AJTCCM VOL. 29 NO. 3 2023 107
ORIGINAL RESEARCH: ARTICLE
Background. Transbronchial lung cryobiopsy (TBLC) in the diagnosis of diuse parenchymal lung disease (DPLD) has shown a promising
yield in recent times, with low post-procedural mortality and morbidity.
Objectives. To compare the yield of TBLC and conventional transbronchial forceps lung biopsy (TBLB).
Methods. A prospective study was carried out in patients with DPLD over a period of 1 year in a tertiary respiratory care institute in New
Delhi, India. All 87 patients enrolled underwent both TBLB and TBLC. e procedures were performed in the bronchoscopy suite under
conscious sedation and local anaesthesia, with an attempt to take a minimum of three biopsy specimens by conventional TBLB followed by
TBLC. A 1.9 mm cryoprobe with a freezing time of 4 - 5 seconds was used. An Arndt endobronchial blocker was used to control bleeding
along with locally administered medications.
Results. TBLB and TBLC led to a denitive diagnosis in 27 (31.0%) and 69 (79.3%) cases, respectively. e commonest diagnoses were
hypersensitivity pneumonitis, sarcoidosis and pulmonary tuberculosis. TBLC led to additional diagnoses in 42 cases (48.3%). Pneumothorax
was observed in 12 cases (13.8%), and moderate bleeding occurred in 63 (72.4%). ere were no procedure-related deaths.
Conclusion. TBLC had a better diagnostic yield than conventional TBLB in DPLD. It has the potential to become a safe day-care procedure
in a resource-limited setting, if certain precautions are taken.
Keywords. Diuse parenchymal lung disease, transbronchial forceps lung biopsy, transbronchial lung cryobiopsy, bleeding, pneumothorax.
Afr J Thoracic Crit Care Med 2023;29(3):e799. https://doi.org/10.7196/AJTCCM.2023.v29i3.799
Diuse parenchymal lung disease (DPLD) is a heterogeneous group
of >200 pulmonary disorders that have been classied into numerous
subtypes based on their clinical, radiological and histopathological
profiles.[1-3] The diagnostic yield of conventional fibreoptic
bronchoscopy-guided transbronchial forceps lung biopsy (TBLB)
is variable and inuenced by factors such as the size of the sample
harvested, the presence of crush artifacts and operator expertise.[3] TBLB
yield is relatively good in bronchocentric disease suchassarcoidosis,
hypersensitivity pneumonitis (HSP), and malignancies such as
lymphangitis and bronchoalveolar cell carcinoma. However, its yield
decreases in cases of peripheral pathologies and pathologies with
spatial heterogeneity such as usual interstitial pneumonia (UIP)
and nonspecic interstitial pneumonia (NSIP). Surgical lung biopsy
remains the gold-standard procedure for tissue collection in DPLD,
but it cannot be performed in many patients owing to respiratory
impairment and medical comorbidities. It is performed in the operating
room under general anaesthesia and requires mandatory insertion of
an endotracheal tube. In recent years, transbronchial lung cryobiopsy
(TBLC) has emerged as a useful alternative with a good diagnostic yield.
In a comparison of complications following video-assisted thorascopic
surgical lung biopsy and TBLC by Ravaglia etal.,[4] TBLC was associated
with fewer days of hospitalisation than surgical lung biopsy (2.6 v. 6.1;
p<0.001), and 1 of 297 patients (0.003%) died in the TBLC group
compared with 4 of 250 (0.016%) in the surgical lung biopsy group.
