1. Assessment and Prognosis of Patients with IPF

2. Educational Activity Learning Objective
Utilize indicators of disease status to diagnose, assess, and manage patients with IPF

3. US Demographics of IPF Incidence Prevalence50
100
150
200
250
300
45-54
55-64
65-74
75+
Male
Female 20 40 60 80
120
Prevalence
Incidence
Per 100,000
Incidence: > 30,000 patients/year
Prevalence: > 80,000 current patients
Age of onset: most 40–70 years
Two-thirds > 60 years old at presentation
Males > females
US Demographics of IPF
Currently, more than 80,000 adults in the United States have IPF, and more than 30,000 new cases are diagnosed each year. Most IPF patients are between 40 and 70 years old at onset. Approximately two-thirds of patients are over 60 years old at presentation, with a mean age of 66 years at diagnosis. The disease is more common in males than in females, but there is no evidence for racial or ethnic predilection.
In an analysis using age, medical claim, and differential diagnosis criteria, Raghu and colleagues estimated a US prevalence of 89,000 cases and a US incidence of 34,000 new cases per year.
ATS/ERS. Am J Respir Crit Care Med. 2000;161:
Raghu G, et al. Am J Respir Crit Care Med. 2006;174:
American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International Consensus Statement. Am J Respir Crit Care Med. 2000;161:
Raghu G, Weycker D, Edelsberg J, Bradford WZ, Oster G. Incidence and prevalence of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2006;174:

4. Risk Factors for IPF Risk factors Possible associated factors Familial
Smoking
Possible associated factors
Environment (eg, wood or metal dust)
Gastroesophageal reflux disease (GERD)
Infectious agents
Risk Factors for IPF
A number of potential risk factors for the development of IPF have been identified. Familial IPF, characterized by two or more cases of idiopathic interstitial pneumonia in first-degree relatives, accounts for less than 5% of total IPF cases. A pattern of autosomal dominance with reduced penetrance is likely. Several genes associated with familial pulmonary fibrosis are known, though mutations have been identified in only about 10% of individuals with familial pulmonary fibrosis. Some of the genes involved in familial IPF include surfactant protein C, TERT (telomerase reverse transcriptase), and TERC (telomerase RNA component). A case illustrating familial IPF is included in this compendium.
Cigarette smoking is also a risk factor, with odds ratios from various geographic regions ranging from 1.6 to 2.9 in ever-smokers. Various environmental exposures in rural/agricultural areas and in urban and manufacturing settings have been linked to IPF, with metal dust and wood dust exposure showing the most prominent associations. Chronic aspiration secondary to gastroesophageal reflux disease (GERD) is common in patients with IPF, although a causative link has not been established. Several viruses (eg, Epstein- Barr virus, cytomegalovirus, and hepatitis C) have been associated with IPF; however, there is no clear evidence for a viral etiology.
ATS/ERS. Am J Respir Crit Care Med. 2000;161:
Raghu G, et al. Am J Respir Crit Care Med. 2006;174:
American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International Consensus Statement. Am J Respir Crit Care Med. 2000;161:
Raghu G, Weycker D, Edelsberg J, Bradford WZ, Oster G. Incidence and prevalence of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2006;174:

5. Meta-analysis: Exposures and Risk of IPF
OR (95% CI)
Population Attributable Risk, %
Smoking
1.58 (1.3, 2.0) 49
Agriculture
1.65 (1.2, 2.3) 21
Livestock
2.17 (1.3, 3.7)
4.1
Wood Dust
1.94 (1.3, 2.8)
5.0
Metal Dust
2.44 (1.7, 3.4)
3.4
Stone/sand/silica
1.97 (1.1, 3.6)
3.5
Meta-analysis: Exposures and Risk of IPF
Several environmental exposures have been implicated in the development of IPF. Data on this slide are from a meta-analysis of 6 case-controlled studies from the UK, US, and Japan.
The summary odds ratios for the exposures range from 1.5 to 2.5. The authors suggest that IPF is heterogeneous and may be caused by a number of factors. Eliminating smoking and agricultural exposure could decrease IPF by a substantial amount.
Taskar VS, Coultas DB. Is idiopathic pulmonary fibrosis an environmental disease? Proc Am Thorac Soc. 2006;3:
Taskar VS, Coultas DB. Proc Am Thorac Soc. 2006;3:

