ORIGINAL ARTICLE INFECTIOUS DISEASES

Bronchoscopy as an indicator of tracheobronchial fungal infection in

non-neutropenic intensive-care unit patients

€ Yazıcıo
O. glu Moçin1, Z. Karakurt1, F. Aksoy2, G. G€ or1, M. Partal3, N. Adıg€
ung€ uzel1, E. Acart€
urk1, S. Batı Kutlu4, R. Baran5 and
H. Erdem6
1) Pulmonology and Respiratory Intensive Care Unit, Sureyyapasa Chest Diseases and Thoracic Surgery Training and Research Hospital, Istanbul, Turkey,
2) Department of Pathology, Sureyyapasa Chest Diseases and Thoracic Surgery Training and Research Hospital, Istanbul, Turkey, 3) Department of
Microbiology, Sureyyapasa Chest Diseases and Thoracic Surgery Training and Research Hospital, Istanbul, Turkey, 4) Department of Infectious Diseases and
Clinical Microbiology, Sureyyapasa Chest Diseases and Thoracic Surgery Training and Research Hospital, Istanbul, Turkey, 5) Department of pulmonology ,
Acibadem Fulya Hospital, Istanbul, Turkey and 6) Department of Infectious Diseases and Clinical Microbiology, GATA Haydarpasa Training Hospital, Istanbul,
Turkey

Abstract

We aimed to establish that a bronchoscopic view can be as reliable as microbiology, and support an empirical tracheobronchial fungal
infection (TBFI) treatment decision. We retrospectively studied 95 respiratory failure patients with suspected TBFI admitted to the
intensive-care unit (ICU) in 2008 with sticky secretions, hyperaemic mucosa, and whitish plaques on bronchoscopic view. Patients not
suspected of having TBFI were chosen as a control group (n = 151). Broncheoalveolar lavage (BAL) fluid was cultured, and biopsy samples
were taken from the lesions. Biopsy samples positive for fungi were defined as ‘proven’, only BAL-positive (+ fungi) cases were ‘probable
TBFI’, and BAL-negative (– fungi) cases were ‘possible TBFI’. BAL (+ fungi) and BAL (– fungi) in the control group were defined as
‘colonization’ and ‘no TBFI’, respectively. The sensitivity, specificity and positive and negative predictive values of BAL (+ fungi) were 85.1%
(63/74), 81.4% (140/172), 66.3% (63/95), and 92.7% (140/151), respectively. Biopsies were performed in 78 of 95 patients, and 28 were
proven TBFI with fungal elements, and 100% were BAL (+ fungi). Probable TBFI was seen in 30 of 95 patients with BAL (+ fungi), and
possible TBFI (BAL(– fungi)) in 25 of 95. Among the 95 patients, microbiology revealed fungi (90.5% Candida species; 9.5% Aspergillus) in 63
(66.3%). In the controls, the colonization and no TBFI rates were 11 of 151 and 140 of 151, respectively. Observing sticky secretions,
hyperaemic mucosa and whitish plaques by bronchoscopy is faster than and may be as reliable as microbiology for diagnosing TBFI. These
findings are relevant for empirical antifungal therapy in suspected TBFI patients in the ICU.

Keywords: Bronchoscopy, fungal infection, intensive-care unit, respiratory failure

Original Submission: 3 February 2012; Revised Submission: 26 September 2012; Accepted: 14 November 2012
Editor: E. Roilides
Article published online: 22 November 2012
Clin Microbiol Infect 2013; 19: E136–E141
10.1111/1469-0691.12112

tool for the pulmonologist [1,2]. Endobronchial lesions can

Corresponding author: H. Erdem, Department of Infectious
Diseases and Clinical Microbiology, GATA Haydarpasa Training
Hospital, Istanbul, Turkey
E-mail: hakanerdem1969@yahoo.com
Introduction
Flexible bronchoscopy (FB) is an extremely crucial method in
the intensive-care unit (ICU) and an important diagnostic
be observed and diagnostic specimens, lavage and brush
materials can be easily obtained by FB [3]. Accordingly, FB
has a considerable place in the management of tracheobron-
chial fungal infections (TBFIs). However, the diagnosis of TBFI
by microbiology and pathology analysis takes 2–3 days at a
minimum. Combined with the high rate of colonization [4],
this means that, particularly in mechanically ventilated
patients [5], a rational therapeutic approach may be delayed
or obscured. Only a few studies have documented fungal
disease in critically ill, non-neutropenic patients [4,6,7]. To