Comparison of the diagnostic yield of transbronchial lung biopsies
by forceps and cryoprobe in diuse parenchymal lung disease
M S Khot,1 MBBS, DNB (Respiratory Medicine); A Chakraborti,1 MBBS, DTCD, DNB (Respiratory Medicine);
J K Saini,1 MBBS, MD ; P Sethi,1 MBBS, MD; S Mullick,2 MBBS, MD; R Saxena,3 MBBS, MS;
A R Wani,1 MBBS, DNB (Respiratory Medicine)
1 Department of Pulmonary Medicine, National Institute of Tuberculosis and Respiratory Diseases, New Delhi, India
2 Department of Pathology, National Institute of Tuberculosis and Respiratory Diseases, New Delhi, India
3 Department of oracic Surgery, National Institute of Tuberculosis and Respiratory Diseases, New Delhi, India
Corresponding author: J K Saini (jitendr[email protected]om)
Study synopsis
What the study adds. Compared with transbronchial forceps lung biopsy, transbronchial lung cryobiopsy (TBLC) led to additional
diagnoses in 42 (48.3%) of 87 patients with clinicoradiological features of diuse parenchymal lung disease.Pneumothorax was observed
in 12 cases (13.8%) and moderate bleeding in 63 (72.4%). TBLC without rigid bronchoscopy or advanced airway devices under conscious
sedation hada good diagnostic yield with an acceptable adverse events prole.
Implications of the ndings. TBLC under conscious sedation is not resource intensive and can be carried out in settings with limited
resources.
108 AJTCCM VOL. 29 NO. 3 2023
ORIGINAL RESEARCH: ARTICLE
However, few studies have compared the diagnostic yield of TBLC and
surgical lung biopsy.
TBLC has met the need to obtain sufficient lung tissue for
diagnosis with relatively few complications. In most studies of
TBLC, advancedairway protection, rigid bronchoscopic intubations
and fluoroscopy-guided probe placement have been used. In
the present study, we aimed to investigate the diagnostic ecacy
and safety of TBLC using a simpler combination of a flexible
bronchoscope and an Arndt endobronchial blocker without the
above resource-intensive techniques.
Methods
is was a prospective, single-centre, comparative observational
study conducted over a period of 1 year in the bronchoscopy suite
at a tertiary respiratory care institute in New Delhi, India. Informed
written consent was obtained from the patients before each
procedure, in the language of their choice. Exclusion criteria included
thrombocytopenia, coagulation disorders, and clinical conditions
that contraindicate bronchoscopy as per the British oracic Society
(BTS) guideline.[5] e study protocol was approved by the institute
ethical committee (ref. no. NITRD/PGEC/2017/6109).
Patients with clinicoradiological features of DPLD were initially
evaluated by a team comprising pulmonologists and radiologists to
determine the need for lung biopsy. A detailed clinical history was
taken, including exposure to drugs and pets, occupational exposures
and a smoking history, and a chest radiograph and a high-resolution
computed tomography (HRCT) scan of the thorax were done.
Routine blood tests, including a total leucocyte count, platelet count
and measurement of the prothrombin time, were done.
All procedures were done in the bronchoscopy suite, without an
anaesthetist present. Anticoagulants were withheld for an appropriate
length of time prior to the procedure. e biopsy site was determined
according to the maximum abnormality seen on the HRCT scan.
e analgesia and sedation protocol used was as follows:
Patients were nebulised for 5 minutes with 3 mL 4% lignocaine
with 2 mL normal saline, 10 minutes before the procedure.
ree to ve sprays of 10% lignocaine were used for pharyngeal
anaesthesia. Loss of the gag reflex was taken as indicating
adequate anaesthesia.
Injections of 2 mg midazolam and 25 µg fentanyl were given
initially at the start of the procedure.
Lignocaine 1% was used in 1.5 - 2 mL aliquots in a spray-as-you-
go technique. e working channel of the bronchoscope was used
for administration.
Additional injections of 0.5 mg midazolam were given according
to the patient’s condition. Top-ups were provided if the patient
showed signs of discomfort such as excessive coughing or
restlessness, up to a cumulative dose of 5 mg.
A CO2 monitor was not used. The pulmonologist monitored
sedation by clinical assessment, using clinical signs such as heart
rate, blood pressure, level of consciousness and pupil size.