6. IIP Classification Diagnosis Radiology Distribution Pathology IPF/UIP
Fibrosis, HC
Basilar, peripheral
Temporal heterog, FF, fibrotic and normal lung, microscopic HC
NSIP
GGO +/- fibrosis
Diffuse interstitial inflammation +/- fibrosis
COP
GGO, nodules, consolidation
Patchy upper lungs, small airways, alveolar
Granulation tissue plugs in alveolar ducts and alveoli
AIP
GGO, consolidation
Diffuse, random
Hyaline membranes, immature fibroblasts in alveolar spaces and interstitium to variable degree
RB-ILD
Bronchiectasis, GGO
Upper lungs, bronchocentric
Respiratory bronchiolitis surrounded by Ms in alveoli
DIP
Basilar, peripheral, alveolar
Alveolar Ms in air spaces diffusely in the biopsy
LIP
GGO, nodules, cysts
Patchy
Lymphoid hyperplasia
IIP Classification
A joint statement of the American Thoracic Society (ATS) and European Respiratory Society (ERS) was produced to standardize the classification of the idiopathic interstitial pneumonias (IIPs) and to establish a uniform set of definitions and criteria for the diagnosis of IIPs. The classification of IIPs included 7 clinical/radiologic/pathologic entities that are listed in this slide in order of relative frequency:
Idiopathic pulmonary fibrosis/usual interstitial pneumonia
Nonspecific interstitial pneumonia
Cryptogenic organizing pneumonia
Acute interstitial pneumonia
Respiratory bronchiolitis-associated interstitial lung disease
Desquamative interstitial pneumonia
Lymphoid interstitial pneumonia
Histologic, lung distribution, and pathologic characteristics of these conditions are summarized in this table.
HC, honeycombing; GGO, ground glass opacity; FF, fibrotic foci; M, macrophage
Adapted from Thannickal VJ, et al. Annu Rev Med. 2004;55:
Adapted from Strollo DC. Am J Respir Cell Mol Biol. 2003;29(3 Suppl):S10-S18.
American Thoracic Society. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med. 2002;166:
Thannickal VJ, Toews GB, White ES, Lynch JP 3rd, Martinez FJ. Mechanisms of pulmonary fibrosis. Annu Rev Med. 2004;55:
Strollo DC. Imaging of idiopathic interstitial lung diseases. Concepts and conundrums. Am J Respir Cell Mol Biol. 2003;29(3 Suppl):S10-S18.

7. Diagnosing Chronic Exertional Dyspnea
Neuromuscular
Pulmonary
Cardiac
Vascular
Others
NM disease, Malnutrition, Diaphragm dysfunction
Asthma, COPD, ILD
Cardiomyopathy, R-to-L shunt
Pulmonary Hypertension
AVM
Anemia, Anxiety, Obesity, Deconditioning, Hyperthyroidism, Connective Tissue Disease
Obstructive PFTs
yes no
Asthma, COPD
ILD or emphysema/ILD
Diagnosing Chronic Exertional Dyspnea
Since chronic exertional dyspnea can result from a variety of causes, it is important that a patient presenting with this symptom be diagnosed correctly. The differential diagnosis includes neuromuscular, pulmonary, cardiovascular, and other causes.
The primary pulmonary conditions to be differentiated are asthma, COPD, and ILD, and only IPF patients manifest basilar Velcro® crackles. A definitive diagnosis of IPF cannot be made solely on the basis of a clinical examination; however, a confident diagnosis of IPF can be made on the basis of an HRCT scan with typical features in conjunction with consistent PFT and clinical findings. In indeterminate cases, a surgical lung biopsy with histopathology is necessary.
A histologic finding of a pattern of usual interstitial pneumonia (UIP) supports a diagnosis of IPF when combined with clinical, serologic, and radiologic evidence. However, other conditions are associated with UIP, so an accurate diagnosis must be based on all available evidence.
HRCT scan
Not diagnostic
Typical & consistent
Surgical Lung Biopsy
Confident diagnosis

8. Current Definition of IPF
Distinct chronic fibrosing interstitial pneumonia
Unknown cause
Limited to the lungs
Has typical HRCT findings
Associated with a histologic pattern of UIP
Current Definition of IPF
Consensus statements by the American Thoracic Society and European Respiratory Society (ATS/ERS) define IPF as a distinct type of chronic fibrosing interstitial pneumonia of unknown cause that is limited to the lungs. There are typical HRCT findings that are often present. The histopathologic pattern of IPF is usual interstitial pneumonia (UIP), shown in the lower panel.
Revised guidelines are expected in 2010.
ATS/ERS Consensus Statement. Am J Respir Crit Care Med. 2002;165:
American Thoracic Society. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med. 2002;165:

