Diagnostico de Aspergilosis Invasiva

8/17/2015
Diagnosis of invasive aspergillosis
Official reprint from UpToDate

www.uptodate.com 2015 UpToDate

Author
Kieren A Marr, MD
Section Editor
Carol A Kauffman, MD
Deputy Editor
Anna R Thorner, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jul 2015. | This topic last updated: Nov 17, 2014.
INTRODUCTION The term "aspergillosis" refers to illness due to allergy, airway or lung invasion, cutaneous infection, or extrapulmonary dissemination
caused by species of Aspergillus, most commonly A. fumigatus, A. flavus, and A. terreus. Aspergillus species are ubiquitous in nature, and inhalation of
infectious conidia is a common event. However, tissue invasion is uncommon and occurs most frequently in the setting of immunosuppression associated
with receipt of therapy for hematologic malignancies or hematopoietic cell or solid organ transplantation.
The diagnosis of invasive aspergillosis will be reviewed here. The epidemiology, clinical manifestations, and treatment of invasive aspergillosis are
discussed separately; the diagnosis of invasive aspergillosis in HIV-infected patients, as well as the diagnosis of other syndromes caused by Aspergillus
spp, are also presented elsewhere. (See "Epidemiology and clinical manifestations of invasive aspergillosis" and "Treatment and prevention of invasive
aspergillosis" and "Allergic bronchopulmonary aspergillosis" and "Clinical manifestations and diagnosis of chronic pulmonary aspergillosis" and "Diagnosis
and treatment of invasive pulmonary aspergillosis in HIV-infected patients".)
DIAGNOSTIC MODALITIES Aspergillus species are frequently inhaled into the airways but, because of effective conidial clearance in the majority of
individuals, disease usually does not result. Because we inhale conidia constantly, culture isolation of Aspergillus species from the airway does not
necessarily indicate disease. Thus, the diagnosis of invasive aspergillosis is based upon both isolating the organism (or markers of the organism) and the
probability that it is the cause of disease. The latter is a function of the hosts risk factors for disease (eg, immune status) and the clinical presentation.
Demonstration of hyphal elements invading tissues (from biopsy of any affected site, such as the lung or skin) represents a proven diagnosis [1].
Given the above issues, the diagnosis of invasive aspergillosis is often referred to within a scale of certainty: possible, probable, or proven [1,2]. These
definitions have been developed in order to maintain consistency in clinical and epidemiologic studies, not to drive therapeutic decision making.
Direct examination of respiratory specimens Respiratory specimens are usually stained with calcofluor white with 10 percent potassium hydroxide
to detect the presence of fungal elements [3]. Gomori methenamine silver can be used to stain cytology preparations. Organisms can be observed as
narrow (3 to 6 microns wide), septated hyaline hyphae with dichotomous acute angle (45) branching [4]. However, several filamentous fungi, including
Scedosporium spp and Fusarium spp, have similar appearances to Aspergillus spp on direct microscopy.
Culture Culture of the organism, in combination with evidence of tissue invasion on histopathology, or culture from a normally sterile site, provides the
most certain evidence of invasive aspergillosis [1]. However, both microscopic examination and culture are insensitive [5], and therapy should not be
withheld in the absence of such confirmation. Furthermore, performing a biopsy is not feasible in some patients due to bleeding risk or risk of other
complications. In patients with risk factors and clinical and/or radiographic features that are suggestive of invasive aspergillosis, culture of Aspergillus spp
from respiratory secretions provides adequate evidence of invasive disease.
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Aspergillus is a rapidly growing fungus in the laboratory and is often visible in culture within one to three days of incubation. However, identification of the
species requires sporulation in order to microscopically examine spore-bearing structures.
Occasionally, organisms can be difficult to identify due to slow sporulation. Slow sporulating organisms may have been disregarded as non-pathogens in
the past. However, more recently, slow-sporulating species (eg, Aspergillus lentulus, Neosartorya udagawae) with variable susceptibility profiles have been
identified and implicated in invasive infections [6]. (See "Treatment and prevention of invasive aspergillosis", section on 'Antifungal resistance'.)
Many patients with documented invasive aspergillosis have negative cultures. This has been observed in surveillance studies, and the prevalence of
negative cultures varies depending upon the population being evaluated. As an example, in multicenter surveillance studies, only 25 to 50 percent of
hematopoietic cell transplant recipients who met criteria for invasive aspergillosis based upon galactomannan antigen results had positive cultures [7,8].
The predictive value of positive sputum or bronchoalveolar lavage (BAL) cultures is dependent upon both the host and the clinical presentation. In a study
that evaluated the predictive value of lower respiratory tract cultures in different patient populations with probable or proven invasive pulmonary aspergillosis,
the positive predictive value was highest in hematopoietic cell transplant recipients, patients with hematological malignancies, and granulocytopenic
patients (72 percent), compared with solid organ transplant recipients and patients receiving glucocorticoids (58 percent) and HIV-infected patients (14
