Biopsy is necessary for the diagnosis of IPF

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Biopsy is necessary for the diagnosis of IPF
Nesrin Mogulkoç Pulmonary Medicine
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ATS/ERS International Multidisciplinary Consensus
Classification Of Idiopathic Interstitial
PneumoniasGeneral Principles and Recommendations

• Co-chairs William D. Travis, M.D.
• Talmadge King, Jr. M.D.
• Am J Respir Crit Care Med 2002 165 277

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Diffuse Parenchymal Lung Disease

Idiopathic interstitial pneumonias
DPLD of known cause (e.g. drugs, dust exposure,
collagen vascular disease)
Granulomatous DPLD (e.g. sarcoidosis)
Other forms of DPLD (e.g. LAM, HX, eosin. pneum.)
Idiopathic Iinterstitial Pneumonia other than IPF
Idiopathic pulmonary fibrosis (IPF)
Respiratory bronchiolitis/ Interst. lung dis.
(RBILD)
Desquamative interstitial pneumonia (DIP)
Acute interstitial pneumonia (AIP)
Cryptogenic organising pneumonia (COP)
Lymphocytic interstitial pneumonia (LIP)
Nonspecific interstitial pneumonia (NSIP)
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Proportion of patients with IPF, NSIP, DIP/RBILD
and COP among IIPs

• Series IPF 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

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Diffuse Parenchymal Lung Disease

Idiopathic interstitial pneumonias
DPLD of known cause (e.g. drugs, dust exposure,
collagen vascular disease)
Granulomatous DPLD (e.g. sarcoidosis)
Other forms of DPLD (e.g. LAM, HX, eosin. pneum.
etc.)
IIP other than idiopathic pulmonary fibrosis
Idiopathic pulmonary fibrosis (IPF)
Respiratory bronchiolitis/ Interst. lung dis.
(RBILD)
Desquamative interstitial pneumonia (DIP)
Acute interstitial pneumonia (AIP)
Cryptogenic organising pneumonia (COP)
Lymphocytic interstitial pneumonia (LIP)
Nonspecific interstitial pneumonia (NSIP)
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to provide a specific diagnosis
Biopsy is necessary in IPF
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History, physical exam, clinical chemistry, PFT,
Chest Xray
Possible IIP
Not IIP
HRCT
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Pathology
HRCT
Lymphangitis carcinomatosa
Lymphoma
Sarcoidosis
Septal thickening
UIP
NSIP
Irregular reticular / linear opacities
Collagen vascular disease
Asbestosis
Cystic airspaces / honeycombing
Hypersensitivity pneumonitis
Lymphangioleiomyomatosis
Langerhans cell histiocytosis
Nodules
Miliary TB
Fungal infection
Ground-glass attentuation
RB/ILD
DIP
Consolidation
LIP
Alveolar proteinosis
Chronic eosinophilic pneumonia
BOOP/COP
DAD/ARDS
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History, physical exam, clinical chemistry, PFT,
Chest Xray
Possible IIP
Not IIP
HRCT
Typical of IPF (50)
Ø
IPF (50)
suggestive of
Other ILD ?
specific ILD
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HRCT Criteria of IPF

• Reticular abnormality and/or traction
  bronchiectasis with basal and peripheral
  predominance
• Honeycombing with basal and peripheral
  predominance
• 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 met
• Probable IPF 1 and 3 are met

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UIP Progression of Fibrosis on HRCT
Late Extensive Honeycombing

• Early
• Reticular

Moderate Subpleural Honeycombing
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Honeycombing
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Honeycombing (5)
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Honeycombing (5)
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Rating of ? scores
agreement ? score
perfect substantial moderate fair slight poor gt 0.8 0.6 - 0.8 0.4 - 0.6 0.2 - 0.4 0.0 - 0.2 0.0
Landis JR, Koch GG. 1977
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Kappa coefficients of agreement between 11
radiologists for HRCT diagnosis(Aziz et al.
Thorax 2004)
Diagnosis Kappa (of first choice diagnosis)
IPF 0.50
NSIP 0.38
RBILD/DIP 0.30
COP 0.37
EAA 0.59
Sarcoidosis 0.62
Overall 0.48
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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