9. Diagnostic Criteria for IPF Without a Surgical Lung Biopsy
Major Criteria
Exclusion of other known causes of ILD
Evidence of restriction and/or impaired gas exchange
HRCT: bibasilar reticular abnormalities with minimal ground-glass opacities (honeycombing is characteristic*)
TBB or BAL that does not support an alternative diagnosis
Minor Criteria
Age > 50 years
Insidious onset of otherwise unexplained dyspnea on exertion
Duration of illness > 3 months
Bibasilar, inspiratory, Velcro® crackles
Diagnostic Criteria for IPF Without a Surgical Lung Biopsy
Presence of all of the major diagnostic criteria as well as at least 3 of the minor criteria increases the likelihood of a correct diagnosis of IPF.
Major diagnostic criteria include:
Exclusion of other known causes of interstitial lung disease (ILD) such as drug toxicities, environmental exposures, and connective tissue diseases
Abnormal pulmonary function studies that include evidence of restriction and/or impaired gas exchange
Bibasilar reticular abnormalities with minimal ground glass opacities on HRCT. Honeycombing is characteristic, but is not always present, and is not one of the major criteria
Transbronchial lung biopsy (TBB) or bronchoalveolar lavage (BAL) showing no features to support an alternative diagnosis
Minor diagnostic criteria include:
Age > 50 years
Insidious onset of otherwise unexplained dyspnea on exertion
Duration of illness > 3 months
Bibasilar, inspiratory crackles (dry or “Velcro®” type in quality)
Please note that criteria are currently under revision (2010).
All major criteria and at least 3 minor criteria must be present to increase the likelihood of an IPF diagnosis
Criteria currently under revision (2010)
*Not included in current guidelines
ATS/ERS. Am J Respir Crit Care Med. 2000;161:
American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International Consensus Statement. Am J Respir Crit Care Med. 2000;161:

10. Pulmonary Function Tests
Normal PFTs or resting ABG do not exclude IPF
Restriction (not always seen)
Reduced FVC and TLC
Normal or increased FEV1/FVC ratio
Impaired gas exchange
Decreased DLCO, PaO2
Increased P(A-a)O2 gradient
Desaturation on exercise oximetry
Pulmonary Function Tests
Although the typical findings of pulmonary function tests (PFTs) in IPF are consistent with restrictive impairment, PFTs or arterial blood gases (ABGs) may be normal. Typical findings of airway restriction include a reduced forced vital capacity (FVC) and total lung capacity (TLC). The forced expiratory volume in 1 second (FEV1) and FVC are often decreased because of the reduction in lung volume, but the FEV1/FVC ratio is either maintained or increased.
There is impaired gas exchange reflected in a decrease in carbon monoxide diffusion in the lung (DLCO) and alveolar oxygen partial pressure (PaO2). With exercise, there is an increase in oxygen desaturation with an increased alveolar-arterial O2 (P[A-a]O2) gradient. During exercise, 20% to 30% of the exercise-induced widening of the P(A-a)O2 gradient may be caused by some impairment of oxygen diffusion. Notably, the abnormalities identified at rest do not accurately predict the effects seen with exercise.
ATS/ERS. Am J Respir Crit Care Med. 2000;161:
American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International Consensus Statement. Am J Respir Crit Care Med. 2000;161:

11. Serologic Tests Can Help Identify Other Conditions
ESR
ANA
CCP (for RA)
CK and aldolase
Anti-myositis panel with Jo-1 antibody
ENA panel
Scl-70
Ro (SSA)
La (SSB)
Smith
RNP
Connective tissue diseases
Serologic Tests Can Help Identify Other Conditions
Laboratory evaluation of patients with suspected IPF is helpful to rule out other causes of clinical symptoms. These biomarker tests do not correlate with the extent or activity of pulmonary fibrosis and do not predict therapeutic responsiveness. The following serologic tests may suggest an alternative diagnosis:
Hypersensitivity pneumonitis
Hypersensitivity panel
(if exposure history)
Erythrocyte sedimentation rate (ESR) is a nonspecific indicator of tissue inflammation. ESR may be elevated in patients with IPF but is not diagnostic
Antinuclear antibody (ANA) elevations occur in 10% to 20% of IPF patients, but titers are rarely high. High titers suggest a connective tissue disease
Anticyclic citrullinated peptide antibody (CCP) is a marker for rheumatoid arthritis
Creatinine kinase (CK) and aldolase are muscle injury markers. Elevation of these enzymes in serum suggests myocardial infarction
An antimyositis panel with Jo-1 antibody is useful for detecting systemic autoimmune diseases. Anti-Jo-1 is an antibody to histidyl-tRNA synthase commonly found in polymyositis and dermatomyositis patients
An anti-Extractable Nuclear Antigen (ENA) panel is a screen for autoimmune diseases, especially collagen vascular diseases
The hypersensitivity panel is a collection of tests for antibodies to common antigens from microbial, fungal, and animal sources
ATS/ERS. Am J Respir Crit Care Med. 2000;161:
American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International Consensus Statement. Am J Respir Crit Care Med. 2000;161:

12. HRCT Diagnosis of IPF
IPF Findings
Irregular reticular opacities
Subpleural, posterior, lower-lobe predominance
Traction bronchiectasis
Honeycombing
Minimal ground-glass opacities
Mild lymph node enlargement
Consider Alternative Diagnosis
Pleural effusion
Pleural thickening
Moderate ground-glass opacities
Nodules
Scattered cysts
HRCT Diagnosis of IPF
The typical IPF pattern observed on HRCT includes irregular reticular abnormalities with a subpleural, posterior, lower-lobe predominance. Traction bronchiectasis and subpleural honeycombing are associated with advanced disease. The amount of ground-glass opacity is limited and usually seen only in areas of reticulation. Mild lymph node enlargement may also be seen. Since radiologic evidence of pleural disease is not usually found in IPF, an alternate diagnosis should be considered if pleural effusion and/or pleural thickening are observed. The presence of moderate ground-glass opacities, nodules, and cysts (other than honeycomb cysts) also warrants consideration of an alternate diagnosis. Prone scans are often best for showing subtle abnormalities.
Prone scans are best for showing subtle abnormalities
ATS/ERS. Am J Respir Crit Care Med. 2000;161:
American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International Consensus Statement. Am J Respir Crit Care Med. 2000;161:

13. Extensive honeycombing
Advanced IPF HRCT
Extensive honeycombing
Traction
bronchiectasis
Reticular opacities
Advanced IPF HRCT
Prone HRCT near the lung bases shows extensive reticulation, traction bronchiectasis, and gross honeycombing with a subpleural predominance. This appearance indicates advanced IPF.
Basal and subpleural predominance
Image courtesy of W. Richard Webb, MD.

14. Pathological Sections Demonstrating UIP
a. Peripheral accentuation of disease
b. Transition into uninvolved lung
Fibrosis
Fibroblast
focus
Normal lung
Normal
lung
d. High power image of fibroblastic foci
c. Microscopic honeycombing
Myofibroblasts
Chronic inflammation
Chronic inflammation
Pathological Sections Demonstrating UIP
UIP is the pathology characteristic of IPF.
The 4 sections in this slide illustrate the cardinal features of UIP:
At scanning magnification, fibrosis is variable in distribution, forming band-like or donut-shaped outlines throughout the biopsy. These areas of fibrosis correspond to the periphery of lung lobules, ie, peripheral lobular accentuation of fibrosis.
Another important diagnostic feature of UIP is the presence of the “fibroblast foci” seen at the edges where fibrosis and normal lung interface. These are believed to be the specific sites of ongoing injury in UIP, in contrast to the more diffuse damage that presumably underlies fibrosis in “nonspecific interstitial pneumonia” (the conceptual counterpoint of UIP), both in terms of mechanism as well as survival.
Microscopic honeycombing consists of small mucous-filled cysts lined by airway epithelia and surrounded by fibrosis with variable chronic inflammation.
The fibroblast foci are illustrated here at the leading edge of subpleural fibrosis. The fibroblasts constituting the lesion are classified as myofibroblasts, similar to those seen in wounds at other sites (such as skin). Sparse chronic inflammation can be seen beneath the lesion.
Minimal chronic inflammation
Minimal chronic inflammation
Mucus-filled
cysts
Courtesy of Kevin O. Leslie, MD.
Courtesy of Kevin O. Leslie, MD.
Pleura
Images courtesy of Kevin O. Leslie, MD.

