Neves et al.

BMC Infectious Diseases (2020) 20:229

https://doi.org/10.1186/s12879-020-04954-3

RESEARCH ARTICLE Open Access

The role of mini-bronchoalveolar lavage

fluid in the diagnosis of pulmonary
tuberculosis in critically ill patients
Cynthia Pessoa Neves1,2, Allyson Guimarães Costa1,2,3,4*, Izabella Picinin Safe1,2, Alexandra de Souza Brito1,2,
Jaquelane Silva Jesus2, Afranio Lineu Kritski5, Marcus Vinicius Guimarães Lacerda1,2,6, Miguel Viveiros7 and
Marcelo Cordeiro-Santos1,2

Abstract
Background: The detection of Mycobacterium tuberculosis (MTB) in the intensive care unit (ICU) presents several
challenges, mainly associated to the clinical state of the patient. The presence of HIV infection further aggravates
this scenario, requiring a reliable collection method, with better performance in the microbiological/molecular
techniques to be used. We evaluated the performance of two methods for sample collection, mini bronchoalveolar
lavage (Mini-BAL) and endotracheal aspirate (ETA), for diagnosis of pulmonary tuberculosis (PTB) in critically ill
patients.
Methods: This prospective study involved 26 HIV positive ICU internalized patients, with presumptive PTB who
required mechanical ventilation. Two samples were obtained prospectively from 26 HIV ICU patients with presumptive
PTB by Mini-BAL and ETA. The samples were processed for smear microscopy, Löwenstein-Jensen medium and the
BACTEC Mycobacteria Growth Indicator Tube 960 system®. We define as confirmed PTB patients with positive MTB
culture. Furthermore, all samples obtained through the Mini-BAL were analyzed by Xpert® MTB/RIF.
Results: Our results demonstrated that the respiratory samples obtained by Mini-BAL were able to increase MTB
detection in critically ill patients with presumptive PTB. The Mini-BAL allowed 30% increased recovery and guaranteed
enough sample volume for processing in all methods. In addition, the larger volume of the samples obtained with this
technique enabled the Xpert® MTB/RIF molecular test for diagnosis of TB.
Conclusions: The Mini-BAL showed be an acceptable alternative to ETA in this population, since these critically ill and
often-immunocompromised patients are more likely to develop complications related to invasive procedures.
Keywords: Pulmonary tuberculosis, Intensive care medicine, Diagnosis, Mini-BAL

* Correspondence: [email protected]
1
Programa de Pós-Graduação em Medicina Tropical, Universidade do Estado
do Amazonas (UEA), Manaus, AM, Brazil
2
Instituto de Pesquisa Clínica Carlos Borborema, Fundação de Medicina
Tropical Dr. Heitor Vieira Dourado (FMT-HVD), Manaus, AM, Brazil
Full list of author information is available at the end of the article

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Neves et al. BMC Infectious Diseases (2020) 20:229 Page 2 of 7