Supplemental oxygen was provided via nasal prongs. Procedures
were done without using any articial airway or assisted ventilation.
A breoptic bronchoscope was used (Fujinon, model no. EB-530T;
Fujilm, Japan). TBLB and TBLC were done sequentially. A exible
cryoprobe of size 1.9 mm diameter and 900 mm length was used
(Erbecryo; Erbe Elektromedizin GmbH, Germany). Pulse rate,
blood pressure, oxygen saturation and the electrocardiogram were
monitored prior to and throughout the procedure.
Patients were kept nil per month before the procedure (2 hours for
liquids and 4 hours for solids). e breoptic bronchoscope (inner
working diameter 2.8 mm) was introduced orally through a mouth
guard. An 9F Arndt endobronchial blocker (Cook Medical, USA)
was hooked along with the bronchoscope and advanced through the
airway. e Arndt blocker was then freed from the bronchoscope at
the opening of the lobar bronchus that we planned to biopsy. Fig.1
shows the Arndt blocker hooked onto the bronchoscope and the view
inside the airways. e airways were inspected. Biopsy forceps were
advanced through the working channel, and biopsy material was
collected in saline water. e Arndt blocker was inated whenever
bleeding was encountered.
After checking the freezing time of the cryoprobe (1.9 mm)
by dipping its tip in sterile water, it was advanced through the
working channel in a similar way to forceps. When the probe
reached the pleura, it was retracted by 1 cm and freezing was done
for 4-6seconds. e bronchoscope along with the cryoprobe was
then immediately retracted, and the biopsied material collected in
saline water. e Arndt blocker was inated by 5 cm of air and the
bronchoscope was reintroduced to check for any bleeding and to
check the position of the inated Arndt blocker, aer which the
Arndt blocker was deflated. Biopsy specimens were transferred
to the pathologists in a formalin container for further processing.
A chest radiograph was done 2 hours after completion of the
procedure to rule out pneumothorax. For both TBLB and TBLC,
an attempt was made to take a minimum of three biopsy specimens,
preferably from dierent sites, as far as was possible in terms of
patient parameterssuch as oxygen saturation, haemodynamics and
bleeding. Bleeding associated with the procedure was quantied
as none, mild, moderate or severe according to the BTS guideline
on exible bronchoscopy.[5] Haematoxylin and eosin-stained slides
were reviewed by the pathologists. Diagnoses were made after
multidisciplinary discussion (MDD) involving pulmonologists,
pathologists and radiologists. As per the study protocol, all patients
AB
C
Fig.1. (A) Hooking of the Arndt blocker on the bronchoscope, (B) scope
view with the Arndt blocker inated, and (C) scope view with the Arndt
blocker deated.
AJTCCM VOL. 29 NO. 3 2023 109
ORIGINAL RESEARCH: ARTICLE
underwent TBLC, not only those who were unfit for surgical
lungbiopsy.
Patient data were entered into SPSS (Statistical Package for the Social
Sciences) version 21 (IBM, USA), and qualitative and quantitative
analysis was done. A t-test for means and proportions was done when
required, with p<0.05 taken to be signicant.
Results
A total of 87 patients were enrolled in our study after informed
consent had been obtained. e characteristics of the study population
are set out in Table1. e most common site of transbronchial lung
biopsy was the right lower lobe (n=60; 69.0%), followed by the le
lower lobe (n=18; 20.7%) and the right middle lobe (n=9; 10.3%).
