ACCME/DisclosuresThe USCAP requires that anyone in a position to influence or control the content of CME disclose

any relevant financial relationship WITH COMMERCIAL INTERESTS which they or their

spouse/partner have, or have had, within the past 12 months, which relates to the content of

this educational activity and creates a conflict of interest.

Dr. Thomas V. Colby and Sara Tomassetti declare they have no conflict(s) of interest to

disclose.

Transbronchial Cryobiopsy in Diffuse Lung Disease

Overview and Update

Sara Tomassetti MD

Thomas V. Colby MD

Transbronchial Cryobiopsy 1. Background and Technique

Dr. Tomassetti

Historic Background of Cryobiopsy

• A correct diagnosis of IIPs and particularly Fibrosing Interstitial Lung Diseases (f-ILDs) requires a multidisciplinary approach, and, when appropriate, intergration of CR data with histological findings.

• Surgical lung biopsy is still considered the gold standard to provide lung samples large enough for identification of complex patterns such as usual interstitial pneumonitis (UIP) and other f-ILDs.

• However, this procedure has significant morbidity and mortality and is performed in minority of patients.

From surgery to less invasive biopsy methods.

Surgical Lung Biopsy

Transbronchial Lung Biopsy

Bronchoscopic Lung Cryobiopsy

UIP-pattern can be identified in a small

minority of TBBx with a very high specificity

(92-100%) and pos pred value (86-100%)

Slide courtesy A Cavazza

Why is TBBx not used in fibrotic ILD diagnosis

Very Low Sensitivity (30% for Expert Pathologists)

Low negative predictive value (50%): the presence of TBB findings consistent with alternative diagnosis (ie. DIP, NSIP, ALI) does not rule out UIP.

Higher risks Higher accuracy

Lower risks High accuracy

Lower risks Lower accuracy

Cryobiopsy: the technique.

The gas at the tip expands due to the sudden difference in pressure (Joule-Thomson effect), resulting in a drop in temperature at the tip of the probe.

Courtesy of A Cavazza

Cryoprobe with water iceball

Cryoprobe with tissue-iceball

Cryobiopsy: The equipment is simple

Different sizes of Cryoprobes

Standardization is needed for those performing Cryobiopsy… Deep sedation/Concious sedation? Rigid/Flexible? How many samples? How many segments? Different lobes?

● General anesthesia (Propofol/Remifentanil)

● Spontaneous breathing

● Rigid Tracheochoscope (Storz 14 mm-33 cm)+ fiberoptic bronchoscope (6.2 mm)

● Fogarty balloon

● Fluoroscopic control (+/- radial EBUS)

● Erbokryo CA, ERBE, Tubingen, Germany (CO2)

● Cryoprobe 2.4 mm

● A distance of approximately <= 10 mm from the thoracic wall

● A perpendicular relation between the thoracic wall and the probe

● The probe is cooled for approximately 5-6 s

TRANSBRONCHIAL CRYOBIOPSY (POLETTI’S PROTOCOL)

Cryobiopsy video

Video #1 – The tools.

Video # 2 – Intubation with rigid bronchoscope,

Storz 14.

Video #3 – The insertion of the Fogarty balloon.

Video # 4 – The cryobiopsy.

Transbronchial Cryobiopsy 2. Pathologic Specimens

Dr. Colby

TB

Cryobiopsy TBBx VATS

Slide courtesy A. Cavazza MD

Cryobiopsy:

the specimens

Slide courtesy A. Cavazza MD

Diagn Pathol 2011; 6: 53

Specimen Size

Alveolar Tissue

TBBx

CryoBx

Cryobiopsy: Size of specimens

STUDY # Patients Mean Size (mm2)

Babiak 2009 41 15.1

Fruchter 2013 (Lung Tx) 40 10

Kropski 2013 25 64.2

Casoni 2014 69 43.1

Pajares 2014 39 14.7

Griff 2014 52 30.4

Forli Study (in prep) 310 44.8

BUT….Not all cryobiopsies are created equal. A bad cryobiopsy is no better than a bad TBBx.

Suboptimal Cryobiopsies: Examples

Too small

Bronchial wall only

Procedural Hemorrhage in Smoker

CryoBx Artifacts

Airspace fluid or not?

Artifact: “Implanted” Bronchiolar Epith.

