mycoses

Diagnosis,Therapy and Prophylaxis of Fungal Diseases

Original article

Utility of galactomannan antigen detection in bronchoalveolar

lavage fluid in immunocompromised patients
Kyle R. Brownback, Lucas R. Pitts and Steven Q. Simpson
Division of Pulmonary and Critical Care Medicine, University of Kansas Medical Center, Kansas City, KS, USA

Summary

Diagnosis of invasive pulmonary aspergillosis (IPA) is a challenging process in immunocompromised patients. Galactomannan (GM) antigen detection in bronchoalveolar
lavage (BAL) fluid is a method to detect IPA with improved sensitivity over conventional studies. We sought to determine the diagnostic yield of BAL GM assay in a
diverse population of immunocompromised patients. A retrospective review of 150
fiberoptic bronchoscopy (FOB) with BAL for newly diagnosed pulmonary infiltrate in
immunocompromised patients was performed. Patient information, procedural details
and laboratory studies were collected. BAL and serum samples were evaluated for GM
using enzyme-linked immunoassay. Of 150 separate FOB with BAL, BAL GM was
obtained in 143 samples. There were 31 positive BAL GM assays. In those 31 positive
tests, 13 were confirmed as IPA, giving a positive predictive value of 41.9%. There was
one false negative BAL GM. Of the 18 false positive BAL GM, 4 were receiving piperacillintazobactam and 11 were receiving an alternative beta-lactam antibiotic. BAL GM
assay shows excellent sensitivity for diagnosing IPA. There was a significant number of
false positive BAL GM assays and several of those patients were receiving beta-lactam
antibiotics at the time of bronchoscopy.

Key words: Aspergillosis, bronchoalveolar lavage, galactomannan, immunodeficiency.

Introduction
Invasive pulmonary aspergillosis (IPA) has become a
leading cause of morbidity and mortality among immunocompromised patients with diverse backgrounds.13
Mortality rates range from 50% to 90% even with
aggressive treatment directed towards fungal organisms.46 Early diagnosis and initiation of therapy may
improve survival in this population.7,8
Establishing an early diagnosis of IPA can be challenging. Obtaining tissue samples to establish a
Correspondence: Dr K. R. Brownback MD, University of Kansas Medical
Center, Division of Pulmonary and Critical Care Medicine, 3901 Rainbow
Boulevard, Mail Stop 3007, Kansas City, KS 66160, USA.
Tel.: +(913) 588 6045. Fax: +(913) 588 4098.
E-mail: kbrownback@kumc.edu
Submitted for publication 7 December 2012
Revised 26 February 2013
Accepted for publication 27 February 2013

doi:10.1111/myc.12074

diagnosis of proven IPA is potentially fraught with

complications, especially in those patients with thrombocytopenia or other coagulapathies, or in those
patients who are too ill to risk a procedural complication. Sputum cultures for Aspergillus species lack the
sensitivity or specificity to establish a diagnosis or to
exclude IPA.911 Galactomannan (GM), a polysaccharide component of the fungal cell wall that is released
when Aspergillus species invade tissue, can be detected
in the serum and supports a diagnosis of invasive
aspergillosis (IA).12,13 However, serum GM test has
variable sensitivity for detecting IA.14,15
Bronchoalveolar lavage (BAL) GM has been recently
explored as an additional way to diagnose IPA. It has
been evaluated in patients following haematopoietic
stem cell transplant (HSCT),16 solid organ transplantation,17,18 intensive care unit (ICU) patients19 and in
those with haematological malignancies.20 In these
various studies, sensitivity ranged from 57% to 88%,
and specificity ranged from 87% to 95.8%.

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Mycoses, 2013, 56, 552558

Galactomannan in BAL from the immunocompromised

In this study, we sought to determine the diagnostic

yield of BAL GM in a wide range of immunocompromised patients, representing a common clinical practice,
who underwent fiberoptic bronchoscopy (FOB) at a tertiary academic medical centre.