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Clinical Microbiology and Infection ª2012 European Society of Clinical Microbiology and Infectious Diseases
CMI
Yazıcıo
the best of our knowledge, no one has yet assessed the value
of the bronchoscopic inspection in TBFIs to provide clues for
rational antifungal treatment. In our respiratory ICU, patients
in whom we observed sticky secretions accompanied by
hyperaemic and irregular mucosa, followed by whitish
plaques and subsequent nodules, were frequently confirmed
by microbiology and histopathology to have TBFI. It is
already known that fungal disease may manifest as mucosal
plaques in infants, older adults who wear dentures, patients
being treated with antibiotics, chemotherapy, or radiation
therapy, and those with cellular immunodeficiency [8–11].
Recently, bronchoscopy TBFI findings in immunocompro-
mised patients were summarized in a review [12]. We
hypothesized that patients with these bronchoscopic findings
could alert us to suspect TBFI in critically ill patients in the
ICU.
In this study, which is the first and the largest of its kind, we
evaluated the detection of whitish plaques by bronchoscopic
examination of the tracheobronchial tree, relative to the
clinical and laboratory data, in non-neutropenic ICU patients
with acute respiratory failure (ARF), to provide evidence for
empirical antifungal treatment.
Materials and Methods
This retrospective, observational, case–control study was
conducted in the respiratory ICU of Sureyyapasa Chest
Diseases and Thoracic Surgery Training and Research Hospital,
Istanbul, Turkey. Our unit is labelled as a level III ICU, and has
a 20-bed capacity. The criterion for inclusion of patients in the
study was clinical suspicion of TBFI [12] during FB in a patient
with ARF [13]. The study was carried out between 1 January
and 31 December 2008. All invasive procedures, including FB,
were performed as a result of clinical indications, and all
patients provided signed informed consent. We obtained
hospital approval from the Institutional Review Board for this
study.
FB (Olympus)
FB was performed for aspiration of secretions and for
diagnostic analyses in eligible intubated patients. The nasal
route was used for observing the upper level of the vocal
cords in all non-intubated patients.
The bronchoscopic view for suspected TBFI
TBFI was suspected when whitish, sticky secretions, oedema-
tous hyperaemic mucosa and/or mucosal plaque formation
were observed. When TBFI was suspected, a bronchial
mucosal biopsy was performed in all eligible cases.
Clinical Microbiology and Infection ª2012 European Society of Clinical Microbiology and Infectious Diseases, CMI, 19, E136–E141
glu Mocßin et al.
Bronchoscopy as an indicator of TBFI E137
Modified definitions of TBFI
We prepared a flow chart (Fig. 1) for definitions of ‘proven’,
‘probable’ and ‘possible’ TBFIs, and ‘colonization’ or ‘no TBFI’,
with the aid of guidelines [5]. Proven TBFI: in the case of
suspected TBFI, tissue biopsy and tracheobronchial washing
reveal fungi. Probable TBFI: in the case of suspected TBFI, the
pathology findings are negative, but the microbiology results of
tracheobronchial washing reveal fungi. Possible TBFI: TBFI is
suspected, but pathology and microbiology findings are
negative for fungi. Colonization: tracheobronchial washing
reveals fungi without bronchoscopic suspicion of TBFI. No
TBFI: patients have no bronchoscopic findings of TBFI, and
have negative histology or microbiology findings for fungi.
Data collection
Patient demographics, APACHE II scores [14] on admission to
the ICU, reasons for ARF [13], pneumonia [1,2], chronic
obstructive pulmonary disease exacerbation, infections follow-
ing thoracic surgery, chronic parenchymal diseases, pre-ICU
locations, mechanical ventilation, day of bronchoscopic sam-
pling, length of pre-ICU stay, tracheostomy, diabetes mellitus,
steroid use, tracheal complications and laboratory data were
recorded.
Pathology
Biopsy samples were examined after staining with Grocot and
periodic acid–Schiff reagent. TBFI was characterized by
disintegration of the surface epithelium, acute inflammatory
cell infiltration and fibrin in the bronchial and tracheal mucosa,
and yeast-like pseudohyphae among the necrotic cells [15,16].
The type of fungus was not determined. Patients were further
separated into two groups according to whether the histopa-
thology findings were positive or negative for fungi.
Microbiology
Bronchial and tracheal washings were cultured onto Sabou-
raud’s dextrose agar, and a microbiological culture analyser
(mini API; Biomerieux, Marcy l’Etoile, France) was used for
mould and yeast identification. Candida was classified into
albicans and non-albicans; further differentiation of Candida
could not be performed, owing to inadequate laboratory
resources. Aspergillus was identified by inoculating bronchial
and tracheal washings onto Sabouraud’s dextrose agar;
colonies that were fast-growing and white, yellow, yellow–