Background Mini-BAL was first used successfully in 1987 for the

An increasing proportion (3–16%) of patients diagnosed diagnosis of opportunistic infection in AIDS patients
with active tuberculosis (TB) require intensive care [1–3]. [12]. It is a simple, less invasive and low-cost method.
In countries with high TB and human immunodeficiency Since then, it has been used for diagnosis and prognosis
virus (HIV) burden [i.e. Brazil], TB/HIV co-infection of lung injury and related pulmonary diseases, including
accounts between 69 and 93% of TB cases admitted at an immunocompromised patients [9, 13, 14]. However, to
intensive care unit (ICU), usually associated with acute re- date it has not been studied whether the Mini-BAL
spiratory failure (ARF) and mechanical ventilation (MV) would be useful for the diagnosis of PTB in critically ill
[3, 4]. Patients with TB admitted to the ICU have a poor patients. In this study, we evaluated the performance of
prognosis and are associated with increasing costs for the two methods for sample collection, Mini-BAL and ETA,
health system when compared to a patient with uncompli- for presumptive PTB critically ill patient’s diagnosis at a
cated TB [5, 6]. referral hospital for TB in PLWH located in the Brazilian
The diagnosis of pulmonary tuberculosis (PTB) in ICU Amazon.
settings presents challenges, mainly to obtain fast and
reliable microbiological confirmation. In people living Methods
with HIV (PLWH) and critically ill patients, the diagno- Ethical issue and study population
sis of TB may be more difficult due to the greater fre- This study was approved by the Ethics Committee at
quency of paucibacillary forms in advanced stages of Fundação de Medicina Tropical Dr. Heitor Vieira Dourado
immunodepression and develop complications related to (CEP/FMT-HVD #process: 1.531.521/2016). Signed in-
invasive procedures [7]. formed consent was obtained from each participant or legal
Microbiological sampling from a mechanically venti- representative for the use of biological materials and publi-
lated patient will require an endotracheal aspirate (ETA), cation of data. All procedures are in accordance with the
a non-directed bronchial lavage or a bronchoalveolar Resolution 466/12 from the Brazilian Ministry of Healthy
lavage (BAL) [7]. Although it is an easy-to-perform, low- and also with the Helsinki Declaration.
cost and non-invasive method, the ETA has several limi- This prospective study (October 2016 and July 2017)
tations, such as low specificity and high false positive involved 53 ICU internalized patients (> 18 years old),
rates for the diagnosis of pulmonary infections [8]. with presumptive PTB diagnosis who required MV at
The bronchoscopic procedures (i.e. BAL) are expen- FMT-HVD (Fig. 1). Twenty-seven individuals were ex-
sive, require qualified human resources, suitable devices cluded for presenting complications that prevented the
(e.g. size of the bronchoscope according to the size of accomplishment of the procedures (ETA and Mini-BAL)
endotracheal tube); and it requires care with operationa- and/or were already undergoing treatment for PTB for
lization, monitoring and decontamination of equipment. more than 2 weeks.
Furthermore, is unavailable in many HIV and TB en- Before procedure of the collection, all vital signs were
demic settings [9, 10]. In addition, the BAL has been as- monitored, inspiratory fraction of O2 was increased to
sociated with several complications in patients receiving 1.0 and sedation was maintained with bolus of 3-5 mg
MV, especially with acute respiratory distress syndrome. intravenous midazolam.
Other related complications are hypoxemia, pneumo-
thorax, cardiac arrhythmias and bleedings. Therefore,
the risks/benefits of BAL should be carefully considered Sample collection randomization
in the critical patient scenario prior to the application, Sample collection was performed using the ETA and
using the technique when less invasive methods presents Mini-BAL methods. Two samples were obtained from
limitations or are not effective for diagnosis [10]. each patient and the order of collection techniques
Critically ill patients are more likely to develop com- performed was randomized using the website Random
plications related to invasive procedures. Therefore, it is [https://www.random.org/]. Briefly, List Randomizer
necessary that less invasive diagnostic strategies be used function was used, which randomized the method of the
instead of BAL. An alternative method for obtaining re- according with list provided.
spiratory samples in mechanically ventilated patients is
the mini bronchoalveolar lavage (Mini-BAL); a simple, ETA sample collection
less invasive and low-cost method. It is defined as a ETA collection was performed using a sterile suction
blind and sterile technique for collection of the lower catheter of size 12 French (Fr) introduced through the
respiratory specimen by a tracheal tube (50 cm) and in- endotracheal tuber (ET) until resistance was encoun-
stillation of saline solution. The amount of instilled solu- tered (level of the carina in the trachea), retracted ap-
tion may range from 20 to 150 ml. However, small proximately 2 cm and sample collected in a sterile
amounts of fluid (e.g. 20 ml) are commonly used [11]. container by suction. The samples were aspirated into a
Neves et al. BMC Infectious Diseases (2020) 20:229 Page 3 of 7