Materials and methods

We performed a retrospective review of all patients at
the University of Kansas Medical Center who underwent
FOB with BAL from January 1, 2010 through January
1, 2012. The patients medical records were screened
for the presence of conditions associated with a compromised immune system. Such conditions included the
presence of a haematogenous or solid organ malignancy
for which the patient was currently receiving chemotherapy within 14 days of bronchoscopy, receipt of an
allogenic bone marrow or haematopoietic stem cell
transplantation, receipt of a solid organ transplantation,
infection with human immunodeficiency virus (HIV),
neutropenia for greater than 10 days duration and temporally related to the onset of disease and diagnosis of
an autoimmune disorder for which the patient was
being treated with immune suppressants. Immune suppressants were considered as T-cell immunosuppressants or a minimum dose of greater than 0.3 mg kg 1
of prednisone equivalent for greater than 3 weeks. One
hundred and thirty-three patients were identified who
met these criteria, and these patients underwent FOB
with BAL on 150 occasions.
After patients were appropriately identified, their
medical records were evaluated for patient characteristics, procedural details, symptoms prior to FOB, imaging
characteristics, results of diagnostic studies, eventual
diagnosis and survival at 30 and 90 days following
bronchoscopy. All data were collected with the approval
of the University of Kansas Medical Center institutional
review board, project HSC #12949.
All BAL fluid was collected via FOB performed by
members of the Division of Pulmonary and Critical Care
Medicine at the University of Kansas Medical Center. All
patients or their surrogate decision maker signed
informed consent prior to procedural initiation. The
patients had a new finding of pulmonary infiltrates, and
were selected for FOB with BAL at the discretion of the
attending physician based on patient symptoms, medical history and differential diagnosis. FOB was performed in either an endoscopy suite or in the ICU. The
bronchoscope was introduced through either the oropharynx or an endotracheal or tracheostomy tube when
present. BAL was performed in the lung lobe deemed to
be the most afflicted based on radiographic analysis of

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Mycoses, 2013, 56, 552558

the chest and the opinion of the performing physician.

BAL involved the instillation of 350 ml aliquots of normal saline through the suction channel of the bronchoscope, with lavage fluid recovered through suction.
There may have been slight variability in the procedural
details as determined by patient tolerance. Volume of
BAL fluid instilled and subsequently collected was not
routinely recorded. Transbronchial biopsies were
performed at the discretion of the proceduralist when it
was deemed necessary to enhance diagnostic yield and
only when they presented minimal risk to the patient.
Galactomannan enzyme-linked immunoassay (EIA)
was performed on available BAL samples at the discretion of the treating physicians. All GM testing was
performed per the manufacturers recommendations
(Platelia Aspergillus Galactomannan EIA, Viracor-IBT
laboratories, Lees Summit, MO, USA.) An optical density (OD) greater than or equal to 0.5 was considered
a positive result for both serum and BAL samples.
Patients were classified as having either proven, probable or possible IA as per the Revised Definitions of Invasive Fungal Disease from the European Organization for
Research and Treatment of Cancer/Invasive Fungal
Infections Cooperative Group and the National Institute
of Allergy and Infectious Diseases Mycoses Study Group
(EORTC/MSG) Consensus Group.21 Proven IA required
histopathological identification of septated, acutely
branching, filamentous fungi accompanied by evidence
of associated tissue damage. Probable IA was defined by
the presence of three factors: host immunocompromise;
clinical criteria of a lower respiratory tract infection
with presence of either a cavity, air-crescent sign or
dense and well-circumscribed lesions on chest computed
tomography and mycological criteria of recovery of
Aspergillus on culture, GM antigen detected in serum or
BAL fluid or positive b-D-glucan assay in serum. Possible
IA is defined as having host factors and clinical criteria
present, but without mycological criteria. The classification of possible IA was not considered in our cohort as all
patients who underwent FOB with BAL had appropriate
host factors and a clinical concern for invasive fungal
infection, and therefore met criteria for possible IA.
Statistical analysis was performed using a statistical
software program (GraphPad Prism 5; GraphPad
Software Inc., La Jolla, CA, USA). Proportions were
compared using the Cox proportional hazard model
and a hazard ratio was calculated.

Results
From January 1, 2010 until January 1, 2012, 133
immunocompromised patients underwent FOB with

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K. R. Brownback et al.