percent) [9]. The positive predictive value was highest in BAL cultures, in part because the prevalence of invasive aspergillosis is higher amongst patients
who have radiographic abnormalities warranting bronchoscopy. Clinical and radiographic findings suggestive of invasive aspergillosis were present
significantly more often among infected patients compared with uninfected patients.
Histopathology In the setting of invasive disease, organisms can be observed in biopsy specimens as narrow (3 to 6 microns wide), septated hyaline
hyphae with dichotomous acute angle (45) branching (picture 1 and picture 2). The organism can be seen using Gomori methenamine silver or periodic
acid-Schiff staining. However, several filamentous fungi, including Scedosporium spp and Fusarium spp, have similar appearances to Aspergillus spp in
histopathologic sections. Since the treatment of infections caused by these fungi may differ, it is important to confirm genus and species by culture. (See
"Clinical manifestations and diagnosis of Fusarium infection", section on 'Diagnosis' and "Epidemiology, clinical manifestations, and diagnosis of
Scedosporium infection", section on 'Histopathology'.)
Histopathologic examination can usually distinguish the above organisms from the Mucorales order (the agents of mucormycosis), which appear as broad,
non-septate hyphae that exhibit right angle branching (picture 3 and picture 4). Occasionally, this distinction can be difficult, especially when small hyphal
fragments are present or when the organism folds back on itself to create "pseudo-septations." Determining whether the fungus is one of the Mucorales or
another fungus is important because the Mucorales are not susceptible to voriconazole, which is the treatment of choice for invasive aspergillosis. (See
"Mucormycosis (zygomycosis)" and "Treatment and prevention of invasive aspergillosis".)
Galactomannan antigen detection Galactomannan is a polysaccharide that is a major constituent of Aspergillus cell walls and that is also present
in the cell walls of a number of other fungal species. Early techniques to detect this antigen utilized methods such as latex agglutination, which were not
sufficiently sensitive for diagnostic use. More recent assays that use a double sandwich enzyme immunoassay (EIA) have higher sensitivity and are
available for use on serum samples as an adjunctive test for the diagnosis of aspergillosis. The antibody that is used in the double-sandwich EIA detects
multiple epitopes on galactofuranose side chains of galactomannan; although once described as an "Aspergillus-specific" assay, we now know that
antibody recognition of galactofuranose residues can occur with multiple conditions, including infection with other fungi (see 'Caveats' below). The Platelia
galactomannan assay has been approved by the US Food and Drug Administration (FDA) using serum and bronchoalveolar lavage fluid.
Interpretation The galactomannan EIA is performed with an optical read-out that is interpreted as a ratio relative to the optical density (OD) of a
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threshold control provided by the manufacturer; this ratio is called the OD index. Initial use of the test, largely in Europe, utilized a relatively high OD index
(1 to 1.5) as a cut-off for positivity in order to ensure few false-positive results. Subsequent studies demonstrated that lower thresholds (0.5 to 0.7) provide
relatively better performance [10,11]. The assay cleared by the FDA has a suggested threshold OD index of 0.5; thus, an OD index 0.5 is considered to
be a positive result.
Serum In some patients, galactomannan antigen can be detected in the serum before the presence of clinical signs or symptoms of invasive
aspergillosis. Several studies have assessed its test characteristics, and the performance of the test has been addressed in a review and meta-analysis
[12,13]. Some inconsistency in the reported performance of the test has been introduced by studies that used different cut-offs for positivity, as well as
other variables, such as different populations evaluated and testing on patients receiving concurrent antifungal drugs. One review noted that the sensitivity
of the test varied from 30 to 100 percent, whereas specificity remained relatively high and constant (>75 percent) [14].
A meta-analysis that included 27 studies with a total of 4000 patients (mainly with hematologic malignancies) reported that overall sensitivity and
specificity of the galactomannan EIA for proven invasive aspergillosis were 71 percent (95% CI 68-74 percent) and 89 percent (95% CI 88-90 percent),
respectively [13]. When combining proven and probable cases, the sensitivity and specificity were 61 percent (95% CI 59-63 percent) and 93 percent (95%
CI 92-94 percent), respectively.
Subgroup analyses suggested that the assay performs better in patients who have a hematologic malignancy or who have received hematopoietic cell
transplant; in comparison, the test performance may be limited in solid organ transplant recipients [13]. Whether this is related to biologic differences in
the type of invasive disease, such as degree of fungal burden, is unclear. Few cases were included in the studies that have been performed; more patients
who have different underlying diseases will need to be studied to establish the usefulness of this assay in disparate populations.
Caveats The following caveats should be considered when using the galactomannan EIA:
The sensitivity of detecting galactomannan in serum is decreased by concomitant administration of mold-active antifungal therapy [15].
