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Pulmonol. 2020;xxx(xx):xxx---xxx

www.journalpulmonology.org

REVIEW

Bronchoscopic sampling techniques in the era of

technological bronchoscopy
M. Mondoni a , R.F. Rinaldo a , P. Carlucci a , S. Terraneo a , L. Saderi b ,
S. Centanni a , G. Sotgiu b,∗

a
Respiratory Unit, ASST Santi Paolo e Carlo, San Paolo Hospital, Department of Health Sciences, Università degli Studi di Milano,
Milan, Italy
b
Clinical Epidemiology and Medical Statistics Unit, Department of Medical, Surgical, Experimental Sciences, University of
Sassari, Sassari, Italy

Received 27 May 2020; accepted 2 June 2020

KEYWORDS
Abstract Flexible bronchoscopy is a key diagnostic and therapeutic tool. New endoscopes
Bronchoscopy;
and technologically advanced navigational modalities have been recently introduced on the
Biopsy techniques;
market and in clinical practice, mainly for the diagnosis of mediastinal lymph adenopathies and
Lung cancer;
peripheral lung nodules. Bronchoscopic sampling tools have not changed significantly in the last
Pulmonary infections;
three decades, with the sole exception of cryobiopsy.
Pulmonary nodules;
We carried out a non-systematic, narrative literature review aimed at summarizing the sci-
Bronchoalveolar
entific evidence on the main indications/contraindications, diagnostic yield, and safety of the
lavage
available bronchoscopic sampling techniques.
Performance of bronchoalveolar lavage, bronchial washing, brushing, forceps biopsy, cry-
obiopsy and needle aspiration techniques are described, focusing on indications and diagnostic
accuracy in the work-up of endobronchial lesions, peripheral pulmonary abnormalities, inter-
stitial lung diseases, and/or hilar-mediastinal lymph adenopathies. Main factors affecting the
diagnostic yield and the navigational methods are evaluated.
Preliminary data on the utility of the newest sampling techniques (i.e., new needles, triple
cytology needle brush, core biopsy system, and cautery-assisted transbronchial forceps biopsy)
are shown.

Abbreviations: ACCP, American College of Chest Physicians; CLM, confocal laser microscopy; CT, computed tomography; cTBNA, con-
ventional transbronchial needle aspiration; BW, bronchial washing; BAL, bronchoalveolar lavage; EBB, endobronchial forceps biopsy; EBNA,
endobronchial needle aspiration; EBUS-TBNA, endobronchial ultrasound transbronchial needle aspiration; EUS-B-FNA, endoscopic ultrasound
(with bronchoscope) fine needle aspiration; EBUS-ca-TBFB, endobronchial ultrasound guided cautery-assisted transbronchial forceps biopsy;
EMN, electromagnetic navigation bronchoscopy; IPF, idiopathic pulmonary fibrosis; rEBUS, radial probes endobronchial ultrasound; PPL,
peripheral lung lesion; ROSE, rapid on-site evaluation; SLB, surgical lung biopsy; TBNA, transbronchial needle aspiration; TBLC, transbronchial
lung cryobiopsy; TB, tuberculosis; TBB, transbronchial biopsy; UIP, usual interstitial pneumonia.
∗ Corresponding author at: Clinical Epidemiology and Medical Statistics Unit, Departrment of Medical, Surgical and Experimental Medicine,

University of Sassari, Via Padre Manzella 4, Sassari, Italy.

E-mail address: [email protected] (G. Sotgiu).

https://doi.org/10.1016/j.pulmoe.2020.06.007
2531-0437/© 2020 Sociedade Portuguesa de Pneumologia. Published by Elsevier España, S.L.U. This is an open access article under the CC
BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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2 M. Mondoni et al.

Take Home Message: A deep knowledge of bronchoscopic sampling techniques is crucial in the
era of technological bronchoscopy for an optimal management of respiratory diseases.
© 2020 Sociedade Portuguesa de Pneumologia. Published by Elsevier España, S.L.U. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).

