Biopsy is Biopsy is necessarynecessary for the for the diagnosis of IPFdiagnosis of IPF

NesrinNesrin MoğulkoçMoğulkoç

Pulmonary Medicine

AATSTS/E/ERSRS International International Multidisciplinary Consensus Multidisciplinary Consensus

Classification Of Idiopathic Interstitial Classification Of Idiopathic Interstitial PneumoniasPneumonias

General Principles and RecommendationsGeneral Principles and Recommendations

Co-chairs: William D. Travis, M.D.

Talmadge King, Jr. M.D.

Am J Respir Crit Care Med 2002; 165: 277

DPLD of known cause (e.g. drugs, dust exposure, collagen vasculardisease)

Idiopathic interstitial

pneumonias

Granulomatous DPLD (e.g. sarcoidosis)

Other forms of DPLD(e.g. LAM, HX, eosin. pneum.)

Diffuse Parenchymal Lung Disease

Idiopathic Iinterstitial Pneumonia other than IPF

Idiopathicpulmonary

fibrosis (IPF)

Desquamative interstitialpneumonia (DIP)

Acute interstitial pneumonia (AIP)

Lymphocytic interstitialpneumonia (LIP)

Nonspecific interstitialpneumonia (NSIP)

Cryptogenic organisingpneumonia (COP)

Respiratory bronchiolitis/Interst. lung dis. (RBILD)

SeriesSeries IPF NSIP DIP/RBILD COPIPF NSIP DIP/RBILD COP

Bjoraker et al. 62% 14% 10% 2%1998

Nagai et al. 58% 28% - 14%1998

Travis et al. 55% 29% 16% -2000

Nicholson et al. 47% 36% 17% -2000

Proportion of patients with IPF, NSIP, Proportion of patients with IPF, NSIP, DIP/RBILD and COP among IIPsDIP/RBILD and COP among IIPs

DPLD of known cause (e.g. drugs, dust exposure, collagen vasculardisease)

Idiopathic interstitial

pneumonias

Granulomatous DPLD (e.g. sarcoidosis)

Other forms of DPLD(e.g. LAM, HX,

eosin. pneum. etc.)

Diffuse Parenchymal Lung Disease

IIP other thanidiopathic

pulmonary fibrosis

Idiopathicpulmonary

fibrosis (IPF)

Desquamative interstitialpneumonia (DIP)

Acute interstitial pneumonia (AIP)

Lymphocytic interstitialpneumonia (LIP)

Nonspecific interstitialpneumonia (NSIP)

Cryptogenic organisingpneumonia (COP)

Respiratory bronchiolitis/Interst. lung dis. (RBILD)

