raghu nieuw

Idiopathic Pulmonary FibrosisEvidence Based Guidelines for Diagnosis and Management*

· Clinical presentation– Older age (6th – 7th decades of life)– Men > women– Unexplained chronic exertional dyspnea, crackles, finger

clubbing· Incidence and prevalence

– No large-scale studies to base formal estimates– Incidence = 6.8-16.3/100,000– Prevalence = 14-42.7/100,00

Large database of health care claims in health plan

(Raghu 2006)

Idiopathic Pulmonary Fibrosis


· Specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause

· Occurring in adults; limited to the lungs · Histologic and/or radiologic pattern of Usual Interstitial

Pneumonia (UIP)· Requirement

– Exclusion of other forms of Idiopathic interstitial pneumonia and Interstitial lung diseases associated with environmental exposure, medication, or systemic disease

Definition: Idiopathic Pulmonary Fibrosis


· Careful history and physical exam· Focus on environmental exposures, medication use, co morbidities · Family medical history· Use questionnaires (e.g., ILD questionnaire –http://www.chestnet.org)· No validated questionnaires to exclude known cause(s) for ILD· Exclude connective tissue (CT) diseases

– Established criteria for specific CT disease– Index of clinical suspicion for CT disease in patients <50 yrs (esp.

women)

Exclusion of Other Known Causes for Pulmonary Fibrosis


· Summary of evidence -No reliable data on the role of screening serologies in patients with

suspected IPF. -Connective tissue disease (CTD) can present with a UIP -ILD has been described as the sole clinical manifestation of CTD

and can precede the overt manifestation of a specific connective tissue disease

Question: Should serological testing for connective tissues disease be used in the evaluation of suspected IPF?


· Recommendation: Serological testing for connective tissue disease should be performed in the evaluation of IPF (weak recommendation, very low quality evidence). (votes : 23 for the use of serological testing, none against, no abstentions)

· Values: A high value on distinguishing connective tissue disease from IPF and low value on cost.

· Remarks: – Serological evaluation should be performed even in the absence of

signs or symptoms of connective tissue disease( include rheumatoid factor, anti-cyclic citrullinated peptide, and anti-nuclear antibody titer and pattern

– The routine use of other serological tests is of unclear benefit

Question: Should serological testing for connective tissues disease be used in the evaluation of suspected IPF?


· Summary of evidence -Prominent lymphocytosis (>40%) in BAL suggests diagnosis of

chronic hypersensitivity pneumonitis -8% of patients with UIP pattern on HRCT may have BAL findings

suggestive of dx other than IPF (Ohshimo et al. AJRCCM 2009) -Unclear whether BAL adds significant diagnostic specificity to a

careful exposure history and clinical evaluation

Question: Should BAL Cellular Analysis be Performed in the Diagnostic Evaluation of Suspected IPF?


· Recommendation: BAL cellular analyses should not be performed in the dx evaluation of IPF (weak recommendation; low quality of evidence) (votes : 4 for the use of BAL; 18 against the use of BAL; 1 abstention)

· Values: High value on additional risk and cost; low value on possible improved specificity of dx

· Remarks: BAL cellular analysis should be considered at the discretion of the treating physician based on availability and experience at their center

Question: Should BAL Cellular Analysis be Performed in the Diagnostic Evaluation of Suspected IPF?


· Summary of evidence -the specificity and positive predictive value of UIP pattern

identified by transbronchial biopsy has not been rigorously studied.

-The sensitivity and specificity of this approach for the diagnosis for UIP pattern is unknown.

-it is also unknown how many and from where transbronchial biopsies should be obtained.

Question: Should transbronchial lung biopsy be used in the evaluation of suspected IPF?


· Recommendation: Trans bronchial biopsy should not be used in the evaluation of IPF (weak recommendation, low quality evidence). (Votes: none for the use of trans bronchial biopsy, 23 against the use of trans bronchial biopsy, no abstentions)

· Values: This recommendation places a high value on the additional morbidity of trans bronchial lung biopsy in patients with IPF and low value on possible diagnostic specifcity.

Question: Should transbronchial lung biopsy be used in the evaluation of suspected IPF?