brown, brown to black or green in colour were accepted as
positive.
Bacterial cultures were quantified and microorganisms with
>104 CFUs/mL were assessed as indicative of an infection
requiring bronchial washing. Urine, blood, tracheal aspirate
and other examples were also examined when needed.
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E138 Clinical Microbiology and Infection, Volume 19 Number 3, March 2013
Bronchoscopy findings such as:
• Whitish, sticky secretions, oedematous hyperaemic mucosa, and/or mucosal plaque formation on
vocal cord, epiglottis and upper or lower part of tracheal mucosa
Absent Present Suspected TBFI
No TBFI
Bronchial lavage culture for fungi Pathology for fungi
Negative Positive Fungi present Fungi absent
No TBFI Colonization
Proven TBFI Probable TBFI
Antifungal therapy was initiated according to the national
guidelines for non-neutropenic patients, in the form of
intravenous fluconazole (10 mg/kg twice daily as a loading
dose for the first day, and subsequently 10 mg/kg once daily as
a maintenance dose) or classical amphotericin B (0.5–1 mg/kg
intravenously as a single dose per day) as the first choice
before culture results were available. If Aspergillus was iden-
tified, treatment was switched to voriconazole (6 mg/kg twice
daily for the first day as a loading dose, and subsequently 4 mg/
kg once daily as a maintenance dose). If renal or liver function
test abnormalities, or allergic reactions, were detected, or
culture results were obtained, caspofungin (70 mg per day
intravenously as a loading dose, and a maintenance dose of
50 mg/day) or liposomal amphotericin B (5 mg/kg intrave-
nously as a single dose per day) were substituted. In the case of
patients with plaque formation, the duration of treatment was
4–8 weeks, depending on observations of changes in the
plaques. When there was no plaque formation, the duration of
treatment was 2–4 weeks, and in those patients with candi-
daemia the duration of treatment was 14 days, or until the
final blood culture was negative for fungi.
Statistical analysis
Descriptive analyses were used for the evaluation of the data,
with SPSS statistical software (SPSS version 15.0; SPSS,
Chicago, IL, USA). Data were expressed as median, interquar-
tile range (25–75%), and percentage (%), where appropriate.
The Mann–Whitney U-test was used for non-parametric data,
and the chi-square test was used for dichotomous variables. A
p-value of <0.05 was assumed to be significant.
Results
During the study period, 634 patients were admitted to our
respiratory ICU, and 246 underwent bronchoscopy for various
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Clinical Microbiology and Infection ª2012 European Society of Clinical Microbiology and Infectious Diseases, CMI, 19, E136–E141
CMI
Bronchial lavage culture for fungi
Positive for fungi Negative for fungi
FIG.1. Flow chart of suspected
tracheobronchial fungal infection (TBFI)
Possible TBFI
by bronchoscopy.
reasons. TBFI was suspected in 95 patients (case group), and
the other 151 patients were accepted as the control group.
The demographic data and ICU outcomes of all of the study
subjects are summarized in Table 1. Both groups were similar
with respect to demographics, comorbidities, APACHE II
score on admission to the ICU, and mortality rates. However,
the case group had a higher rate and longer duration of
invasive mechanical ventilation than the control group. The
length of stay in the ICU was significantly greater in the case
group.
Fungal cultures of BAL fluids were positive in 74 patients
(30.1%). In the case group (n = 95), 63 patients (66.3%) had
a positive fungal culture; in the control group (n = 151), 11
patients (7.3%) had a positive fungal culture. The sensitivity,
specificity and positive and negative predictive values of the
bronchoscopic view of TBFI as compared with BAL fluid
results were as follows: 85.1% (63/74), 81.4% (140/172),
66.3% (63/95), and 92.7% (140/151), respectively. Among
the 95 case patients, the microbiology results of 63 (66.3%)
revealed fungi (90.5% Candida species; 9.5% Aspergillus).
Biopsies were performed in 78 patients; the other 17
patients refused the biopsy. Bronchoscopy was performed
in 32 of the 95 case patients via the nasal route, and eight of
these patients had plaque formations on the vocal cords.
Four of these cases were intubated after bronchoscopy, as
they were unresponsive to non-invasive mechanical venti-
lation. The remaining patients had bronchoscopy via an
endotracheal tube. Histopathology revealed fungi in 28
(35.9%) patients; 50 (64.1%) showed no fungi. Patients
defined as TBFI ‘proven’, ‘probable’, ‘possible’, ‘coloniza-
tion’ and ‘no TBFI’ according to the bronchoscopic view,
BAL fluid culture and histopathology are summarized in
Fig. 2.
Bronchoscopy was performed in the first 3 days of ICU
admission in the majority of patients (73.3%). The median time
to bronchoscopy in the ICU was 2 days (interquartile range:
CMI glu Mocßin et al.
Yazıcıo Bronchoscopy as an indicator of TBFI E139