%40-50%40-50

%47-64%47-64

%14-36%14-36

%10-17%10-17

%4-12%4-12<%2<%2

<%2<%2

tto provide a specific diagnosiso provide a specific diagnosis

Biopsy is Biopsy is necessarynecessary in IPF in IPF

History, physical exam, clinical chemistry, PFT, Chest Xray

Not IIP Possible IIP

HRCT

Septal thickeningSeptal thickening

Irregular Irregular reticularreticular / / linear opacitieslinear opacities

Cystic airspacesCystic airspaces / / honeycombinghoneycombing

NodulesNodules

Ground-glass attentuationGround-glass attentuation

ConsolidationConsolidation

HRCTHRCTPathologyPathology

Lymphangitis carcinomatosaLymphangitis carcinomatosa

LymphomaLymphoma

SarcoidosisSarcoidosis

UIPUIP

Collagen vascular diseaseCollagen vascular disease

AsbestosisAsbestosis

Hypersensitivity pneumonitisHypersensitivity pneumonitis

LymphangioleiomyomatosisLymphangioleiomyomatosis

Langerhans’ cell histiocytosisLangerhans’ cell histiocytosis

Miliary TBMiliary TB

Fungal infectionFungal infection

DIPDIP

LIPLIP

Alveolar proteinosisAlveolar proteinosis

Chronic eosinophilic pneumoniaChronic eosinophilic pneumonia

BOOP/COPBOOP/COP

DAD/ARDSDAD/ARDS

NSIPNSIP

RB/ILDRB/ILD

History, physical exam, clinical chemistry, PFT, Chest Xray

HRCT

Typical of IPF (~50%) ∅ IPF (~50%) suggestive of Other ILD ? specific ILD

Not IIP Possible IIP

HRCT Criteria of IPFHRCT Criteria of IPF1. Reticular abnormality and/or traction

bronchiectasis with basal and peripheral predominance

2. Honeycombing with basal and peripheral predominance

3. Atypical features are absent – Micronodules are not present– Peribronchovascular nodules are not present– Consolidation is not present– Ground glass attenuation, if present, is less extensive than

reticular opacity – Mediastinal adenopathy, if present, is not extensive enough to be

visible on chest X-ray

Definite IPF: all 3 are metProbable IPF: 1 and 3 are met

UIP: Progression UIP: Progression oof Fibrosis f Fibrosis oon n HRHRCCTT

Early:Early:

ReticularReticular

Late:Late:ExtensiveExtensive

HoneycombingHoneycombingModerate:Moderate:SubpleuralSubpleural

HoneycombingHoneycombing

Honeycombing

Honeycombing (5%)

Honeycombing (5%)

Rating of κ scores

Landis JR, Koch GG. 1977

agreement κ score

•perfect

•substantial

•moderate

•fair

•slight

•poor

> 0.8

0.6 - 0.8

0.4 - 0.6

0.2 - 0.4

0.0 - 0.2

= 0.0

Kappa coefficients of agreement between 11 radiologists for HRCT diagnosis

(Aziz et al. Thorax 2004)

DiagnosisDiagnosisKappa Kappa ((of first choiceof first choice

diagnosisdiagnosis))

IPFIPF 0.500.50

NSIPNSIP 0.380.38

RBILD/DIPRBILD/DIP 0.300.30

COPCOP 0.370.37

EAAEAA 0.590.59

SarcoidosisSarcoidosis 0.620.62

OverallOverall 0.480.48

Accuracy of Clinical & Radiological Diagnosis of IPF

• 59 patients with surgical biopsies

• clinical diagnosis or radiological diagnosis

• clinical diagnosis of IPF

- 97% specific

- 62% sensitive

• HRCT diagnosis of IPF

- 90% specific

- 79% sensitive Raghu et al, 1999

Accuracy of HRCT Diagnosis in IPF

A confident diagnosis is made in only about two-thirds of patients with IPF

History, physical exam, clinical chemistry, PFT, Chest Xray

HRCT

Typical of IPF (~50%) ∅ IPF (~50%) suggestive of Other ILD ? specific ILD

Ø IPF No TBBx TBBx TBBx diagnosis BAL BAL BAL

Surgical lung biopsy (3 locations, min. 2cm3)

UIP NSIP RB-ILD DIP DAD COP LIP ∅ IIP

Not IIP Possible IIP

tto assess disease activityo assess disease activity

Biopsy is Biopsy is necessarynecessary in IPF in IPF

UIP: fibroblast foci

• Extent Of Fibroblastic foci Predict Mortality In Idiopathic Pulmonary Fibrosis T.E. King Jr., AJRCCM 2001:164;1025-32.

• The frequency of fibroblastic foci in usual interstitial pneumonia and their relationship to disease progression Nicholson AG, AJRCCM 2002; 166: 173-7.

• Relationship between histopathologic features and course of IPF/UIP Titto L, Thorax 2006:61:1091-5.

Fibroblastic foci in UIP

Site of initial injury that triggers fibrosing process?

