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Background. Transbronchial biopsy (TBB) with a cryoprobe, also known as transbronchial lung cryobiopsy (TBLC), has become a well-
established modality for sampling lung parenchyma. TBLC is performed under general anaesthesia in the majority of centres, utilising rigid
or exible bronchoscopy. In resource-constrained settings, however, most diagnostic bronchoscopies, including TBB, are performed under
conscious sedation with exible bronchoscopy without the presence of a specialist anaesthetist.
Objectives. Given the paucity of evidence on TBLC performed under conscious sedation for interstitial lung diseases (ILD), specically in
a resource-constrained setting, we aimed to describe its utility in a pilot study.
Methods. We prospectively enrolled the rst 20 patients who underwent TBLC for ILD at a large tertiary hospital in South Africa. All TBLCs
were performed under conscious sedation using a cryoprobe. Patients were actively monitored for complications. e nal diagnosis and
decision regarding need for a surgical biopsy were made at a multidisciplinary meeting that included at least two specialist pulmonologists
with an interest in ILD, a thoracic radiologist, and an anatomical pathologist with an interest in ILD.
Results. ree patients experienced complications. Two (10%) developed a pneumothorax (neither required any intervention). Bleeding that
required 10 minutes of tamponade with the endobronchial blocker was observed in one case. is patient experienced no haemodynamic
or respiratory compromise and was discharged the same day. ere were no complications arising from the use of conscious sedation.
Adenitive diagnosis was made in 17/20 (85%) of the patients.
Conclusion. TBLC performed at an experienced bronchoscopy centre using a cryoprobe under conscious sedation with a dedicated sedationist
was safe and well tolerated. Furthermore, it had a high diagnostic yield, and surgical lung biopsy was avoided in 85% of the patients.
Keywords. Cryobiopsy, interstitial lung disease, conscious sedation.
Afr J Thoracic Crit Care Med 2025;31(1):e2618. https://doi.org/10.7196/AJTCCM.2025.v31i1.2618
Transbronchial biopsy (TBB) with a cryoprobe, or transbronchial
lung cryobiopsy (TBLC), has become a well-established modality for
sampling lung parenchyma.[1] In fact, in 2022 European Respiratory
Society guidelines on TBLC in the diagnosis of interstitial lung diseases
(ILD) it was suggested that TBLC could be the rst-line investigation
to obtain histopathological data in a patient with undiagnosed ILD,
rather than surgical lung biopsy (SLB), particularly if patients are unt
to undergo SLB.[2]
With TBLC, lung parenchyma is subjected to cryofixation by a
liquid cryogen to sample tissue for histological examination. e
main advantage over traditional forceps TBB is the size of the biopsy
specimen (4-5 times larger) and the absence of crush artifacts.[3]
Arecent systematic review and meta-analysis reported a diagnostic
yield of ~80% for TBLC.[4] However, in the largest retrospective study
to date (N=1 024), a denitive diagnosis was achieved in >90% of
cases. TBLC is generally considered a safe procedure, with clinically
e utility of transbronchial cryobiopsy performed under
conscious sedation for interstitial lung diseases in a resource-
constrained setting
A D Buckley, MB ChB, FCP (SA) ; N Singh, FCP (SA), Cert Pulmonology (SA) ; B W Allwood, FCP (SA), PhD ;
U Lalla, FCP (SA), Cert Pulmonology (SA) ; C F N Koegelenberg, FCP (SA), PhD
Division of Pulmonology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University and Tygerberg Hospital, Cape Town, South Africa
Corresponding author: C F N Koegelenberg (coeniefn@sun.ac.za)
Study synopsis
What the study adds. ere is a paucity of evidence for the use of transbronchial lung cryobiopsy (TBLC) for the diagnosis of interstitial lung
diseases (ILD) in resource-constrained settings, especially when performed under conscious sedation. In this pilot study, TBLC performed
under conscious sedation was safe and well tolerated, and had a high diagnostic yield.
Implications of the ndings. TBLC under conscious sedation can safely be rolled out in resource-constrained settings as a rst-line
diagnostic procedure when lung tissue needs to be obtained in patients with ILD, as its yield is comparable to TBLC under general
anaesthesia. It potentially avoids surgical lung biopsy in >80% of cases, together with the need for general anaesthesia.
AJTCCM VOL. 31 NO. 1 2025 29
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signicant bleeding (4%) and pneumothorax (6%) being the most
common complications reported.[5]
TBLC is performed under general anaesthesia in most centres, with
a rigid or exible bronchoscope.[2,3] In resource-constrained settings,
however, the majority of diagnostic bronchoscopies, including
TBB and endobronchial ultrasound-guided transbronchial needle
aspiration, are performed under conscious sedation without the
presence of a specialist anaesthetist.[6]
Given the paucity of evidence on TBLC performed under conscious
sedation for ILD, specically in a resource-constrained setting, we
aimed to describe its utility in a pilot study.