15. Conditions Associated with an HRCT Pattern of UIP
IPF
Toxic drug reactions
Chronic hypersensitivity pneumonitis
Connective tissue diseases
Asbestosis
Acute interstitial pneumonia
Conditions Associated with an HRCT Pattern of UIP
UIP is one of the hallmarks of IPF, but is not unique to IPF. The conditions which are associated with a histologic pattern of UIP include IPF, asbestosis, chronic hypersensitivity pneumonitis, connective tissue diseases (systemic sclerosis, polymyositis, rheumatoid arthritis), toxic drug reactions (bleomycin, amiodarone, and nitrofurantoin), and acute interstitial pneumonia.
Many of these conditions can be identified in the clinical workup and by serologic screening for autoantibodies.
Meltzer EB, Noble PW. Idiopathic pulmonary fibrosis. Orphanet J Rare Dis. 2008;3:8.
Kinder BW, Collard HR, Koth L, et al. Idiopathic nonspecific interstitial pneumonia: lung manifestation of undifferentiated connective tissue disease? Am J Respir Crit Care Med. 2007;176: 15

16. Which Variables Predict Histopathologic UIP?
Age
Male Sex
Ever smoker
HRCT Score
Alveolar
Interstitial
Pulmonary Function
FVC, % pred
DLCO, % pred
6MWT
Desat < 88%
Distance
Odds Ratio
1.11
1.96
1.28
0.61
17.20
0.18
0.48
0.63
1.06
P-value
<
0.08
0.54
0.007
0.12
0.57
0.41
0.91
Which Variables Predict Histopathologic UIP?
This retrospective study1 of 97 patients with biopsy-proven IPF and 38 patients with other IIPs sought to determine if clinical variables could predict a histopathologic diagnosis of IPF in patients without honeycomb change on HRCT.
Table 1. HRCT Scoring System.2 Patients in this study had interstitial scores < 2.
Increasing age and average total HRCT interstitial score on HRCT scan of the chest correlated with a biopsy confirmation of IPF. The alveolar score, based on ground glass opacity (GGO), was a negative predictor of IPF. Sex, pulmonary function, presence of desaturation, or distance walked during a 6-minute walk test did not help discriminate pulmonary fibrosis from other IIPs. The authors derive a quantitative probability of IPF score from analysis of data from this training group, which may prove useful after validation in a test population.
Fell CD, Martinez FJ, Liu LX, et al. Clinical predictors of a diagnosis of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2010;181:
Kazerooni EA, Martinez FJ, Flint A, et al. Thin-section CT obtained at 10-mm increments versus limited three-level thin-section CT for idiopathic pulmonary fibrosis: correlation with pathologic scoring. AJR Am J Roentgenol. 1997;169:
HRCT Score
Alveolar
Interstitial
No alveolar disease
No interstitial disease 1
GGO < 5% of lobe
Septal thickening but no honeycomb 2
GGO < 25% of lobe
Honeycomb change < 25% of lobe 3
GGO 25–49% of lobe
Honeycomb change 25–49% of lobe 4
GGO 50–75% of lobe
Honeycomb change 50–75% of lobe 5
GGO > 75% of lobe
Honeycomb change > 75% of lobe
Fell CD, et al. Am J Respir Crit Care Med. 2010;181:

17. Role of Bronchoscopy in the Diagnosis of IPF
Bronchoalveolar lavage (BAL) included in diagnosis in 2000 ATS/ERS guidelines
What can BAL contribute to refining the diagnosis of suspected IPF?Ohshimo study
n = 74 patients with confident IPF diagnosis
All met ATS/ERS 2000 criteria except for BAL
BAL cut-off levels
30% for lymphocytosis
3% for granulocytosis
Role of Bronchoscopy in the Diagnosis of IPF
The role of bronchoalveolar lavage (BAL) in diagnosis of IPF has been evolving. BAL helps in the differential diagnosis of extrinsic allergic alveolitis (EAA), sarcoidosis, pneumocystis carinii pneumonia, and malignancy. In the 2000 ATS/ERS guidelines for diagnosis of IPF, transbronchial lung biopsy (TBB) or BAL showing no features to support an alternative diagnosis was a major criterion for the exclusion of other diseases in the absence of a surgical lung biopsy. In the 2002 ATS/ERS guidelines, a confident CT diagnosis of IPF with consistent clinical features was considered to be sufficient to make an accurate diagnosis of IPF without surgical biopsy.
Ohshimo and colleagues did a retrospective study of patients with suspected IPF to evaluate the utility of BAL for the diagnosis of IPF. This study focused on 74 patients who met the 2000 ATS/ERS criteria for IPF in the absence of a surgical lung biopsy, except for the major criterion of BAL/TBB evidence. The goal of the study was to assess the contribution of BAL to the diagnosis and identify which patients with confident IPF diagnoses actually had different diseases. A 30% lymphocyte level was used as a cutoff for positivity, as was a 3% granulocyte level.
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:
American Thoracic Society/European Respiratory Society. International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med. 2002;165:
Ohshimo S, Bonella F, Cui A, et al. Significance of bronchoalveolar lavage for the diagnosis of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2009;179:
ATS/ERS. Am J Respir Crit Care Med. 2000;161:
ATS/ERS. Am J Respir Crit Care Med. 2002;165:
Ohshimo S, et al. Am J Respir Crit Care Med. 2009;179: 17