BAL. Seventeen patients underwent FOB with BAL on

two occasions, which provided data on 150 separate
FOB with BAL. There were 57 female patients and 76
male patients. The average age of the patients was
50.4 years. The majority of patients had a history of
receiving an HSCT or were actively receiving chemotherapy. For full details of patient characteristics, see
Table 1.
Of the 150 FOB with BAL, a diagnosis was achieved
in 81 instances (diagnostic yield: 56.0%). Thirty-seven
patients were diagnosed with a viral pneumonia/pneumonitis, with metapneumovirus and respiratory syncytial virus being the most common viruses isolated.
Fifteen patients had IPA, 9 patients had bacterial
pneumonia, 6 patients had Pneumocystis jirovecci pneumonia, 6 patients had a miscellaneous fungal pneumonia and 11 patients had another diagnosis (Table 2).
Invasive pulmonary aspergillosis

Fifteen patients were diagnosed with IPA, two with

proven IPA and 13 with probable IPA. Fourteen of the
fifteen patients diagnosed with IPA had BAL GM
obtained. The two patients diagnosed with proven IPA
had transbronchial biopsies performed with histopathological findings consistent with IPA. None of the 13
other patients with probable IPA underwent transbronchial biopsies. The average age was 41.3 years
(range 1958 years). Seven of the patients were
female. The majority of patients with IPA had received
HSCT. For full details of IPA patient characteristics,
see Table 3.
Of the patients diagnosed with IPA, 12 (80%) had
chest symptoms (cough, sputum, dyspnoea or pleuritis), 9 of the 15 (60%) were experiencing fevers and 2
(13.3%) were asymptomatic. On radiographic examination, 9 of the 15 (60%) patients had consolidating
infiltrates, 5 (33%) had nodular infiltrates and 1
(6.7%) had a reticular infiltrate. Five of the 15 (33%)
patients had a cavitary infiltrate, 3 (20%) had air-crescent sign and 3(20%) had halo sign present. Eight of
the patients diagnosed with IPA were receiving antifungal prophylaxis at the time of diagnosis. Fourteen
patients with IPA had BAL GM ordered; 13 were positive (92.9%). Six patients diagnosed with IPA had a
positive b-D-glucan assay.
When the cell counts from BAL fluid were examined, 6 of the 15 (40%) IPA patients had monocyte
predominant BAL fluid, whereas 8 (53.3%) patients
had neutrophil predominant BAL fluid and 1(6.7%)
patient had lymphocyte predominant fluid. All of the
patients diagnosed with IPA were treated with

554

Table 1. Patient characteristics.

Age
Female (male)
Diagnosis1
Haematopoietic stem cell transplantation
Matched sibling donor transplant
Matched unrelated donor transplant
Double unit cord blood transplant
Mismatched unrelated donor transplant
Autologous transplant2
CMV donor + recipient +
CMV donor + recipient
CMV donor recipient +
CMV donor recipient
Receiving chemotherapy for malignancy
Type of malignancy
Acute myeloid leukaemia
Non-Hodgkins lymphoma
Acute lymphoblastic leukaemia
Hodgkins lymphoma
Chronic myeloid leukaemia3
Multiple myeloma
Myelodysplastic syndrome
Pancreatic neuroendocrine carcinoma
History of solid organ transplantation
History of lung transplantation
History of liver transplantation
History of heart transplantation
History of renal transplantation
HIV infection
Autoimmune disease on immunosuppresants
Total patients
Patient features
Neutropenic
Medications received
Systemic corticosteroids
Tacrolimus
Cyclosporine
Sirolimus
Mycophenolate mofetil
Patients on 1 immunosuppressant
Patients on 2 immunosuppressants
Patients on 3 immunosuppressants
Chemotherapy used
Cytarabine
Hyper-CVAD (cyclophosphamide,
vincristine and doxorubicin)
Clofarabine
ABVD (doxorubicin, bleomycin,
vinblastine, dacarbazine)
CHOP (cyclophosphamie, doxorubicin,
vincristine, prednisone)
Bortezomib
Midostaurin
Bendamustine
Denileukin diftitox
Prednisone/hydroxyurea
Brentuximab

50.4 years
(1981 years)
57 (76)
60
25
22
7
3
3
19
9
7
22
47
20
9
7
3
3
2
2
1
20
7
7
2
4
7
5
133
41
59
32
13
7
22
42
38
5
19
7
5
3
3
2
2
2
1
1
1

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Galactomannan in BAL from the immunocompromised

Table 3. Details of patients with invasive pulmonary aspergillosis.

Table 1. (continued)
Etoposide
DVP (daunorubicin, vincristine, prednisone)
Patient symptoms
Chest symptoms (cough, dyspnoea, pleuritis)
Fever
Both fever and chest symptoms
No symptoms
Predominant radiographic findings
Consolidation
Ground-glass opacities
Tree-in-bud opacities
Reticular infiltrates
Nodular infiltrates

1
1
115
83
75
27

N
Female
Average age

52
37
9
26
26

Some patients carried multiple diagnoses (i.e. a patient who had

an HSCT but whose disease had relapsed, and was receiving systemic chemotherapy again).

