Hamlet

1
Hamlets DelightNew Guidelines for IPF

• CRC 2011
• Ted Marras, MD FRCPC
• Toronto Western Hospital / University Health
  Network

2
Declarations

• Potential conflicts of interest
• Financial
• Study participation Actelion, Boehringer-Ingelhei
  m, Gilead, Intermune
• Grant support CPFF, CIHR
• Other
• Clinical and academic interest in ILD
• Off label use of therapies
• None of the medications mentioned have a formal
  indication for treating IPF

3
Objectives

• Considering revised guidelines for idiopathic
  pulmonary fibrosis (IPF)
• 1. Consider appropriate investigations and
  diagnostic algorithm for IPF
• 2. Select a management strategy that is most
  appropriate for a given IPF patient
• 3. Select an appropriate strategy of clinical
  follow-up for a given IPF patient

4
IPF

• What is it?
• Chronic, progressive fibrosis of the lung
• Unknown cause
• Why is it bad?
• Stiff lung ? dyspnea
• Scarred lung ? poor gas exchange
• Poor prognosis (difficult to quantify)

5
IPF - HRCT

• Peripheral, basal predominant
• Reticulations, interlobular septal thickening,
  intralobular reticulations
• Honeycombing

6
IPF - Histology UIP
A) Heterogeneity, traction emphysema B)
Subpleural fibrosis, fibroblast foci C)
Fibroblast focus D) Microscopic
honeycombing Raghu. Clin Chest Med 2004.
25(4)621-36.
7
IPF - Natural history
Raghu AJRCCM 183.788-824. 2011
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ATS / ERS / JRS / ALAT

• Provide evidence- based recommendations on
  diagnosis and management of IPF
• Joint Taskforce
• 22 Pulmonary physicians
• 4 Chest radiologists
• 4 Lung pathologists
• 3 Health care librarians
• 1 Expert methodologist (respirologist)
• Raghu et al. AJRCCM 2011, 183788-824

9
Recommendations

• Reviewed published data
• Recommendations on questions
• Direction yes / no
• Strength strong / weak
• Evidence quality
• Voted on by committee members

10
Recommendations
Raghu et al. AJRCCM 2011, 183788-824
11
Recommendations
Raghu et al. AJRCCM 2011, 183788-824
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Objectives

• Considering revised guidelines for idiopathic
  pulmonary fibrosis (IPF)
• 1. Consider appropriate investigations and
  diagnostic algorithm for IPF
• 2. Select a management strategy that is most
  appropriate for a given IPF patient
• 3. Select an appropriate strategy of clinical
  follow-up for a given IPF patient

13
Diagnosis Excluding Connective Tissue Disease

• Should a CTD serologic evaluation be performed in
  all people with suspected IPF?
• No reliable data

14
Diagnosis Excluding Connective Tissue Disease

• Should a CTD serologic evaluation be performed in
  all people with suspected IPF?
• No reliable data

Question Recommendation Recommendation Recommendation Vote Yes/No/Abs
Question Direction Strength Evidence quality Vote Yes/No/Abs
CTD serology? Yes Weak Very low 23/0/0
Even in absence of overt CTD RF, anti-CCP,
ANA (ENA Jo-1, Scl-70, etc. may be helpful)
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Diagnosis Utility of BAL /
TBBx

• BAL may help differentiate HP
• TBBx may help with granulomatous disorders
• Should BAL / TBBx be performed in all people with
  suspected IPF?

16
Diagnosis Utility of BAL /
TBBx

• BAL may help differentiate HP
• TBBx may help with granulomatous disorders
• Should BAL / TBBx be performed in all people with
  suspected IPF?

Question Recommendation Recommendation Recommendation Vote Yes/No/Abs
Question Direction Strength Evidence quality Vote Yes/No/Abs
BAL? No Weak Low 4/18/1
TBBx? No Weak Low 0/23/0
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Diagnosis Multi-disciplinary discussion
(MDD)

• IPF diagnosis usually requires expertise from
  clinicians, radiologists, pathologists
• Proper communication increases inter-observer
  agreement
• Should MDD be used in evaluating suspected IPF?

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Diagnosis Multi-disciplinary discussion
(MDD)

• IPF diagnosis usually requires expertise from
  clinicians, radiologists, pathologists
• Proper communication increases inter-observer
  agreement
• Should MDD be used in evaluating suspected IPF?