Methods
Study design and participants
We prospectively enrolled the first 20 patients who underwent
TBLC for ILD at Tygerberg Hospital in Cape Town, South Africa.
e institution is a 1 380-bed referral hospital that provides tertiary
service to ~3.5 million people. e capturing and deidentication of
data were approved by the Stellenbosch University Health Research
Ethics Committee (ref. no. N16/02/020).
Patient selection
Adults aged >18 years with suspected ILD were selected for TBLC
following discussion in a multidisciplinary team (MDT) meeting
comprising pulmonologists and radiologists. Patients required
diuse interstitial pulmonary inltrates for consideration. In these
cases, the MDT meeting deemed histopathology necessary to make
or conrm a denitive diagnosis, which was not possible with the
available clinical, radiological, serological and other laboratory
data. Potential cases were reviewed with the bronchoscopist to
ensure accessibility to the aected areas. Pulmonary hypertension
(right ventricular systolic pressure >40 mmHg on echocardiogram),
bleeding diathesis, lack of patient consent and haemodynamic
instability were outright exclusion criteria.
Basic demographic and clinical data
Demographic information included age (years) and sex. Smoking
status, defined as current smoker, non-smoker and ex-smoker
(smoking cessation >6 months prior to the day of procedure),
was documented for all. Comorbidities and HIV status were also
recorded.
Bronchoscopy and procedural sedation
All procedures were performed in an experienced centre with a
dedicated bronchoscopy suite and by a single pulmonologist with
>20years of experience in bronchoscopy. A exible bronchoscope
with a 3.2 mm working channel was used, and an oral bite guard
(Fig.1) was inserted for oral intubation. Supplementary oxygen was
given via nasal prongs at 5-15 L/min.
Conscious sedation was achieved with a combination of fentanyl
(100 µg/2 mL) with a bolus of 50 µg followed by 25-50 µg boluses
as needed, and propofol (200 mg/20 mL) with a 0.5-1 mg/kg
intravenous loading dose followed by 0.5 mg/kg increments every
3-5 minutes as required, targeting an Observer’s Assessment of
Alertness/Sedation (OAAS) scale of 2-3 (Table1).[7] A dedicated
and experienced member of the team served as the sedationist,
ensuring that the required level of sedation was achieved on the
OAAS scale.
An endobronchial blocker (7.0 Fr/65 cm Arndt Endobronchial
Blocker Set (Cook Medical, USA) (Fig.2) was attached with an
adjustable loop to the distal tip of the bronchoscope and introduced
into a segment or subsegment of the targeted lobe. e balloon was
inated, and its position was endoscopically conrmed (Fig.3).
All TBLC specimens were taken from the same lobe (dierent
segments or subsegments); in no patient was more than one lobe
sampled. e target lobe and segment(s) were identied prior to the
procedure at a combined meeting that was attended by at least three
specialist pulmonologists.
A cryoprobe attached to the controller (ERBECRYO 2; Erbe
Elektromedizin GmbH, Germany) was inserted past the deflated
Table1. Observer’s Assessment of Alertness/Sedation (OAAS)
scale
5 Awake and responds readily to name spoken in normal tone
4 Lethargic response to name spoken in normal tone
3 Response only aer name is called loudly and/or repeatedly
2 Response only aer name is called loudly and aer mild
shaking
1 Does not respond when name is called and aer mild
shaking
Fig. 1. Patients were orally intubated via a plastic bite guard.
Supplementary nasal oxygen was routinely administered.
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balloon to the periphery of the lung, and its position was conrmed
using uoroscopy (Fig.4). e operator aimed to keep the probe at
least 2 cm away from the visceral pleura and used uoroscopy to guide
the cryoprobe into dierent subsegments. During the rst procedure,
a 1.1 mm exible probe with a sheath (Erbe Elektromedizine GmbH,
Germany) was used, and specimens were retrieved through the
sheath. For the following 19 cases, a 1.7 mm exible probe (Erbe
Elektromedizine GmbH, Germany) was used. A freezing time of
6-10 seconds was applied, aer which the bronchoscope together
with the TBLC specimen was removed en bloc. A dedicated balloon
operator inated the bronchial blocker as soon as this manoeuvre was
completed, tamponading the target segment or subsegment. Once the
specimen was retrieved from the tip of the probe, the endoscopist
reintubated the patient and rapidly navigated the bronchoscope
back to the target segment, using the bronchial balloon blocker as
a physical guide. e bronchoscope camera was placed against the
balloon to inspect for bleeding distal to the ination point (Fig.5).
e balloon was only deated if it was deemed safe to do so (no
excessive bleeding). e procedure was repeated until at least ve
Fig.3. e balloon was inated, and its position was endoscopically
conrmed.