TABLE 1. Patient group demographics and intensive-care antifungal therapy, as these patients died before the decision
unit (ICU) data of patients with suspected tracheobronchial to initiate therapy could be made. Renal supplement dialysis
fungal infection (TBFI) was not required for any of the patients while they were in the
No TBFI ICU. Mortality rates in the ICU in the proven, probable and
Suspected suspected: possible TBFI cases were 28.6% (8/28), 21.4% (9/42), and
TBFI: case control p-value
24.0% (6/25), respectively. In the control group, the mortality
Number of patients 95 151
Demographic data rates in the ICU for patients with colonization and no TBFI
Age in years (range) 66 (56–72) 66 (56–76) 0.46 were 45.5% (5/11) and 24.3% (34/140), respectively. None of
Gender, male/female 70/25 98/53 0.15
Comorbidities, n (%) the patients who died underwent an autopsy.
COPD 63 (66.3) 94 (62.3) 0.52
Diabetes 18 (18.9) 22 (14.6) 0.37
Cancer 12 (12.6) 19 (12.6) 0.99
ICU data
APACHE II score (range) 22 (17–27) 22 (17–26) 0.83 Discussion
Reason for ARF, n (%)
Pneumonia 35 (36.8) 57 (37.7) 0.93
COPD exacerbation 58 (61.1) 89 (58.9)
Cardiogenic oedema 1 (1.1) 2 (2.0)
Restrictive lung disease 1 (1.1) 2 (1.3) In this study, we showed that endobronchial inflammatory
Mechanical ventilation lesions detected by FB revealed that the majority of mucosal
IMV, n (%) 63 (66.3) 79 (52.3) 0.030
IMV (days) (range) 8 (3–15) 4 (2–9) 0.009 plaques were related to invasive fungal disease in critically ill,
NIMV, n (%) 65 (68.4) 109 (72.2) 0.53
NIMV (days) (range) 8 (4–10) 5 (2–10) 0.07 non-neutropenic patients. Although bacterial infections signif-
Tracheostomy, n (%) 21 (22.1) 25 (16.6) 0.28
Length of ICU stay in days (range) 11 (7–20) 8 (4–14) 0.007 icantly contribute to mortality in the ICU, fungal diseases are
ICU mortality, n (%) 22 (23.2) 39 (25.8) 0.64
increasingly being seen in non-neutropenic, critical patients
ARF, acute respiratory failure; COPD, chronic pulmonary obstructive disease;
IMV, invasive mechanical ventilation; NIMV, non-invasive mechanical ventilation. [17,18]. In the EPIC-II study, which evaluated the prevalence
and outcomes of infections in the ICU, fungal isolates
constituted 21% of all positive blood cultures [19]. In another
1–4). Plaques were mostly seen at the tracheal mucosa next to study, as many as 5.5% of the ICU patients, in the absence of
the vocal cords, at the distal part of the trachea, or at the neutropenia, had a confirmed Candida infection [4]. Previously,
bilateral bronchial mucosa. Table 2 shows the relationship several authors have also reported the occurrence of invasive
between plaque formation and the laboratory data. pulmonary aspergillosis in COPD patients, with a very high
In the case group, empirical antifungal treatment was given mortality rate [20–24].
in 82 cases after observing typical TBFI, on the basis of the On the whole, data related to TBFI in non-neutropenic
patient’s clinical results. Antifungal treatment for suspected patients hospitalized in the ICU are lacking. In the present
TBFI, before any microbiology and histopathology results had study, histopathology showed yeast-like pseudohyphae among
been acquired, was given to 26 of 28 proven TBFI patients, 31 the necrotic cells and the surface epithelium, acute inflamma-
of 42 probable TBFI patients, and 25 of 25 of possible TBFI tory cell infiltration, and fibrin in the bronchial and tracheal
patients. In the control group, no patient received empirical mucosa. Blood vessel invasion by fungi was not found in any of
antifungal treatment. Two patients whose histology and BAL our cases. In a review that evaluated the distribution of fungal
culture results were positive for fungi did not receive species in TBFI, Aspergillus species (53%) and Coccidioides