Other Tissues found in Cryobx’s

Visceral Pleura

Pulmonary Arteries

Parietal Pleura/Skeletal Muscle

Pleura present in ~30% patients in Forli study

Retrospective review of 524 cryobiopsies in 310 ILD patients

1-6 biopsies for each patient

Pleura in 92 patients (29.7%)

In 33 patients (10.6%) biopsies were inadequate (normal/minimal nonspecific changes)

In 277 patients (89.4%) biopsies were adequate

Cryobiopsies Forlì Hospital (Italy), March 2011-January 2015

Transbronchial Cryobiopsy 3. Complications

Dr. Tomassetti

Complications of Lung Bx

- Pneumothorax - Prolonged air leak (>5 days post procedure) - Post procedure chest pain - Bleeding (severe when require interventions

such as surgery, ICU, transfusion) - Transient Resp. Failure NOS - Fever - Pneumonia/empyema - Acute exacerbation (def. Collard AJRCCM 2007) - Death

Complications of CryoBx

- Pneumothorax - Prolonged air leak (>5 days post procedure) - Post procedure chest pain - Bleeding (severe when require interventions

such as surgery, ICU, transfusion) - Transient Resp. Failure NOS - Fever - Pneumonia/empyema - Acute exacerbation (def. Collard AJRCCM 2007) - Death

Complications of VATS Biopsy

- Pneumothorax

- Prolonged air leak (>5 days post procedure) 3-12%

- Post procedure chest pain 52%

- Bleeding (severe when require interventions such as surgery, ICU, transfusion)

- Transient Resp. Failure NOS

- Fever

- Pneumonia/empyema

- Acute exacerbation (def. Collard AJRCCM 2007)

- Death 2-4%

Acute Exacerbation of IPF after SLB

Kondoh et al., Respiratory Medicine (2006) 100, 1753–1759

Mortality at 90 days 2-4% (mainly IPF pts)

Kreider ME, et al. Ann Thorac Surg 2007 Kondoh Y, et al. Respir Med 2006 Bensard et al., Chest 1993

Safety of CryoBx compared to VATS for the diagnosis of ILDs

Our centre (Forli) experience

Cryo 297, VATS 150

(14 VATS subsequent to non-diagnostic-Cryo).

Cryo vs VATS: our centre data

Surgical Lung Biopsy (VATS) Tranbronchial Lung Cryobiopsy (TBCB) p valuePatients, N 150 297

Age, median (range) 59 (15-74) 60 (21-78) 0,278

Genre, N, %

Male 85 56,7% 172 57,9%0,801

Female 65 43,3% 125 42,1%

Smoking, N, %

current smoker 21 14,0% 40 13,5%

0,968

former smoker 63 42,0% 124 41,8%

non smoker 65 43,3% 133 44,8%

FVC % pred, median (range) 80,0 (20,0 - 136,0) 86,0 (37,0 - 137,0) 0,072

FEV1 % pred, median (range) 83,0 (33,0 - 133,0) 88,0 (36,0 -144,0) 0,034

DLco %pred, median (range) 57,0 (19,0 - 122,0) 58,8 (14,0 -121,0) 0,078

Tiffenau Index, median (range) 86 (62,0 - 105,0) 86 (60,0 -124,0) 0,85

Hystologic pattern, N, %

DIP/RBILD 11 7,3% 12 4,0%

0,013

UIP 74 49,3% 92 31,0%

NSIP 23 15,3% 25 8,4%

DAD 1 0,7% 4 1,3%

OP 8 5,3% 31 10,4%

HP 7 4,7% 24 8,1%

Sarc 8 5,3% 22 7,4%

16 10,7% 36 12,1%

Not diagnostic pattern, N, % 2 1,3% 51 17,2%

Other (neoplasms, eosinophilic pneumonia, follicolar bronchiolitis, alveolar proteinosis, vasculitis, AFOP, DIPNECH, PLCH)

Summarized in the next slide…

Cryo has significantly less complications and shorter hospitalization

compared to VATS

All adverse events, excluding PNX:

• Cryo 6/297 0,2%

• VATS 20/150 13%

Median time of Hospitalization, days:

• Cryo 2.6 (0-17)

• VATS 6.1 (3-48)

P<0.0001

P<0.0001

Cryo: PNX is the most frequent procedure related event

CRYO, N=297

• Pneumothorax, 20% (N=60)

->Chest drainage 15% (46/297), 76%(46/60)

VATS, N=150

• Pneumothorax is part of the procedure,

-> 100% chest drainage

Prolonged air leak

Cryo

0.3%

(1§/297)

VATS

3.3%

(5*/150)

P

0.035

§ prolonged chest tube; * Prolonged chest tube 3/5; 1 emopatch; 1 surgical revision

Cryo: rare complications.