Fig. 1 Study and laboratorial analysis flowchart of the ICU internalized patients

sterile polypropylene collector tube (bronco collector; [15]. Furthermore, all samples obtained through the
Cremer®, Brazil). Mini-BAL were analyzed by the molecular test Xpert®
MTB/RIF (Fig. 1).
Mini-BAL sample collection
The Mini-BAL collection was performed by a sterile Liquid and solid culture test
long suction catheter of size 12 French (Fr) inserted The liquid and solid culture were performed with re-
through the ET and blindly advanced into the distal air- spiratory specimens digested and decontaminated using
ways till resistance is felt then the catheter was wedged the N-acetyl-L-cysteine-sodium hydroxide (NALC-
in that position. 20 ml of Sodium Chloride 0.9% were in- NaOH) method [16]. Liquid culture tubes (Mycobacteria
stilled through the catheter and aspirate was collected in Growth Indicator Tube - MGIT) were incubated at
a sterile polypropylene collector tube (bronco collector; 37 °C in the BD BACTEC MGIT 960 system® [Becton
Cremer®, Brazil) container by suction [11]. After these Dickinson, Franklin Lakes, NJ, USA]) instrument and
proceedings, the probe was delicately removed using monitored automatically. The solid culture tubes (Löw-
turning movements. enstein-Jensen [LJ] medium) were incubated at 37 °C
and were inspected once weekly or until Mycobacterium
Sample transport and microbiology processing colonies were seen. The tubes were maintained until it
All the samples were transported to TB Laboratory at became positive or for 42 days of maximum for negative
FMT-HVD within 30 min of collection. The specimens samples. All the positive tubes were further confirmed
were processed according to standard sample treatment by Ziehl–Neelsen (ZN) staining method and further
procedures to smear microscopy, liquid and solid culture confirmed by MPT64 protein specific detection immune
Neves et al. BMC Infectious Diseases (2020) 20:229 Page 4 of 7

chromatographic test (SD Bioline Kit, Standard Diagnos- samples could be processed, significantly number higher
tics, Inc., Korea) [15]. than by ETA (p = 0.018). The median age was 35 years
(IQR: 29–46), with a predominance of male (73%). 92%
Molecular test Xpert® MTB/RIF of the patients were HIV+, 46% were treated for PTB
Molecular test Xpert® MTB/RIF was performed with re- and 23% evolved to death (clinical outcome). The hypox-
spiratory specimens digested and decontaminated using emia was observed with ETA and Mini-BAL procedures
the NALC-NaOH method [16]. The specimens were respectively in 3 (11.5%) and in 2 (7.7%) patients (data
processed on the day of collection and 1 mL was tested not shown).
in an Xpert® MTB/RIF cartridge-based. Rapid molecular
assays were performed in GeneXpert® System (Cepheid,
Sunnyvale, CA, USA) and all GeneXpert® protocols were Volume recovery in mini-BAL was superior of the ETA
provided by Cepheid company. The medium sample volume was 3 ml (IQR: 2–5) for
ETA and 10 ml (IQR: 6–11) for Mini-BAL (p < 0,0001).
Diagnosis of PTB The Mini-BAL allowed 30% increased recovery and
Case definition of PTB was used the following criteria: guaranteed sufficient sample volume for processing in all
person with presumptive severe TB and growth MTB in methods (Fig. 2).
MGIT or solid LJ culture in at least one sample obtained
by Mini-BAL or ETA.
Comparison between mini-BAL and EDTA collection for
Statistical analysis diagnosis PTB
Data were stored in the Microsoft Excel software The MTB was identified in 3 (14%) and 5 (19%) samples
(v.2010) and statistically analyzed using the GraphPad of ETA and Mini-BAL (p = 0,653), respectively (Table 2).
Prism (v.5, San Diego, CA, USA). Descriptive analysis Five confirmed TB cases were observed. Two samples
was performed using number (n) and percent (%) for contaminated in solid culture with LJ medium in both
qualitative data and median and IQR for quantitative techniques. ETA failed to detect TB in solid culture in
data. Statistical Analysis were assembled to Chi-squared two samples. Also, cases of false positive or negative in
test was used to study association between qualitative smear microscopy/MGIT/culture of ETA was identified,
variables and comparison between groups was per- with one sample detected only in microscopy of ETA
formed using Mann-Whitney Test for quantitative vari- sample. Moreover, 5 samples obtained with the Mini-
ables. Statistical difference was considered in all cases at BAL had the diagnosis for MTB confirmed by the mo-
p < 0.05. lecular method Xpert® MTB/RIF (Table 2). Furthermore,
the mean time to detection (TTD) of the mini-BAL sam-
Results ples in the MGIT system was lower (8.2 days) but was
Patients demographic and clinical data not significantly different from the TTD of the ETA (9.0
Table 1 summarizes of the patient’s demographic and days) (p = 0,134) (data not shown).
clinical data. Of the total 26 patients included, five pa-
tients the ETA was not performed due to insufficient
volume for the diagnostic tests (< 1 mL), smaller than
optimal volume (5-10 mL) for liquid and solid culture,
beyond the Xpert® MTB/RIF. In addition, all Mini-BAL