False-positive serum results have been demonstrated in patients who are receiving certain beta-lactam antibiotics, such as intravenous piperacillintazobactam, due to the presence of galactomannan (or a cross-reactive antigen) in the antibiotic formulations [12,16]. False-positive results may
persist for as long as five days after discontinuation of piperacillin-tazobactam [16,17]. Results of more recent studies suggest that current
preparations of piperacillin-tazobactam rarely react with the assay [18,19]. False-positive galactomannan results have also been reported with
intravenous amoxicillin-clavulanate, a formulation that is not available in the United States [20].
Many fungi demonstrate galactomannans (or polysaccharides containing galactofuranose residues) on their cell walls. False-positive results of the
Aspergillus galactomannan EIA may be seen with infections caused by organisms that share cross-reacting antigens. These include filamentous
Ascomycetes that cause similar disease presentations (eg, Fusarium species [21]) and others (Penicillium species [22], Histoplasma capsulatum
[23]).
False-positive results are more likely to occur during the first 100 days following hematopoietic cell transplantation (HCT) and in patients with
gastrointestinal tract mucositis caused by chemotherapy or graft-versus-host disease (GVHD) [24]. The proposed mechanism is that galactomannan
in foods or bacteria having cross-reactive epitopes may translocate across the intestinal mucosa during periods of reduced mucosal integrity [12].
Another possible cause of false-positive galactomannan EIA results is contamination of foods with Aspergillus or closely related fungi, such as
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Penicillium spp. One report noted false-positive results associated with ingestion of large numbers of frozen ice-pops in the setting of gastrointestinal
GVHD [25]. Possible causes included Penicillium contamination of the ice pop wrappers and a food additive in the ice pops, such as sodium
gluconate.
False-positive results have been reported in patients who received transfusions of blood products that were collected in bags produced by a single
manufacturer (Fresenius Kabi, Germany) but not in patients who received blood products that were collected in bags produced by other
manufacturers [26].
Some false-positive results have been reported in children, in whom the assay has been less well studied. However, results of recent studies suggest
relatively little false positivity, with similar risks as demonstrated in adults [27].
Role of testing Studies evaluating the serum galactomannan EIA report relatively low (<50 percent) and high (>90 percent) positive and negative
predictive values, respectively. These values are largely a function of the low prevalence of disease, even when measured in high-risk populations (which is
usually <20 percent). One should thus consider the clinical context to determine the probability of infection [14]. (See "Glossary of common biostatistical
and epidemiological terms", section on 'Predictive values'.)
Some investigators have suggested using the serum galactomannan EIA for screening (weekly or twice weekly) in order to detect invasive aspergillosis
prior to the development of clinical signs or symptoms. Screening as a means to guide preemptive therapy or to withhold empiric treatment of fever has yet
to be validated in randomized trials. More prospective studies are necessary to address the issue of when an antifungal can be withheld in this setting
and/or when the antigen result alone should guide therapy. (See "Treatment and prevention of invasive aspergillosis", section on 'Preemptive therapy'.)
The utility of the serum galactomannan EIA has been best established in the setting of suspected disease. In the setting of clinical disease suspicion,
prevalence is higher, assuring better predictive performance.
Some investigators have suggested a role for serial galactomannan testing in patients with documented invasive aspergillosis, both as a prognostic
measure of effectiveness of antifungal therapy and to differentiate between worsening fungal infection and worsening radiographic findings developing as a
result of the host immune response [28-32]. The prognostic value of the serum galactomannan EIA is discussed separately. (See "Treatment and
prevention of invasive aspergillosis", section on 'Prognostic factors'.)
Bronchoalveolar lavage fluid The galactomannan EIA detects fungal antigens even when the organism does not grow in the laboratory, providing
an indication of potentially invasive disease. The galactomannan EIA performed on BAL fluid provides additional sensitivity compared with culture,
estimated in most studies to exceed 70 percent [33-36].
The optimal threshold OD index for positivity continues to be debated; a higher threshold OD index results in lower sensitivity but higher specificity for
invasive aspergillosis. A retrospective study was performed in which 251 patients who were at risk for invasive aspergillosis and who presented with
unexplained nodular lesions or consolidation on lung imaging underwent galactomannan EIA testing of BAL fluid [36]. The patients had a variety of
underlying diseases, including solid organ transplantation in 29 percent, hematologic malignancy in 20 percent, and non-hematologic malignancy in 13
percent. Using a threshold OD index of 0.8, the sensitivity of galactomannan antigen testing of BAL fluid for diagnosing proven or probable invasive
