3/31/2016 1 Transbronchial Cryobiopsy in Diffuse Lung Disease Overview and Update Thomas V. Colby MD Sara Tomassetti MD Disclosure Dr. Colby has nothing to disclose 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.
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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.
Median time of Hospitalization, days:• Cryo 2.6 (0‐17)• VATS 6.1 (3‐48)
P<0.0001
P<0.0001
Ravaglia C et al, Respiration 2016
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
Ravaglia C et al, Respiration 2016
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%
Ravaglia C et al, Respiration 2016
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
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?
Median survival IPF 50.5mo (47‐53)NOT IPF 56.6mo (55‐57)
Cryo: survival analysis by subgroups
IPF
iNSIPCVD‐ILDSR‐ILDDRUG‐ILD
HP
Poletti V et al, unpublished
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.
What supports the use of Cryo in ILD:
1. diagnostic accuracy
2. prognostic significance
3. impact in the MDD
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?
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.
2. Kappa coefficient of agreement
0.74
0.84
STEP 5 BIOPSYTomassetti S et al, Am J Respir Crit Care Med, 2016
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2. Kappa coefficient of agreement
0.74
0.84
STEP 5 BIOPSY
3. Observers’ self reported confidence levels
Tomassetti S et al, Am J Respir Crit Care Med, 2016
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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