Question Recommendation Recommendation Recommendation Vote Yes/No/Abs
Question Direction Strength Evidence quality Vote Yes/No/Abs
MDD? Yes Strong Low 0/23/0

• Not possible for many practitioners
• Efforts to promote verbal communication should be
  made

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Diagnosis

• Consider
• Clinical
• Radiology - HRCT
• Histology - surgical lung biopsy

20
Diagnosis
HRCT

• Relevant features
• Distribution subpleural / basal predominant
• Reticulation
• Honeycombing traction bronchiectasis
• Absence of inconsistent features
• Upper lobe predominant
• Peribronchial predominant
• GGO gt reticulation
• Profuse micronodules
• Discrete cysts multiple, bilateral, away from
  HC
• Diffuse mosaicism
• Consolidation

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Diagnosis
HRCT

• HRCT classification for suspected IPF
• UIP pattern (1,2,3,4)
• Possible UIP pattern (1,2,4)
• Inconsistent with UIP (4 not fulfilled)
• Subpleural / basal
• Reticulation
• Honeycombing traction bronchiectasis
• Absence of inconsistent features

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Diagnosis
Histology

• Relevant features
• Fibrosis subpleural / paraseptal HC
• Patchy
• Fibroblast foci
• Absence of inconsistent features
• Hyaline membranes
• Organizing pneumonia
• Granulomas
• Marked inflammation away from HC
• Predominantly airway centred

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Diagnosis
Histology

• Histologic classification for suspected IPF
• UIP pattern (1,2,3,4)
• Probable UIP pattern (1 and 2 or 3 and 4) or HC
  only
• Possible UIP pattern (1,4)
• Not UIP pattern (4 not fulfilled)
• Fibrosis subpleural / paraseptal HC
• Patchy
• Fibroblast foci
• Absence of inconsistent features

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Diagnosis HRCT /
Histology
HRCT Surgical biopsy IPF?
UIP Not done (clinically typical) UIP / Probable / Possible Not UIP Yes Yes No
Consistent with UIP (lack HC / traction bronchiectasis) UIP / Probable Possible UIP Not UIP Yes Probable No
Inconsistent with UIP (inconsistent features) UIP All others Possible No
Multidisciplinary discussion recommended
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Diagnosis HRCT /
Histology
HRCT Surgical biopsy IPF?
UIP Not done (clinically typical) Not UIP Yes Yes No
Consistent with UIP (lack HC / traction bronchiectasis) UIP / Probable Possible UIP Not UIP Yes Probable No
Inconsistent with UIP (inconsistent features) UIP All others Possible No
Multidisciplinary discussion recommended
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Diagnosis HRCT /
Histology
HRCT Surgical biopsy IPF?
UIP Not done (clinically typical) UIP / Probable / Possible Not UIP Yes Yes
Consistent with UIP (lack HC / traction bronchiectasis) UIP / Probable Possible UIP Not UIP Yes Probable No
Inconsistent with UIP (inconsistent features) UIP All others Possible No
Multidisciplinary discussion recommended
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Diagnosis HRCT /
Histology
HRCT Surgical biopsy IPF?
UIP Not done (clinically typical) UIP / Probable / Possible Not UIP Yes Yes No
Consistent with UIP (lack HC / traction bronchiectasis) UIP / Probable Possible UIP Not UIP Yes Probable No
Inconsistent with UIP (inconsistent features) UIP All others Possible No
Multidisciplinary discussion recommended
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Diagnosis HRCT /
Histology
HRCT Surgical biopsy IPF?
UIP Not done (clinically typical) UIP / Probable / Possible Not UIP Yes Yes No
Possible UIP (lack HC) UIP / Probable Possible UIP Not UIP Yes Probable No
Inconsistent with UIP (inconsistent features) UIP All others Possible No
Multidisciplinary discussion recommended
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Diagnosis HRCT /
Histology
HRCT Surgical biopsy IPF?
UIP Not done (clinically typical) UIP / Probable / Possible Not UIP Yes Yes No
Possible UIP (lack HC) UIP / Probable Possible UIP Not UIP Yes Probable No
Inconsistent with UIP (inconsistent features) UIP All others Possible No
Multidisciplinary discussion recommended
30
Diagnosis HRCT /
Histology
HRCT Surgical biopsy IPF?
UIP Not done (clinically typical) UIP / Probable / Possible Not UIP Yes Yes No
Possible UIP (lack HC) UIP / Probable Possible UIP Not UIP Yes Probable No
Inconsistent with UIP (inconsistent features) UIP All others Possible No
Multidisciplinary discussion recommended
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Diagnosis HRCT /
Histology
HRCT Surgical biopsy IPF?
UIP Not done (clinically typical) UIP / Probable / Possible Not UIP Yes Yes No
Possible UIP (lack HC) UIP / Probable Possible UIP Not UIP Yes Probable No
Inconsistent with UIP (inconsistent features) UIP All others Possible No
Multidisciplinary discussion recommended
32
Diagnosis HRCT /
Histology
HRCT Surgical biopsy IPF?
UIP Not done (clinically typical) UIP / Probable / Possible Not UIP Yes Yes No
Possible UIP (lack HC) UIP / Probable Possible UIP Not UIP Yes Probable No
Inconsistent with UIP (inconsistent features) UIP All others Possible No
Multidisciplinary discussion recommended
33
Diagnosis HRCT /
Histology
HRCT Surgical biopsy IPF?
UIP Not done (clinically typical) UIP / Probable / Possible Not UIP Yes Yes No
Possible UIP (lack HC) UIP / Probable Possible UIP Not UIP Yes Probable No
Inconsistent with UIP (inconsistent features) UIP All others Possible No
Multidisciplinary discussion recommended
34
Diagnosis
Suspected IPF
yes
Identifiable cause?
Not IPF
35
Diagnosis
Suspected IPF
yes
Identifiable cause?
Not IPF
no
HRCT
UIP
IPF
36
Diagnosis
Suspected IPF
yes
Identifiable cause?
Not IPF
no
HRCT
possible UIP or inconsistent with UIP
UIP
Surgical Biopsy
IPF
37
Diagnosis
Suspected IPF
yes
Identifiable cause?
Not IPF
no
HRCT
possible UIP or inconsistent with UIP
Not UIP
UIP
Surgical Biopsy
IPF
38
Diagnosis
Suspected IPF
yes
Identifiable cause?
Not IPF
no
HRCT
possible UIP or inconsistent with UIP
Not UIP
UIP
Surgical Biopsy
UIP, probable, possible
IPF
See table
39
Objectives