aspergillosis was 86 percent and the specificity was 91 percent, whereas an OD index threshold 0.5 resulted in a sensitivity of 93 percent and a
specificity of 87 percent. As noted above, the FDA considers an OD index of 0.5 to be positive for galactomannan EIA in both serum and BAL fluid.
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It is important to note that false-positive results occur, and these are especially common in the setting in which the detection of fungi in the airways
represents colonization as occurs in lung transplant recipients or when the fluid that is used for BAL washes is contaminated with galactomannan.
However, one study performed in lung transplant recipients suggested that specificity is high (95 percent) [33]. Many centers have begun to utilize this
assay on BAL fluid as an adjunct to other diagnostic tests when invasive aspergillosis is suspected. Because performance may be dependent on technical
variables, such as type and amount of BAL fluid, institutions should establish specific protocols for testing.
The use of the galactomannan assay on BAL fluid from lung transplant recipients is discussed in greater detail separately. (See "Fungal infections
following lung transplantation", section on 'Galactomannan, beta-D-glucan, and PCR'.)
Other specimen types Although the galactomannan assay has been approved by the FDA for use only on serum and bronchoalveolar lavage fluid,
galactomannan can also be detected in other samples, including cerebrospinal fluid and pleural fluid, depending on the clinical context [37].
Beta-D-glucan assay 1,3-Beta-D-glucan, a cell wall component of many fungi, is detected by the beta-D-glucan assay. There are several different
commercial assays available in different countries. The Fungitell assay has been cleared by the FDA as an aid to diagnose invasive fungal infections.
These assays utilize the same principal as serum endotoxin assays, measuring activation of Factor G. Since the different marketed tests utilize different
horseshoe crab substrates and different methods to measure output, performance may be variable. The output of the serum assay currently available in the
United States is based on spectrophotometer readings, in which optical density is converted to beta-D-glucan concentrations; the results are interpreted
as negative (range <60 pg/mL), indeterminate (60 to 79 pg/mL), or positive (>80 pg/mL) [38]. Importantly, these cut-offs were defined in the clinical context
of identifying breakthrough invasive fungal infections (primarily, invasive candidiasis) in people who were undergoing treatment for hematologic
malignancies. Precise cut-offs to optimize performance of the assay as an aid to diagnose invasive aspergillosis have not been defined and may be
different. In a 2011 meta-analysis that included 16 studies evaluating beta-D-glucan assays for the diagnosis of invasive fungal infections, the pooled
sensitivity was 77 percent (95% CI 67-84 percent) and the pooled specificity was 85 percent (95% CI 80-90 percent) [39]. A 2012 meta-analysis that
included six cohort studies of patients with hematologic malignancies noted a lower sensitivity (50 percent, 95% CI 34-65 percent) and a higher specificity
(99 percent, 95% CI 97-100 percent) than previously reported; however, there were few cases of invasive aspergillosis tested to provide definitive
conclusions [40]. In individual studies, the sensitivity has ranged from 55 to 95 percent and the specificity has ranged from 77 to 96 percent [38,41-45]. As
in studies evaluating other fungal diagnostics, likely reasons for the differences in sensitivity and specificity between studies are that different thresholds
were considered positive, different assays were used, patient populations varied, and study design was not uniform. Despite the substantial heterogeneity
among different studies, the beta-D-glucan assay has good accuracy for distinguishing patients with proven or probable invasive fungal infections from
patients without invasive fungal infection [39].
One study compared performance of the galactomannan EIA with the beta-D-glucan assay in sera from 105 patients with invasive aspergillosis and 50
healthy blood donors [46]. Results demonstrated a higher specificity with the galactomannan test (97 versus 82 percent) but a lower sensitivity (81 versus
49 percent).
Caveats The following caveats should be considered when using the beta-D-glucan assay:
The beta-D-glucan assay is not specific for Aspergillus species and can be positive in patients with a variety of invasive fungal infections, including
candidiasis and Pneumocystis jirovecii (formerly P. carinii). Although the beta-D-glucan assay may be positive in patients with a variety of invasive
fungal infections, it is typically negative in patients with mucormycosis or cryptococcosis [43,44,47,48]. (See "Epidemiology, clinical manifestations,
and diagnosis of Pneumocystis pneumonia in non-HIV-infected patients", section on 'Beta-D-glucan assay'.)
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The specificity of the assay can be decreased by multiple other clinical variables; the following factors have been reported to cause false-positive
results [47]:
Hemodialysis with cellulose membranes
Intravenous immunoglobulin
Albumin
Use of cellulose filters for intravenous administration
Gauze packing of serosal surfaces
Intravenous amoxicillin-clavulanic acid (a formulation that is not available in the United States) [49]
Bloodstream infections with certain bacteria, such as Pseudomonas aeruginosa [50,51]
Role of testing The beta-D-glucan assay may be used for detecting invasive fungal infections early in the course of infection, prior to the onset of
