Download IPF Diagnostic Methods and Differential Diagnosis” slide kit

IPF DIAGNOSTIC METHODS AND
DIFFERENTIAL DIAGNOSIS
CONTENT
Importance of early diagnosis
IPF diagnosis based on HRCT
Initial clues to suspect IPF
Risks and benefits of surgical lung biopsy
Guidelines for Diagnosis
Histopathologic criteria for UIP pattern
Diagnostic algorithm for IPF
Combining patterns in the diagnosis of IPF
Exclusion of other known causes
Patient population in clinical trials: ASCEND
Other tests and tools
Patient population in clini cal trials: INPULSIS®
HRCT criteria for UIP pattern
References
IMPORTANCE OF EARLY DIAGNOSIS
• Diagnosis of idiopathic pulmonary fibrosis (IPF)
remains challenging and is often delayed1,2
Survival from the time of evaluation adjusted
for age and FVC across quartiles of delay4
• On average, diagnosis is delayed 1-2 years from
onset of symptoms1,2
• About 50% of IPF patients are initially
misdiagnosed for aging, cardiac disease,
emphysema, bronchitis, asthma or COPD2,3
• Early and accurate diagnosis is necessary to
help ensure timely access to appropriate
interventions4
• A delay in diagnosis and proper treatments
results in higher risk of death independent of the
severity of the disease.4
1. Schoenheit G, et al. Chron Respir Dis 2011;8:225–231. 2. Collard HR, et al. Respir Med 2007;101:1350–1354.
3. Meltzer EB, et al. Orphanet J Rare Dis 2008;3:8. 4. Lamas DJ, et al. Am J Respir Crit Care Med 2011;184:842–847.
INITIAL CLUES TO SUSPECT IPF
Patients with IPF may present the following symptoms:
Non-productive,
dry and hacking
cough1,2
Unexplained
dyspnoea
on exertion1-3
Bibasilar
inspiratory
velcro crackles2
Finger
clubbing1,2
Restrictive
pattern on
pulmonary
function tests5
1. Schoenheit G, et al. Chron Respir Dis 2011;8:225–231. 2. Meltzer EB, et al. Orphanet J Rare Dis 2008;3:8.
3. Lamas DJ, et al. Am J Respir Crit Care Med 2011;184:842–847. 4. Kim DS, et al. Proc Am Thorac Soc 2006;3:285–292.
GUIDELINES FOR DIAGNOSIS
According to current guidelines (ATS/ERS/JRS/ALAT 2011)
a diagnosis of IPF requires the following diagnostic criteria:1
The presence of a usual interstitial pneumonia (UIP) pattern on high-resolution
computed tomography (HRCT) in patients not subjected to surgical lung biopsy
Exclusion of other known interstitial lung diseases (ILDs) (e.g., domestic and
occupational environmental exposures, connective tissue disease, and drug toxicity)
Specific combinations of HRCT and surgical lung biopsy pattern in patients
subjected to surgical lung biopsy
1. Raghu G, et al. Am J Respir Crit Care Med 2011;183:788–824.
DIAGNOSTIC ALGORITHM FOR IPF
Based on these criteria, the
2011 guidelines
(ATS/ERS/JRS/ALAT) provide
a diagnostic algorithm for
clinicians to follow for the best
possible standard in
diagnosing IPF.1
Suspected IPF
Yes
Identifiable causes for ILD?
No?
HRCT
UIP*
Possible UIP*
Inconsistent w/ UIP*
Surgical Lung Biopsy
Not UIP†
UIP†
Probable UIP†/Possible UIP†
Non-classifiable †
MDD
IPF
IPF/Not IPF per Table 6
1. Raghu G, et al. Am J Respir Crit Care Med 2011;183:788–824.
Not IPF
EXCLUSION OF OTHER KNOWN CAUSES
Given the fact that early symptoms of IPF
are often non-specific and can also occur in
other ILDs or respiratory diseases, it is of
particular importance to exclude known
causes of ILD, due to differences in
prognosis and treatment responses . This is
done by obtaining a careful medical history
and physical examination.1-4
The medical history and examination
should focus on:
Medical history
 Medication use
 Previous or
concurrent illness
 Environmental or
occupational
exposures
 Smoking history
 Family history of
respiratory diseases
Physical
examination
 Auscultation
 Finger clubbing
 Extrapulmonary
signs
1. Meltzer EB, et al. Orphanet J Rare Dis 2008;3:8.
2. Raghu G, et al. Am J Respir Crit Care Med 2011;183:788–824. 3. Ryu JH, et al. Mayo Clin Proc 2007;82:976–986.
4. American Thoracic Society. Am J Respir Crit Care Med 2000;161:646–664.
OTHER TESTS AND TOOLS
Bronchoalveolar lavage (BAL) cellular
analysis
Serologic testing for connective tissue
disease
• The 2011 guidelines recommend, however, that
BAL cellular analysis should not be performed in
the diagnostic evaluation of IPF in the majority of
individuals, but may be appropriate for a
minority.1
• Serologic testing is valuable to rule out
connective tissue disease, as this may present
with UIP pattern.2
• BAL cellular analysis may be useful in excluding
other conditions, especially chronic
hypersensitivity pneumonitis which may mimic
IPF.2
• Tests should include rheumatoid factor, anticyclic citrullinated peptide, and anti-nuclear
antibody titer and pattern.1,2
• Serologic evaluation should be performed even
in the absence of signs or symptoms of
connective tissue disease.1,2
• The evidence regarding whether or not BAL
generally increases accuracy of IPF diagnosis is
currently still unclear.1
1. Raghu G, et al. Am J Respir Crit Care Med 2011;183:788–824.
2. Du Bois RM. Eur Respir Rev 2012;21:141–146.
HRCT CRITERIA FOR UIP PATTERN
Since the past years,
HRCT has become
central to the
diagnostic pathway of
IPF.1
HRCT provides critical
data needed to
determine whether
surgical lung biopsy or
further tests are
required to achieve a
specific diagnosis of
IPF.2
UIP pattern1
Possible UIP pattern1
Inconsistent with UIP1
All 4 features
All 3 features
Any of the 7 features
 Subpleural, basal predominance
 Subpleural, basal predominance
 Upper or mid-lung predominance
 Reticular abnormality
 Reticular abnormality
 Absence of features listed in the
“not UIP pattern” section
 Absence of features listed in the
“not UIP pattern” section
 Peribronchovascular
predominance
 Honeycombing with or without
traction bronchiectasis
 Extensive ground-glass
abnormality (extent > reticular
abnormality)
 Profuse micronodules (bilateral,
predominantly upper lobes)
 Discrete cysts (multiple, bilateral,
away from areas of
honeycombing)
 Diffuse mosaic attenuation/airtrapping (bilateral, in ≥3 lobes)
 Consolidation in
bronchopulmonary
segment(s)/lobe(s)
1. Raghu G, et al. Am J Respir Crit Care Med 2011;183:788–824.
2. Ryu JH, et al. Mayo Clin Proc 2007;82:976–986.
IPF DIAGNOSIS BASED ON HRCT
UIP pattern:
In conjunction with the exclusion of other known
causes of ILDs, the evidence of a UIP pattern on
HRCT is considered sufficient for a definitive
diagnosis of IPF.1
Possible UIP pattern:
According with 2011 guidelines, if HRCT findings
yield a possible UIP pattern, lung biopsy may be
necessary to confirm the diagnosis of IPF.1
If patients with a possible UIP pattern on HRCT are
assessed by experienced experts, HRCT could be used for
the diagnosis of IPF and histological confirmation might not
be essential to obtain this diagnosis.2
In about two thirds of the cases IPF can be
diagnosed by clinical and radiological criteria.
Thus, surgical lung biopsy is needed in about one
third of cases to achieve the ultimate diagnosis,
which requires multidisciplinary cooperation.3
Surgical lung biopsy
needed for diagnosis
Diagnosis based on
radiological and
clinical findings
Inconsistent with UIP pattern:
