JCM Accepts, published online ahead of print on 11 April 2007 J. Clin. Microbiol. doi:10.1128/JCM.00077-07 Copyright 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.
Bronchoalveolar lavage galactomannan in the diagnosis of invasive pulmonary
aspergillosis among solid organ transplant recipients.
Cornelius J. Clancy1,2*, Reia A. Jaber1, Helen L. Leather1, John R. Wingard1,
Benjamin Staley3, L. Joseph Wheat4, Christina L. Cline1, Kenneth H. Rand1, Denise
1Department of Medicine, University of Florida College of Medicine, Gainesville, FL;
2North Florida/South Georgia Veterans Health System, Gainesville, FL; 3Shands
Teaching Hospital Department of Pharmacy, Gainesville, FL; 4MiraVista Diagnostics,
University of Florida College of Medicine Box 100277 JHMHC Gainesville, FL 32610 Phone: 352-379-4027 Fax: 352-379-4015 e-mail: [email protected]
Running title: BAL galactomannan and solid organ transplant Key words: Aspergillus; galactomannan; bronchoalveolar lavage; solid organ transplant; diagnosis
We review the experience at our institution with galactomannan (GM) testing of
bronchoalveolar lavage (BAL) fluid in the diagnosis of invasive pulmonary aspergillosis
(IPA) among solid organ transplant recipients. Among 81 patients for whom BAL GM
was ordered (heart, n=24; kidney, n=22; liver, n=19; lung, n=16), there were five cases of
proven or probable IPA. All five patients had BAL GM 2.1 and survived following
antifungal therapy. The sensitivity, specificity, positive and negative predictive values
for BAL GM at a cut-off 1.0 were 100%, 90.8%, 41.7% and 100%, respectively. The
sensitivity of BAL GM was better than conventional tests such as serum GM or BAL
cytology and culture. Moreover, a positive BAL GM diagnosed IPA several days to four
weeks before other methods in three patients. Twelve patients had BAL GM 0.5 but no
evidence of IPA. Among these, lung transplant recipients accounted for 41.7% (5/12) of
the false positive results, reflecting frequent colonization of airways in this population.
Excluding lung transplants, the specificity and positive predictive value for other solid
organ transplants increased to 92.9% and 62.5%, respectively (cut-off 1.0). In
conclusion, BAL GM facilitated more rapid diagnoses of IPA and institution of
antifungal therapy among non-lung solid organ transplant recipients, and helped to rule-
Invasive pulmonary aspergillosis (IPA) is a devastating disease in
immunosuppressed patients. The incidence of IPA is roughly 15% among allogeneic
hematopoietic stem cell transplant (HSCT) recipients and neutropenic patients with
hematologic malignancies, and generally slightly lower among solid organ transplant
recipients (5,7,13,15,21). Case fatality rates are as high as 50-90% despite aggressive
antifungal therapy (5,11,13,21). Prompt diagnoses of IPA improve survival (6,23), but
they are difficult to make due to the inadequacies of conventional diagnostic methods. At
present, diagnosis generally depends upon the cultivation of Aspergillus from respiratory
tract samples or the detection of hyphae within biopsy specimens. These approaches are
limited by the insensitivity of cultures and the invasiveness of transbronchial biopsies.
Presumptive diagnoses based on the evolution of lesions detected by thoracic CT
scanning facilitate the institution of therapy in the absence of culture or biopsy results
(2,3,12,24), but this strategy is limited by low sensitivity and a lack of specificity for IPA
compared to other infectious processes (25). Moreover, classic halo and air-crescent
signs are well-described among neutropenic hosts, but are less common in solid organ
Not surprisingly, there is much interest in alternative diagnostic methods that
might complement conventional approaches (9). Best studied among these is a
commercially available double-sandwich ELISA that detects galactomannan (GM), a cell
wall polysaccharide of most Aspergillus and Penicillium species that is released into
serum during growth in tissue (Platelia ELISA, BioRad). The overall sensitivity of the
serum ELISA is approximately 61%-71%, with specificity of 89%-93% (16). The test
performs best among HSCT recipients and patients with hematologic malignancies,
populations with the highest incidence of IPA (16). Experience among patients
undergoing solid organ transplantation is much more limited. In studies of lung and liver
transplant recipients, the sensitivities of the assay were 30% and 56%, respectively (4,8),
with specificities of 93%-95% and 87%-94%, respectively (4,8,10).