e mean (standard deviation) numbers of biopsy samples taken
by conventional TBLB and TBLC were 3.1 (0.61) and 2.17 (0.7),
respectively. e macroscopic and microscopic features of the biopsy
specimens obtained are described in Table2. e TBLC specimens
were signicantly larger in size than those obtained by conventional
TBLB (p<0.0001; t-test). Crush artifacts were found in none of the
TBLC specimens, but were detected in 51 (58.6%) of the TBLB
samples. e diagnostic yield of TBLB in our study was 31.0% (n=27),
and that of TBLC was 79.3% (n=69). The final histopathological
diagnoses are listed in Table3. e same histopathological diagnosis
was obtained by TBLC and TBLB in 27 patients. TBLC led to additional
diagnoses in 42 patients (48.3%), while 18 (20.7%) had inconclusive
reports for both the procedures. e most common diagnoses were
pulmonary sarcoidosis, pulmonary tuberculosis (PTB) and HSP. UIP
was diagnosed in 6 patients, only with TBLC. Forceps TBLB was
associated with mild bleeding in the majority of cases (n=57; 65.5%),
while with TBLC the majority had moderate bleeding (n=63; 72.4%).
In those patients with a conrmed histopathological diagnosis, the
MDD diagnosis was the same. For the rest (20.7%), in whom the
histopathological diagnosis was uncertain, MDD diagnoses were
deferred. ey were referred to the thoracic surgeons for work-up for
surgical lung biopsy. Pneumothorax was a complication in 12 patients
(13.8%). Eleven were managed conservatively with high-ow oxygen
therapy, and 1 required placement of an intercostal tube, which was
removed 3 days aer the procedure. No patient experienced oxygen
desaturation events during the TBLB procedure, but 30 patients
(34.5%) experienced such events during TBLC. Seventy-two patients
(82.8%) were t to go home on the day of the procedure. ere were
no deaths in our study.
Discussion
It is oen challenging to arrive at a specic diagnosis in a patient
withDPLD. Without histopathological confirmation, it can be
dicult to make a diagnosis by means of radiological features, clinical
history and other biomarkers, because there are areas of overlap.
Conventional TBLB has been found to provide insucient samples
and a poor diagnostic yield. Surgical lung biopsy is associated with
significant morbidity and mortality. In recent years, TBLC has
been shown to have a good diagnostic yield with relatively few
complications and has emerged as a promising alternative to surgical
interventions. In the present study, the diagnostic yield of TBLC was
signicantly higher than that of conventional TBLB (79.3% v. 31.1%).
In a study by Ravaglia etal.,[6] a specic pathological diagnosis was
achieved in 614/699 cases (87.9%). e most common diagnosis
was UIP (37.5%), followed by NSIP or organising pneumonia
(OP)/NSIP (9.4%) and OP (8.3%). In a study by Wälscher etal.,[7] a
histopathological pattern diagnosis was possible in 80 cases (73.4%),
with a nonspecic disease pattern seen in 29 (26.6%). e most
common pathological diagnosis was NSIP, reported in 22 patients
(20.2%), with UIP and smoking-related interstitial lung disease
(ILD) each reported in 11 patients (10.1%). In a study by Kropski
etal.,[8] the diagnostic yield of TBLC was 20/25 (80%), with UIP the
most common diagnosis (n=7/25, 20.8%), bronchiolitis obliterans
organising pneumonia, desquamative interstitial pneumonia,
malignancy and drug-induced ILD being diagnosed in 2 cases each
(8%) and HSP and constrictive bronchiolitis in 1 case each (4%).