• Considering revised guidelines for idiopathic
  pulmonary fibrosis (IPF)
• 1. Consider appropriate investigations and
  diagnostic algorithm for IPF
• 2. Select a management strategy that is most
  appropriate for a given IPF patient
• 3. Select an appropriate strategy of clinical
  follow-up for a given IPF patient

40
IPF Treatment
Treatment Recommendation Recommendation Recommendation Vote Yes/No/Abs
Treatment Direction Strength Evidence quality Vote Yes/No/Abs
Steroids alone No Strong Very low 0 / 21 / 2
Colchicine No Strong Very low 0 / 21 / 2
Cyclosporine No Strong Very low 0 / 18 / 4
Steroid Aza / CY No Strong Low 0 / 21 / 2
Steroid Aza NAC No Weak Low 3 / 17 / 3
NAC alone No Weak Low 5 / 15 / 3
IFN gamma No Strong High 0 / 17 / 6
Bosentan No Strong Moderate 0 / 10 / 13
Etanercept No Strong Moderate 0 / 18 / 4
Anticoagulation No Weak Very low 1 / 20 / 2
Pirfenidone No Weak Low-mod 4 / 10 / 17
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IPF Treatment
Treatment Recommendation Recommendation Recommendation Vote Yes/No/Abs
Treatment Direction Strength Evidence quality Vote Yes/No/Abs
Steroids alone No Strong Very low 0 / 21 / 2
Colchicine No Strong Very low 0 / 21 / 2
Cyclosporine No Strong Very low 0 / 18 / 4
Steroid Aza / CY No Strong Low 0 / 21 / 2
Steroid Aza NAC No Weak Low 3 / 17 / 3
NAC alone No Weak Low 5 / 15 / 3
IFN gamma No Strong High 0 / 17 / 6
Bosentan No Strong Moderate 0 / 10 / 13
Etanercept No Strong Moderate 0 / 18 / 4
Anticoagulation No Weak Very low 1 / 20 / 2
Pirfenidone No Weak Low-mod 4 / 10 / 17
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IPF Treatment
Treatment Recommendation Recommendation Recommendation Vote Yes/No/Abs
Treatment Direction Strength Evidence quality Vote Yes/No/Abs
Steroids alone No Strong Very low 0 / 21 / 2
Colchicine No Strong Very low 0 / 21 / 2
Cyclosporine No Strong Very low 0 / 18 / 4
Steroid Aza / CY No Strong Low 0 / 21 / 2
Steroid Aza NAC No Weak Low 3 / 17 / 3
NAC alone No Weak Low 5 / 15 / 3
IFN gamma No Strong High 0 / 17 / 6
Bosentan No Strong Moderate 0 / 10 / 13
Etanercept No Strong Moderate 0 / 18 / 4
Anticoagulation No Weak Very low 1 / 20 / 2
Pirfenidone No Weak Low-mod 4 / 10 / 17
Small physiologic benefit, may have significant
toxicities
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IPF Treatment
Treatment Recommendation Recommendation Recommendation Vote Yes/No/Abs
Treatment Direction Strength Evidence quality Vote Yes/No/Abs
Steroids alone No Strong Very low 0 / 21 / 2
Colchicine No Strong Very low 0 / 21 / 2
Cyclosporine No Strong Very low 0 / 18 / 4
Steroid Aza / CY No Strong Low 0 / 21 / 2
Steroid Aza NAC No Weak Low 3 / 17 / 3
NAC alone No Weak Low 5 / 15 / 3
IFN gamma No Strong High 0 / 17 / 6
Bosentan No Strong Moderate 0 / 10 / 13
Etanercept No Strong Moderate 0 / 18 / 4
Anticoagulation No Weak Very low 1 / 20 / 2
Pirfenidone No Weak Low-mod 4 / 10 / 17
Limited data, safe, maybe cheap preparation
not standardized
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IPF Treatment
Treatment Recommendation Recommendation Recommendation Vote Yes/No/Abs
Treatment Direction Strength Evidence quality Vote Yes/No/Abs
Steroids alone No Strong Very low 0 / 21 / 2
Colchicine No Strong Very low 0 / 21 / 2
Cyclosporine No Strong Very low 0 / 18 / 4