Introduction Methods

Flexible bronchoscopy represents an essential diagnostic We carried out a non-systematic, narrative literature
and therapeutic tool when managing patients with compli- review. The search engine Pubmed was used to retrieve the
cated and difficult-to-treat respiratory diseases.1 After the most relevant articles on the above-mentioned topic. The
introduction of the first fiberoptic instruments in 1967, new search was conducted without any time restrictions. Only
types of endoscopes were developed: video-bronchoscopes epidemiological studies performed on adult human beings
(i.e., endoscopes with a video camera at the distal tip) can and written in English were selected. The following key-
significantly improve the quality of the images, ultrathin words were combined to address our research question:
instruments (i.e., diameter size <3 mm) can explore distal bronchoscopy; sampling methods; bronchoscopic tools; nee-
airways beyond segmental bronchi, echo-bronchoscopes can dle aspiration; biopsy techniques; bronchoalveolar lavage;
significantly improve the diagnostic accuracy for mediastinal bronchial washing.
lymph adenopathies.2---4
The widespread use of sensitive computed tomogra- Results
phy, magnetic resonance imaging, and positron emission
tomography have broadened the clinical indications of
Bronchoalveolar lavage
bronchoscopy and have provided an accurate guide for endo-
scopic samplings.3,5,6
Bronchoalveolar lavage (BAL) is a safe and minimally inva-
Flexible bronchoscopy is usually recommended for the
sive bronchoscopic sampling method recommended for
diagnosis and staging of lung cancer, diagnosis of respiratory
patients with several lung medical conditions (e.g., immune-
tract infections (both in immunocompetent and immuno-
mediated, inflammatory, and infectious diseases). It can
compromised patients) and of interstitial lung diseases.
provide specimens for cytological and microbiological exams
Furthermore, its use is required for patients with hemop-
(Table 1).17
tysis, with unexplained cough and stridor/wheezing, and
It is contraindicated in patients with cardiopulmonary
staging of thoracic malignancies.1,3,7---11
instability and/or with a severe haemorrhagic diathesis and
Flexible bronchoscopy, performed under conscious seda-
It could rarely exacerbate interstitial lung diseases (ILD).18,19
tion and with topical anesthesia, is safe in all age
Transient hypoxemia and low-grade fever within the first
groups, including the elderly, with serious complications
24 h after lavage are the most frequent adverse events.1,6
and mortality occurring in 1.1% and 0.04% of the cases,
BAL is performed after the assessment of the tracheo-
respectively.1,3,12,13
bronchial tree and before any biopsies.15,17,20
Bronchoscopic procedures comprehensively assess endo-
The bronchoscope should advance as far as possible to
bronchial abnormalities (e.g., airway stenosis, bleeding,
the complete occlusion of the bronchial lumen of a third
secretions, etc.) and frequently are adopted to collect
or fourth bronchial subsegment, in a wedged position. Room
specimens for microbiological and/or pathological exams,1,3
temperature sterile saline is employed: 100−300 ml, divided
quality and quantity of which is key to increase diagnostic
into three to five aliquots, are introduced through the suc-
accuracy (e.g., idiopathic pulmonary fibrosis, IPF, and lung
tion channel of the bronchoscope. A volume higher than 5%
cancer).14,15
of the original one (ideally >30%) is collected using a nega-
New endoscopes and technologically advanced naviga-
tive suction pressure (<100 mm Hg) avoiding airway collapse.
tional modalities have been recently introduced, mostly for
the diagnosis of mediastinal lymph adenopathies and periph-
eral lung nodules.16 Interstitial lung diseases
With the sole exception of cryobiopsy, bronchoscopic BAL is helpful in patients with suspected ILD21 both for the
sampling tools have not changed significantly in the last diagnosis itself and the differential ascertainment. A high
three decades.16 resolution chest CT should be performed within 6 weeks for
The aim of this review is to summarize the scientific evi- the optimal identification of the sampling anatomical area.17
dence on the main indications/contraindications, diagnostic A differential cellular count for the identification of
yield, and safety of the available bronchoscopic sampling the inflammatory pattern (i.e., lymphocytic, neutrophilic,
techniques. eosinophilic, and mast cellular), may be useful in the dif-