overt clinical findings. One study evaluated a screening strategy in which 95 patients receiving chemotherapy for acute leukemia underwent beta-D-glucan
testing twice weekly in the absence of fever and daily in the presence of fever [52]. Screening appeared to shorten the time interval between suspected
infection and established diagnosis, when compared with waiting for clinical signs and symptoms of disease. However, this strategy has not been validated
in randomized trials. (See "Treatment and prevention of invasive aspergillosis", section on 'Preemptive therapy'.)
Polymerase chain reaction Investigational DNA detection assays (eg, by polymerase chain reaction [PCR]) have shown mixed results, with some
studies suggesting superior performance compared with antigen-based assays and others reporting the opposite [15,38,41,53-57]. Results of multiple
assays that use different technologies and microbial targets have been reported. A systemic review and meta-analysis suggested that sensitivity and
specificity of PCR to detect invasive aspergillosis was 88 and 75 percent. However, this review emphasized that results cannot be generalized with
nonhomogeneity of methods and patients evaluated [58].
Assays under development While multiple assays are under development, recent publications have focused on two promising tests as aids to
diagnose aspergillosis. A lateral flow device (LFD) that detects an extracellular antigen secreted by Aspergillus species using a monoclonal JF5 antibody
has been studied and found to have reasonable performance in patients at risk for aspergillosis (hematologic malignancy, solid organ transplant). In a
case-control study, performance of the LFD compared with galactomannan and PCR was relatively comparable when applied to serum [59]. Other studies
have compared performance of the LFD with the galactomannan and beta-D-glucan assays on BAL fluid, finding promising results in patients with
hematologic malignancies, solid organ transplant, or respiratory disease [60,61]. Another promising technology relies on detection of secondary
metabolites in human breath using thermal desorption-gas chromatography/mass spectrometry. Results of a small prospective study that enrolled patients
diagnosed with proven or probable invasive aspergillosis reported high sensitivity (94%, 95% CI 81 to 98 percent) and specificity (95% CI 79 to 98 percent)
[62]. While both assays require more study to define performance parameters, each appears promising. [62].
Combining assays Most studies comparing the performance parameters of different assays (the galactomannan EIA, beta-D-glucan assay, LFD, and
PCR for use on BAL fluid emphasize the insensitivity of culture for isolation of Aspergillus species and suggest that the best approach may be to combine
assays [61]. In a total of 78 BAL fluid samples, the sensitivity of all four methods ranged from 70 to 88 percent. The combination of the galactomannan EIA
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and either PCR or LFD increased sensitivity to 94 to 100 percent without compromising specificity. The beta-D-glucan assay applied on BAL fluid resulted
in high false-positive rates.
Precipitin antibodies Detection of precipitin antibodies may be useful for the diagnosis of allergy to various molds, including Aspergillus, but has no
role in the diagnosis of invasive aspergillosis. (See "Allergic bronchopulmonary aspergillosis", section on 'Diagnosis'.)
Imaging Imaging is an important component of the diagnostic evaluation. The lungs are the most commonly affected site in invasive aspergillosis;
computed tomography (CT) scanning of the lungs often helps to support the diagnosis (image 1). In patients with clinical findings suggestive of sinus
involvement, CT of the sinuses should be performed (image 2). When brain involvement is suspected, brain magnetic resonance imaging is indicated
(image 3 and image 4).
The imaging findings associated with invasive pulmonary aspergillosis, such as nodules with surrounding hypoattenuation, termed the halo sign, can be
seen with other angioinvasive pulmonary infections (image 1). However, this finding most often represents invasive aspergillosis because it is the most
common mold to cause invasive infection. The "reversed halo" sign has been described to be potentially a more pathognomonic pattern for mucormycosis,
as the inner zone of hypoattenuation corresponds with early progression of necrosis with the agents of mucormycosis [63]. Imaging findings in patients
with invasive aspergillosis are presented in greater detail separately. (See "Epidemiology and clinical manifestations of invasive aspergillosis", section on
'Imaging'.)
APPROACH TO DIAGNOSIS Culture of Aspergillus spp in combination with the histopathologic demonstration of tissue invasion by hyphae provides
definitive evidence of invasive aspergillosis. However, biopsy is frequently not feasible due to the risks of complications (eg, bleeding risk in patients with
thrombocytopenia). A rational first step to establishing the diagnosis of invasive aspergillosis involves the use of noninvasive modalities, such as serum
biomarkers (galactomannan and beta-D-glucan assays), and obtaining sputum and/or bronchoalveolar lavage (BAL) specimens for fungal staining and
culture. When BAL is performed, a sample should be sent for galactomannan antigen testing.
A positive sputum fungal stain and/or culture should prompt therapy of hosts who are at risk for invasive aspergillosis. The galactomannan assay is
relatively specific for invasive aspergillosis, and, in the right clinical context, provides adequate evidence of invasive pulmonary disease. In contrast, a
