagnosis.
Diagnosis of IPA is reliant on a very high degree of suspicion, especially
in the setting in which a patient presents with nonpulmonary findings or
complaints. Indeed, the first signs of infection may indicate dissemination
to other organs, such as the brain, skin, liver, kidneys, or bone. Also, Asper-
gillus species may invade pulmonary parenchyma to the pleural space, ribs,
mediastinum, esophagus, or heart. Involvement of the pericardium or myo-
cardium can be the clinical presentation, especially in severely immune sup-
pressed patients. Isolation of A. fumigatus in blood is uncommon [108,109].
In a 10-year retrospective review in one cancer center, true aspergillemia was
seen only in patients with very high risk (hematologic malignancies), and A.
terreus was a more frequent cause, whereas A. fumigatus more frequently
indicated pseudoaspergillemia [109]. Finally, Aspergillus species can cause
a local, noninvasive form of cutaneous infection, especially at sites associ-
ated with trauma or a breech in the cutaneous barrier (ie, catheters) [110].
Therapy can be either prophylactic, empiric, pre-emptive, or specific,
based on the degree of certainty of diagnosis. No randomized studies have
definitively confirmed a role for prophylactic antifungals, although studies
have examined the utility of systemic and aerosolized amphotericin B for-
mulations, and itraconazole. It is not clear whether aerosolized amphoteri-
cin formulations are effective at decreasing rates of aspergillosis in high-risk
886 K.A. Marr et al / Infect Dis Clin N Am 16 (2002) 875–894

patients. Although this strategy has the strength of delivering the antifungal
drug directly to lungs, potentially avoiding systemic toxicities, drawbacks
include difficulties in administration because of bronchospasm, and failure
to prevent other infections, such as candidiasis. Studies evaluating the role
of itraconazole have confirmed that this drug is effective in preventing candi-
diasis, but the inclusion of relatively low-risk patients with hematologic malig-
nancies reduced the power of these studies, limiting definitive assessment of
aspergillosis risks [111–113]. Large studies in high-risk patients are ongoing.
Empiric therapy during neutropenia, based on the presence of persistent
fever, was established in early investigations that documented fewer fungal
infections in patients treated with conventional amphotericin B deoxy-
cholate compared with nontreated controls [114,115]. The results of a sub-
sequent large, randomized trial suggested that the use of liposomal
amphotericin B is associated with fewer toxicities and a reduced number
of breakthrough fungal infections [116]. Because most breakthrough infec-
tions were caused by Candida species, it is not clear whether one drug is
more effective at reducing the number of invasive mold infections. Results
of another more recent trial suggest that voriconazole may be an acceptable
alternative as well [117]. It seems reasonable that these more expensive for-
mulations be considered in people with very high risks for mold infection
and toxicities associated with amphotericin B deoxycholate.
Effective therapy of established IPA requires both antifungals and with-
drawal (or reduction) of immunosuppressive therapy. In addition, satisfac-
tory responses may be hastened by adjunctive surgical excision of focal
lesions (see later).
Until recently, administration of high doses (>1 mg/kg/d) of amphoteri-
cin B has been considered the gold standard antifungal therapy for any form
of invasive disease, particularly in people who are immunocompromised and
at risk for extrapulmonary invasion. Although lipid-based formulations of
amphotericin B are currently approved for use in patients who fail or are
intolerant of amphotericin B deoxycholate, these agents seem to be appro-
priate first-line agents in people with pre-existing, and those who are at par-
ticularly high risk for, nephrotoxicity. No randomized studies, however,
have confirmed that these formulations result in better outcome in patients
with established invasive aspergillosis.
Itraconazole is accepted as an alternative therapy for invasive infec-
tion, although no randomized studies have been performed [119,120]. The
availability of a new well-absorbed oral liquid and an intravenous formula-
tion may increase the use of this compound. This drug has also been used
successfully as sequential oral therapy following initial therapy with ampho-
tericin B [121]. A drug within the echinocandin class of antifungals (caspo-
fungin, [Cancidas]) was approved by the FDA for use as a salvage agent,
should standard therapy fail or result in unacceptable toxicities. Most
recently, voriconazole was approved for use as a first-line agent, based on
a randomized trial showing superior efficacy compared to amphotericin B
 K.A. Marr et al / Infect Dis Clin N Am 16 (2002) 875–894 887