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Table 1 Summary of bronchoscopic sampling techniques and methods of guidance according to the target lesion.
Endobronchial Peripheral Hilar and Interstitial
lesions pulmonary mediastinal lymph lung diseases
lesions adenopathies
BW BAL TBNA BAL
EBB TBB (fluoroscopy or newer navigational EBUS-TBNA TBB (fluoroscopy-guided)
modalities-guided)
EBNA TBNA (fluoroscopy or newer navigational EUS-B-FNA Cryobiopsy (fluoroscopy,
modalities-guided) rEBUS-, CLM- and Cone Beam
CT-guided)
Brushing Brushing (fluoroscopy or newer navigational EBUS-ca-TBFB
modalities-guided)
Cryobiopsy Criobiopsy (EMN and rEBUS-guided)
Triple brush (EMN and Cone Beam-guided)
GenCut Core Biopsy (EMN and Cone
Beam-guided)
BW: bronchial washing; BAL: bronchoalveolar lavage; CLM: confocal laser microscopy; EBB: endobronchial forceps biopsy; EBNA: endo-
bronchial needle aspiration; TBB: transbronchial biopsy; TBNA: conventional transbronchial needle aspiration; rEBUS: radial probes
endobronchial ultrasound; EBUS-TBNA: endobronchial ultrasound transbronchial needle aspiration; EUS-B-FNA: endoscopic ultrasound
(with bronchoscope) fine needle aspiration; EBUS-ca-TBFB: endobronchial ultrasound guided cautery-assisted transbronchial forceps
biopsy.

ferential diagnosis of interstitial lung diseases. A minimal TB disease in HIV-positives ranges from 10 to 30%, increas-
volume of 5 mL of a pooled BAL sample is needed for BAL ing to 85.7% and 52---95% when nucleic acid amplification
cellular analysis (the optimal volume is 10---20 ml). techniques and culture are adopted, respectively.27---29 In
Bloody fluid, with increasing colour intensity in sequen- immunocompromised hosts with invasive aspergillosis, BAL
tial aliquots, can suggest a diffuse alveolar haemorrhage22 can help detect fungal hyphae (34---64% of the cases) and
(microscopic diagnosis supported by hemosiderin-laden galactomannan antigen (sensitivity and specificity of respec-
macrophages).17 Cloudy (i.e., milky or light brown-beige tively 79---90% and 84---94%), and can increase the rate of
colour) fluid with flocculent material settling by gravity culture positivity (23---85%).1,30,31
within 15−20 min and PAS-positive amorphous debris sug- BAL shows a low accuracy in the diagnosis of peripheral
gests a pulmonary alveolar proteinosis (PAP). lung malignancies (mean sensitivity 43%), whereas lym-
An increased number of CD-1a cells (>5% of BAL cells) phangitic carcinomatosis and pulmonary lymphoma may be
strongly suggests pulmonary Langerhans cell histiocytosis.23 diagnosed using BAL samples.6,32,34
BAL cellular pattern may help discriminate IPF from
eosinophilic pneumonia (eosinophilia >25%), sarcoidosis
(high proportion of lymphocytes and CD4/CD8 ratio), and Bronchial washing
infections.15
In patients with a fibrotic interstitial lung disease BAL Bronchial washing (BW) consists of instillation and sub-
lymphocytosis of at least 30% may suggest nonspecific inter- sequent aspiration of saline mixed up with bronchial
stitial pneumonia and extrinsic allergic alveolitis.24 secretions, into a specific bronchial trap. It may be useful
A recent retrospective study that aimed to study the role to assess the microbiology of central airways secretions.6 In
of bronchoscopy in acute respiratory failure related to ILD, the diagnosis of TB, BW smear microscopy and Xpert MTB/RIF
failed to demonstrate a different management and mortality show a sensitivity of 25---41% and 80---92.3% and a specificity
between patients with positive and negative BAL findings.25 of 87.7---95.8% and 81.6---98.6%, respectively.27,33---35
A limited diagnostic support was found for endobronchial
lung cancers (mean sensitivity: 47%). (Table 1).
Peripheral pulmonary lesions The diagnostic yield of bronchoscopy when bioptic tech-
BAL should be used for patients with slowly resolving/non- niques (i.e., endobronchial needle aspiration and forceps
resolving pneumonia (sensitivity >70%).1,26 BAL can play biopsy) are used is not affected by BW.36
a key role in the TB diagnosis for sputum smear-
negative patients or in those in whom sputum cannot
be collected.27 BAL diagnosis of pulmonary TB relies on Needle aspiration
smear microscopy (sensitivity range: 4.7---58.0%), nucleic
acid amplification techniques (sensitivity: 31.3---83.8%; Needle aspiration, which is the most versatile bronchoscopic
specificity: 92.4---98.2%), and culture (highest diagnostic sampling technique, is recommended for the diagnosis
accuracy).27 of endobronchial and peripheral lesions and in case of
BAL can help rule out opportunistic infections in immuno- hilar/mediastinal lymph adenopathies (Table 1).37,38
compromised hosts,1 with a sensitivity up to 98% for A thin (25---19 gauge), retractable needle attached to
Pneumocistis jiroveci. Sensitivity of smear microscopy for the distal tip of a flexible catheter is inserted into the