positive beta-D-glucan assay can occur in the setting of various invasive fungal infections, including candidiasis.
Patients with clinical and radiographic findings that are suggestive of an invasive fungal infection but in whom both the serum galactomannan assay and
fungal stain and culture of the sputum are negative (or are not able to be obtained) should ideally undergo bronchoscopy with BAL. Lung biopsy should be
performed if feasible. Studies have demonstrated that bronchoscopy is safe and frequently yields important diagnostic information, especially when
performed early in the evaluation and/or treatment of patients with pulmonary infiltrates [64,65].
Options for biopsy include bronchoscopy with transbronchial biopsy, computed tomography-guided transthoracic needle biopsy, and video-assisted
thorascopic surgery. The most appropriate technique depends upon the location of the lesion(s), the individual patients risk of complications from each
procedure, and the necessity to establish the diagnosis. The decision regarding the need for a histopathologic diagnosis must be made on a patient-bypatient basis.
INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. The Basics patient
education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have
about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics
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patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best
for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also
locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.)
Basics topic (see "Patient information: Invasive aspergillosis (The Basics)")
SUMMARY AND RECOMMENDATIONS
Aspergillus conidia are frequently inhaled into the airways but, because of effective clearance in the majority of individuals, disease usually does not
result. Because we inhale conidia constantly, culture isolation of Aspergillus species from the airway does not necessarily indicate disease. Thus,
the diagnosis of invasive aspergillosis is based upon both isolating the organism (or markers of the organism) and the probability that it is the cause
of disease. (See 'Diagnostic modalities' above.)
Culture in combination with evidence of tissue invasion on histopathology or culture from a normally sterile site provides the most certain evidence of
invasive aspergillosis. However, both microscopic examination and culture are insensitive and therapy should not be withheld in the absence of such
confirmation. (See 'Culture' above.)
Performing a biopsy is not feasible in some patients due to the risk of bleeding or other complications. In patients with risk factors and clinical and/or
radiographic features that are suggestive of invasive aspergillosis, culture of Aspergillus spp from respiratory secretions or finding typical hyphae on
staining of respiratory secretions provides adequate evidence to warrant therapy. (See 'Culture' above.)
Aspergillus organisms observed in biopsy specimens are typically narrow (3 to 6 microns wide), septated hyaline hyphae with acute angle branching
(picture 1 and picture 2). However, several filamentous fungi including Scedosporium spp and Fusarium spp have similar appearances to Aspergillus
spp in histopathologic sections. The treatment of infections caused by these fungi may differ, so it is important to confirm genus and species by
culture. (See 'Histopathology' above.)
Histopathologic examination can usually distinguish Aspergillus spp and the other fungi described above from the Mucorales, which appear as broad,
non-septate hyphae that exhibit right angle branching (picture 3 and picture 4). Determining whether the fungus is a Mucorales is important because
these molds are not susceptible to voriconazole, which is the treatment of choice for invasive aspergillosis. (See 'Histopathology' above.)
Galactomannan is a major constituent of Aspergillus cell walls that is released during growth of hyphae. A double sandwich enzyme immunoassay
(EIA) that detects the galactomannan antigen is available for use on serum and bronchoalveolar lavage (BAL) fluid as an adjunctive test for the
diagnosis of aspergillosis. The utility of the serum galactomannan assay has been best established in the setting of suspected disease in patients
with hematologic malignancies. (See 'Galactomannan antigen detection' above.)
1,3-Beta-D-glucan, a cell wall component of many fungi, is detected by the beta-D-glucan assay. However, this assay is not specific for Aspergillus
species and can be positive in patients with a variety of invasive fungal infections, including candidiasis and Pneumocystis jirovecii (formerly P.
carinii). (See 'Beta-D-glucan assay' above.)
A rational first step to establishing the diagnosis of invasive aspergillosis involves the use of noninvasive modalities, such as serum biomarkers
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(galactomannan and beta-D-glucan assays) and obtaining sputum for fungal staining and culture. If the diagnosis is not made by these methods, a
more invasive approach is indicated when feasible. Options include bronchoscopy with BAL, transbronchial biopsy, computed tomography-guided
transthoracic needle biopsy, and video-assisted thorascopic surgery. When BAL is performed, a sample should be sent for galactomannan antigen
testing. (See 'Approach to diagnosis' above.)
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Topic 15717 Version 20.0
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GRAPHICS
Aspergillus fumigatus
Silver-stain of lung tissue (x400) shows septate hyphae with ac ute

