transbronchialcryobiopsyin diffuse lung disease overview ... · transbronchialcryobiopsyin diffuse...

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Transbronchial Cryobiopsy in Diffuse Lung DiseaseOverview and Update

Thomas V. Colby MDSara Tomassetti MD

Disclosure

Dr. Colby has nothing to disclose

Transbronchial Cryobiopsy1. Background and Technique

Dr. Tomassetti

Historic Background of Cryobiopsy• A correct diagnosis of IIPs and particularly Fibrosing

Interstitial Lung Diseases (f‐ILDs) requires amultidisciplinary approach and, when appropriate,intergration of CR data with histological findings.

• Surgical lung biopsy is still considered the goldstandard to provide lung samples large enough foridentification of complex patterns such as usualinterstitial pneumonitis (UIP) and other f‐ILDs.

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

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From surgery to less invasive biopsy methods.

Surgical Lung Biopsy

Transbronchial Lung Biopsy

Bronchoscopic Lung Cryobiopsy

UIP-pattern can be identified in a minority of TBBx with a very high specificity (92-100%)

and positive pred value (86-100%)S Tomassetti et al, Res Research 2012

Slide courtesy A Cavazza

Why is TBBx not used in fibrotic ILD diagnosis

Very Low Sensitivity (30% )Low negative predictive value (46%‐55%): the presence of TBB findings consistent with alternative diagnosis (ie. DIP, NSIP, ALI) does not rule out UIP.

Complications: pneumothorax 8% (5/64), requiring chest tube 1/5 (20%). One pneumomediastinum (2%).

S Tomassetti et al, Res Research 2012

Berbescu et al, Chest 2006

Higher risksHigher accuracy

Lower risksHigh accuracy

Lower risksLower accuracy

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Cryobiopsy: the technique. Cryobiopsy: The equipment

Different sizes of Cryoprobes

The gas at the tip expands due to the sudden difference inpressure (Joule‐Thomson effect), resulting in a drop intemperature at the tip of the probe.

Cryoprobe with water iceball

Cryoprobe with tissue‐iceball

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Standardization is needed …

Deep sedation/Concious sedation?

Rigid/Flexible?

How many samples? How many segments? Differentlobes?

Standardization is needed … ongoing international protocol

Deep sedation/Concious sedation?

Rigid/Flexible?

How many samples? How many segments? Differentlobes?2 in each lobe, at least two lobes (min 4 max 6)

Hetzel, Poletti, Wells, Costabel et al, European Multicenter Study

The endoscopy room

The anesthesiologist

fluoroscopy guide

2 endoscopy nurses1 bronchoscopist

rigid bronch

Fogarty positioning trough the rigid bronchoscope

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The cryoprobe is inserted through the operative channel of the fibrobronchoscope

Transbronchial Cryobiopsy2. Pathologic Specimens

Dr. Colby

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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.

Procedural Hemorrhage in Smoker

CryoBx Artifacts

Airspace fluid or not?

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Artifact: “Implanted” Bronchiolar Epith. Other Tissues found in Cryobx’s

Visceral Pleura

Pulmonary Arteries

Parietal Pleura/Skeletal MusclePleura present in

~30% patients in Forli study

Transbronchial Cryobiopsy3. Complications

Dr. Tomassetti

Events complicating lung biopsy for ILDs

‐ Pneumothorax

‐ Prolonged air leak

‐ Post procedure chest pain

‐ Bleeding

‐ Transient Resp. Failure NOS

‐ Fever

‐ Pneumonia/Empyema

‐ Acute Ex / DeathMost Serious

Most Frequent

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Events complicating lung biopsy for ILDs

‐ Pneumothorax

‐ Prolonged air leak

‐ Post procedure chest pain

‐ Bleeding

‐ Transient Resp. Failure NOS

‐ Fever

‐ Pneumonia/Empyema

‐ Acute Ex / Death

CRYOSLB

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

Ravaglia C et al, Respiration 2016

Prolonged air leak(>5 days post procedure)

§ 1 Prolonged chest tube* 3 Prolonged chest tube; 1 emopatch; 1 surgical revision

Cryo0.3%

(1§/297)

VATS 3.3%

(5*/150) P 0.035


Cryo: less frequent complications

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

Resp failure NOS 2§ (0.7%)

Seizures 2§ (0.7%)

Bleeding(not severe)° 13 (5.5%)


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Complications not found with Cryocompared 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.Ravaglia C et al, Respiration 2016

Cryo has significantlyless 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


Mortalityfollowing surgicallung biopsy for interstitial lung

disease.

