1. FACULTY Title Affiliation
3/28/2014
NAVIGATING the NEW ERA in IPF: Diagnosing Idiopathic Pulmonary Fibrosis
FACULTY
Title
Affiliation

2. Learning Objectives
Explain the considerations associated with clinical evaluation, imaging, and biopsy, in terms of differentially diagnosing IPF
Identify opportunities for interdisciplinary collaboration and consultation and key aspects of guideline recommendations that can facilitate early and accurate IPF diagnosis

3. Interstitial Lung Diseases
Diverse group of disorders that involve the distal pulmonary parenchyma
Typical presentation
Progressive dyspnea and dry cough
Abnormal pulmonary physiology
Abnormal CXR and/or HRCT
Etiology
Idiopathic
Systemic diseases (connective tissue disorders)
Toxic, radiologic, environmental, occupational exposures

4. Interstitial Lung Diseases
ILD of Known Cause or Association
Medications
Radiation
Connective Tissue Disease
Vasculitis & DAH
Hypersensitivity Pneumonitis
Pneumoconioses
Idiopathic Interstitial Pneumonias
Sarcoidosis & Other Granulomatous Diseases
Other
LAM
Pulmonary LCH
Eosinophilic Pneumonias
Alveolar Proteinosis
Genetic Syndromes
Adapted from: ATS/ERS Guidelines for IIP. AJRCCM. 2002;165:

5. Major Idiopathic Interstitial Pneumonias
Category
Clinical-Radiologic-Pathologic Diagnosis
Associated Radiographic and/or Pathologic pattern
Chronic fibrosing
IPF
UIP
Idiopathic nonspecific interstitial
Pneumonia (iNSIP)
NSIP
Smoking-related
Respiratory bronchiolitis-ILD (RB-ILD)
Respiratory bronchiolitis
Desquamative interstitial pneumonia (DIP)
Desquamative interstitial pneumonia
Acute/ subacute
Cryptogenic organizing pneumonia (COP)
Organizing pneumonia
Acute interstitial pneumonia (AIP)
Diffuse alveolar damage
Travis et al. Am J Respir Crit Care Med. 2013;188:

6. Other Idiopathic Interstitial Pneumonias
Category
Clinical-Radiologic-Pathologic Diagnosis
Associated Radiographic and/or Pathologic pattern
Rare
Idiopathic lymphoid interstitial pneumonia (iLIP)
Lymphoid interstitial pneumonia
Idiopathic pleuroparenchymal fibroelastosis (IPPFE)
Pleuroparenchymal fibroelastosis
Unclassifiable
Unclassifiable IIP
Many
Travis et al. Am J Respir Crit Care Med. 2013;188:

7. Diffuse Parenchymal Lung Disease (DPLD)
DPLD of known cause, eg, drugs or association, eg, collagen vascular disease
Idiopathic interstitial pneumonias
Granulomatous DPLD, eg, sarcoidosis
Other forms of DPLD, eg, LAM, HX, etc
Idiopathic pulmonary fibrosis
IIP other than idiopathic pulmonary fibrosis
Desquamative interstitial pneumonia
Respiratory bronchiolitis interstitial lung disease
Cryptogenic organizing pneumonia
Acute interstitial pneumonia
Nonspecific interstitial pneumonia (provisional)
Lymphocytic interstitial pneumonia
Pleuroparenchymal fibroelastosis
Travis WD, et al; ATS/ERS Committee on Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med. 2013;188(6):

8. Idiopathic Pulmonary Fibrosis
Normal Lungs
Usual Interstitial Pneumonia

9. Idiopathic Pulmonary Fibrosis
Peripheral lobular fibrosis of unknown cause
Clinical impact
Exertional dyspnea
Cough
Functional and exercise limitation
Impaired quality-of-life
Risk for acute respiratory failure and death
Median survival time of 3-5 years
Two new drugs approved by the FDA in October 2014
Nintedanib (Ofev)
Pirfenidone (Esbriet)

10. Diagnosis Matters! IPF/UIP Confers a Poor Prognosis
Parameter
HR (95% CI)
IPF Dx
28.46 (5.5, 147)
Age
0.99 (0.95, 1.03)
Female sex
0.31 (0.13, 0.72)
Smoker
0.30 (0.13, 0.72)
Physio CRP
1.06 (1.01, 1.11)
Onset Sx (yrs)
1.02 (0.93, 1.12)
CTfib score ≥ 2
0.77 (0.29, 2.04)
Cumulative Proportion Surviving
Time (years)
Correct diagnosis  appropriate management
Flaherty KR, et al. Eur Respir J. 2002;19:

11. Higher Mortality Associated With Delays in Accessing Care
Survival
Years
Lamas DJ, et al. Am J Respir Crit Care Med. 2011;184:

12. 2011 ATS/ERS Diagnostic Criteria for IPF
UIP pattern on HRCT without surgical biopsy OR
Definite/possible UIP pattern on HRCT with a surgical lung biopsy showing definite/probable UIP
Exclusion of known causes of ILD*
AND
*also known as diffuse parenchymal lung disease, DPLD
Raghu G, et al. Am J Respir Crit Care Med. 2011;183:

13. Idiopathic Pulmonary Fibrosis
Normal Lung
Usual Interstitial Pneumonia

14. Idiopathic Pulmonary Fibrosis
Normal Lung
Fibroblastic focus in
Usual Interstitial Pneumonia

15. Prevalence of IPF is Increasing Medicare Beneficiaries Age ≥ 65 Years
Lancet Respir Med Jul;2(7): doi: /S (14) Epub 2014 May 27.
Idiopathic pulmonary fibrosis in US Medicare beneficiaries aged 65 years and older: incidence, prevalence, and survival,
Raghu G1, Chen SY2, Yeh WS2, Maroni B2, Li Q3, Lee YC3, Collard HR4.
Author information
Abstract
BACKGROUND:
Published data for the epidemiology of idiopathic pulmonary fibrosis in the USA are scarce. We sought to estimate the incidence, prevalence, and mortality risk of idiopathic pulmonary fibrosis among US Medicare beneficiaries.
METHODS:
We used administrative claims from a 5% random sample of Medicare beneficiaries (aged 65 years and older) from the years as a data source. Idiopathic pulmonary fibrosis was defined by International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes. We estimated annual incidence and cumulative prevalence of idiopathic pulmonary fibrosis, median survival time of patients, and potential risk factors for diagnosis of idiopathic pulmonary fibrosis and death between 2001 and We also estimated incidence and prevalence using more restrictive algorithms for diagnosis.
FINDINGS:
The annual incidence of idiopathic pulmonary fibrosis in the Medicare population remained stable between 2001 and 2011, with an overall estimate of 93·7 cases per 100 000 person-years (95% CI 91·9-95·4) across the study period. The annual cumulative prevalence increased steadily from 202·2 cases per 100 000 people in 2001 to 494·5 cases per 100 000 people in Among newly diagnosed patients with Medicare (mean age 79·4 years [SD 7·2], 54% female, 91% white), the median survival time was 3·8 years (95% CI 3·5-3·8). Older age and male sex were associated with a higher incidence of disease and shorter survival time after diagnosis. Mortality risk was lower in patients diagnosed in more recent years (median survival time 3·3 years [95% CI 3·0-3·8] in 2001 vs 4·0 years [3·8-4·5] in 2007).
INTERPRETATION:
The incidence and prevalence of idiopathic pulmonary fibrosis in people aged 65 years and older in the USA are substantially higher than previously reported, and prevalence is increasing annually, even in the subgroups based on more restrictive algorithms for diagnosis. Patients with idiopathic pulmonary fibrosis aged 65 years and older were living longer in 2011 than they were 10 years before, which could partly account for the steady increase in prevalence.
Median survival = 3.8 years
Factors associated with lower survival
Age, index year, male sex
Raghu G, et al. Lancet Respir Med. 2014;2(7):

16. Incidence of IPF Risk factors for higher incidence Age Male sex
Hispanic ethnic origin
Geography
Lowest
Highest
Medium
Raghu G, et al. Lancet Respir Med. 2014;2(7):

17. When Should I Suspect ILD?
One from Column A and one from Column B
Column A
Exertional Dyspnea
Non-productive Cough
Family History of ILD
Column B
Abnormal CXR
Crackles
Exertional Desaturation
Spirometry (low FVC) or low DLCO
“ACES”