Bronchoscopy in the Respiratory ICU, N = 246

Bronchoscopy findings such as:

Whitish, sticky secretions, oedematous hyperaemic mucosa, and/or mucosal plaque formation on
vocal cords or/and epiglottis or/and upper or lower part of tracheal mucosa

No TBFI N = 151 Suspected TBFI N = 95

Absent Present

Bronchial lavage culture for fungi Pathology for fungi Bronchial lavage culture for fungi
N = 151 N = 78 N = 17

(–) N = 140 (+) N = 11 Fungi present Fungi absent BAL(+) N = 12 BAL(–) N = 5

N = 28 N = 50

No TBFI Colonization
BAL (+) BAL (–)
BAL (+)
FIG. 2. The results of suspected N = 30 N = 20
N = 28

tracheobronchial fungal infection (TBFI)

Proven TBFI N = 28 Probable TBFI N = 42 Possible TBFI N = 25
by bronchoscopy. ICU, intensive-care unit.

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Clinical Microbiology and Infection ª2012 European Society of Clinical Microbiology and Infectious Diseases, CMI, 19, E136–E141
E140 Clinical Microbiology and Infection, Volume 19 Number 3, March 2013 CMI

TABLE 2. The relationship of plaque development and the were performed on our patients, and fungal pneumonia was
laboratory data of 95 patients with suspected tracheobron- not evaluated with lung biopsy. Wood et al. [31] performed a
chial fungal infection (TBFI) study in a level 1 trauma ICU, where they included 62 patients
Plaque Plaque whose BAL fluid was positive for Candida. They suggested that
Variables (+), n = 56 (–), n = 39 p-value isolation of Candida from BAL fluid in quantities below the
Fungi, n (%) (BAL fluids) diagnostic threshold for ventilator-associated pneumonia in
Candida albicans 4 (7.1) 5 (12.8) 0.09
Candida non-albicans 25 (44.6) 17 (43.5) this population does not require antifungal therapy. However,
Aspergillus spp. 6 (10.7) 0 we treated the majority of patients who were biopsy-negative,
Candida albicans + non-albicans 3 (5.4) 0
Isolation of pathogenic bacteria from because their clinical severity and bronchoscopic appearance
BAL fluid, n (%)
Pseudomonas aeruginosa 10 (17.8) 7 (17.9) 0.30 were identical to those of histologically proven cases.
Methicillin-resistant Staphylococcus 11(19.6) 4 (10.3)
aureus Delisle et al. performed a study to investigate Candida
Klebsiella pneumonia 5 (8.9) 4 (10.3)
Enterococci 18 (1.7) 1(2.7) colonization and its associated risk factors, and to examine the
Acinetobacter baumannii 13 (23.2) 2 (5.1)
Escherichia coli 3 (5.4) 1(2.7) clinical outcomes, in patients with clinical suspicion of venti-
Other enteric bacteria 2 (3.6) 3(7.8)
Isolation of multiple bacteria (>2) 32 (57.1) 18 (46.1) 0.29 lator-associated pneumonia with concordant Candida coloni-
Histopathology for fungi (+), n (%) 26/48 (54) 2/30 (6.7) 0.0001 zation (n = 114) and without Candida colonization (n = 525)
BAL, bronchoalveolar lavage. [32]. They stated that it is unclear whether Candida coloniza-
tion is causally related to poor outcome, or whether it is a
immitis (16%) were reported to be the most frequent. The marker for increased morbidity and mortality in the ICU.
patients in this review were mostly immunocompromised, and The mortality rate in our patients with Candida colonization
the percentage of Candida was very low (6%) [12]. In contrast, was greater than in the respiratory tract Candida colonization
in our study, the Candida isolates were responsible for 90.5% group of Delisle et al. (45.5% vs. 32.4%), and they also did not