It has been suggested that the moderate sensitivity and relatively low positive
predictive value of serum GM in diagnosing IPA might be improved by testing
bronchoalveolar lavage (BAL) samples (8,14). Among HSCT recipients and patients
with hematologic malignancies, detection of GM within BAL samples added to the
sensitivity of both BAL culture and serum GM detection (1,14,17-20). While the
specificity of BAL GM detection has generally been good (14,17), high rates of false
positive results were reported in at least one study (22). To date, there have been no
studies of BAL GM detection among solid organ transplant recipients. The objectives of
this study are to review our experience with BAL GM detection among solid organ
transplant recipients and to assess the utility of the assay in the diagnosis of IPA.
Methods. Identification of patients. We reviewed all cases of solid organ transplant recipients from
the Shands Teaching Hospital at the University of Florida who had BAL fluid tested for
GM between September 2004 and September 2006. BAL was performed according to
the methods of individual pulmonologists. In general, the bronchus of the lobe in which
consolidation was imaged by chest radiograph or chest CT scan was wedged, and 50 mL
of 0.9% sterile saline solution at room temperature was instilled with a syringe through
the working channel of the bronchoscope. The total volume of saline solution instilled
into the lung was typically 150 mL, and 50 to 100 mL of BAL fluid was recovered. The
BAL was sent unprocessed on dry ice via overnight mail to MiraVista Diagnostics
Platelia™ Aspergillus EIA. The Platelia™ Aspergillus EIA (Bio-Rad Laboratories,
Redmond, WA) was performed at MiraVista Diagnostics (Indianapolis, IN) according to
the manufacturers’ procedures. Although the Platelia™ Aspergillus EIA is not FDA-
cleared for testing BAL, accuracy in BAL was validated at MiraVista Diagnostics. First,
100 µL of the Platelia® treatment solution was added to 300 µL of the BAL or serum
specimen, which was then heated for four minutes in a heat block (Fisher Scientific,
Chicago, IL) at 104ºC, followed by centrifugation at 10,000 x g for 10 minutes. Next, 50
µL of the supernatant and 50 µL of the horseradish peroxidase-labeled monoclonal
antibody (EBA-2) were incubated in the antibody pre-coated microplates for 90 minutes
at 37ºC. The plates were washed five times, after which they were incubated with 200 µL
of substrate chromogen reaction solution for 30 ± 5 minutes in the dark at room
temperature. The reaction was stopped with sulfuric acid. Finally, within 30 minutes of
adding the sulfuric acid, the plates were read at 450 nm with a reference filter of 620/630
nm. An OD index of 0.5 was considered positive. All positive samples were retested and
considered positive only if the repeat test was also positive. Tests were performed as
samples were received and results were reported the same day for negative specimens
and after the confirmation the next day for positive specimens.
Case definitions. Proven, probable and possible IPA was defined using modified
EORTC-MSG criteria [http://www.doctorfungus.org/lecture/eortc_msg_rev06.htm], and
assigned by physician investigators in a blinded fashion. In the event of disagreement, a
consensus was reached by the investigators. BAL GM results were not made available to
the investigators until the reviews were finished. The results are not included in the
Definition of positive BAL GM. BAL GM results were reported as numerical values to
the physicians caring for patients. The physicians made all management decisions.
Interpretive cut-off values for positive BAL GM have not been established, but in this
review we adopted the 0.5 cut-off proposed for serum testing.
ACCEPTED Data analysis. The sensitivity, specificity, positive and negative predictive values were
calculated for BAL GM, serum GM, BAL cytology and culture. The optimal cutoff for
BAL GM was determined by receiver operating characteristic (ROC) analysis. Factors
associated with IPA were determined using Fisher’s exact test and expressed in 2-by-2
contingency tables; p-values <0.05 were considered significant.