angle branc hing c harac teristic of Aspergillus fumigatus.
Courtesy of Harriet Provine.
Graphic 68747 Version 4.0
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Aspergillus bronchopneumonia histopathology
(Panel A) Magnified view of a slic e of lower lobe shows multiple foc i of nec rosis,
some c learly c entered on airways (arrows) as indic ated by their intimate
assoc iation with pulmonary arteries. The lung parenc hyma adjac ent to the
nec rotic regions is hemorrhagic .
(Panel B) Photomic rograph shows small c olonies of Aspergillus (arrow) within a
bronc hial lumen (L) and wall (W). Extension of fungus c an also be seen into the
adjac ent pulmonary artery, whic h is partly oc c luded by thrombus (T). An
infiltrate of neutrophils (N) is evident in the adjac ent lung.
Reproduced with permission from: Mller NL, Fraser RS, Lee KS, Johkoh T. Pulmonary
infections. In: Diseases of the Lung, Lippincott Williams & Wilkins, Philadelphia 2002.
Copyright 2002 Lippincott Williams & Wilkins. www.lww.com.
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Rhizopus arrhizus hyphae in lung tissue
Hyphae in lung tissue, hematoxylin and eosin stain.

Courtesy of www.doctorfungus.org. Copyright 2007.
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8/17/2015
Mucorales hyphae
Fine needle aspiration of right lower lobe of lung showing aseptate