of all TBFIs, whereas Aspergillus species were responsible for treat these patients with antifungal drugs. The mortality rate of
only 9.5%. We were unable to subclassify the Candida isolates, patients with no TBFI was nearly similar to that of the TBFI
because of inadequate laboratory resources. When whitish cases (proven, probable, and possible), and lower than that of
plaques were detected on bronchoscopic examination, TBFI the Candida colonization group. The length of ICU stay in the
was confirmed histopathologically in more than half of the study of Delisle et al. was nearly seven times higher than in our
cases. Consequently, the detection of whitish plaques by FB study (59.9 vs. 8 days).
should alert the treating clinician to the presence of an invasive Kontoyiannis et al. performed a study to evaluate the BAL
fungal disease, according to our data. results for diagnosis of fungal infections [33]. Our study
In a prospective and post-mortem study performed in showed the BAL results for diagnosis of TBFI were similar
critically ill and non-neutropenic patients, various factors, such according to sensitivity and negative predictive values (85.1%,
as antibiotic use, duration of antibiotic treatment, mechanical 92.7% versus 85%, 93%, respectively) and higher in specificity
ventilation period, age, acute respiratory distress syndrome, and positive predictive value when compared to the study
parenteral nutrition, and gender, did not affect Candida done by Kontoyiannis et al. (81.4%, 66.3% versus 60%, 42%
isolation from the lungs [25]. respectively) [33].
According to our data, antifungal treatment is strictly There are some limitations to our study. First, we could not
indicated when whitish tracheobronchial plaques are detected subclassify Candida species and perform antifungal susceptibility
on bronchoscopic examination, as TBFI was confirmed histo- tests, owing to inadequate laboratory resources. Moreover, we
pathologically in a couple of days in more than half (54%) of the did not perform post-mortem biopsies to further determine the
cases. In this study, TBFIs caused by non-albicans types of exact cause of death and to assess Candida invasion in other
Candida constituted three-quarters of all biopsy-proven Can- tissues. Our data are from patients with ARF, the majority of
dida infections. Non-albicans Candida species are known to whom had chronic obstructive pulmonary disease and used
have higher resistance to fluconazole [26–28]. The treating inhaler steroids, and for this reason our TBFI rates might be
clinician should also bear in mind that an early start of rational higher, and our results should not be generalized for all patients.
antifungals in invasive fungal disease has a profound impact on In conclusion, in our study, cases of suspected TBFI
mortality [6,29]. In the present study, we did not have following a specific bronchoscopic view were nearly always
antifungal susceptibility test results. verified by a positive fungal culture in the tracheobronchial
Meersseman et al. [30] showed that, in 77 pneumonia lavage fluids. In the presence of plaque in the airway mucosa,
patients in whom tracheal lavage revealed Candida, no Candida the chance of a positive pathology finding for fungi appears to
could be histologically detected post-mortem. No autopsies be increased. Our results might be helpful to intensivists

