Hamlet’s Delight
New Guidelines for IPF
CRC 2011
Ted Marras, MD FRCPC
Toronto Western Hospital / University Health Network
Declarations
Potential conflicts of interest
Financial
– Study participation: Actelion, BoehringerIngelheim, 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
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
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)
IPF - HRCT
Peripheral, basal predominant:
• Reticulations, interlobular septal thickening,
intralobular reticulations
• Honeycombing
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.
IPF - Natural history
Raghu AJRCCM
183.788-824. 2011
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, 183:788-824
Recommendations
Reviewed published data
Recommendations on questions
• Direction – yes / no
• Strength – strong / weak
• Evidence quality
Voted on by committee members
Recommendations
Raghu et al. AJRCCM 2011, 183:788-824
Recommendations
Raghu et al. AJRCCM 2011, 183:788-824
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
Diagnosis
Excluding Connective Tissue Disease
• Should a CTD serologic evaluation be
performed in all people with suspected IPF?
• No reliable data
Diagnosis
Excluding Connective Tissue Disease
• Should a CTD serologic evaluation be
performed in all people with suspected IPF?
• No reliable data
Recommendation
Question
CTD
serology?
Direction
Strength
Evidence
quality
Yes
Weak
Very low
Vote
Yes/No/Abs
23/0/0
Even in absence of overt CTD: RF, anti-CCP, ANA
(ENA – Jo-1, Scl-70, etc. may be helpful)
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?
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?
Recommendation
Question
Vote
Yes/No/Abs
Direction
Strength
Evidence
quality
BAL?
No
Weak
Low
4/18/1
TBBx?
No
Weak
Low
0/23/0
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?
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?
Recommendation
Question
MDD?
Direction
Strength
Evidence
quality
Yes
Strong
Low
Vote
Yes/No/Abs
0/23/0
• Not possible for many practitioners
• Efforts to promote verbal communication should be made
Diagnosis
Consider:
• Clinical
• Radiology - HRCT
• Histology - surgical lung biopsy
Diagnosis
HRCT
Relevant features
1. Distribution subpleural / basal predominant
2. Reticulation
3. Honeycombing + traction bronchiectasis
4. Absence of inconsistent features:
–
–
–
–
–
–
–
Upper lobe predominant
Peribronchial predominant
GGO > reticulation
Profuse micronodules
Discrete cysts – multiple, bilateral, away from HC
Diffuse mosaicism
Consolidation
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)
1.
2.
3.
4.
Subpleural / basal
Reticulation
Honeycombing + traction bronchiectasis
Absence of inconsistent features
Diagnosis
Histology
Relevant features
1. Fibrosis + subpleural / paraseptal HC
2. Patchy
3. Fibroblast foci
4. Absence of inconsistent features:
–
–
–
–
–
Hyaline membranes
Organizing pneumonia
Granulomas
Marked inflammation away from HC
Predominantly airway centred
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)
1.
2.
3.
4.
Fibrosis + subpleural / paraseptal HC
Patchy
Fibroblast foci
Absence of inconsistent features
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
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
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
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
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
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
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
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
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
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
Diagnosis
Suspected IPF
Identifiable cause?
yes
Not IPF
Diagnosis
Suspected IPF
Identifiable cause?
no
HRCT
UIP
IPF
yes
Not IPF
Diagnosis
Suspected IPF
Identifiable cause?
yes
no
HRCT
possible UIP or
inconsistent with UIP
UIP
Surgical Biopsy
IPF
Not IPF
Diagnosis
Suspected IPF
Identifiable cause?
yes
Not IPF
no
HRCT
possible UIP or
inconsistent with UIP
UIP
Surgical Biopsy
IPF
Not
UIP
Diagnosis
Suspected IPF
Identifiable cause?
yes
Not IPF
no
HRCT
possible UIP or
inconsistent with UIP
UIP
Surgical Biopsy
IPF
Not
UIP
UIP, probable,
possible
See table
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
IPF Treatment
Recommendation
Treatment
Vote
Yes/No/Abs
Direction
Strength
Evidence
quality
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
IPF Treatment
Recommendation
Treatment
Vote
Yes/No/Abs
Direction
Strength
Evidence
quality
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
IPF Treatment
Recommendation
Treatment
Vote
Yes/No/Abs
Direction
Strength
Evidence
quality
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
IPF Treatment
Recommendation
Treatment
Vote
Yes/No/Abs
Direction
Strength
Evidence
quality
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
IPF Treatment
Recommendation
Treatment
Vote
Yes/No/Abs
Direction
Strength
Evidence
quality
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
IPF Treatment
Recommendation
Treatment
Vote
Yes/No/Abs
Direction
Strength
Evidence
quality
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
IPF Treatment
Recommendation
Treatment
Vote
Yes/No/Abs
Direction
Strength
Evidence
quality
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
IPF Treatment
Recommendation
Treatment
Vote
Yes/No/Abs
Direction
Strength
Evidence
quality
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
IPF Treatment
Recommendation
Treatment
Vote
Yes/No/Abs
Direction
Strength
Evidence
quality
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
“Nonpharmacologic” Treatment
Recommendation
Treatment
Vote
Yes/No/Abs
Direction
Strength
Evidence
quality
Pulmonary
rehabilitation
Yes
Weak
Low
19 / 0 / 3
Oxygen
Yes
Strong
Very low
18 / 0 / 4
Transplantation
Yes
Strong
Low
21 / 0 / 1
Transplant
Who to consider?
Discuss at diagnosis
Detailed evaluation:
• Advanced at diagnosis
• With objective deterioration
Transplant
Who to consider?
Discuss at diagnosis
Detailed evaluation:
• Advanced at diagnosis
• With objective deterioration
Baseline
Longitudinal
•
•
•
•
•
•
•
•
Severe dyspnea
DLCO<40%
6MW SaO2 < 88%
Extensive HC on HRCT
Increasing dyspnea
FVC decrease >10%*
DLCO decrease >15%*
Progression on HRCT
* Absolute measure
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 < 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
Additional Treatment
Recommendation
Treatment
Vote
Yes/No/Abs
Direction
Strength
Evidence
quality
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
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
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. 510% FVC decline)
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)