Survival in IPF patients categorised by fibroblastic Survival in IPF patients categorised by fibroblastic foci score in the lung biopsyfoci score in the lung biopsy

tto o predict prognosis and to predict prognosis and to identify a identify a more treatable process than more treatable process than

originally suspectedoriginally suspected

Biopsy is Biopsy is necessarynecessary in IPF in IPF

IPF: worst case of an ILD

100

Bjoraker JA Am J Respir Crit Care Med. 1998;157:199

80

60 Other

40 NSIP

20

IPF

0 0 2 4 6 8 10 12 14 16 18

Years

Flaherty et al., Thorax, 2003

0 6 8 102 4

0

20

40

60

80

100 BBypyp=NSIP &=NSIP &HRCT=NSIP/HRCT=NSIP/UdtmUdtm

BBypyp=UIP &=UIP &, , HRCT=NSIP/HRCT=NSIP/UdtmUdtm

BBypyp=UIP &=UIP &HRCT=UIPHRCT=UIP

Follow up Time (years)

Cum

ulat

ive

prop

ortio

n su

rviv

ing

BBx-Diagnosisx-Diagnosis::NSIP: n = 23, UIP: n = 73

HRCTHRCT-Diagnosis:-Diagnosis:NSIP: n = 44, UIP: n = 27

Udtm: n = 25

UIP pattern (histology vs HRCT) Flaherty et al Thorax 2003

• HRCT UIP 2.08• SLBx UIP 3.99• SLBx of UIP and HRCT of other/NSIP 5.76• HRCT of NSIP and SLBx of NSIP >9

• Pattern of UIP on HRCT or Bx = poorer prognosis in IPF

(median survival in years)

to rto recognise ecognise purerpurer cohorts of cohorts of patients with regard patients with regard

investigation of cause and investigation of cause and treatment strategiestreatment strategies

Biopsy is Biopsy is necessarynecessary in IPF in IPF

‘Importance of the lung biopsy for drug trials’

Stricter criteria for IPF, greater

understanding of the ‘entity’ NSIP and

problems with overlap, need for confident

diagnosis of UIP/IPF for international drug

trials

Biopsy may be Biopsy may be necessarynecessary in in ILDILD

tto exclude neoplastic and o exclude neoplastic and infectious processes that infectious processes that

occasionally mimic chronic, occasionally mimic chronic, progressive interstitial diseaseprogressive interstitial disease

Conditions mistaken for ILD

• Infection

• Cancer– Lymphoma– BAC– lymphangitis carcinomatosa

Am J Respir Crit Care Med Vol 170. pp 904–910, 2004

Does the interactive diagnostic process improve Does the interactive diagnostic process improve the interobserver agreement?the interobserver agreement?

Idiopathic Interstitial PneumoniaWhat Is the Effect of a Multidisciplinary Approach to Diagnosis?

Kevin R. Flaherty, Talmadge E. King, Jr., Ganesh Raghu, Joseph P. Lynch III, Thomas V. Colby,William D. Travis, Barry H. Gross, Ella A. Kazerooni, Galen B. Toews, Qi Long, Susan Murray,Vibha N. Lama, Steven E. Gay, and Fernando J. Martinez

Information provided

Type of decision

Participants Output

Step 1 HRCT InvidualCliniciansClinicians

RadiologistsRadiologistsFirst Diagnosis & Confidence

Step 2HRCT +

clinical dataInvidual

CliniciansClinicians

RadiologistsRadiologistsDiagnosis & Diagnosis & ConfidenceConfidence

Step 3HRCT +

clinical dataGroup

CliniciansClinicians

RadiologistsRadiologistsDiagnosis & Diagnosis & ConfidenceConfidence

Step 4

HRCT +

clinical data + surgical biopsy

Group

CliniciansClinicians

RadiologistsRadiologists

Pathologists

Diagnosis & Diagnosis & ConfidenceConfidence

Step 5HRCT+

clinical data + surgical biopsy

Group

CliniciansClinicians

RadiologistsRadiologists

Pathologists

Consensus Consensus Diagnosis & Diagnosis & ConfidenceConfidence

Organisational Scheme(Review of 58 cases)

Interobserver agreement at each diagnostic step

Step

Clinicians

[κ (95% CI) ]

Radiologists

[ κ (95% CI)]

Clinicians–Radiologists

[κ (95% CI)]

All Observers

[κ (95% CI)]