e diagnostic yield of TBLC in the present study was similar to
that in the above studies, but the histopathological diagnoses
dier. In these studies, idiopathic interstitial pneumonias (IIPs)
such as NSIP, UIP and OP were more prevalent than in our study,
in which the UIP pattern was seen in only 6.8% of patients. HSP
and sarcoidosis were common diagnoses in our study (17.2%). is
nding may be due to the fact that unlike the developed Western
world, where IIP constitutes 65% of ILD, in India the commonest
ILD diagnosed is HSP, accounting for ~47.3% of cases.[9,10] In our
study, 17.2% of patients were diagnosed as having PTB aer their
Table1. Clinical characteristics of the patients (N=87)
n (%)*
Age (years), mean (SD) 50 (14.5)
Male gender 45 (51.7)
Patients discharged on day of procedure 72 (82.8)
Smoking status
Current smokers 18 (20.7)
Ex-smokers 12 (13.8)
Never smokers 57 (65.5)
Spirometry parameters, mean (SD)
FVC (%) 69 (19)
FEV1 (%) 72 (22)
FEV1/FVC ratio 81.2 (9.2)
DLCO (%) 42 (16.8)
Exposure to oending agents (other than tobacco smoke)
Birds or pets 6 (6.9)
Organic/inorganic dust 9 (10.3)
HRCT features
Reticulonodular shadows 18 (20.7)
Consolidation 12 (13.8)
Bronchiectasis 9 (10.3)
Cyst 9 (10.3)
Cavity 3 (3.4)
Lymphadenopathy 15 (17.2)
Fibrosis 21 (24.1)
Ground-glass opacities 24 (27.6)
Honeycombing 27 (31.0)
Mosaic attenuation 3 (3.4)
SD = standard deviation; FVC = forced vital capacity; FEV1 = forced expiratory volume in
1second; DLCO = diusing capacity for carbon monoxide; HRCT = high-resolution computed
tomography.
*Except where otherwise indicated.
110 AJTCCM VOL. 29 NO. 3 2023
ORIGINAL RESEARCH: ARTICLE
biopsy revealed necrotising granuloma. is
was a learning experience for us, because in a
tuberculosis-endemic country such as India,
we should always keep an infectious cause
in mind when a patient has radiological
features suggestive of ILD. PTB shares many
radiological features with sarcoidosis and
HSP and may therefore masquerade as an
ILD. e diagnosis becomes more dicult
in an inadequately treated patient with
PTB, because the clinical features in such
cases are sometimes not prominent, and
radiological evidence of fibrosis and/or
lymphadenopathy may lead the physician to
suspect an ILD.
With regard to complications, moderate
bleeding was associated with TBLC in the
majority (72.5%) of patients in the present
study. Massive life-threatening bleeding did
not occur in any patient. In the study by
Ravaglia etal.,[6] moderate to severe bleeding
was seen in 13% of patients, and no patient
had a fatal haemorrhage. In the MULTICRIO
study,[11] 6.5% of the 124 patients had moderate
bleeding. Bleeding rates in our study were
therefore considerably higher than in other
contemporary studies, but bleeding was
managed conservatively in all cases and no
patient required intensive care unit admission.
In a meta-analysis, Johannson etal.[12] found
high levels of heterogeneity among studies
reporting bleeding aer TBLC (mean 26.6%,
range 0 - 78%).[12] They postulated that the
varying rates of bleeding may be due to
differences in procedural technique (e.g.
duration of freeze time, probe positioning),
inconsistent definitions of adverse events
such as bleeding, and differences in study
populations. In our study, echocardiography
was not part of the pre-procedure work-up.
We suspect that undiagnosed pulmonary
hypertension in some patients may have
resulted in our relatively high rate of bleeding.
The rate of pneumothorax in our study
was 13.8%, which is similar to the pooled
estimate of 12% (95% confidence interval
3 - 21) emerging from the meta-analysis by
Johannson et al.[12] despite the fact that we
did not use a fluoroscopy-guided biopsy
technique. is nding is reassuring, because
in a resource-limited country such as India,
routine use of uoroscopy may not always be
feasible. Furthermore, none of our patients
had a large air leak, as 11 pneumothoraces
resolved on high-ow oxygen therapy and only
1 patient required intercostal tube placement
with a 3-day hospital stay. Ravaglia et al.[6]
found that cryobiopsies using a 2.4 mmprobe
were associated with increased rates of
pneumothorax compared with 1.9 mm probes,
but had similar diagnostic yields. We used the
1.9 mm probe in our study, which may have
reduced the risk of pneumothorax while not
decreasing the diagnostic yield. Pneumothorax
is also dependent on the number of biopsy
sites and the number of biopsy samples taken.