Results. Description of patient population. Eighty-one solid organ transplant recipients from
our medical center had Platelia ELISA performed by MiraVista Diagnostics on BAL
fluid over a two year period [Table 1]. BAL was performed for the following reasons:
respiratory symptoms (n=61), fever/sepsis and abnormal imaging study of the chest
(n=17), abnormal chest X-ray findings during routine clinic visit (n=2), and routine BAL
surveillance following lung transplant (n=1).
Five patients had IPA (liver transplant, n=1; heart transplant, n=1; kidney
transplant, n=3) [Table 2]. According to modified EORTC/MSG criteria, two patients
were classified as proven IPA and three as probable IPA. No patients fulfilled criteria for
Performance of diagnostic tests and radiological studies. BAL GM. Seventeen patients had at least one BAL GM 0.5 (12 patients had BAL GM
1.0) [Tables 2 and 3, Figure 1]. Only one patient was receiving an agent with anti-
mould activity for prophylaxis at the time of BAL collection (ABLC; 5 mg/kg); this
patient had proven IPA and a GM level of 8.83 (patient #1 in Table 2).
The sensitivity, specificity, and positive and negative predictive values (PPV and
NPV, respectively) of BAL GM at various interpretive cut-offs are presented in Table 4.
All five patients with IPA had BAL GM levels 2.1 (range 2.1-10.12). A cut-off 0.5
yielded sensitivity and NPV of 100%, with relatively low specificity and PPV [Table 4].
Increasing the cut-off to 1 improved the specificity [Table 4]. As shown in the receiver
operating curve [Figure 2], further increasing the cut-off to 1.5 and 2 improved
BAL cytology and culture, and serum GM. BAL fluid was sent for cytology in 78
patients (including 4 of 5 patients with IPA) and culture in all patients. The sensitivity of
cytology and culture were 50% and 40%, respectively [Table 4].
Serum GM was ordered for 38 patients, including 4 of the 5 patients with IPA. In
each case, serum and BAL GMs were collected within three days of one another. Only
one patient with IPA demonstrated a serum GM level 0.5 (0.93; sensitivity of serum
GM: 25%). Moreover, two patients with IPA had 4 serum GMs that were negative
within a week of a positive BAL GM (patients #1 and 2, Table 2). The specificity, PPV
and NPV of serum GM (positive test defined as a single value 0.5) are compared to
BAL GM, cytology and culture in Table 4. The concordance between serum and BAL
ACCEPTED Test results and radiological findings significantly associated with IPA. The following
test results and radiological findings were more closely associated with IPA than
alternative diagnoses [Table 6]: 1) BAL GM > 1.0; 2) cavitary lung lesions on chest CT
scan; 3) BAL cytology consistent with mould; and 4) positive BAL culture for
Aspergillus or cytology for mould. Chest X-ray and/or CT were performed in 78 patients
at our medical center. We did not find any association between IPA and serum GM
levels or nodules/nodular infiltrates without cavities. Indeed, nodular lesions were
described in a range of diagnoses, including bacterial pneumonia (n=6), pulmonary
histoplasmosis (n=2), pulmonary nocardiosis (n=2), disseminated methicillin-resistant
Staphylococcus aureus (MRSA) or enterococcal infection (n=2), Rhodococcus
pneumonia (n=1), cytomegalovirus pneumonitis (n=1), lung cancer(n=1) and
bronchiolitis obliterans organizing pneumonia (n=1). Two patients with IPA had nodular
lesions and cavities. An air-crescent sign was detected in only one patient, who was
found to have pulmonary nocardiosis but not IPA.