All patient who had received autologous transplants in this

study had not yet engrafted and were neutropenic at time of
bronchoscopy.
3
All patients with chronic myeloid leukaemia were in blast crisis
and receiving systemic chemotherapy at time of bronchoscopy.

Table 2. Patient diagnoses.

Viral pneumonia or pneumonitis
Rhinovirus
Respiratory synctial virus
Cytomegalovirus
Herpes simplex virus
Influenza virus
Metapneumovirus
Adenovirus
Bacterial pneumonia
Staphylococcus aureus
Pseudomonas aueriginosa
Klebsiella pneumoniae
Burkholderia cepacea
Alcaligines xylosoxidans
Nocardia species
Invasive pulmonary aspergillosis
Proven invasive pulmonary aspergillosis
Probable invasive pulmonary aspergillosis
Pneumocystis jirovecci pneumonia
Other fungal pneumonia
Candida glabrata
Scedosporium apiospermum
Rhizopus species
Histoplasmosis
Other diagnoses
Obliterative bronchiolitis
Mycobacterium avium-intracellulare
Acute eosinophilic pneumonia
Diffuse alveolar haemorrhage
Non-specific interstitial pneumonia
Lung transplant rejection

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37
4
9
4
3
6
9
2
9
3
2
1
1
1
1
15
2
13
6
6
2
1
1
2
11
4
2
2
1
1
1

History of haematopoietic stem

cell transplantation
Matched sibling
donor transplant
Matched unrelated
donor transplant
Mismatched unrelated
donor transplant
Double unit cord
blood transplant
Autologous transplant1
CMV donor + recipient +
CMV donor recipient
CMV donor + recipient
CMV donor recipient +
Receiving chemotherapy
Hodgkins lymphoma
receiving ABVD2 regimen
Non-Hodgkins lymphoma
receiving denileukin diftitox
History of lung transplantation
History of HIV infection
On immune suppressants for
connective tissue disorder
Neutropenic
Patients receiving
1 immunosuppressant
Patients receiving
2 immunosuppressants
Receiving systemic
corticosteroids
Receiving tacrolimus
Receiving cyclosporine
Receiving mycophenolate mofetil
Positive serum GM
Positive BAL GM
Positive culture of Aspergillus species
Positive serum b-D-glucan assay
Presence of halo sign
Presence of air-crescent sign

7 (8)
41.3 years
(1958)
11

Per cent of
patients with
IPA with
underlying
condition

73.3

6
2
1
1
1
3
3
2
2
2
1

13.3

1
1
0
1

6.7
0
6.7

6
5

40
33.3

40

60

4
1
3
6/14
13/14
5/15
8/13
3/14
3/14

26.7
6.7
20
41.9
92.9
33.3
61.5
21.4
21.4

Patient with autologous transplant was not engrafted and

neutropenic at time of bronchoscopy.

ABVD regimen is doxorubicin, bleomycin, vinblastine and

decarbazine.

antifungal therapy. Eleven of the 15 (73.3%) patients

survived at 30 days following FOB, and 10 (66.7%)
survived at 90 days following bronchoscopy. This is
compared to the cases without IPA, in which 117 of

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K. R. Brownback et al.

Table 4. Diagnoses in false positive BAL galactomannan assay.

Viral pneumonitis
Bacterial pneumonia
Disseminated histoplasmosis
Aspiration pneumonitis
Drug toxicity
Obliterative bronchiolitis
Candida glabrata pneumonia
Diffuse alveolar haemorrhage
No diagnosis, but without clinical deterioration without receiving
antifungal therapy
Patients receiving beta-lactam antibiotics at time of BAL GM
collection

5
4
1
1
1
1
1
1
3
15

Figure 1 Kaplan-Meier curve of survival of patients with and

without aspergillosis demonstrating no significant differences in

mortality between the two groups.

