Aspergillus species were first described in 1729 as ubiquitous
saprophytic filamentous fungi commonly found in the environment.[1,2] The name
is derived from the microscopic appearance of the conidia, or spores, of the
fungus that radiate from a central structure resembling an aspergilluma
device used for sprinkling holy water. Over 80% of human infections are due to A
fumigatus and A flavus. Infections due to
A niger, A terreus, and A nidulans constitute an additional 10%, and other less
common species, approximately 9%.
Invasive aspergillosis is a life-threatening complication of
anticancer therapy. The overall mortality rate associated with this infection
has been as high as 100% among untreated patients. In immunocompromised
patients, crude mortality rates of 86%, 66%, and 99% have been reported for
invasive pulmonary aspergillosis, sinus aspergillosis, and cerebral
aspergillosis, respectively. Attributable mortality rates of 65% have been
reported among amphotericin B recipients. The mean crude mortality rates for
invasive pulmonary aspergillosis in bone marrow transplant recipients have been
90% (range: 33% to 100%), and for leukemia, neutropenia, and aplastic anemia
patients, 77% (range: 13% to 100%).
The last 50 years have seen an increase in the incidence of
invasive fungal infection in cancer patients. A survey of autopsies performed
since 1919 among patients who died of cancer demonstrated that this increase
occurred after 1950 in patients with acute leukemia or lymphoma rather than in
those with solid-tissue malignancies.[6,7] This phenomenon was paralleled by the
introduction of more effective antineoplastic agents such as nitrogen mustard,
the folate antagonists, prednisone, and mercaptopurine (Purinethol) between 1946
and 1952 and broad-spectrum antibacterial agents such as penicillin,
streptomycin, and the tetracyclines from 1941 to 1948.
More effective anticancer agents allowed patients to survive
longer at the cost of increased myelosuppression, immunosuppression, and
consequent bacterial infection. In turn, effective antibacterial therapy allowed
patients who would have otherwise succumbed to bacterial infection to survive
long enough to develop opportunistic fungal infection. Consequently, the
incidence of invasive aspergillosis has been rising in the cancer patient
population. Factors cited as contributing to this phenomenon include a
greater number of patients undergoing hematopoietic stem cell transplantation;
use of unrelated stem cell donors which, in turn, is associated with an
increased incidence of graft-vs-host disease and corticosteroid therapy; and
greater dose intensities of cytotoxic and immunosuppressive regimens
administered for a variety of cancers.
Risk factors for invasive fungal infection include prolonged
periods of severe neutropenia (absolute neutrophil count less than 0.5 × 109/L
for more than 10 days), treatment for acute myeloid leukemia with cytarabine
plus an anthracycline or high-dose cytarabine-based remission induction
regimens,[9,10] indwelling venous access devices, delayed engraftment due to
low hematopoietic stem cell dose in hematopoietic stem cell transplantation,
allogeneic hematopoietic stem cell transplantation, immunosuppressive
treatment of graft-vs-host disease, and management of high-risk patients
outside of a high-efficiency particulate air-filtered nursing unit.[14,15]
A successful approach to the prevention and management of
filamentous fungal infection is based on a thorough understanding of the
pathogenesis of infection by these microorganisms. Opportunistic filamentous
molds such as Aspergillus spp are acquired by inhaling microscopic conidia that
are borne on ambient air currents within the environment. Oral inhalation,
compared to nasal inhalation, increases the likelihood that the conidia will
bypass the protective filtering effect of the upper airways and pass into the
periphery of the lower respiratory tree. This is more likely to occur under
conditions of low humidity, when the otherwise hygroscopic conidia have the
smallest diameter and are able to defeat the filtering effect of the upper
airways. Conidia enter the upper or lower airways and come to rest on the
respiratory epithelium where they germinate into invasive hyphae forms.
In the absence of an adequate host immune response, the hyphae
spread locally in the host tissues and then disseminate to other visceral sites
such as the brain, myocardium, liver, spleen, kidneys, or skin. It is not
surprising that the majority of infections due to Aspergillus spp typically
involve the sinuses and the lungs.
The diagnosis of invasive aspergillosis is based on an index of
suspicion in high-risk patients, the clinical and radiologic findings at
anatomic sites most likely to be involved with these fungi, morphologic
demonstration of compatible fungal structures in methenamine silver-stained
tissue biopsies, and the isolation of the pathogen in a microbiological culture
from involved tissues (Table 1).[17-19] More recently, non-culture-based
techniques that rely on detection of galactomanan cell wall antigens by latex
agglutination or enzyme-linked immunosorbent assays or of genomic material
by polymerase chain reaction[21,22] in urine, serum, cerebrospinal fluid, and
bronchoalveolar lavage fluid have shown promise in establishing the diagnosis of
invasive aspergillosis. However, these tests are not routinely available in
North America. The Mycoses Study Group of the National Institute of Allergy and
Infectious Diseases in the United States and the Invasive Fungal Infections
Group of the European Organization for Research and Treatment of Cancer have
developed criteria by which the certainty of the diagnoses can be
The probability that a susceptible host will encounter a
critical innoculum of Aspergillus conidia can be reduced significantly by
removing the conidia from the ambient air; that is, by managing the patient
during the period of highest risk in nursing units equipped with high-efficiency
particulate air filters with or without laminar air flow. Such systems are able
to remove particles larger than 0.3 µm in diameter with 99.97% efficiency.