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(diagnostic yield: 60% vs. 45%, respectively), although stud-

Table 2 Factors which can influence the diagnostic yield
ies have shown that TBNA is still a underused sampling
of bronchoscopic sampling techniques in the diagnosis of
technique.43,44
peripheral pulmonary lesions.
Recently, new navigational methods, which may be
Lesion size coupled with fluoroscopy, have been adopted to sample
CT bronchus sign presence peripheral lesions. TBNA guided by electromagnetic navi-
Navigational modalities employment gation bronchoscopy (EMN) showed a diagnostic yield of
ROSE presence 46.3%, while needle aspiration guided by radial probes
Malignant nature of the lesion endobronchial ultrasounds (rEBUS) of 49.5−62.5%.44,45 When
added to TBB, rEBUS-TBNA significantly increases the
accuracy of bronchoscopy in the diagnosis of peripheral
working channel of the endoscope and is pushed into the lesions.45
target lesion, while the catheter is moved back and forth
for few seconds at its proximal end. The vacuum inside the
syringe causes tissue to be suctioned into the needle.37,38 Hilar and mediastinal lymph adenopathies
The needle may be inserted in an endobronchial lesion under Conventional transbronchial needle aspiration (i.e., not
direct endoscopic vision and into a hilar/mediastinal lymph guided by ultrasounds) was introduced by Wang in 1984.42
node, through the tracheobronchial wall, with or without American College of Chest Physician (ACCP) guidelines
endoscopic ultrasound guidance. Fluoroscopy and/or other showed a sensitivity of 78% in the diagnosis and staging
navigational techniques are necessary to reach peripheral of non-small cell lung cancer, with a complication rate of
lung abnormalities.38 0.3%.46,47 It was also used for the diagnosis of sarcoidosis
The collected specimen may be smeared on a glass slide stage I and II and mediastinal tuberculosis (sensitivity of
or directly placed in formalin solution (technique named 72---79% and 65---100%, respectively %).27,48---50
formalin-fixed, paraffin-embedded cell-block). Rapid on- Currently, cTBNA has been replaced by endobronchial
site evaluation (ROSE) of the aspirates may be performed, ultrasound (EBUS)-guided TBNA: it includes an echobron-
allowing bronchoscopists to stop sampling when sufficient choscope (i.e., a bronchoscope with a convex probe at
material has been harvested for diagnosis and molecular the distal end) and allows a real-time visualization of the
analysis, thus potentially avoiding useless samplings and lymph nodes and mediastinal vessels. Unlike cTBNA, EBUS-
reducing the complications of bronchoscopy.36,37 TBNA can diagnose lymph adenopathies sized <1 cm and
lymph node stations without endobronchial landmarks.6,47
Endobronchial lesions EBUS-TBNA shows a higher sensitivity and negative predic-
Endobronchial needle aspiration (EBNA) is a useful and safe tive value (89% and 91%, respectively) than conventional
technique adopted for the diagnosis of endobronchial lesions technique in the diagnosis and staging of NSCLC.39,47 Its sen-
(mainly lung neoplasms). sitivity in the diagnosis of sarcoidosis and tuberculous lymph
It has a mean sensitivity of 56%, with a rate of adenopathies is 79---84%51,52 and 87%, respectively. Both con-
complications (mostly minor bleedings) <1%.36,39,40 It sig- ventional and ultrasound-guided techniques increase the
nificantly increases the accuracy of bronchoscopy in the diagnostic accuracy of bronchoscopy when combined with
diagnosis of central lung cancers when combined with endo- other sampling techniques (bronchial and transbronchial for-
bronchial forceps biopsy. EBNA is particularly helpful in ceps biopsy and BAL).51,52
sampling submucosal/peribronchial (i.e., growing in deeper Recently, a new needle aspiration technique, named
layers of the airways) and necrotic lesions. Needle can pen- endoscopic ultrasound (with bronchoscope) fine needle aspi-
etrate the mucosa and can sample neoplasms spreading in ration (EUS-B-FNA) has been proved to be effective53 :
the deeper layers.36 an ultrasound guided needle aspiration of mediastinal
In the diagnosis of endobronchial tuberculosis, Altin et al. lymph adenopathies is performed with an echobronchoscope
reported a lower sensitivity of EBNA than forceps biopsy in introduced in the esophagu,.53 Transbronchial and trans-
the detection of granulomas (19% vs 84%, respectively).27,41 esophageal needle sampling can be performed with the same
instrument, in the same endoscopic session, and by the same
Peripheral pulmonary lesions operator (i.e., a trained pulmonologist), thus maximizing
Transbronchial needle aspiration with the guidance of fluo- time and reducing costs. The transesophageal approach can
roscopy has been adopted to sample peripheral lung lesions be also used to sample nodes within reach of EBUS, when the
(both nodules and masses) since 1984 (Fig. 1B).42 A recent clinical conditions contraindicate the transbronchial route
systematic review and meta-analysis showed a diagnostic (e.g., respiratory failure, cough, etc.).54,55
yield of 53% and a rate of complications <9%, with pneu- The combined approach increases the accuracy of
mothorax and bleeding being the most frequent events.43 endosonography and is now recommended by international
Several clinical and procedural variables may affect its accu- guidelines.56
racy: CT bronchus sign, an underlying malignant process, EUS-B-FNA may safely diagnose extra-thoracic targets,
diameter of the lesions >3 cm, and ROSE employment are such as abdominal lymph nodes, liver and left adrenal glands
the most important predictive factors of a positive aspirate metastatic lesions.57 Both EBUS-TBNA and EUS-B-FNA may
(Table 2). Notably, data on comparison between TBNA and diagnose lung parenchymal lesions adjacent to the central
transbronchial forceps biopsy (TBB) in studies where both airways and the esophagus.58,59
procedures were performed in the same patients showed Needle size does not significantly affects the diagnostic
a significant diagnostic advantage when TBNA is performed yield.60