Not surprisingly, positive BAL cultures for either Aspergillus sp. or Penicillium
sp. were significantly associated with BAL GM 1.0 (p=0.003). The presence of hyphal
elements on cytology was also associated with BAL GM 1.0 (p=0.001). These
associations were noted whether the elevated GM represented a true- or false-positive
ACCEPTED Impact of BAL GM on the time to diagnosis of IPA. In two patients with proven or
probable IPA (patients #1 and 2 in Table 2), BAL GM was the first positive test for the
disease, occurring one and four weeks before a positive brain biopsy and pleural fluid
culture, respectively. In a third patient (#5 in Table 2), the BAL culture revealed both A. fumigatus and Penicillium. Since cultures took several days to grow, however, a positive
BAL GM shortened the time to diagnosis and the institution of antifungal therapy. In the
remaining two patients with IPA, BAL GM was positive and cytology revealed hyphae
The most notable finding of our study was that BAL GM added to the sensitivity
of conventional methods for the diagnosis of IPA, while maintaining excellent specificity
(90.8% at a cut-off 1.0). The sensitivity of BAL GM was 100%, compared to 50%,
40% and 25% for cytology, cultures and transbronchial biopsy results, respectively, and
25% for serum GM 0.5. In three patients (#1, 2 and 5 in Table 2), a positive BAL GM
suggested IPA several days to four weeks before a diagnosis was available by other
methods. Conversely, we found that a negative BAL GM effectively excluded the
diagnosis of IPA (NPV=100% at a cut-off 1.0). Moreover, in the two cases of IPA in
which serial bronchoscopies were performed, clinical responses to antifungal therapy
were associated with decreases in BAL GM levels to < 0.5. In our experience, therefore,
BAL GM was a useful adjunct to conventional tests in diagnosing, excluding and
following IPA among solid organ transplant recipients.
The major shortcoming of the test was false positive results, as was also reported
in at least one previous study of patients with hematologic malignancies (22). In our
series, the PPV was 41.7% using a cut-off 1.0 and 29.4% using a cut-off 0.5. None
of the false positive tests occurred among patients receiving piperacillin-tazobactam or
other antimicrobials previously linked to false positive serum results. Rather, both true-
and false positive BAL GMs were significantly associated with cultures that yielded
Aspergillus or Penicillium sp., and/or cytology that revealed hyphal elements. Moreover,
the extent to which a GM level was positive did not differ for patients with and without
IPA. These observations imply that BAL GM reflected the presence of moulds but did
not distinguish between invasive disease and colonization.
The performance of BAL GM among our lung transplant recipients merits
particular consideration for two reasons. First, there were no cases of proven or probable
IPA, fungal tracheobronchitis or bronchial anastomotic infections among patients
receiving lung transplants, which precluded any assessment of the diagnostic utility of the
test in this population. Second, lung transplant recipients accounted for almost half of the
false positive test results (41.7% (5/12) at a cut-off 0.5, and 42.9% (3/7) at a cut-off
1.0). The high rate of false positives is not surprising. While aspergillosis has been
reported in about 6% of patients receiving lung transplants, Aspergillus species can be
detected in cultures of airway samples from 25%-30% of patients (21). Indeed, BAL
cultures were positive for Aspergillus in three of the sixteen lung transplant recipients in
this study, all of whom had extremely high GM levels (8.1, 7.14 and 3.04). If we
exclude the lung transplant recipients from our analysis, the specificity and PPV among
patients receiving other solid organ transplants increase to 92.9% and 62.5%, respectively
Based on our data, we cannot conclusively define interpretive criteria for BAL
GM. In part, this is due to the relatively small sample size and the low number of IPA
cases in our study. In addition, the distribution of data limited our ability to draw
conclusions about cut-offs in the 1.0-2.0 range; all five proven or probable cases were
associated with levels 2.1, but only two false-positive cases exhibited levels between
1.0 and 2.0. As the cut-off was increased from 1.0 to 2.0, therefore, sensitivity did not
differ and specificity improved minimally [Figure 2]. Increasing the cut-off from 0.5 to
1.0, on the other hand, was associated with more dramatic improvements in test
performance, and the elimination of five false-positive cases.
Since bronchoscopy is commonly utilized in the evaluation of solid organ
transplant recipients with respiratory symptoms and/or abnormal findings on imaging
studies, BAL GM is easy to incorporate into standard clinical practices. In addition to
making more rapid diagnoses, facilitating the prompt institution of antifungal therapy and
helping to rule out IPA, BAL GM might also lessen the need for invasive procedures like
tissue biopsy to establish definitive diagnoses. Despite the test’s appeal, potential
obstacles to its successful widespread use include a lack of standardized methodologies
for collecting BAL fluid, and uncertainties about the causes of false positive results and
the impact of antifungal agents on the sensitivity of the test. Clearly, issues such as
optimal methodologies, interpretive criteria and the most rational use of BAL GM in
widespread clinical practice merit assessment in well-designed prospective studies.