hyphae (Papanic olaou stain, x400).
Reproduced with permission from: Silveira FP, Husain S. Fungal infections in
lung transplant recipients. Curr Opin Pulm Med 2008; 14:211. Copyright
2008 Lippincott Williams & Wilkins.
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Computed tomography (CT) pulmonary aspergillosis
Halo sign (A) c onverting to an air-c resc ent sign (B) after neutrophil
rec overy.
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Reproduced with permission from: Maertens J, Meersseman W, Van

Bleyenbergh P. New therapies for fungal pneumonia. Curr Opin Infect Dis
2009; 22:183. Copyright 2009 Lippincott Williams & Wilkins.
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Aspergillus sinusitis
An 87-year-old man with diabetes mellitus and biopsy-proved

aspergillosis of paranasal sinuses. Coronal T1-weighted magnetic
resonanc e image (MRI) obtained after injec tion of c ontrast material
shows abnormal soft tissue filling ethmoidal air c ell c omplex, nasal
c avity, and maxillary sinus. Note subfrontal intrac ranial extension with
dural thic kening and abnormal enhanc ement (arrows).
From: Ashdown BC, Tien RD, Felsberg GJ. Aspergillosis of the brain and
paranasal sinuses in immunocompromised patients: CT and MR imaging
findings. AJR Am J Roentgenol 1994; 162:155. Reprinted with permission
from the American Journal of Roentgenology.
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Aspergillus brain abscesses
A 44-year-old man with hairy-c ell leukemia and biopsy-proved c erebral

aspergillosis.
(A) Computed tomography sc an obtained after injec tion of c ontrast
material shows multiple ring-enhanc ing lesions with surrounding edema
and mass effec t.
(B) T2-weighted magnetic resonanc e image (at slightly lower level
than A) shows mutiple hypointense rings (arrows) with surrounding
edema in right c erebral hemisphere. Rings are irregular and relatively
poorly formed.
from: the American Journal of Roentgenology.
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Aspergillus cortical infarct with hematoma
A 58-year-old man with a kidney transplant. Unenhanc ed c omputed

tomography (CT) sc an shows hematoma c omplic ating a c ortic al infarc t
in left frontal lobe. Note intraventric ular extension of hemorrhage.
Autopsy showed Aspergillus thrombosis and vasc ular invasion. The
patient died before c erebral angiography c ould be performed; a
myc otic aneurysm c ould not be identified at autopsy.
from: the American Journal of Roentgenology.
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Disclosures
Disclosures: Kieren A Marr, MD Grant/Research/Clinical Trial Support: Pfizer [Antifungals (Voriconazole, anidulafungin)]; Astellas
[Transplant infections (Liposomal amphotericin B, micafungin, isavuconazole)]. Consultant/Advisory Boards: Astellas [Antifungals (Liposomal
amphotericin B, micafungin, isavuconazole)]; Merck [Antifungals (Posaconazole)]; Cidara Therapeutics [Antifungals (Antifungals)]; Chimerix
Therapeutics [Antivirals (Antivirals)]. Patent Holder: MycoMed Technologies [Aspergillosis (Fungal diagnostics)]. Equity Ow nership/Stock
Options: MycoMed Technologies [Aspergillosis (Fungal diagnostics)]. Carol A Kauffm an, MD Nothing to disclose. Anna R Thorner, MD
Nothing to disclose.
Contributor disclosures are review ed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a
multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is
required of all authors and must conform to UpToDate standards of evidence.
Conflict of interest policy
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Diagnostico de Aspergilosis Invasiva

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Diagnostico de Aspergilosis Invasiva

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Diagnosis of invasive aspergillosis

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Diagnosis of invasive aspergillosis

Diagnosis of invasive aspergillosis

Diagnosis of invasive aspergillosis

Diagnosis of invasive aspergillosis

Diagnosis of invasive aspergillosis

Diagnosis of invasive aspergillosis

Diagnosis of invasive aspergillosis

Diagnosis of invasive aspergillosis

Diagnosis of invasive aspergillosis

Diagnosis of invasive aspergillosis

Diagnosis of invasive aspergillosis

Diagnosis of invasive aspergillosis

Diagnosis of invasive aspergillosis

Silver-stain of lung tissue (x400) shows septate hyphae with ac ute

Diagnosis of invasive aspergillosis

Aspergillus bronchopneumonia histopathology

Diagnosis of invasive aspergillosis

Graphic 57220 Version 10.0

Diagnosis of invasive aspergillosis

Rhizopus arrhizus hyphae in lung tissue

Hyphae in lung tissue, hematoxylin and eosin stain.

Diagnosis of invasive aspergillosis

Fine needle aspiration of right lower lobe of lung showing aseptate

Diagnosis of invasive aspergillosis

Computed tomography (CT) pulmonary aspergillosis

Diagnosis of invasive aspergillosis

Reproduced with permission from: Maertens J, Meersseman W, Van

Diagnosis of invasive aspergillosis

An 87-year-old man with diabetes mellitus and biopsy-proved

Diagnosis of invasive aspergillosis

Aspergillus brain abscesses

A 44-year-old man with hairy-c ell leukemia and biopsy-proved c erebral

Diagnosis of invasive aspergillosis

Aspergillus cortical infarct with hematoma

A 58-year-old man with a kidney transplant. Unenhanc ed c omputed

Diagnosis of invasive aspergillosis

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