Table 1 Demographic and clinical data of the of the ICU

internalized patients enrolled in study
Demographic and Clinical Data ETAa Mini-BALb
(n = 26) (n = 26)
Age (years, median [IQR]) 35 [29–46]
Sex, (male/female) 19/7
HIV+, n (%) 24 (92)
TB-treatment, n (%) 12 (46)
Outcome (death), n (%) 6 (23)
Gold-Standard Eligible Samples, n (%) 21c (81) 26 (100)
Fig. 2 Median of Volume recovery in Mini-BAL and ETA of the ICU
a
Endotracheal Aspirate; Mini bronchoalveolar lavage; c5 samples of ETA
b
internalized patients
had volume < 1 ml
Neves et al. BMC Infectious Diseases (2020) 20:229 Page 5 of 7

Table 2 Results of diagnosis methods used for presumptive PTB respiratory failure [14], cytological diagnosis of interstitial
in critically ill patients of the ICU internalized disorders with ARF and MV [23], concentration and ab-
Diagnosis Methods Description Collection Techniques sorption of antibiotics [24] and the safety and diagnostic
ETA mini-BAL P value accuracy of transbronchial biopsy [25]. Possible complica-
(n = 21a) (n = 26) tions such as hypoxemia, arrhythmia and bleeding were
Smear microscopy-positive, n (%) 6 (29) 5 (19) 0.451 also evaluated in each technique.
Culture MGIT-positive, n (%) 4 (21) 5 (19) 0.987 In our study, Mini-BAL allowing the recovery of median
Culture LJ-positive, n (%) 3 (16) 5 (19) 0.653 10 mL of respiratory sample (IQR 5-10 mL), significantly
more than the volume recovered (p < 0,0001), with non-
Xpert MTB/RIF®-positive, n (%) – 5 (19) –
a
inferior results to ETA for MTB detection. In addition,
5 samples of ETA had volume < 1 ml
the larger volume of the samples obtained with the Mini-
BAL (10 mL) enabled the Xpert® MTB/RIF molecular test
Discussion for diagnosis of TB. An adequate sample volume may be
The detection of MTB in the ICU presents several chal- critical for the diagnosis of TB. For example, a sample
lenges, mainly associated to the clinical state of the pa- volume of 6 mL or more of cerebrospinal fluid (CSF) was
tient. The presence of HIV infection further aggravates associated with higher MTB detection in patients with
this scenario, requiring a reliable collection method, with suspected tuberculous meningitis using Xpert® MTB/RIF
better performance in the microbiological/molecular tech- Ultra or solid culture as a diagnostic method [26]. For
niques to be performed. The diagnosis of TB in HIV in- PTB, greater sputum volume may have a positive impact
fected individuals may be more difficult due to the greater on detection of Mycobacterium tuberculosis by Xpert®
frequency of paucibacillary forms in advanced stages of MTB/RIF in smear-negative patients [27].
immunodepression [9, 10]. Our results demonstrated that According to Practice Guideline for clinical microbiology
the Mini-BAL proved to be a viable alternative, since these laboratories that addresses requirements pertaining to la-
critically ill and often immunocompromised patients are boratory testing for mycobacteria and aspects of acceptable
more likely to develop complications related to invasive specimens and rejection criteria, an optimal volume for
procedures. samples of the respiratory tract between 5 and 10 ml is rec-
Patients with TB required ICU care in worldwide, may ommended [28]. Therefore, 7 (27%) ETA samples were
have high rates of co-morbidities related complications considered inadequate because they presented insufficient
this site. In other ICU patients, diagnostic of TB may be volume (< 5 ml) and five (19%) ETA samples were excluded
an incidental co-morbid finding as previously undiag- to insufficient volume for the diagnostic tests (Table 1).