• 9,700 deaths (95% CI 9,209‐10,192)

• overall in‐hospital mortality of 6.4% (95% CI 6.1%‐6.7%)

Mortality following SLB for ILDin the USA: 2000‐2011

Hutchinson JP et al, AJRCCM 2015

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Mortality following SLB for ILDin the USA: 2000‐2011

16% (7,796) deaths following non‐electiveoperations (95% CI 7,361‐8,230)

1.7% (1,695 deaths) following electiveoperations (95% CI 1,506‐1,883)

Hutchinson JP et al, AJRCCM 2015

Mortality following lung Bx for ILDat our center: 2003‐2015


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

Mortality following CryoBx for ILDReview of literature (Medline & Embase)

from 406 ARTICLES to15 STUDIES FOR SAFETY ANALYSIS,

INCLUDING 994 PATIENTS: only one death reported

Mortality for cryobiopsy 0.1%


VATS ONLY

Mortality 1.7%

CRYO

Mortality 0.1%

20% SUBSEQUENT VATS

Mortality 0.34%

Mortality 0.44%

CRYOBIOPSY HAS A LOWER DIAGNOSTIC YIELD COMPARED TO SLB (80% vs 98%), BUT IS SIGNIFICANTLY SAFER.

The mortality of a combined diagnostic algorithm Cryo+/‐VATS appears to be lower than VATS only

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BOTTOM LINE IT IS SAFE

Transbronchial Cryobiopsy4. Pathologic Diagnosis

Dr. Colby

BOTTOM LINE – IT WORKS !!

Sarcoidosis PLCH

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?Hypersensitivity pneumonitis UIP

Smoking Related ILD Questions You Should Have

How easy are they to interpret ?Comparison to TTBx ?Comparison to Surgical Lung Biopsy ?

Diagnostic accuracyConfidence of diagnosis

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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 Sizemm2

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 patientBiopsies 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 consecutivespecimens.

Forli Study: Slide Review

Two reviewers: T Colby, A CavazzaBlinded to clinical and other pathologistHistologic criteria: As for a SLBx*First, second, third choice diagnosesConfidence (Hi vs Lo) of primary diagnosis

* Some SLBx’s are no larger than a cryobiopsy

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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

HistologicDiagnosis

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

TVC and AC Agreement for UIP vs non‐UIPKappa = 0.72

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Transbronchial Cryobiopsy5. Clinical management implications

Dr. Tomassetti

The utility of lung Bx for ILDs

Lung Bx is not always indicated: histopathology is required only when the clinical radiological picture does not allow a confident diagnosis of ILD (e.g. a half of IPF cases).

Histopathology alone is insufficient to diagnose ILDs:histopathology is no longer the diagnostic gold standard.

MDD is currently the diagnostic gold standard, and the role of pathology is to provide useful information to the MDT.

What supports the use of SLB in ILD

Diagnostic accuracy (sens, spec, ppv and npv) of SLB has never been measured … what would be the gold standard to test SLB, the whole lung ??

The use of SLB is supported by:‐ Historical and cultural heritage‐ Studies showing that:

1. SLB provides useful informations in the MD diagnosis of ILDs

2. SLB can predict prognosis of ILDs

Averill Abraham Liebowthe founding father of ILD

Bjoraker et al, AJRCCM 1998; Hunninghake et al, AJRCCM 2001; Nicholson et al, Thorax 2004; Latsi et al, AJRCCM 2003; Flaherty et al, AJRCCM 2004; Raghu et al, AJRCCM 2011.

What supports the use of Cryo in ILD:

1. diagnostic accuracy

2. impact in the MDD

3. prognostic significance

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Am J Respir Crit Care Med, 2016 Does Cryo impact the multidisciplinary diagnosis of IPF?

AIM to evaluate the impact of Cryo on:

1. MDT diagnostic impression 2. inter‐observer agreement3. Observers’ self reported

confidence levels

Outcome measuresMeasure the change of variables 1, 2 and 3 change after addition of histopathology informations.

and to COMPARE CRYO TO SLB

Tomassetti S et al, Am J Respir Crit Care Med, 2016

C= Wells AU, Costabel UR= Sverzellati N, Carloni AP= Colby TV, Cavazza A, Rossi G

Methodology adopted fromFlaherty KR et al, AJRCCM 2004

1. MDT diagnostic impression

17% of cases in the BLC group and 19% of cases in the SLB group were reclassified as IPF.