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Figure 1 Conventional fluoroscopy-guided transbronchial forceps biopsy (A) and needle aspiration (B) of a right pulmonary mass.

Several studies demonstrated the suitability of Forceps biopsy showed a sensitivity of 72.2---100.0% in the
ultrasound-guided needle aspiration samples for molecular detection of TB granulomas (endobronchial TB), and may be
analysis in advanced NSCLC, on both cytology smears and useful in ruling out malignancies.27,41,73
cell-block preparations.61---63 The most frequent complication is minor bleeding, which
Complications of endosonographic needle aspiration pro- can resolve spontaneously in the majority of the cases or can
cedures are rare (serious adverse events rate of 0.14%).64 be treated with ice-cold saline or vasoconstrictive agents
(e.g., epinephrine). On this basis, caution may be warranted
when sampling is performed for vascularized lesions (i.e.,
Forceps biopsy carcinoids).74,75

Forceps has been adopted to collect lung tissue samples Peripheral lung lesions
through the bronchoscope since the initial implementation A transbronchial biopsy is performed when the lesion can-
of bronchial endoscopy (Table 1).65 not be directly assessed with the bronchoscope: it is wedged
in the bronchus pertaining to the anatomical site of the
lesion, and the closed forceps are pushed in the peripheral
Endobronchial lesions area of the lung, opened at 5−6 mm from the lesion and
Endobronchial biopsy (EBB) is recommended for the diag- then closed to collect sample (Fig. 1A).6 Fluoroscopy guid-
nosis of visible endobronchial lesions39 : forceps should be ance can improve the sensitivity in case of peripheral focal
opened outside the distal end of the operating channel and and diffuse cancer lesions.6,76,77 Observational studies have
pushed against the lesion providing the right orientation to demonstrated that navigational methods (i.e., electromag-
the instrument, according to the localization of the target netic navigation bronchoscopy, radial probes ultrasounds,
site. The tip of the forceps is then closed, pulled out of the virtual bronchoscopy) and/or ultrathin instruments may
operating channel of the bronchoscope and the specimen is increase the diagnostic yield of conventional, fluoroscopy-
then placed in formalin solution.66 The different character- guided technique (77---84%).44,78---80
istics of the forceps (serrated or smooth edge, fenestrated The diameter of the lesion affects the accuracy of the
or unfenestrated cups, needle between the cups) make it technique: the sensitivity is <35% in case of nodules sized
potentially suitable for specific settings/lesions. However, <2 cm.39 Moreover, sensitivity is 24% performing only a sin-
the diagnostic yield of various forceps biopsy types was not gle biopsy and 70% when six biopsies are collected.81,82 The
statistically different.38 presence of the CT-bronchus sign is associated with a higher
EBB is usually employed for suspected bronchogenic can- yield (Table 2).83,84
cer with a sensitivity of 74%39 : ≥3 biopsies are recommended TBB may increase the sensitivity of BAL for the
for diagnosis, although at least 6 biopsies can provide diagnosis of Pneumocystis jirovecii pneumonia, including
sufficient tissue for immunohistochemical and molecular non---HIV patients.85 In sputum smear negative or sputum
testing.39,67 Several studies36,68,69 demonstrated that the scarce TB patients with peripheral lung lesions, TBB86---88
combination of EBB and endobronchial needle aspiration can may help detect cytological and histological TB findings
achieve the best diagnostic performance. (i.e., necrotizing granulomatous inflammation), ruling out
EBB, when combined with transbronchial biopsy, can malignancies.89
increase the sensitivity of bronchoscopy by 10---20% in the Finally, TBB is a safe and repeatable procedure mon-
diagnosis of sarcoidosis: sampling should be performed itoring early signs of graft rejection in lung transplant
where the mucosa is abnormal and in the first and sec- recipients.90
ond carina if the mucosa seems normal (4---6 endobronchial Mild bleeding and pneumothorax are the most frequent
biopsies); 30% with normal mucosa may have positive complications. Pneumothorax can occur in 1---5% of the
EBB.70---72 cases; its variability can depend on the use of mechani-