1 0.41 (0.29, 0.52) 0.72 (0.57, 0.86) 0.39 (0.29, 0.49) NA

2 0.51 (0.37, 0.64) 0.80 (0.67, 0.93) 0.44 (0.34, 0.54) NA

3 0.67 (0.54, 0.79) 0.78 (0.65, 0.91) 0.55 (0.44, 0.66) NA

4 0.75 (0.64, 0.86) 0.84 (0.72, 0.96) 0.78 (0.70, 0.86) 0.79 (0.71, 0.86)

5 0.86 (0.76, 0.95) 0.90 (0.80, 0.99) 0.88 (0.81, 0.96) 0.88 (0.81, 0.94)

Interobserver agreement at each diagnostic step

Step

Clinicians

[κ (95% CI) ]

Radiologists

[ κ (95% CI)]

Clinicians–Radiologists

[κ (95% CI)]

All Observers

[κ (95% CI)]

1 0.41 (0.29, 0.52) 0.72 (0.57, 0.86) 0.39 (0.29, 0.49) NA

2 0.51 (0.37, 0.64) 0.80 (0.67, 0.93) 0.44 (0.34, 0.54) NA

3 0.67 (0.54, 0.79) 0.78 (0.65, 0.91) 0.55 (0.44, 0.66) NA

4 0.75 (0.64, 0.86) 0.84 (0.72, 0.96) 0.78 (0.70, 0.86) 0.79 (0.71, 0.86)

5 0.86 (0.76, 0.95) 0.90 (0.80, 0.99) 0.88 (0.81, 0.96) 0.88 (0.81, 0.94)

AJRCCM 2007; 175: 1054 – 1060

Idiopathic Interstitial PneumoniaDo Community and Academic Physicians

Agree on Diagnosis?

Kevin R. Flaherty, Adin-Cristian Andrei, Talmadge E. King, Jr., Ganesh Raghu, Thomas V. Colby, Athol Wells, Nadir Bassily, Kevin Brown, Roland

du Bois, Andrew Flint, Steven E. Gay, Barry H. Gross, Ella A. Kazerooni, Robert Knapp, Edmund Louvar, David Lynch, Andrew G. Nicholson, John Quick, Victor J. Thannickal, William D. Travis, James Vyskocil, Frazer A.

Wadenstorer, Jeffrey Wilt, Galen B. Toews, Susan Murray, and Fernando J. Martinez

Final Diagnosis Agreement:Different among Community/Academic

Physicians?

Flaherty KR, et al. AJRCCM 2007; 175: 1054

• n = 39 pat. with ILD, retrospective review

• Agreement in final diagnosis among 6 groups

academic/community

clinicians/radiologists/pathologists

• Final agreement was better within academic

centers (kappa = 0.55 to 0.71) than within

community centers (kappa = 0.32 to 0.44)

Surgical Lung BiopsySpecial risk in IPF!

• 60 pat with UIP (46 idiopathic, 14 associated with collagen/vasc dis) from Mayo Clinic 1986 - 1995

• 10/60 (=17%) died within 30 days after surgical biopsy

3/16 (19%) after VATS

7/44 (16%) after thoracotomy and biopsy

• All 10 who died had IPF, 5 of these were biopsied for accelerated progress

Utz et al, ERJ 2001; 17: 175

Mortality and Risk Factors for Surgical Lung Biopsy in IIP

• 200 pat. with IIP (140 IPF, 46 NSIP, 14 COP), retrospective study

• 4.3% died within 30 days after surgical biopsy, no difference between VATS or OLB

no difference between IPF and other IIPs

• Biopsy at time of acute exacerbation: mortality 29% vs 3%

• DLCO<50%: mortality 11% vs 1.4% Park JH et al, Eur J Cardiothorac Surg 2007

sarcoid

UIP

NSIP

EAAother

sarcoid

UIP

NSIP

EAAother

sarcoid

UIP

NSIP

EAAother

UIP

NSIP

EAAother

UIP

NSIP

EAAother

UIP: HRCTUIP

NSIP

EAAother

UIP: HRCT

UIP

NSIP

EAAother

UIP: HRCT

UIP

NSIP

EAAotherLCH

LAM

UIP

NSIP

EAAother

Biopsy is Biopsy is necessarynecessary for the for the diagnosis of IPFdiagnosis of IPF