Cryo

(297)

VATS

(150)

p

value

° prolonged Fogarty (3 to 20min); saline+antihaemorr drug.

Resp failure NOS 2§ (0.7%) N/A

Seizures 2§ (0.7%) N/A

Bleeding

(not severe)° 13 (5.5%) N/A

Complications not found with Cryo compared to VATS

Cryo

(297)

VATS

(150)

Persistent fever

0 7 (4.37%)

Pneumonia/empyema 0 3 (2%)

Chest wall paresthesia 0 52%§

(21% at 12 months)

§ Sihoe et al, Eur J Cardiothorac Surg. 2004 Jun;25(6):1054-8.

Mortality§ is significantly lower with Cryo compared to VATS

Cryo

(297)

VATS

(150) P value

Mortality§ 1 (0.3%) 4 (2.7%) 0.045

Cause of death was Acute Exacerbation of IPF in all cases

§ at 60days

Safety of CryoBx compared to VATS for the diagnosis of ILDs

Review of literature (Medline & Embase)

from 406 ARTICLES to

15 STUDIES FOR SAFETY ANALYSIS, INCLUDING 994 PATIENTS

Complications of CryoBx for ILD, medline

- Pneumothorax 100*/994, 10% *(70/100 drainage)

- Prolonged air leak 1/994, 0.1%

- Transient Resp. Failure NOS, 0.4%

- Seizure 0.2%

- Death (Acute exacerbation ) 1/994, 0.1%

ESTIMATED DIAGNOSTIC YIELD

CRYOBIOPSY HAS A LOWER DIAGNOSTIC YIELD COMPARED TO SLB (80% vs 98%),

BUT IS SIGNIFICANTLY SAFER.

Including cryo in the diagnostic algorithm of ILD offers advantages in terms of safety: - Mortality for SLB 2% (best possible scenario), - Diagnostic yield of Cryo is 80%, thus performing Cryo before SLB

hypothetically reduces the risk of death to : - 2.1 % for 20% patients (Cryo + SLB) -> 0.42% - 0.1 % for 80% of patients (Cryo only) -> 0.08%

-> The mortality of a combined diagnostic algorithm Cryo+/-VATS appears to be lower than VATS only, even considering the best possible scenario for VATS.

0.5%

Transbronchial Cryobiopsy 4. Pathologic Diagnosis

Dr. Colby

BOTTOM LINE – IT WORKS !!

Intravascular lymphoma

Sarcoidosis

PLCH

?Hypersensitivity pneumonitis

UIP

UIP

UIP

?Collagen Vascular Disease

Smoking Related ILD

Questions You Should Have

How easy are they to interpret ?

Comparison to TTBx ?

Comparison to Surgical Lung Biopsy ?

Diagnostic accuracy

Confidence of diagnosis

TB Cryobiopsy vs. Forceps TBBx

Randomized trial published in 2014*

77 pts randomized

Cryobiopsy clearly superior to traditional Forceps TBBx

(* Pajares et.al. Respirology 2014; 19: 900-906)

Technique Specimen Size mm2

Histologic Dx MMD Dx Complications

Forceps TBBx 3.3 +/- 4.1 74% 51%

TB Cryobiopsy 14.7 +/- 11 34% 29%

1. Bleeding > in Cryobx (NS) 2. PTX similar

Ideally Cryo should be proven against SLBx

But was SLBx ever proven as sueful against a gold standard ? NO

Cryobiopsies (Forli Study 3/11 – 1/15)

524 cryobiopsies in 310 patients with ILD and non- diagnostic clinical-radiologic findings 1-6 Bx’s per patient Biopsies inadequate in 33 pts (10.6%) (Normal tissue or minimal changes) “Adequate” in 277 pts (89.4%)

Here is what we were dealing with: photo of 21 consecutive specimens.