· Usual Interstitial pneumonia (UIP)HRCT images of lung : UIP pattern

Consistent with UIP pattern

Inconsistent with UIP pattern

Histopathology on surgical lung biopsy :UIP pattern

Probable UIP pattern

Possible UIP pattern

Not UIP pattern


UIP Pattern (All four features)· Subpleural, basal predominance· Reticular abnormality· Honeycombing with or without traction

bronchiectasis· Absence of features listed as inconsistent with

UIP pattern

HRCT Criteria for UIP Pattern


HRCT Images: UIP Pattern (Extensive honeycombing)

A B


D

HRCT Images: UIP Pattern (Less severe honeycombing)

C



A C

B D


Honeycombing (HRCT)· Clustered cystic air

spaces· Well defined walls· Typically comparable

diameters (3-10 mm; occasionally as large as 2.5 cm)

· Sub pleural


Consistent with UIP Pattern (All three features)· Subpleural, basal predominance· Reticular abnormality· Absence of features listed as inconsistent with

UIP pattern · (NO HONEY COMBING)



FE

HRCT Images: Consistent with UIP pattern (no honeycombing)



A C

B D F

E


HRCT Images: Consistent with UIP pattern


· Inconsistent with UIP pattern (any of the seven features)– Upper or mid lung predominance– Peribronchovascular predominance– Extensive ground glass abnormality (extent > reticular

abnormality– Profuse micro nodules (bilateral, predominantly upper lobes)– Discrete cysts (multiple, bilateral, away from areas of

honeycombing)– Diffuse mosaic attenuation/air trapping (bilateral, in 3 or more

lobes)– Consolidation in bronchopulmonary segment (s) / lobe(s)



Surgical Lung Biopsy Specimens: Histopathology of UIP Pattern

*

HoneycombspacesPreserved lung

tissueChronicfibrosis Fibroblast focus


Histopathological Criteria for UIP Pattern

· UIP pattern (all four criteria)

– Evidence of marked fibrosis/architectural distortion, +/- honeycombing in a predominantly subpleural/paraseptal distribution

– Presence of patchy involvement of lung parenchyma by fibrosis

– Presence of fibroblast foci– Absence of features against a diagnosis of UIP suggesting

an alternate diagnosis


Histopathological Criteria for UIP Pattern· Probable UIP pattern

– Evidence of marked fibrosis/architectural distortion, +/- honeycombing in a sub pleural /para septal distribution

– Absence of either patchy involvement or fibroblastic foci, but not both

– Absence of features against a diagnosis of UIP suggesting an alternate diagnosis

OR– Honeycomb changes only**

** This scenario usually represents end-stage fibrotic lung disease where honeycombed segments have been sampled but where a UIP pattern might be present in other areas. Such areas are usually represented by overt honeycombing on HRCT and can be avoided by pre-operative targeting of biopsy sites away from these areas using HRCT.



· Possible UIP pattern (all three criteria)

– Patchy or diffuse involvement of lung parenchyma by fibrosis, with or without interstitial inflammation

– Absence of other criteria for UIP

– Absence of features against a diagnosis of UIP suggesting an alternate diagnosis



· Not UIP pattern (any of the six criteria)– Hyaline membranes *– Organizing pneumonia *†– Granulomas †– Marked interstitial inflammatory cell infiltrate away from

honeycombing– Predominant airway centered changes– Other features suggestive of an alternate diagnosis

* Can be associated with acute exacerbation of IPF† An isolated or occasional granuloma and /or a mild component of organizing pneumonia pattern may rarely be coexisting in lung biopsies with an otherwise UIP pattern


DIAGNOSIS OF IPF : Combination of HRCT and Histopathology requires multidisciplinary discussion (MDD)

· UIP

** Non-classifiable fibrosis: a pattern of fibrosis that does not meet the above criteria for UIP pattern and the other idiopathic interstitial pneumonias

† The accuracy of the diagnosis increases with MDD. This is particularly relevant in cases where the radiologic and histopathologic patterns are discordant (e.g. HRCT is inconsistent with UIP and histopathology is UIP). The accuracy of diagnosis is improved with MDD among interstitial lung disease experts compared to clinician-specialists in the community setting.

UIPProbable UIPPossible UIPNon-classifiable

fibrosis**Not UIP

Yes

No

HRCT Pattern Histopathology Pattern (when Surgical lung bx performed)

Dx of IPF ?†


· Consistent with UIP

†† MDD among interstitial lung disease experts should include discussions of the potential for sampling error and a re-evaluation of adequacy of technique of HRCT.