Previous studies have demonstrated that this strategy can reduce the incidence
of proven invasive pulmonary aspergillosis in bone marrow transplant
recipients and the risk of developing clinical pneumonia (pooled weighted
odds ratio = 0.41, 95% confidence interval = 0.28 to 0.61, N = 1,019 randomized
The Centers for Disease Control and Prevention recommend the use
of a protected environment to prevent invasive aspergillosis in cancer patients
with prolonged neutropenia.[36,37] Such environments should be well-sealed and
equipped with high-efficiency particulate air filters, directional air flow,
positive room-air pressure relative to the corridor outside the room, and high
rates of room-air exchange (15 to more than 400 exchanges per hour).
Clinical trials that are evaluating the prophylaxis efficacy of
antifungal agents such as itraconazole (Sporanox) or low-dose amphotericin B
have not been able to demonstrate a treatment effect.
Early initiation of antifungal therapy in patients with
suspected invasive aspergillosis influences survival. The mortality rate for
patients who were or were not treated within 10 days of clinical or radiologic
evidence of invasive aspergillosis was 41% and 90%, respectively. Although
amphotericin B deoxycholate at doses of 1.0 to 1.5 mg/kg/d remains the standard
agent for the treatment of invasive aspergillosis, the high mortality rates
among patients receiving such treatment and the drug-related metabolic and
infusional toxicities limit enthusiasm for this agent.
The lipid-based formulations of amphotericin B administered in
daily doses of 3 to 5 mg/kg have similar efficacy to standard amphotericin B
deoxycholate but significantly lower rates of nephrotoxicity and infusional
toxicities such as chills or rigors. Some investigators advocate the use of
lipid-based formulations of amphotericin B as first-line therapy for
life-threatening invasive fungal infection in (1) patients with preexisting
renal dysfunction defined by a calculated creatinine clearance of less than 50
mL/min; (2) those at high risk of renal dysfunction defined by the concomitant
use of nephrotoxic agents such as cyclosporin, tacrolimus, the aminoglycosides,
or platinum analogs; or (3) those with underlying diseases such as diabetes
mellitus predisposing to renal damage. This position is supported by
pharmacoeconomic analysis, particularly in allogeneic hematopoietic stem cell
Itraconazole administered in daily doses of ³ 400 mg is the
only other agent currently available for both oral and intravenous
administration in the treatment of invasive aspergillosis.[17,18] This agent has
significant limitations with regard to drug interactions and bioavailability,
particularly in the setting of achlorhydria, which is common among cancer
patients. Newer azoles including voriconazole, posaconazole, and ravuconazole
are active against Aspergillus spp; however, their role in clinical disease
remains to be elucidated. Furthermore, the newer echinocandin agents that
inhibit 1,3-beta-d-glucan synthase in the fungal cell wall appear very promising
in the treatment of invasive aspergillosis in animal models.
Duration of Treatment
Treatment is initiated at the point when it is determined that a
patient probably has invasive aspergillosis. Evidence supporting this diagnosis
may be limited to fever and an imaging result consistent with the diagnosis.
Further studies may be needed to substantiate or refute the diagnosis. No
standard total dose of amphotericin B has been established. The duration of
treatment is based on the extent of the infection, the response to therapy, and
the status of the patient’s underlying malignancy. Treatment should
continue until all clinical signs and symptoms have abated and imaging studies
and microbiological culture-based and non-culture-based studies are negative.
Some investigators recommend that treatment be continued throughout subsequent
cytotoxic anticancer therapy.
The response rates in patients with invasive aspergillosis
treated with conventional amphotericin B deoxycholate have ranged from 30% to
40%.[3,4] Response rates for itraconazole recipients have been reported to range
from 39% to 63%.[4,17,18] Surgical excision has been advocated for patients with
invasive pulmonary aspergillosis who are at risk of life-threatening
There is a dearth of data from randomized controlled clinical
trials that evaluated treatments for invasive aspergillosis. Accordingly,
evidence supporting use of the above approaches is based largely on the opinions
of experienced investigators. As the number of cancer patients who are
receiving intensive cytotoxic and immunosuppressive therapy rises, so, in turn,
does the number of patients at risk for Aspergillus infection. Further clinical
trials evaluating the newer treatment modalities are needed.
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