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Clinical Microbiology and Infection ª2012 European Society of Clinical Microbiology and Infectious Diseases, CMI, 19, E136–E141
CMI glu Mocßin et al.
Yazıcıo
attempting to diagnose and treat colonization or infection with
fungi in patients with ARF in the ICU when BAL fluids are
positive for fungi. Thus, ICU patients, particularly those with
ARF, appear to have a greater chance of developing TBFI,
which can be easily detected by bronchoscopic examination. If
tracheobronchial plaques are detected by bronchoscopy, a
definite diagnostic approach and empirical therapy for fungi
should be seriously considered.
Transparency Declaration
All authors declare no dual or conflicting interest.
References
1. Mandell LA, Wunderink RG, Anzueto A et al. Infectious Diseases
Society of America/American Thoracic Society consensus guidelines on
the management of community-acquired pneumonia in adults. Clin
Infect Dis 2007; 44 (suppl 2): 27–72.
2. American Thoracic Society, Infectious Diseases Society of America.
Guidelines for the management of adults with hospital-acquired,
ventilator-associated, and healthcare-associated pneumonia. Am J Respir
Crit Care Med 2005; 171: 388–416.
3. Samarakoon P, Soubani AO. Invasive pulmonary aspergillosis in patients
with COPD: a report of five cases and systematic review of the
literature. Chron Respir Dis 2008; 5: 19–27.
4. Leon C, Alvarez-Lerma F, Ruiz-Santana S et al. Fungal colonization and/or
infection in non-neutropenic critically ill patients: results of the EPCAN
observational study. Eur J Clin Microbiol Infect Dis 2009; 28: 233–242.
5. Azoulay E, Cohen Y, Zahar JR et al. Practices in non-neutropenic ICU
patients with Candida-positive airway specimens. Intensive Care Med
2004; 30: 1384–1389.
6. Ruping MJ, Vehreschild JJ, Cornely OA. Patients at high risk of invasive
fungal infections: when and how to treat. Drugs. 2008; 68: 1941–1962.
7. Xie GH, Fang XM, Fang Q et al. Impact of invasive fungal infection on
outcomes of severe sepsis: a multicenter matched cohort study in
critically ill surgical patients. Crit Care 2008; 12: R5.
8. Martin SJ, Cohen PR, MacFarlane DF, Grossman ME. Cutaneous
manifestations of Strongyloides stercoralis hyperinfection in an HIV-
seropositive patient. Skinmed 2011; 9: 199–202.
9. Pabuccuoglu U, Tuncer C, Sengiz S. Histopathology of candidal
hyperplastic lesions of the larynx. Pathol Res Pract 2002; 198: 675–678.
10. Lipsker D, Chosidow O. White lesions of the oral mucosa. Rev Prat
2002; 52: 389–393.
11. Bodey GP. Fungal infections in the cancer patient. S Afr Med J 1977; 52:
1009–1015.
12. Karnak D, Avery RK, Gildea TR, Sahoo D, Mehta AC. Endobronchial
fungal disease: an under-recognized entity. Respiration 2007; 74: 88–104.
13. American College of Chest Physicians/Society of Critical Care
Medicine Consensus Conference: definitions for sepsis and organ
failure and guidelines for the use of innovative therapies in sepsis. Crit
Care Med 1992; 20: 864–874.
14. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. Apache II: a
severity of disease classification system. Crit Care Med 1985; 13: 818–829.
15. De Pauw B, Walsh TJ, Donnelly JP et al. European Organization for
Research and Treatment of Cancer/Invasive Fungal Infections Coop-
erative Group; National Institute of Allergy and Infectious Diseases
Clinical Microbiology and Infection ª2012 European Society of Clinical Microbiology and Infectious Diseases, CMI, 19, E136–E141
Bronchoscopy as an indicator of TBFI E141
Mycoses Study Group (EORTC/MSG) Consensus Group 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. Clin