Fig.4. An example of uoroscopy. In this case the operator retracted the
probe by 2-3 cm prior to conrming its position again and performing
the biopsy.
Fig. 5. An example of the endoscopic view when the tip of the
bronchoscope is placed against the balloon to inspect for bleeding (in
this case very minor).
Fig.2. A bronchial blocker (7.0 Fr/65 cm Arndt Endobronchial Blocker
Set) was attached to the distal tip of the bronchoscope prior to insertion.
e balloon was only inated once the target segment was identied.
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macroscopically acceptable samples (>5 mm) were obtained (Fig.6).
Finally, the endoscopist inspected the segments in which the
TBLCs were performed and only removed the bronchoscope once
no active bleeding was observed. e endoscopist (experienced in
rigid bronchoscopy) had a rigid bronchoscope readily available and
prepared for each case to ensure prompt response in the event of an
emergency. During the recovery period, patients were positioned with
the lung from which the biopsy was taken in the dependent position.
Post-procedural care and monitoring for complications
A transthoracic ultrasound scan was used to exclude a pneumothorax,
and in all cases in which a pneumothorax could not be excluded,
a chest radiograph was obtained. A pneumothorax was deemed
signicant if any intervention (e.g. chest tube insertion) was required.
Likewise, any bleeding that required more than tamponade by means
of the endobronchial blocker was documented as signicant. All
procedural complications (including those potentially related to
conscious sedation) were documented.
Assessment of diagnostic yield
e nal diagnosis, and a decision regarding the need for a step-up
SLB if TBLC was non-diagnostic, were made at a multidisciplinary
meeting that included at least two specialist pulmonologists with an
interest in ILD, a thoracic radiologist, and an anatomical pathologist
with an interest in ILD.
Statistical analysis
All descriptive numerical data with a normal distribution were
described using means and standard deviations, whereas non-normal
data were described using medians and interquartile ranges (IQRs).
Categorical data were described using frequencies and percentages.
e Statistical Package for Social Sciences version 29 (SPSS) (IBM,
USA) was used to analyse the data.
Results
Baseline demographics and patient characteristics
A total of 20 patients underwent TBLC from June 2023 to May 2024.
Seven (35%) were male, and the median (IQR) age of the patients
was 46 (22) years. Comorbidities included hypertension (n=9),
diabetes mellitus (n=5), HIV infection (n=4) and previous pulmonary
tuberculosis (n=5). Nine patients (45%) were active smokers, 3 (15%)
were ex-smokers and 8 (40%) were non-smokers. No patient had overt
pulmonary hypertension.
Complications
ree patients experienced complications. Two (10%) developed a
pneumothorax aer the procedure. Neither required any intervention,
but one was kept in hospital for 1 day for observation before
discharge. Bleeding that required 10 minutes of tamponade with
the endobronchial blocker was observed in one case. e patient
experienced no haemodynamic or respiratory compromise and was
discharged the same day. ere were no direct complications as a
consequence of conscious sedation or recurrent airway intubation.
Notably, no patient required conversion to a general anaesthetic,
needed vasopressor support, had vocal cord injury, or experienced
any post-procedural aspiration-related sequelae.
Diagnostic yield
e MDT agreed on a clinical, radiological and histological diagnosis
in 17 cases (85%) (Table2). In one case, histological examination
revealed a nonspecic interstitial pneumonitis pattern with features
of respiratory bronchiolitis, which was not consistent with the high-
resolution computed tomography (HRCT) ndings, and in two cases
Table2. Diagnoses conrmed with transbronchial lung
cryobiopsy (N=17)
Diagnosis Subtype n
Hypersensitivity pneumonitis Non-brotic 3
Fibrotic 3
Mixed 1
NSIP Cellular 1
Fibrotic 1
RB-ILD 1
Tuberculosis 2
Pulmonary alveolar proteinosis 2
Lung cancer Adenocarcinoma 1
Lymphoma Marginal zone 1
Nodular sclerosing
Hodgkin’s lymphoma 1
NSIP = nonspecic interstitial pneumonia;
RB-ILD = respiratory bronchiolitis-interstitial lung disease.
Fig.6. Examples of transbronchial cryobiopsy specimens obtained with
a 1.7 mm probe.
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the TBLC histological specimen was considered insucient to make
a clear diagnosis. An SLB was performed in one of these cases, which
diagnosed adenocarcinoma with a micropapillary and lipidic pattern.