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cal ventilation, surrounding emphysema, lesion near to the of water molecules at the interface. After a few seconds of
pleura, and poor expertise of the healthcare worker.6 cooling, the probe is extracted with a specimen, which is
Bleeding can be a risk in patients with coagulopathy dis- placed in formalin.
orders and/or taking anticoagulant and anti-platelet drugs.6 Cryobiopsy may be used with flexible bronchoscopes with
local anaesthesia, deep sedation and/or general anaes-
Interstitial lung diseases thesia, with laryngeal mask or in patient intubated with
Sensitivity of TBB in diffuse lung disease varies widely.91 The orotracheal tube or rigid tracheoscope (during sponta-
main limitations are the small size of the sample and the dif- neous breathing or mechanical ventilation). Intubation with
ficult preservation of the tissue integrity, for which a surgical deep sedation or general anaesthesia and administration of
biopsy or a cryobiopsy may be more suitable.92 Exceptions a bronchial blocker are recommended to prevent severe
are conditions involving the centrilobular region (both at the bleedings in the diagnostic work-up of ILD.102
terminal and respiratory bronchioles or along the lymphatic
distribution, such as sarcoidosis, hypersensitivity pneumoni-
Endobronchial lesions
tis, organizing pneumonia, eosinophilic pneumonias, and
Hetzel et al. demonstrated the higher efficacy of cryobiopsy
lymphangitic spread of malignancy). Sensitivity ranges from
in the diagnosis of endobronchial malignant lesions when
55% in stage I to 80% in stage III93 in sarcoidosis. Higher yield
compared with conventional forceps: it can collect larger
is found when biopsies are performed in >1 lobe and in the
specimens without disrupting the morphological structure.
area of the most affected tissue in stage II/III disease.94
Cryoprobes increase the diagnostic yield of bronchoscopy
Guidelines on Idiopathic Pulmonary Fibrosis (IPF) do not
(up to 95%), without a higher rate of bleeding.98 Sev-
recommend for or against TBB when the HRCT suggest a
eral studies have confirmed these findings,103 including the
probable UIP pattern. In this context, TBB could be only
safety in the diagnosis of carcinoid tumours.104
clinically helpful to exclude mimickers.15,95