This study was supported by the University of Florida Mycology Research Unit (NIH
PO1 AI061537-01 to Drs. Nguyen, Clancy and Wingard). Dr. Wheat is the President and
Director of MiraVista Diagnostics, which performs BAL GM testing as a commercial
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with neutropenia--a prospective study. Radiology. 208:777-82. ACCEPTED Table 1. Demographics of enrolled patients. Age (median, range) ACCEPTED
* 4 patients received multiple organ transplant (2 heart-lung and 2 heart-kidney); they are not listed in the lung or kidney groups. ** 1 patient received lung-kidney transplant; he is not listed in the kidney group. *** 1 patient received liver-pancreas transplant.
Table 2. Clinical characteristics of patients with IPA.
Patient Transplant Reasons for CXR/ CT scan Antibiotics Serum - Cytology Culture of Diagnosis Treatment Outcome prior to or BAL fluid Follow-up at the time BAL fluid
Resection of the brain and thyroid lesions
* transplant status: transplanted organ, time from last transplant to BAL, immunosuppressive regimen Abbreviations: ND: not done; TBBx: transbronchial biopsy; f/u: follow-up Myco: Mycophenolate; Pred: prednisone; Sol: solumedrol; FK506: tacrolimus; Siro: sirolimus; ATG: anti-thymocyte globulin;
Vori: voriconazole; ABLC: amphotericin B lipid complex; Levo: levofloxacin; Mox: moxicyin; Azi: azithromycin; Tim: timemtin; CFX: ceftriaxone; TMP-SMX: trimethoprim-sulfamethoxazole.
1 Follow-up BAL during antifungal therapy: 7.72 (21 days), 0.19 (5 months), 0.26 (9 months) 2 Follow-up serum GAL over the next four days: 0.07, 0.07, 0.06 3 Follow-up BAL GAL during antifungal therapy: 0.13 (2 mos), 0.23 (9 months) 4 Follow-up serum GAL over the next six days: 0.44, 0.06, 0.06, 0.12 5 Follow-up serum GAL during antifungal therapy: 0.11 (4 days), 0.06 (1 month), 0.07 (1 month), 0.07 (2 months)
ACCEPTED Table 3. Clinical characteristics of patients without IPA but with BAL GAL > 0.5.
Patient Transplant Reasons for CXR/ CT scan Antibiotics Serum - Cytology Culture of Diagnosis Treatment Outcome prior to or BAL fluid Follow-up ** or at the time of BAL fluid cause of death ACCEPTED ACCEPTED ACCEPTED
* transplant status: transplanted organ, time from last transplant to BAL, immunosuppressive regimen ** time from BAL to follow-up or death Abbreviations: ND: not done; f/u: follow-up; SOB: short of breath; MSOF: multisystem organ failure; MDR: multi-drug resistant; PCP: pneumocystis pneumonia. CyA: cyclosporin A; Myco: mycophenolate; Pred: prednisone; Sol: solumedrol; FK506: tacrolimus; Sicro: sicrolimus; Aza: azathioprine; Vori: voriconazole; Flu: fluconazole; CEF: cefipime; Vanc: vancomcyin; Azi: azithromycin; Tim: timemtin; CFX: ceftriaxone; metro: metronidazole; gati: gatifloxacin; TMP-SMX: trimethoprim-sulfamethoxazole. Table 4. Performance of diagnostic tests. Sensitivity ACCEPTED Table 5. Concordance between serum and BAL GM levels.
(number of patients) (number of patients) (number of patients)
ACCEPTED Table 6. Factors associated with IPA.
Culture positive for Aspergillus sp.
Cavitary lesions observed on chest CT or
ACCEPTED Figure 1. Distribution of BAL GM results.
Eur Arch Otorhinolaryngol (2002) 259 : 274–278 Jussi Laranne · Leo Keski-Nisula · Riitta Rautio · Markus Rautiainen · Mari Airaksinen OK-432 (Picibanil) therapy for lymphangiomas in childrenReceived: 20 July 2001 / Accepted: 26 October 2001 Abstract Lymphangiomas are benign, soft tumors that sent as soft, non-tender masses. Lymphangiomas maymost often affect the head and neck area, u
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