18. ILD Features Similarities Differences Dyspnea Cough Bibasilar crackles
Progressive
Exertional
Cough
Non-productive
Bibasilar crackles
Restrictive ventilatory defect
Exertional desaturation
ILD on HRCT
Prior/current exposures
Extrapulmonary findings
Sarcoidosis
Connective tissue disease
Joint involvement
Serologies
HRCT
Honeycombing
Ground glass
Distribution of abnormalities
Histopathology

19. Pulmonary Function Tests
Spirometry
Reduced FVC and TLC
Normal or increased FEV1/FVC ratio
Restriction often accompanied by some obstruction
Impaired gas exchange
Decreased DLCO, PaO2
Desaturation on exercise oximetry
Increased A-aPO2 gradient
Normal PFTs do not exclude ILD
Emphysema + Interstitial Lung Disease

20. Mnemonic for Diagnosing ILD
Infectious
Inhalational
Immunologic
Iatrogenic
Idiopathic
Cardiovascular
Neoplastic

21. What Should I Do if I Suspect ILD?
Specific diagnosis
Clinical
picture
Radiologic pattern (HRCT)
Pathologic pattern (lung biopsy)
Accessed August 2014.

22. High Resolution CT scan
Inspiratory supine and expiratory supine
< 1.25mm axial reconstruction
High spatial frequency reconstruction (“bone”) algorithm
Prone imaging in select cases
No IV contrast
Accessed August 2014.

23. UIP Pattern Usual interstitial pneumonia (UIP) pattern. (a–d)
Sequential high-resolution
computed tomography images
through the lung demonstrate
a classic UIP pattern with evidence
of diffuse reticulation,
traction bronchiectasis, and subpleural,
basilar honeycombing.
In the absence of a known underlying
etiology, this appearance
is diagnostic of idiopathic
pulmonary fibrosis, for which
surgical biopsy is not indicated.
Hodnett PA, et al. Am J Respir Crit Care Med. 2013;188:

24. Possible UIP Pattern traction bronchiectasis
Possible usual interstitial
pneumonia (UIP) pattern.
(a–d) Sequential high-resolution
computed tomography images
through the lungs also show
a possible UIP pattern. In this
case, in addition to subpleural reticulation
and traction bronchiectasis
(arrows in c and d) there
is also evidence of subpleural
ground-glass attenuation in the
same areas of increased reticulation.
Again, in the absence of
a known etiology, this pattern
also requires open lung biopsy
confirmation. Biopsy confirmed
UIP.
traction bronchiectasis
Hodnett PA, et al. Am J Respir Crit Care Med. 2013;188:

25. HRCT Criteria for UIP + - Possible UIP Pattern UIP Pattern
Subpleural, basal predominance +
Reticular abnormality
Honeycombing
(+/- traction bronchiectasis) -
Absence of “inconsistent” features
Raghu G, et al. Am J Respir Crit Care Med. 2011;183:

26. Inconsistent With UIP distinct lobular pattern Findings inconsistent
with a usual interstitial pneumonia
pattern—chronic hypersensitivity
pneumonitis. (a–d)
Sequential high-resolution
computed tomography images
obtained in inspiration through
the lungs. In this case, in addition
to diffuse reticulation and
traction bronchiectasis, there is
also evidence of numerous foci
of decreased lung attenuation
and vascularity, many with a distinct
lobular pattern (arrows in
a–d) strongly suggestive of the
diagnosis of chronic hypersensitivity
pneumonitis, a diagnosis
later confirmed by obtaining
a detailed clinical history revealing
prolonged use of a hot tub.
In the absence of a convincing
clinical history, confirmation of
this diagnosis may be obtained
by bronchoalveolar lavage.
Hodnett PA, et al. Am J Respir Crit Care Med. 2013;188:

27. HRCT features inconsistent with IPF
Inconsistent Features
Upper lobe predominant
Peribronchovascular predominance
Ground-glass > extent of reticular abnormality
Profuse micronodules
Discrete cysts
Diffuse mosaic attenuation/gas-trapping
Consolidation
Raghu G, et al. Am J Respir Crit Care Med. 2011;183:

28. What Should I Do if HRCT Confirms ILD?
Specific diagnosis
Clinical
picture
Radiologic pattern (HRCT)
Pathologic pattern (lung biopsy)
Accessed August 2014.