Brushing Peripheral lung lesions

Schumann et al. evaluated the accuracy in the diagnosis of
Endobronchial lesions and peripheral lung abnormalities peripheral lesions with the guidance of rEBUS: the diagnos-
Brushing consists of a rigid central wire surrounded by tic yield of 74.2% was not significantly higher in comparison
brushes of various sizes and shapes. A brush inserted through with that of EBUS-guided forceps biopsy (61.3%); however,
the operating channel performs both a back and forth and samples were significantly larger than those collected by
a spinning movement on the surface of the mucosa. Cyto- TBB.105
logical material may be smeared on glass slides or placed in Other studies showed a diagnostic yield of 69---85% when
formalin solutions. The diameter or the length of the brush guided by ultrasounds or EMN, and confirmed the advan-
does not affect the diagnostic yield6 (mean sensitivity in the tage of larger samples and a better preserved architecture,
diagnosis of endobronchial malignancy: 61%).39 Addition of thus improving the specimen quality for the molecular
bronchial brushing to forceps biopsy and needle aspiration diagnosis.106---110
does not increase the sensitivity of bronchoscopy.36,40,69 Mild bleeding and pneumothorax were the most common
It showed a diagnostic yield of 47---54% in the diagno- incidental adverse events.
sis of peripheral lesions,39 which is usually lower than that
reported for TBB and TBNA, even if guided by novel methods
Interstitial lung diseases
of navigation (Table 1).39,44,80
Transbronchial lung cryobiopsy (TBLC) is a minimally inva-
Quantitative cultures of protected brushing (i.e., a
sive alternative to surgical lung biopsy (SLB), which is the
double-lumen catheter brush system with a distal occlud-
gold standard in the histopathological diagnosis of many
ing plug to prevent secretions from entering the catheter
ILD. Conventional forceps biopsies are inadequate in dis-
during passage through the bronchoscope channel) can be
eases characterized by a heterogeneous histological pattern
performed to diagnose pneumonia in critically ill patients,
and in those with histological abnormalities located at the
(mean sensitivity: 89%).96,97
periphery of the secondary lobule (e.g., usual interstitial
Minor bleeding is the most likely incidental complication.
pneumonia, UIP).102
Larger biopsy size and lack of crush artifact make cry-
Cryobiopsy obiopsy more suitable for the diagnosis of diffuse lung
diseases if compared with conventional forceps biopsy.111
Cryoprobe is a therapeutic and diagnostic tool tradition- IPF Guidelines recommend cryobiopsy only in experi-
ally adopted for endobronchial tumour ablation and airway enced centers, when HRCT pattern is probable UIP, inde-
recanalization or by removal of blood clots and foreign terminate for UIP or suggesting an alternative diagnosis.15
bodies.98---100 Tomassetti et al., who recruited 117 patients with fibrotic
Only recently several studies proved its accuracy as endo- ILD needing a pathological diagnosis, demonstrated that the
bronchial and transbronchial biopsy technique (Table 2).101 addition of TBLC was associated to an increased diagnostic
Its activity is based on the principle of the Joule- confidence in the multidisciplinary diagnosis of idiopathic
Thomson effect, wherein the adiabatic expansion of a pulmonary fibrosis, similar to that provided by SLB.112
compressed gas leads to a rapid cooling. The cooled tip Samples should be taken under fluoroscopic guidance
of the cryoprobe, inserted in the working channel of the in the distal part of the lung parenchyma, avoiding high
bronchoscope, adheres to the tissue due to crystallization density fibrotic areas. Biopsy should be performed at a dis-

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tance >1 cm from the pleura to reduce the occurrence of node is identified with EBUS while an electrocautery knife
pneumothorax.113 is advanced through the working channel of the endoscope
As suggested by Ravaglia et al., collection of ≥2 samples toward the airway wall. Then, cautery is applied and the
from two different segments in the same lobe or from differ- knife inserted through the tracheal/bronchial wall defect
ent lobes in case of inter-lobar radiographic heterogeneity (under EBUS real-time guidance), created by the cautery
is recommended to increase the diagnostic yield.102,113---115 edge. After the penetration, the knife is withdrawn and a
A systematic review and meta-analysis showed a pooled spiked forceps advanced into the lymph node to collect the
diagnostic yield of 79%.116 sample.123,124
Two studies evaluated the accuracy of cryobiopsy in com- Two observational studies showed a higher sensitivity in
parison with surgical biopsy: Romagnoli et al. found a poor comparison with that of EBUS-TBNA in the diagnosis of sar-
concordance between TBLC and SLB (concordant coeffi- coidosis and lymphoma.123,124
cient (k): 0.22, percentage agreement: 38%),117 whereas a Another study proved an increased sensitivity of EBUS
multicentre, prospective study , found a histopathological forceps biopsy in patients with mediastinal lymph nodes in
agreement of 70.8% (weighted k: 0.70) and a final diagnostic whom ROSE of EBUS-TBNA failed to show positive findings.125
agreement of 76.9% (k: 0.62).118
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