Infect Dis. 2008; 46: 1813–1821.
16. Luna M, Candidiasis. In: Connor DH, Chandler FW, Schwartz DA,
Manz HS, Lack EE, eds, Pathology of infectious diseases. Hong Kong,
Stanford: Application & Large G, 1997; 953–964
17. Morace G, Borghi E. Fungal infections in ICU patients: epidemiology
and the role of diagnostics. Minerva Anestesiol 2010; 76: 950–956
18. Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis
in the United States from 1979 through 2000. N Engl J Med 2003; 348:
1546–1554.
19. Vincent JL, Rello J, Marshall J et al. International study of the prevalence
and outcomes of infection in intensive care units. JAMA 2009; 302:
2323–2329.
20. Ader F, Nseir S, Le Berre R et al. Invasive pulmonary aspergillosis in
chronic obstructive pulmonary disease: an emerging fungal pathogen.
Clin Microbiol Infect 2005; 11: 427–429.
21. Bulpa PA, Dive AM, Garrino MG et al. Chronic obstructive pulmonary
disease patients with invasive pulmonary aspergillosis: benefits of
intensive care? Intensive Care Med 2001; 27: 59–67.
22. Rello J, Esandi ME, Mariscal D, Gallego M, Domingo C, Valles J. Invasive
pulmonary aspergillosis in patients with chronic obstructive pulmonary
disease: report of eight cases and review. Clin Infect Dis 1998; 26:
1473–1475.
23. Dimopoulos G, Piagnerelli M, Berre J, Eddafali B, Salmon I, Vincent JL.
Disseminated aspergillosis in intensive care unit patients: an autopsy
study. J Chemother 2003; 15: 71–75.
24. Meersseman W, Vandecasteele SJ, Wilmer A, Verbeken E, Peetermans
WE, Van Wijngaerden E. Invasive aspergillosis in critically ill patients
without malignancy. Am J Respir Crit Care Med 2004; 170: 621–625.
25. el-Ebiary M, Torres A, Fabregas N et al. Significance of the isolation of
Candida species from respiratory samples in critically ill, non-neu-
tropenic patients An immediate postmortem histologic study. Am J
Respir Crit Care Med. 1997; 156: 583–590.
26. Nguyen MH, Peacock JE, Jr, Morris AJ et al. The changing face of
candidemia: emergence of non-Candida albicans species and antifungal
resistance. Am J Med 1996; 100: 617–623.
27. Pfaller MA, Jones RN, Messer SA, Edmond MB, Wenzel RP. National
surveillance of nosocomial blood stream infection due to species of
Candida other than Candida albicans: frequency of occurrence and
antifungal susceptibility in the SCOPE program. SCOPE participant
group. Surveillance and Control of Pathogens of Epidemiologic. Diagn
Microbiol Infect Dis. 1998; 30: 121–129.
28. Pfaller MA, Messer SA, Gee S et al. In vitro susceptibilities of Candida
dubliniensis isolates tested against the new triazole and echinocandin
antifungal agents. J Clin Microbiol 1999; 37: 870–872.
29. Mulanovich VE, Kontoyiannis DP. Fungal pneumonia in patients with
hematologic malignancies: current approach and management. Curr
Opin Infect Dis 2011; 24: 323–332.
30. Meersseman W, Lagrou K, Spriet I et al. Significance of the isolation of
Candida species from airway samples in critically ill patients: a
prospective, autopsy study. Intensive Care Med 2009; 35: 1526–1531.
31. Wood GC, Mueller EW, Croce MA, Boucher BA, Fabian TC. Candida
sp. isolated from bronchoalveolar lavage: clinical significance in critically
ill trauma patients. Intensive Care Med 2006; 32: 599–603.
32. Delisle MS, Williamson DR, Perreault MM, Albert M, Jiang X, Heyland
DK. The clinical significance of Candida colonization of respiratory tract
secretions in critically ill patients. J Crit Care 2008; 23: 11–17.
33. Kontoyiannis DP, Reddy BT, Torres HA et al. Pulmonary candidiasis
in patients with cancer: an autopsy study. Clin Infect Dis 2002; 34:
400–403.
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