nosed sub clinical disease which only manifests during To our knowledge, this is the first study to show that
hospitalization [6, 17]. Mortality is high for patients with samples obtained by the Mini-BAL are viable for the
active TB and respiratory failure, mainly associated with molecular diagnosis of TB (i.e. Xpert® MTB/RIF) in crit-
delay in the TB diagnosis. As shown in our report (23%), ically ill patients. All samples obtained by the Mini-BAL
other studies have shown similar data, ranging between could be processed in the Xpert machine, without occur-
25 and 65% mortality [4, 18]. rence of errors or indeterminate results.
ICU patients present particularities, especially in cases Our study is limited due to small sample size. How-
presumptive PTB critical ill [6]. The sampling collections ever, the techniques were randomized in each patient to
with ETA technique in these patients may sometimes be mitigate possible bias, may become the Mini-BAL an ac-
restricted by persistent severe hypoxemia or cardiovascu- ceptable alternative to tracheal aspiration for the evalu-
lar instability, presence of small endotracheal tubes and/or ation of suspected tuberculosis in critically ill patients
the unavailability of a bronchoscopist [14]. Thus, the diag- admitted at an intensive care unit (ICU).
nosis of cases presumptive PTB critical with Mini-BAL
seems to be a viable alternative, since this method is less- Conclusion
invasive, easily performed at the bedside method and of- In summary, Mini-BAL presented similar results for the
fering quality samples for microbiological identification, diagnosis of PTB when compared to ETA. Furthermore,
especially in middle- and low-income countries. respiratory samples obtained by Mini-BAL were able to
Although insufficient data regarding the utility of be tested for M. tuberculosis detection, as well as, greater
Mini-BAL to TB diagnosis, some studies have applied recovery of specimens, in critically ill patients with pre-
the technique for the diagnosis of ventilator-associated sumptive PTB, showing an acceptable alternative to ETA
pneumonia, including in immunocompromised patients in this population. Future research is needed to validate
[9, 19–22]. In addition, Mini-BAL was used for the bio- these results, establish their general applicability, and de-
marker identification in patients with lung injury [13], termine the influence of the laboratorial diagnostic in
evaluated inflammation in patients with acute hypoxemic clinic and patient follow-up.
Neves et al. BMC Infectious Diseases (2020) 20:229 Page 6 of 7

Abbreviations Xpert MTB/RIF test on tracheal aspirate samples for diagnosis of pulmonary
ARF: Acute respiratory failure; ETA: Endotracheal aspirate; HIV: Human tuberculosis: a prospective burden. Lancet Respir Med. 2015;3:621–30.
immunodeficiency virus; ICU: Intensive care unit; LJ: Lowenstein Jensen; 3. Ferreira MD, CPD N, Souza AB, Beraldi-Magalhães F, Migliori GB, Kritski AL,
MGIT: Mycobacteria growth indicator tube; Mini-BAL: Mini bronchoalveolar et al. Predictors of mortality among intensive care unit patients coinfected
lavage; MTB: Mycobacterium tuberculosis; MV: Mechanical ventilation; with tuberculosis and HIV. J Bras Pneumol. 2018;44:118–24.
PTB: Pulmonary tuberculosis; TB: Tuberculosis; TTD: Time to detection 4. Silva DR, Menegotto DM, Schulz LF, Gazzana MB, Dalcin PT. Mortality
among patients with tuberculosis requiring intensive care: a retrospective
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