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Accuracy of HRCT Diagnosis in IPF

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

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History, physical exam, clinical chemistry, PFT,
Chest Xray
Not IIP
Possible IIP
HRCT
Typical of IPF (50)
suggestive of
Other ILD ?
Ø
IPF (50)
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
Ø
IIP
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to assess disease activity
Biopsy is necessary in IPF
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UIP fibroblast foci
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Fibroblastic foci in UIP

• Extent Of Fibroblastic foci Predict Mortality In
  Idiopathic Pulmonary Fibrosis T.E. King Jr.,
  AJRCCM 20011641025-32.
• 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 2006611091-5.

Site of initial injury that triggers fibrosing
process?
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Survival in IPF patients categorised by
fibroblastic foci score in the lung biopsy
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to predict prognosis and to identify a more
treatable process than originally suspected
Biopsy is necessary in IPF
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IPF worst case of an ILD
100
80
60
Other
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NSIP
20
IPF
0
0
2
4
6
8
10
12
14
16
18
Years
Bjoraker JA Am J Respir Crit Care Med.
1998157199
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BypNSIP HRCTNSIP/Udtm
100
80
BypUIP , HRCTNSIP/Udtm
Bx-Diagnosis NSIP n 23, UIP n
73 HRCT-Diagnosis NSIP n 44, UIP n 27
Udtm n 25
60
Cumulative proportion surviving
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BypUIP HRCTUIP
20
0
0
6
8
10
2
4
Follow up Time (years)
Flaherty et al., Thorax, 2003
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UIP pattern (histology vs HRCT) Flaherty et al
Thorax 2003
(median survival in years)

• 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 gt9
• Pattern of UIP on HRCT or Bx poorer prognosis
  in IPF

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to recognise purer cohorts of patients with
regard investigation of cause and treatment
strategies
Biopsy is necessary in IPF
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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
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Biopsy may be necessary in ILDto exclude
neoplastic and infectious processes that
occasionally mimic chronic, progressive
interstitial disease
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Conditions mistaken for ILD

• Infection
• Cancer
• Lymphoma
• BAC
• lymphangitis carcinomatosa

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Does the interactive diagnostic process improve
the interobserver agreement?
Idiopathic Interstitial Pneumonia What 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
Am J Respir Crit Care Med Vol 170. pp 904910,
2004
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Organisational Scheme (Review of 58 cases)
Information provided Type of decision Participants Output
Step 1 HRCT Invidual Clinicians Radiologists First Diagnosis Confidence
Step 2 HRCT clinical data Invidual Clinicians Radiologists Diagnosis Confidence
Step 3 HRCT clinical data Group Clinicians Radiologists Diagnosis Confidence
Step 4 HRCT clinical data surgical biopsy Group Clinicians Radiologists Pathologists Diagnosis Confidence
Step 5 HRCT clinical data surgical biopsy Group Clinicians Radiologists Pathologists Consensus Diagnosis Confidence
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Interobserver agreement at each diagnostic step
Step Clinicians ? (95 CI) Radiologists ? (95 CI) CliniciansRadiologists ? (95 CI) All Observers ? (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)
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Interobserver agreement at each diagnostic step
Step Clinicians ? (95 CI) Radiologists ? (95 CI) CliniciansRadiologists ? (95 CI) All Observers ? (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)
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Idiopathic Interstitial Pneumonia Do 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
AJRCCM 2007 175 1054 1060
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Final Diagnosis AgreementDifferent among
Community/Academic Physicians?

• n 39 pat. with ILD, retrospective review
• Agreement in final diagnosis among 6 groups
  academic/community clinicians/radiologists/path
  ologists
• Final agreement was better within academic
  centers (kappa 0.55 to 0.71) than within
  community centers (kappa 0.32 to 0.44)

Flaherty KR, et al. AJRCCM 2007 175 1054
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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

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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
• DLCOlt50 mortality 11 vs 1.4
• Park JH et al, Eur J
  Cardiothorac Surg 2007

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Biopsy is necessary for the diagnosis of IPF
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