HRCT results that are inconsistent with a UIP
pattern necessitate lung biopsy to make a
diagnosis.1
1. Raghu G, et al. Am J Respir Crit Care Med 2011;183:788–824.
2. Raghu G, et al. Lancet Respir Med 2014;2:277–284. 3. Kaarteenaho R. Respir Res 2013;14:43.
RISKS AND BENEFITS OF SURGICAL LUNG BIOPSY
Before deciding to
perform a lung
biopsy the
potential benefits
must be weighed
against the
potential risks.1
Benefits
Confirm a diagnosis if HRCT is
unclear or atypical1,2
Determination of cellular
characteristics of affected lung
tissue for prognosis2
Risks
Prolonged air leak (6-12%)3-5
Mortality (3-5%)3-5
Pneumonia3-5
Need for mechanical
ventilation4
Pneumothorax5
Haemothorax5
Increased risk of exacerbation
in patients diagnosed with
IPF3-5
1. Raghu G, et al. Am J Respir Crit Care Med 2011;183:788–824. 2. Kaarteenaho R. Respir Res 2013;14:43.
3. Park JH, et al. Eur J Cardiothorac Surg 2007;31:1115–11193. 4. Sigurdsson MI, et al. Ann Thorac Surg 2009;88:227–232.
5. Fibla JJ, et al. Interact Cardiovasc Thorac Surg 2012;15:276–279.
HISTOPATHOLOGICAL CRITERIA FOR UIP PATTERN
In order to narrow the diagnosis, biopsy results must meet certain criteria: 1
Definite UIP
Probable UIP
All 4 features
All 3 criteria
Evidence of marked
fibrosis/architectural
distortion, ± honeycombing
in a predominantly
subpleural/paraseptal
distribution
Evidence of marked
fibrosis/architectural
distortion, ± honeycombing
Presence of patchy
involvement of lung
parenchyma by fibrosis
Absence of features against
a diagnosis of UIP
suggesting an alternate
diagnosis (see “Not UIP”
tab)
Absence of either patchy
involvement or fibroblastic
foci, but not both
Presence of fibroblast foci
Absence of features against
a diagnosis of UIP
suggesting an alternate
diagnosis
Possible UIP
•
OR
Patchy or diffuse
involvement of lung
parenchyma by fibrosis,
with or without interstitial
inflammation
Absence of other criteria for
UIP (see “Definite UIP” tab)
Absence of features against
a diagnosis of UIP
suggesting an alternate
diagnosis (see “Not UIP”
tab)
Honeycomb changes only
1. Raghu G, et al. Am J Respir Crit Care Med 2011;183:788–824.
Not UIP
Any of the 6 criteria
Hyaline membranes
Organizing pneumonia
Granulomas
Marked interstitial
inflammatory cell infiltrate
away from honeycombing
Predominant airwaycentered changes
Other features suggestive of
an alternate diagnosis
COMBINING PATTERNS IN THE DIAGNOSIS OF IPF
Particularly in cases
of discordant
radiologic and
histopathologic
patterns a
multidisciplinary
discussion among
experienced
clinicians,
radiologists and
pathologists may
lead to a greater
diagnostic
clarification and
improve the accuracy
of diagnosis.1
Combination of HRCT and surgical lung biopsy for the diagnosis of IPF1
(requires multidisciplinary discussion)
HRCT pattern
UIP
Possible UIP
Inconsistent with UIP
Surgical lung biopsy pattern
UIP
Probable UIP
Possible UIP
Nonclassifiable fibrosis
Not UIP
UIP
Probable UIP
Possible UIP
Nonclassifiable fibrosis
Not UIP
UIP
Probable UIP
Possible UIP
Nonclassifiable fibrosis
Not UIP
Diagnosis of IPF?
Yes
Yes
Yes
Yes
No
Yes
Yes
Probable
Probable
No
Possible
No
No
No
No
Bold type indicates combinations of HRCT and surgical lung biopsy patterns that correspond with a diagnosis of IPF.
1. Raghu G, et al. Am J Respir Crit Care Med 2011;183:788–824.
PATIENT POPULATION IN CLINICAL TRIALS –
ASCEND TRIAL
Recent clinical trials that served as a basis for the approval of two new medications for IPF differed regarding their inclusion criteria.
The ASCEND study enrolled patients without a surgical biopsy only if they showed a definite UIP pattern on HRCT.