Steroid Aza / CY No Strong Low 0 / 21 / 2
Steroid Aza NAC No Weak Low 3 / 17 / 3
NAC alone No Weak Low 5 / 15 / 3
IFN gamma No Strong High 0 / 17 / 6
Bosentan No Strong Moderate 0 / 10 / 13
Etanercept No Strong Moderate 0 / 18 / 4
Anticoagulation No Weak Very low 1 / 20 / 2
Pirfenidone No Weak Low-mod 4 / 10 / 17
Supportive study, several limitations
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IPF Treatment
Treatment Recommendation Recommendation Recommendation Vote Yes/No/Abs
Treatment Direction Strength Evidence quality Vote Yes/No/Abs
Steroids alone No Strong Very low 0 / 21 / 2
Colchicine No Strong Very low 0 / 21 / 2
Cyclosporine No Strong Very low 0 / 18 / 4
Steroid Aza / CY No Strong Low 0 / 21 / 2
Steroid Aza NAC No Weak Low 3 / 17 / 3
NAC alone No Weak Low 5 / 15 / 3
IFN gamma No Strong High 0 / 17 / 6
Bosentan No Strong Moderate 0 / 10 / 13
Etanercept No Strong Moderate 0 / 18 / 4
Anticoagulation No Weak Very low 1 / 20 / 2
Pirfenidone No Weak Low-mod 4 / 10 / 17
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IPF Treatment
Treatment Recommendation Recommendation Recommendation Vote Yes/No/Abs
Treatment Direction Strength Evidence quality Vote Yes/No/Abs
Steroids alone No Strong Very low 0 / 21 / 2
Colchicine No Strong Very low 0 / 21 / 2
Cyclosporine No Strong Very low 0 / 18 / 4
Steroid Aza / CY No Strong Low 0 / 21 / 2
Steroid Aza NAC No Weak Low 3 / 17 / 3
NAC alone No Weak Low 5 / 15 / 3
IFN gamma No Strong High 0 / 17 / 6
Bosentan No Strong Moderate 0 / 10 / 13
Etanercept No Strong Moderate 0 / 18 / 4
Anticoagulation No Weak Very low 1 / 20 / 2
Pirfenidone No Weak Low-mod 4 / 10 / 17
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IPF Treatment
Treatment Recommendation Recommendation Recommendation Vote Yes/No/Abs
Treatment Direction Strength Evidence quality Vote Yes/No/Abs
Steroids alone No Strong Very low 0 / 21 / 2
Colchicine No Strong Very low 0 / 21 / 2
Cyclosporine No Strong Very low 0 / 18 / 4
Steroid Aza / CY No Strong Low 0 / 21 / 2
Steroid Aza NAC No Weak Low 3 / 17 / 3
NAC alone No Weak Low 5 / 15 / 3
IFN gamma No Strong High 0 / 17 / 6
Bosentan No Strong Moderate 0 / 10 / 13
Etanercept No Strong Moderate 0 / 18 / 4
Anticoagulation No Weak Very low 1 / 20 / 2
Pirfenidone No Weak Low-mod 4 / 10 / 17
48
IPF Treatment
Treatment Recommendation Recommendation Recommendation Vote Yes/No/Abs
Treatment Direction Strength Evidence quality Vote Yes/No/Abs
Steroids alone No Strong Very low 0 / 21 / 2
Colchicine No Strong Very low 0 / 21 / 2
Cyclosporine No Strong Very low 0 / 18 / 4
Steroid Aza / CY No Strong Low 0 / 21 / 2
Steroid Aza NAC No Weak Low 3 / 17 / 3
NAC alone No Weak Low 5 / 15 / 3
IFN gamma No Strong High 0 / 17 / 6
Bosentan No Strong Moderate 0 / 10 / 13
Etanercept No Strong Moderate 0 / 18 / 4
Anticoagulation No Weak Very low 1 / 20 / 2
Pirfenidone No Weak Low-mod 4 / 10 / 17
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Nonpharmacologic Treatment
Treatment Recommendation Recommendation Recommendation Vote Yes/No/Abs
Treatment Direction Strength Evidence quality Vote Yes/No/Abs
Pulmonary rehabilitation Yes Weak Low 19 / 0 / 3
Oxygen Yes Strong Very low 18 / 0 / 4
Transplantation Yes Strong Low 21 / 0 / 1
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Transplant Who to
consider?