[118]. There are currently no definitive data to support the use of combina-
tion antifungal regimens.
The optimal duration of therapy is unknown, and should be judged based
on the degree and rate of immune reconstitution and extent of fungal inva-
sion at diagnosis. Practice guidelines suggest that initial ‘‘induction’’ therapy
be continued until infection is stabilized radiographically and microbiolog-
ically, and maintenance therapy with an alternative, perhaps less toxic oral
formulation can be considered until complete resolution of radiographic
findings and immune reconstitution [63].
Responses to antifungal agents are variable, and clinical response and
overall mortality are highly dependent on the hosts’ underlying immune def-
icit at the time of diagnosis, clinical manifestations, and whether immune-
reconstitution occurs during therapy [121–123]. A large multicenter study
reporting outcomes of invasive aspergillosis demonstrated that response to
therapy is highly dependent on the underlying disease of the host (Fig. 4a)
[121]. This observation may be explained by the variable responses associated
with different clinical manifestations, and the degree to which the host is able
to reconstitute immunity. In a review of the literature reported subsequent to
1995, Lin et al [122] demonstrated that the case-fatality rate is highly depend-
ent on the presenting manifestation (Fig. 4b). The accompanying observa-
tion that patients with hematologic malignancies and HSCT more
frequently develop disseminated disease, and less frequently have localized
findings of aspergilloma or tracheobronchitis relative to AIDS patients, may
explain at least part of the differences in outcomes. Finally, recovery of
immunity may be one of the most important parameters dictating outcomes
in patients with hematologic malignancies. Studies have found that the single
most important predictor of mortality in allogeneic HSCT recipients is
receipt of high total doses of corticosteroids [123].
Resection of aspergillomas and lesions in close proximity to large vessels
and vital organs (ie, pericardium), and those presenting with significant
hemoptysis, is advisable. The role of surgical resection of other pulmonary
lesions has long been debated, in part because of the bias inherent with
reported outcomes. There is suggestion that surgical resection of isolated,
single lesions is associated with better survival; however, the presence of a
single lesion itself is indicative of early diagnosis and improved outcome
compared with multiple foci of disease [124]. Two studies have demon-
strated that surgical resection should be considered in patients who undergo
subsequent HSCT [124,125], or perhaps by extrapolation, subsequent
courses of myeloablative chemotherapy.
Because prolonged granulocytopenia and persistent use of corticosteroids
are associated with disseminated infection and poor outcomes, common
sense suggests a role for recombinant human cytokines or colony-stimulat-
ing factors, or possibly granulocyte transfusions. Because there is currently a
paucity of data demonstrating efficacy of adjunctive immunotherapy, rec-
ommendations await further study.
888 K.A. Marr et al / Infect Dis Clin N Am 16 (2002) 875–894

Fig. 4. (a) Complete or partial responses (y-axis) to standard therapy of aspergillosis in each of
the patient populations listed. (Data from Patterson TF, Kirkpatrick WR, White M, et al.
Invasive aspergillosis: disease spectrum, treatment practices, and outcomes. I3 Aspergillus Study
Group. Medicine (Baltimore) 2000;79:250–60.) (b) Case-fatality rate (y-axis) in patients with
different clinical manifestations of aspergillosis. (Data from Lin S, Schranz J, Teutsch S.
Aspergillosis case-fatality rate: systematic review of the literature. Clin Infect Dis 2001;32:
358–66.) The low response rates associated with infection in patients who have received
hematopoietic stem cell transplantation or have underlying hematologic malignancies, and high
response rates in patients after solid organ transplants (a) correspond to the case fatality rates of
the most common manifestations of infection (disseminated or invasive aspergillosis and semi-
invasive or tracheobronchitis, respectively [b]). HSCT ¼ hematopoietic stem cell transplanta-
tion; IPA ¼ invasive pulmonary aspergillosis; SOT ¼ solid organ transplants.

The future
Aspergillus species are now appreciated as important fungal pathogens
that cause disease in both immune-competent and immune-suppressed
patients. Although the impact of these organisms in certain immunosup-
pressed populations has reached critical proportions in the last 5 years,
knowledge of the pathogenesis, diagnosis, and therapy of infections remains
in a stage of infancy. Many more efforts are needed to provide a sophisti-
cated understanding of disease pathogenesis and progression, in order to
 K.A. Marr et al / Infect Dis Clin N Am 16 (2002) 875–894 889

enable establishment of more effective therapeutic approaches. The roles of

new multiple antifungal drugs, need to be defined by large, well-designed
clinical trials.

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