Discussion
In this pilot cohort, we found TBLC performed under conscious
sedation to be well tolerated with few complications. Furthermore, it
had a high diagnostic yield when a 1.7 mm cryoprobe was used, and
enabled us to avoid SLB in the majority of cases. e overall diagnostic
yield from our TBLC cohort was 85%, which is higher than in many
comparable studies in the existing literature.
e largest meta-analysis, by Rodrigues etal.,[4] described a pooled
diagnostic yield of 77%, rising to 81% in more experienced centres that
had performed >70 procedures. e type of sedation is not specically
described, but the majority of centres perform conventional TBLC
under general anaesthesia with a denitive airway, allowing more
rapid and easy access to the airway aer each sample. When looking at
TBLC performed under conscious sedation, diagnostic yields ranged
from 67% to 90%.[8-10] Notably, the study by Salton etal.[8] reported a
diagnostic yield of 90%, but only included 11 patients. Our results,
which are similar to those at high-volume centres, may be attributable
to the level of experience of the primary operator, but do lend support
to more frequent use of this technique going forward, especially in
resource-constrained settings. Training personnel in advanced
bronchoscopic techniques, as well as strengthening the MDT with
members who have specialised in thoracic radiology and pathology,
will further build up this service.
e most common complications in our study were pneumothorax
not requiring intervention (10%) and moderate bleeding (5%), which
are comparable with rates reported in the literature. In Rodrigues
etal.,[4] the reported pooled incidence was 5.6% (95% condence
interval (CI) 3.8 - 8.2) for pneumothorax requiring chest tube
insertion and 10% (95% CI6.8-14.3) for signicant bleeding (7% for
centres with >70 TBLCs). A further 1.4% of patients (95% CI0.9-2.2)
experienced an acute exacerbation of ILD aer TBLC,[4] which was
not seen in our cohort, possibly owing to patient selection as well
our limited sample size. Our patients did not experience any form of
complication related to the use of conscious sedation, and its use did
not limit the number of samples taken. Notably, there were no deaths
in our cohort.
Smaller individual studies similar to ours, with sample sizes ranging
from 12 to 100, had pneumothorax incidences of 13-20%, with small
proportions of patients requiring chest tube insertion.[8-10] These
studies did not routinely use uoroscopy, however, and although
it has been postulated that use of uoroscopy reduces the risk of
pneumothorax, this has not been consistently shown in the literature.
Probe size is also thought to play a role, with the smallest 1.1 mm
cryoprobe being shown to have the lowest risk for pneumothorax.[11]
Bleeding rates vary widely and significantly between studies,
with another meta-analysis reporting ranges from 0% to 70%, with
a mean incidence of 27%.[12] Discrepancies may arise as a result of
dierences in dening the severity of bleeds, the size of probes used,
the number of samples, and the presence of pulmonary hypertension.
Even when considering these factors, the bleeding rate in our cohort
was similar to that described by Johannson etal.[12] Timely diagnosis
in patients with ILD is a key component of an eective management
strategy.[4] When standard diagnostic pathways, including clinical
evaluation, serological or bronchial lavage ndings and correlation
with HRCT imaging of the chest and followed by an MDT meeting
of pulmonologists and chest radiologists, do not yield a diagnosis,
histopathological sampling may be deemed necessary. With the
current safety prole, it appears that in appropriately selected patients
and in experienced centres, TBLC under conscious sedation is
feasible and safe as a rst-line histopathological sampling procedure,
particularly in resource-constrained areas where general anaesthesia
is not readily available.
A key strength of our pilot study was conrmation that the practice
of performing TBLC under conscious sedation can be continued,
particularly in resource-constrained settings. Limitations include
the relatively small sample size, and the fact that one (experienced)
endoscopist performed all 20 procedures, which limits extrapolation
beyond a large-volume centre and procedures performed by
experienced bronchoscopists.
Conclusion
TBLC performed at an experienced bronchoscopy centre using
a 1.7mm cryoprobe under conscious sedation with a dedicated
sedationist is safe and well tolerated, and has a high diagnostic
yield. Using the proposed technique, accessibility to TBLC may be
significantly and feasibly increased in our resource-constrained
environment.
Data availability. e datasets generated and analysed during the present
study are available from the corresponding author (CFNK) on reasonable
request.
Declaration. e research for this study was done in partial fullment of
the requirements for ADB’s MPhil (Pulmonology) degree at Stellenbosch
University.
Acknowledgements. We would like to thank Mr Daniel Mashishi from
the Division of Epidemiology and Biostatistics at Stellenbosch University
for his contribution to the statistical analysis.
Author contributions. ADB and CFNK contributed to the design and
data analysis. ADB collected the study data. ADB, NS and CK wrote the
rst dra of the manuscript, which was reviewed and edited by all co-
authors.
Funding.None.
Conicts of interest.None.
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Received 8 September 2024. Accepted 6 January 2025. Published 28 March 2025.