• Discuss at diagnosis
• Detailed evaluation
• Advanced at diagnosis
• With objective deterioration

51
Transplant Who to
consider?

• Discuss at diagnosis
• Detailed evaluation
• Advanced at diagnosis
• With objective deterioration

• Baseline
• Severe dyspnea
• DLCOlt40
• 6MW SaO2 lt 88
• Extensive HC on HRCT

• Longitudinal
• Increasing dyspnea
• FVC decrease gt10
• DLCO decrease gt15
• Progression on HRCT

Absolute measure
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Additional Treatment - Acute exacerbations

• AEIPF - Definition
• Acute, clinically significant deterioration of
  unidentifiable cause in a patient with underlying
  IPF
• Diagnostic Criteria
• IPF with unexplained worsening lt 30 days
• HRCT new bilateral GGO and/or consolidation
  superimposed on typical IPF pattern
• No infection by tracheal aspirate or BAL
• Exclude CHF, PE, identifiable acute lung injury
  cause

53
Additional Treatment
Treatment Recommendation Recommendation Recommendation Vote Yes/No/Abs
Treatment Direction Strength Evidence quality Vote Yes/No/Abs
Steroids in AEIPF Yes Weak Very Low 14 / 5 / 1
Mechanical ventilation No Weak Low 2 / 19 / 1
Pulmonary hypertension No Weak Very low 8 / 14 / 1
Asymptomatic GERD Yes Weak Very low 15 / 8 / 0
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Objectives

• Considering revised guidelines for idiopathic
  pulmonary fibrosis (IPF)
• 1. Consider appropriate investigations and
  diagnostic algorithm for IPF
• 2. Select a management strategy that is most
  appropriate for a given IPF patient
• 3. Select an appropriate strategy of clinical
  follow-up for a given IPF patient

55
Monitoring for progression

• Routine PFT
• Sustained change in absolute
• FVC of 10 (e.g. 2L?1.8L)
• DLCO of 15
• (Both associated with mortality, suggestive of
  progression)
• Smaller progressive, sustained changes MAY be
  relevant (e.g. 5-10 FVC decline)

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(No Transcript)
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Monitoring for progression

• Routine PFT
• Sustained change in absolute
• FVC of 10 (e.g. 2L?1.8L)
• DLCO of 15
• (Both associated with mortality, suggestive of
  progression)
• 6MW distance / oximetry too variable over long
  time periods (good discriminative test, not a
  good evaluative test)