The following table of eligibility criteria shows that lack of definite pathologic or surgical evidence automatically led to exclusion from the
study in spite of a possible UIP pattern on HRCT:1
Surgical lung
biopsy
not available
Pathology panel:
definite UIP
Pathology panel:
probable UIP
Pathology panel:
possible UIP
Pathology panel:
Inconsistent w/
UIP or not
classifiable
Radiology panel:
Definite UIP
Eligible
Eligible
Eligible
Eligible
NOT Eligible
Radiology panel:
Possible UIP
NOT Eligible
Eligible
Eligible
NOT Eligible
NOT Eligible
Radiology panel:
Inconsistent with UIP
NOT Eligible
NOT Eligible
NOT Eligible
NOT Eligible
NOT Eligible
An inclusion also required the extent of fibrotic changes on HRCT scan (honeycombing, reticular changes) to be greater than the extent of emphysema. Features
supporting an alternative diagnosis led to exclusion from the trial. 15
1. King TE Jr, et al. N Engl J Med 2014;370:2083-92.
PATIENT POPULATION IN CLINICAL TRIALS –
INPULSIS® TRIALS
The INPULSIS® trials included patients with
a HRCT based definite and possible UIP
diagnosis where a surgical biopsy was not
available (see table).1 This way, a broader
patient population was eligible for enrolment
in INPULSIS® compared to ASCEND.
In cases where a surgical biopsy was
necessary and radiological and pathological
results were contradictory, two field experts
would discuss and reach a consensus as to
whether the patient should be included.16
Eligibility criteria based on chest HRCT if surgical lung
biopsy was not available
To qualify to enter the INPULSIS® trials if a surgical lung biopsy
was not available, the criteria A and B and C; or criteria A and
C; or criteria B and C had to be met.
A
Definite honeycomb lung destruction with basal
peripheral predominance
B
Presence of reticular abnormality and traction
bronchiectasis consistent with fibrosis with basal and
peripheral predominance
C
Atypical features are absent, specifically nodules
consolidation. Ground glass opacity, if present, is less
extensive than reticular opacity pattern
1. Richeldi L, et al. N Engl J Med 2014:2071–82.
REFERENCES
•
Schoenheit G., et al. Living with idiopathic pulmonary fibrosis: an indepth qualitative survey of European patients. Chron Respir Dis
2011;8:225–231.
•
Collard HR., et al. Patient experiences with pulmonary fibrosis. Respir
Med 2007;101:1350–1354.
•
Meltzer EB., et al. Idiopathic pulmonary fibrosis. Orphanet J Rare Dis
2008;3:8.
•
•
Du Bois RM. An earlier and more confident diagnosis of idiopathic
pulmonary fibrosis. Eur Respir Rev 2012;21:141–146.
•
Raghu G., et al. Diagnosis of idiopathic pulmonary fibrosis with highresolution CT in patients with little or no radiological evidence of
honeycombing: secondary analysis of a randomised, controlled trial.
Lancet Respir Med 2014;2:277–284.
•
Kaarteenaho R. The current position of surgical lung biopsy in the
diagnosis of idiopathic pulmonary fibrosis. Respir Res 2013;14:43.
Lamas DJ., et al. Delayed access and survival in idiopathic pulmonary
fibrosis: a cohort study. Am J Respir Crit Care Med 2011;184:842–847. •
•
Kim DS., et al. Classification and natural history of the idiopathic
interstitial pneumonias. Proc Am Thorac Soc 2006;3:285–292.
•
Raghu G., et al. An official ATS/ERS/JRS/ALAT statement: idiopathic
pulmonary fibrosis: evidence-based guidelines for diagnosis and
management. Am J Respir Crit Care Med 2011;183:788–824.
•
Ryu JH., et al. Diagnosis of interstitial lung diseases. Mayo Clin Proc
2007;82:976–986.
•
American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and
•
treatment. International consensus statement. American Thoracic
Society (ATS), and the European Respiratory Society (ERS). Am J
Respir Crit Care Med 2000;161:646–664.
•
Park JH., et al. Mortality and risk factors for surgical lung biopsy in
patients with idiopathic interstitial pneumonia. Eur J Cardiothorac Surg
2007;31:1115–1119.
•
Sigurdsson MI., et al. Diagnostic surgical lung biopsies for suspected
interstitial lung diseases: a retrospective study. Ann Thorac Surg
2009;88:227–232.
•
Fibla JJ., et al. Aggregate risk score for predicting mortality after
surgical biopsy for interstitial lung disease. Interact Cardiovasc Thorac
Surg 2012;15:276–279.
King Talmadge E. Jr, et al. A Phase 3 Trial of Pirfenidone in Patients
with Idiopathic Pulmonary Fibrosis. N Engl J Med 2014.
Richeldi L, et al. Supplement to: Efficacy and safety of nintedanib in
idiopathic pulmonary fibrosis. N Engl J Med 2014:2071–8.
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