29. Known Causes of ILD: History & Physical Exam
Drugs
eg, Amiodarone, bleomycin, nitrofurantoin
Radiation
External beam radiation therapy to thorax
Connective Tissue Diseases
Rheumatoid arthritis
Systemic sclerosis (scleroderma)
Idiopathic inflammatory myopathies
Vasculitis
Occupational/Environmental
Inorganic antigens (Pneumoconioses)
Asbestosis
Coal worker’s pneumoconiosis
Silicosis
Organic antigens (Hypersensitivity Pneumonitis)
Birds
Mold

30. Gottron's Papules in Dermatomyositis
Dermatomyositis: rash, hands
Typical late cutaneous involvement is seen on the extensor aspect of the joints. The lesions are reddish-white, shiny, slightly scaly, and atrophic. #
Accessed July 2014.

31. Mechanic's Hands in Anti-Synthetase Syndrome
Dermatomyositis: ”mechanic's hands"
Cracking of the finger pad skin, commonly involving the first, second, and third fingers, is demonstrated in this patient with dermatomyositis.
Miller FW. Myositis-specific autoantibodies: touchstones for understanding the inflammatory myopathies. JAMA 1993;270: #
Accessed July 2014.

32. Raynaud's Phenomenon
Scleroderma: Raynaud's phenomenon, blanching of hands
The marked pallor of the fourth and fifth digits on the left hand and of the fifth digit on the right hand is characteristic of Raynaud’s phenomenon. Vasospastic changes are common in systemic sclerosis but may also occur in rheumatoid arthritis, systemic lupus erythematosus, and idiopathic Raynaud’s disease. #
Accessed July 2014.

33. Puffy Fingers in Early Scleroderma or Mixed CTD
Scleroderma: edematous changes, hands
Swelling of the distal limbs may develop early in the course of systemic sclerosis. Puffy hands are shown here. #
Accessed July 2014.

34. Advanced Sclerodactyly
Scleroderma: acrosclerosis
Flexion contractures of the fingers are secondary to a tightened indurated skin. This type of change in the fingers is called acrosclerosis (sclerodactyly) and is characteristic of systemic sclerosis. However, skin changes proximal to the metacarpophalangeal joints are more specific for systemic sclerosis than changes only in the fingers. Areas of increased and decreased pigmentation are also visible. #
Accessed July 2014.

35. Digital Clubbing Reynen K, et al. N Engl J Med. 2000; 343:1235
NEJM, 2001

36. Serological Evaluation
Minimum: ANA, RF, CCP (ATS/ERS guidelines)
Based on history & physical exam, consider:
Extractable nuclear antigen (ENA) autoantibody panel
Anti-centromere antibody
ESR & CRP
MPO/PR3 (ANCA) antibodies
Anti-cardiolipin antibodies, lupus anticoagulant
Creatine kinase, aldolase
Hypersensitivity pneumonitis panel
Should be performed before a biopsy

37. 2011 ATS/ERS Diagnostic Criteria for IPF
UIP pattern on HRCT without surgical biopsy OR
Definite/possible UIP pattern on HRCT with a surgical lung biopsy showing definite/probable UIP
Exclusion of known causes of ILD*
AND
*also known as diffuse parenchymal lung disease, DPLD
Raghu G, et al. Am J Respir Crit Care Med. 2011;183:

38. Before You Biopsy… Can you confirm the diagnosis without a biopsy?
Is it safe?
Extensive honeycombing
Pulmonary hypertension
High oxygen requirements
Progressive disease
Avoid a “diagnostic trial” of steroids if possible
Consider referral to an ILD center

39. Diagnosis of IPF by Lung Biopsy
Histopathologic Pattern
UIP
Probable UIP
Possible UIP
Not UIP
Not performed
IPF
Not IPF
+/- IPF
Inconsistent with UIP
Radiologic Pattern
Raghu G, et al. Am J Respir Crit Care Med. 2011;183:

40. Putting it all Together
Physiology
Full PFTs
Gas exchange
6MWT
Radiology
HRCT
History
Exam
Labs
ANA, RF, anti-CCP
Pathology
Summary Diagnosis

41. Conclusions: Diagnosing IPF
IPF is a fibrotic ILD
No identifiable cause for fibrosis
Exposure/CTD are absent
Either…
Characteristic HRCT pattern
UIP-pattern on surgical lung biopsy
Multidisciplinary approach enables an accurate diagnosis

42. 3/28/2014
QUESTIONS and ANSWERS