Forli Study: Slide Review

Two reviewers: T Colby, A Cavazza Blinded to clinical and other pathologist Histologic criteria: As for a SLBx* First, second, third choice diagnoses Confidence (Hi vs Lo) of primary diagnosis

* Some SLBx’s are no larger than a cryobiopsy

UIP Hi Confidence

Pathologist #1 (AC)

DIAGNOSIS Hi Conf (%) Lo Conf (%) TOTAL (%)

UIP 23 17 40

NSIP/OP 0 13 13

HP 4 7.5 11.5

Rb/DIP 1 4 5

PLCH 1.5 2 3.5

Sarcoid 5.5 2 (grans NOS) 7.5

AC Diagnoses after MDD

Histologic Diagnosis

Diagnosis after MDD

Comments

UIP Hi Conf 58 IPF 6 other diagnoses

UIP Lo Conf 27 IPF 19 other diagnoses

NSIP/OP Lo Conf 14 NSIP/OP 22 other diagnoses

AC vs TVC Diagnoses

AC Diagnoses TVC Diagnoses

UIP Hi - 64 UIP Hi and Lo – 57 7 other Dx’s

UIP Lo - 46 UIP Hi and Lo – 35 11 other Dx’s

NSIP Lo - 36 NSIP – 24 UIP Hi and Lo – 6 6 other Dx’s

TVC and AC Agreement for UIP vs non-UIP Kappa = 0.72

Transbronchial Cryobiopsy 5. Clinical management implications

Dr. Tomassetti

Bronchoscopic Lung Cryobiopsy

(BLC) and MultiDiscplinaryDiagnosis

of fibrotic ILD key questions

Does BLC impact the multidisciplinary diagnosis of IPF?

and

How do BLC and VATS compare in the scenario of the dynamic interactions between clinicians, radiologists and pathologists?

Flowchart for inclusion of patients in the prospective database and in this study.

Study Population

117 f-ILDs cases with cryobiopsy or SLB biopsy

BLIND pathologic revision (TV Colby, A Cavazza, G

Rossi) and pathologic consensus.

Sequential addition of standardized clinical data at

diagnosis (SCD-D), HRCT, BAL, cryobiopsy or SLB,

standardized clinical data at follow-up (SCD-FU)

PHASE ONE

PHASE TWO

PHASE I

BLIND pathologic revision (A Cavazza, G Rossi and TV

Colby) and pathologic consensus.

Pathologists’ blind impressions

PHASE II

Sequential addition of standardized clinical data at

diagnosis (SCD-D), HRCT, BAL, cryobiopsy or SLB,

standardized clinical data at follow-up (SCD-FU)

Phase II – organizational scheme

FROM PATHOLOGISTS’ IMPRESSIONS TO MDD

MDD (STEP 6)

Interobserver agreement

0.74

0.84

STEP 5 BIOPSY

MDD: Change of diagnostic impression after Bx

Change in participants’ self reported confidence level

Conclusions

BLC is a new biopsy method that has a meaningful impact on diagnostic confidence in the multidisciplinary diagnosis of ILDs, and may prove useful in the diagnosis of IPF.

This study provides a robust rationale for future studies investigating the diagnostic accuracy of BLC compared to SLB, and the prognostic significance of BLC.

CryoBx Prognostic correlations

- 310 cases …. In progress

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Fruchter O, Fridel L, El Raouf BA, Abdel-Rahman N, Rosengarten D, Kramer MR. Histological diagnosis of interstitial lung diseases by cryo-transbronchial biopsy. Respirology. 2014 Jul;19(5):683-8. Griff S, Ammenwerth W, Schönfeld N, Bauer TT, Mairinger T, Blum TG, Kollmeier J, Grüning W. Morphometrical analysis of transbronchial cryobiopsies. Diagn Pathol. 2011 Jun 16;6:53. Griff S, Schönfeld N, Ammenwerth W, Blum TG, Grah C, Bauer TT, Grüning W, Mairinger T, Wurps H. Diagnostic yield of transbronchial cryobiopsy in non-neoplastic lung disease: a retrospective case series. BMC Pulm Med. 2014 Nov 3;14:171. Hagmeyer L, Theegarten D, Wohlschläger J, Treml M, Matthes S, Priegnitz C, Randerath WJ. The role of transbronchial cryobiopsy and surgical lung biopsy in the diagnostic algorithm of interstitial lung disease. Clin Respir J. 2015 Jan 26. Hernández-González F, Lucena CM, Ramírez J, Sánchez M, Jimenez MJ, Xaubet A, Sellares J, Agustí C. Cryobiopsy in the diagnosis of diffuse interstitial lung disease: yield and cost-effectiveness analysis. Arch Bronconeumol. 2015 Jun;51(6):261-7.

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