135 survived at 30 days (86.7%) and 106 of 135 survived at 90 days (78.5%). The KaplanMeier curve
showing survival differences between the two groups
is shown in Fig. 1. This difference in survival was not
statistically significant, with a hazard ratio of 2.112
(0.64156.953).
Performance of GM assay

Bronchoalveolar lavage GM was obtained in 143 of

the 150 bronchoscopies. There were 31 positive BAL
GM assays, using a cut-off of 0.5 OD as positive, with
an average age in those patients with positive assays
of 50.2 years. Of the 31 positive assays, 13 were diagnosed with proven or probable IPA. This resulted in a
positive predictive value (PPV) of 41.9%. The test had
a sensitivity and specificity for IPA of 92.9% and
86.0% respectively. In 7 of the 13 patients with positive BAL GM who were diagnosed with IPA, the BAL
GM assay was the only positive assay used in making
the diagnosis of IPA.
Of the 18 false positive BAL GM assays, 4 of the 18
were prescribed piperacillintazobactam at the time of
specimen collection. In addition, another 11 patients
with false positive BAL GM were prescribed an alternative beta-lactam antibiotic at the time of BAL GM acquisition. Two of the patients with false positive BAL GM
were infected with another fungal organism: one
patient with Candida glabrata pneumonia, the other with
disseminated histoplasmosis. For full details of diagnoses
in patients with false positive BAL GM, see Table 4.

Discussion
In this study, we report on the diagnostic accuracy of
BAL GM assay when evaluating immunocompromised

556

patients with newly discovered pulmonary infiltrates.

While we did have an exceptional sensitivity with the
BAL GM assay, we also experienced a significant number of false positives, with a PPV of 41.9%. Previously
published data on BAL GM demonstrated a PPV ranging
from 41.7% to 92.5%, when using an index cut-off of
0.5 OD as diagnostic.1620 Some of these differences in
PPV may be due to variations in incidence of IPA
among different cohorts of immunocompromised
patients, or due to geographic variability in the prevalence of Aspergillus species. A potential solution would
be to raise the index cut-off for a positive result for BAL
GM to 1.0 OD, although in our patient population, this
change would decrease our sensitivity to 71.4% and
only increase our PPV to 58.9%. For full details of the
statistical implications of changing the cut-off for positive BAL GM values in our population, see Table 5.
One of the potential sources of false positives in this
study might be the use of beta-lactam antibiotics. Of
the 18 false positive results, 15 patients were receiving
beta-lactam antibiotics at the time of bronchoscopy,
including 4 who were receiving piperacillintazobactam. There have been several reports of false elevation
in serum GM antigens in patients receiving piperacillintazobactam2227 or amoxicillinclavulanic acid.27,28 When
different antibiotics were compared in vitro, piperacillintazobactam expressed a significantly increased GM
level when compared with other antibiotics, including
other beta-lactams.29 However, false positive GM
Table 5. Statistical differences using different cut-offs of positive
BAL GM.

BAL GM
cut-off value

Sensitivity
(%)

Specificity
(%)

Positive
predictive
value (%)

Negative
predictive
value (%)

0.5 OD
0.8 OD
1.0 OD

92.9
71.4
64.3

86.0
93.8
94.6

41.9
55.6
56.3

99.1
96.8
96.1

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Galactomannan in BAL from the immunocompromised

assays from BAL fluid have been reported with the use
of amoxicillinclavulanate, piperacillintazobactam, cefepime, carbapenem and ceftriaxone.30 The direct
effects of antimicrobials leading to false positives in
this patient population are difficult to judge, but
published data strongly suggest that piperacillin
tazobactam is more likely to lead to a falsely elevated
serum GM than other antimicrobials.
The strengths of this study include the large, diverse
population of immunocompromised patients from a
tertiary care medical centre. Information regarding
patient symptoms, extensive laboratory testing and follow-up of patients with IPA also enhance the study.
Potential weaknesses include its retrospective design,
without uniform laboratory testing of all patients or
standardised selection criteria for bronchoscopy. While
the majority of our immunocompromised patients had
BAL GM obtained, there were seven instances where it
was not tested for. Likewise, although bronchoscopy
and BAL techniques are standardised among our bronchoscopists, the retrospective nature of the study prevents us from verifying adherence to these standards.
In summary, we have demonstrated that BAL GM
assay shows excellent sensitivity in the diagnosis of
IPA. It clearly aids in the diagnosis of IPA in situations of high clinical suspicion when a confirmatory
biopsy of tissue is ill-advised. However, given the low
PPV, clinical and radiographic correlation is recommended prior to establishing a diagnosis of IPA.

4
5

6
7

10

11
12

13

14

15

16

Acknowledgment
The authors have no financial disclosures to report
with regards to the preparation and submission of this
manuscript. No funding was sought for or received in
the production of this manuscript, and none of the
authors have competing interests.

Conflicts of interest
The authors have no potential conflicts of interest to
disclose regarding this subject matter.

17

18

19

20

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