UIPProbable UIPPossible UIPNon-classifiable

fibrosis

Not UIP

Yes

Probable††

No

HRCT PatternHistopathology Pattern

(when Surgical lung bx performed) Dx of IPF ?

DIAGNOSIS OF IPF : Combination of HRCT and Histopathology requires multidisciplinary discussion (MDD)


Combination of HRCT and surgical lung biopsy for the diagnosis of IPF (requires multidisciplinary discussion)

· Inconsistent with UIP

†† MDD among interstitial lung disease experts should include discussions of the potential for sampling error and a re-evaluation of adequacy of technique of HRCT.

UIP

Probable UIPPossible UIPNon-classifiable

fibrosisNot UIP

Possible ††

No

HRCT PatternHistopathology Pattern

(When surgical lung bx performed) Dx of IPF?


· Summary of evidence -the diagnosis of IPF is, by definition, multidisciplinary,

drawing on the expertise of experienced clinicians, radiologists, and pathologists.

-proper communication between the various disciplines involved in the diagnosis of IPF (pulmonary, radiology, pathology) has been shown to improve inter-observer agreement among experienced clinical experts as to the ultimate diagnosis (Flaherty et al. 2004 and 2007)

Question: Should a multi-disciplinary discussion be used in the evaluation of suspected IPF?


· Recommendation: A MDD should be used in the evaluation of IPF (strong recommendation, low quality evidence). (Votes: 23 for the use of MDD, none against, no abstentions)

· Values: A high value on the accurate diagnosis of IPF and a low value on the access to and availability of experts for MDD.

· Remarks: –It is recognized that a formal MDD between the treating pulmonologist, radiologist and pathologist is not possible for many practitioners.

–Effort should be made, however, to promote verbal communication between specialties during the evaluation of the case

–Accuracy of diagnosis is improved through MDD among interstitial lung disease (ILD) experts compared to MDD among specialists in the community setting (Flaherty et al. 2007)

–Timely referral to ILD experts is encouraged.

Question: Should a multi-disciplinary discussion (MDD) be used in the evaluation of suspected IPF?


· Exclusion of known causes of ILD (e.g., environmental exposure, connective tissue disease, and drug toxicity

· UIP pattern or HRCT and/or histopathology (surgical lung biopsy)

Or· Specific combinations of HRCT and histopathological

patterns (surgical lung biopsy)

Diagnostic Criteria for IPF


Diagnostic Algorithm for IPF

Suspected IPF

Identifiable causes for ILD?

HRCT

Surgical Biopsy

MDD

IPF/Not IPF per TableIPF Not IPF

Yes

Not UIP

UIP Consistent with UIPInconsistent with UIP

UIPProbable UIP/Possible UIPNon-classifiable fibrosis

No


· IPF ; natural history is variable and unpredictable· Usual interstitial pneumonia (UIP)pattern for both

HRCT and histopathology (surgical lung biopsy) features

· The pattern of UIP : “consistent” and “inconsistent” on HRCT

· The histopathologic features of “probable”, “possible” patterns for UIP and those that are “not UIP”

Summary : Precise Definitions


· In the appropriate clinical setting– The diagnosis of IPF is ascertained if the HRCT images

reveal pattern of UIP (surgical lung biopsy is not required)– Histological features of UIP in surgical lung biopsy is

required for diagnosis of IPF if HRCT images are different than the UIP pattern

– Combinations of HRCT and histopathological criteria are required to diagnose and/or exclude IPF

– Accuracy of diagnosis increases with multidisciplinary discussions between pulmonologists, radiologists, and pathologists experienced in the diagnosis of ILD

Summary : Diagnosis


Natural History of IPF

Clin

ical

Cou

rse

Time

Stable

Slow progression

Rapidprogression

Acuteworsening


· American Thoracic Society· European Respiratory Society· Japanese Respiratory Society· Latin American Thoracic Association· Staffs

– University College, Dublin, Ireland– University of Modena and Reggio Emilia, Italy– Mr. Lance Lucas (ATS)

· Peer Reviewers· Community and Academic pulmonologists

Acknowledgments

raghu nieuw

Health & Medicine