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2. Kappa coefficient of agreement

0.74

0.84

STEP 5 BIOPSYTomassetti S et al, Am J Respir Crit Care Med, 2016


0.74

0.84

STEP 5 BIOPSY

3. Observers’ self reported confidence levels


BLC, P = 0.0003 SLB, P = 0.0016

Cryo has a meaningful impact on MDT diagnosis of ILDs

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Patients who underwent Bronchoscopic Lung Cryobiopsybetween 2011 and 2014

N=310N=5, Excluded for lack of baseline HRCTN=3, Excluded for not significant slides

N=302

Poletti V et al, unpublished

Weighted Kappa coefficient for first choice diagnosis

Histologicpattern AC‐TC TC‐GR GR‐ACUIP 0.67(0.58‐0.75) 0.74 (0.66‐0.80) 0.64 (0.55‐0.71)NSIP 0.39(0.28‐0.52) 0.25 (0.16‐0.38) 0.24 (0.14‐0.38)HP 0.26(O.13‐0.45) 0.30 (0.13‐0.54) 0.31 (0.17‐0.48)SR‐ILD 0.72(0.50‐0.87) 0.42 (0.29‐0.58) 0.41 (0.27‐056)GRANULOMATOSIS 0.90(0.68‐0.98) 0.78 (0.56‐0.92) 0.87 (0.65‐0.97)MALIGNANCIES 0.93(0.64‐1.00) 0.86 (0.56‐0.97) 0.80 (0.51‐0.95)OTHER 0.62(0.38‐0.65) 0.38 (0.27‐0.51) 0.40 (0.27‐0.54)NONDIAGNOSTIC 0.45(0.29‐0.61) 0.08 (0.01‐0.28) 0.06 (0.01 ‐0.23)

Cryo’s prognostic significance: histopathology alone

NOT‐UIP*

UIP

*NSIP/HP/SR‐ILD


months

P=0.24

N N. of death

N %

UIP 116 10 106 91,4%

NOT UIP 75 2 73 97,3%

TOTAL 191 12 179 93,7%

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Cryo’s prognostic significance: histopathology alone

Poletti V et al, unpublishedmonths

UIP

HP

SR‐ILD

NSIP

P=0.56

N N. of events

N %

UIP 116 10 106 91,4%

NSIP 34 1 33 97,1%

HP 17 1 16 94,1%

SR-ILD 24 0 24 100,0%

TOTAL 191 12 179 93,7%

The MDT diagnosis

IPF iNSIP HP CVD‐ILD SR‐ILDDRUG‐REL OTHER

UIP 116 95 5 3 8 1 1 2

NSIP 34 2 16 0 6 0 2 8

HP 17 2 0 11 0 0 0 4

SR-ILD 24 0 0 0 1 16 0 7

TOTAL 191 99 22 14 15 17 3 21


170

Cryo has prognostic significance

NOT‐IPF*

IPF

*iNSIP/HP/CVD‐ILD/SR‐ILD/DRUG‐ILD


months

P=0.01

N N. di eventi

Troncati

N Percentuale

IPF 99 12 87 87,9%

NOT IPF 71 1 70 98,6%

TOTAL 170 13 159 92,4%

Median survival IPF 50.5mo (47‐53)NOT IPF 56.6mo (55‐57)

Cryo: survival analysis by subgroups

IPF

iNSIPCVD‐ILDSR‐ILDDRUG‐ILD

HP


N N. of death

N %

IPF 99 12 87 87,9%

iNSIP 22 0 22 100,0%

HP 14 1 13 92,9%

CVD-ILD 15 0 15 100,0%

SR-ILD 17 0 17 100,0%

DRUG-ILD 3 0 3 100,0%

TOTAL 170 13 157 92,4%

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Cryo’s prognostic impact for ILD

Pathologists recognize on Cryo histologicpatterns that carry prognostic significance, as forSLB, the multidisciplinary approach is helpful toimprove prognostication and to correctlymanage those patients.





Cryo and MD Diagnosis of f-ILDskey questions

Does Cryo impact the multidisciplinary diagnosis ofIPF?

and

How do Cryo and SLB compare in the scenario of thedynamic interactions between clinicians, radiologistsand pathologists?

Tomassetti S et al, AJRCCM 2015

Am J Respir Crit Care Med, 2016

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Does Cryo impact the multidisciplinary diagnosis of IPF?

AIM to evaluate the impact of Cryo on:

1. MDT diagnostic impression 2. inter‐observer agreement3. Observers’ self reported

confidence levels

Outcome measuresMeasure the change of variables 1, 2 and 3 change after addition of histopathology informations.

and to COMPARE CRYO TO SLB


C= Wells AU, Costabel UR= Sverzellati N, Carloni AP= Colby TV, Cavazza A, Rossi G

Methodology adopted fromFlaherty KR et al, AJRCCM 2004

1. MDT diagnostic impression

17% of cases in the BLC group and 19% of cases in the SLB group were reclassified as IPF.