However, there is no consensus regarding the
optimal number of biopsies required for a
condent diagnosis of ILD, or the number of
biopsy sites or segments. Further studies are
required in this area.
Our study had certain limitations. The
sample size was small, and the study was
conducted in a single institution. As both
the procedures, TBLB and TBLC, were
done in same setting, we could not attribute
complications to a single procedure. Routine
echocardiography and work-up for pulmonary
hypertension were not done in our study, and
these would have helped us to identify the
patients with an increased risk of bleeding.
Conclusion
Our study clearly shows that TBLC is a
relatively safe procedure that can be performed
in a day-care setting with a diagnostic yield
much better than that of conventional TBLB.
Head-to-head comparisons with surgical lung
biopsy and TBLC should be done to ascertain
the diagnostic yield of TBLC as opposed to
surgical interventions.
Declaration. e research for this study was
done in partial fullment of the requirements
for KSM’s DNB (Diplomate of National Board)
in Respiratory Medicine degree at the National
Board of Examinations, India.
Table2. Macroscopic and microscopic features of TBLB and TBLC specimens
(N=87patients)
TBLB, n (%)* TBLC, n (%)*
Diameter of biopsy sample (mm), mean (SD) 1.91 (0.964) 3.99 (1.78)
Histopathological ndings
Granuloma 9 (10.3) 18 (20.7)
Necrosis 3 (3.4) 15 (17.2)
Fibroblastic foci 21 (24.1) 30 (34.5)
Septal inammation 15 (17.2) 30 (34.5)
Intra-alveolar macrophages 12 (13.8) 21 (24.1)
Z-N staining AFB 0 0
Alveolar tissue 21 (24.1) 66 (75.9)
Crush artifacts 51 (58.6) 0
TBLB = conventional transbronchial forceps lung biopsy; TBLC = transbronchial lung cryobiopsy; Z-N = Ziehl-Neelsen;
AFB = acid-fast bacilli.
*Except where otherwise indicated.
Table3. Final histopathological diagnoses in TBLB and TBLC biopsy samples
(N=87patients)
Diagnosis TBLB, n (%) TBLC, n (%)
Usual interstitial pneumonia 0 6 (6.8)
Hypersensitivity pneumonitis 3 (3.4) 15 (17.2)
Sarcoidosis 6 (6.8) 15 (17.2)
Idiopathic bronchiolocentric interstitial
pneumonitis
3 (3.4) 3 (3.4)
Pulmonary Langerhans cell histiocytosis 3 (3.4) 3 (3.4)
Pleuroparenchymal broelastosis 0 3 (3.4)
Silicosis 3 (3.4) 3 (3.4)
Pulmonary tuberculosis 6 (6.8) 15 (17.2)
Nonspecic inammation 3 (3.4) 3 (3.4)
Carcinoma 0 3 (3.4)
Inconclusive 60 (68.9) 18 (20.7)
TBLB = conventional transbronchial forceps lung biopsy; TBLC = transbronchial lung cryobiopsy.
AJTCCM VOL. 29 NO. 3 2023 111
ORIGINAL RESEARCH: ARTICLE
Acknowledgements. None.
Author contributions. KSM, AC and ARW: patient enrolment and
work-up, data entry, statistical analysis and manuscript preparation.
JKS: formulation of the study, manuscript preparation and supervision
of bronchoscopies. PS: manuscript preparation, data analysis and
supervision of bronchoscopies. SM: histopathological examination of the
biopsy samples, formulation of the study and manuscript preparation.
RS: work-up of patients, manuscript preparation, conceptualisation and
design of the study, and evaluating patients for surgical lung biopsy.
Funding.None.
Conicts of interest.None.
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Submitted 12 September 2022. Accepted 28 May 2023. Published 19 September 2023.