0.74

0.84

STEP 5 BIOPSYTomassetti S et al, Am J Respir Crit Care Med, 2016

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0.74

0.84

STEP 5 BIOPSY

3. Observers’ self reported confidence levels


BLC, P = 0.0003 SLB, P = 0.0016

Conclusion

Cryobiopsy in ILDs is:‐ Feasible (diagnostic yield, approx 80%)‐ Safe (mortality, approx 0.1%)‐ and has a meaningful impact in the scenario of

dynamic interactions of the MDT, comparable to that of SLB.

Future guidelines should implement Cryo in the diagnostic algorithm of ILDs diagnosis.

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Carbonelli C, Rossi G, Cavazza A. Cryobiopsy and multidisciplinary diagnosis of idiopathic pulmonary fibrosis. Respirology. 2015 May;20(4):685.

Casoni GL, Tomassetti S, Cavazza A, Colby TV, Dubini A, Ryu JH, Carretta E,Tantalocco P, Piciucchi S, Ravaglia C, Gurioli C, Romagnoli M, Gurioli C, ChilosiM, Poletti V. Transbronchial lung cryobiopsy in the diagnosis of fibroticinterstitial lung diseases. PLoS One. 2014 Feb 28;9(2):e86716.

Fruchter O, Fridel L, Rosengarten D, Rahman NA, Kramer MR. Transbronchialcryobiopsy in immunocompromised patients with pulmonary infiltrates: a pilotstudy. Lung. 2013 Dec;191(6):619‐24

Fruchter O, Fridel L, Rosengarten D, Raviv Y, Rosanov V, Kramer MR.Transbronchial cryo‐biopsy in lung transplantation patients: first report.Respirology. 2013 May;18(4):669‐73.

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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‐transbronchialbiopsy. Respirology. 2014 Jul;19(5):683‐8.

Griff S, Ammenwerth W, Schönfeld N, Bauer TT, Mairinger T, Blum TG, KollmeierJ, Grüning W. Morphometrical analysis of transbronchial cryobiopsies. DiagnPathol. 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 innon‐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 inthe diagnostic algorithm of interstitial lung disease. Clin Respir J. 2015 Jan26.

Hernández‐González F, Lucena CM, Ramírez J, Sánchez M, Jimenez MJ, Xaubet A,Sellares J, Agustí C. Cryobiopsy in the diagnosis of diffuse interstitial lungdisease: yield and cost‐effectiveness analysis. Arch Bronconeumol. 2015Jun;51(6):261‐7.

Hetzel J, Eberhardt R, Herth FJ, Petermann C, Reichle G, Freitag L, DobbertinI, Franke KJ, Stanzel F, Beyer T, Möller P, Fritz P, Ott G, Schnabel PA,Kastendieck H, Lang W, Morresi‐Hauf AT, Szyrach MN, Muche R, Shah PL, Babiak A,Hetzel M. Cryobiopsy increases the diagnostic yield of endobronchial biopsy: amulticentre trial. Eur Respir J. 2012 Mar;39(3):685‐90.

Mikolasch TA, Porter JC. Transbronchial cryobiopsy in the diagnosis ofinterstitial lung disease: a cool new approach. Respirology. 2014Jul;19(5):623‐4. doi: 10.1111/resp.12320. Epub 2014 May 25.

Montero Fernández MÁ. Transbronchial cryobiopsy in interstitial lung disease:advantageous costs to benefits ratio. Arch Bronconeumol. 2015 Jun;51(6):257‐8.doi: 10.1016/j.arbres.2015.02.006. Epub 2015 Apr 28.

Pajares V, Puzo C, Castillo D, Lerma E, Montero MA, Ramos‐Barbón D, Amor‐CarroO, Gil de Bernabé A, Franquet T, Plaza V, Hetzel J, Sanchis J, Torrego A.Diagnostic yield of transbronchial cryobiopsy in interstitial lung disease: arandomized trial. Respirology. 2014 Aug;19(6):900‐6.

Poletti V, Casoni GL, Gurioli C, Ryu JH, Tomassetti S. Lung cryobiopsies: aparadigm shift in diagnostic bronchoscopy? Respirology. 2014 Jul;19(5):645‐54.doi: 10.1111/resp.12309. Epub 2014 May 26.

Poletti V, Hetzel J. Transbronchial Cryobiopsy in Diffuse Parenchymal LungDisease: Need for Procedural Standardization. Respiration. 2015 Sep 19. [Epubahead of print]

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transbronchialcryobiopsyin diffuse lung disease overview ... · transbronchialcryobiopsyin diffuse...

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