18. Usefulness of BAL in Diagnosis of IPF: Conclusions
8% of IPF diagnoses were wrong
4% NSIP
4% HP, all with environmental exposures
Absence of lymphocytosis (< 30%) supports IPF diagnosis
Incomplete histologic confirmation
Role of BAL in diagnosis still unclear
Usefulness of BAL in Diagnosis of IPF: Conclusions
BAL results in this study led to a change in diagnosis in 6 of the 74 patients (8%).
Several caveats have a bearing on the interpretation of this work.
The patients with NSIP may also have had IPF, so the diagnosis may have been incomplete, rather than incorrect
It is not clear why the environmental exposures of the patients with HP were not identified during the initial workup
Since surgical lung biopsies were not systematically performed on the patients without lymphocytosis, it is unknown how many do not have UIP consistent with the IPF diagnosis
Though the authors conclude that BAL is a useful diagnostic test in patients with a confident HRCT diagnosis and consistent clinical features in the absence of a surgical biopsy, the true utility is yet to be demonstrated. BAL analysis will be addressed in the revised ATS/ERS guidelines, expected in 2010.
Ohshimo S, et al. Am J Respir Crit Care Med. 2009;179:
Ohshimo S, Bonella F, Cui A, et al. Significance of bronchoalveolar lavage for the diagnosis of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2009;179: 18

19. IPF Prognosis At Time of Diagnosis (Baseline) Follow Up (Dynamic)
Clinical
Dyspnea
Physiologic
DLCO
6MWT desaturation
A-a gradient
Pulmonary hypertension
VO2MAX
Radiologic
HRCT pattern (honeycombing)
Extent of fibrosis
Emerging Markers
Clinical
Dyspnea
Physiologic
Forced vital capacity
DLCO
IPF Prognosis
The prognosis of patients with IPF can be evaluated both at the time of diagnosis and by assessing functional changes over time. Baseline predictors include clinical signs (dyspnea), physiologic variables (gas exchange [DLCO], 6MWT desaturation, A-a gradient, pulmonary hypertension [PH]) and radiologic variables (HRCT pattern). Dynamic changes in dyspnea as well as physiologic parameters such as FVC and DLCO are also associated with mortality in patients with IPF.
Nathan SD, Noble PW, Tuder RM. Idiopathic pulmonary fibrosis and pulmonary hypertension: connecting the dots. Am J Respir Crit Care Med. 2007;175:

20. Baseline HRCT Appearance
Survival
HRCT definite UIP and biopsy UIP
2.1 years
HRCT indeterminate and biopsy UIP
5.8 years
Baseline HRCT Appearance
In this study, Flaherty and colleagues assessed the survival of patients with definite or indeterminate HRCT features in patients with histologic UIP (n = 73) or histologic NSIP (n = 23). The combination of biopsy and HRCT findings separated the patients into groups with different prognoses. Patients with both a definite IPF HRCT finding and histologic diagnosis of UIP had the shortest median survival (2.1 years). Those with histologic UIP and an indeterminate HRCT diagnosis had an intermediate survival (5.8 years) while those with histologic NSIP and an indeterminate IPF or NSIP diagnosis on HRCT had the best median survival (> 9 years, data not shown in slide).
In another study by Lynch and colleagues, thoracic radiologists scored HRCT scans from 315 IPF patients enrolled in a trial evaluating IFN -1b. High overall disease extent, reticulation, and honeycombing each increased the hazard ratio of mortality to about 3.
Flaherty KR, et al. Thorax. 2003;58:
Flaherty KR, Thwaite EL, Kazerooni EA, et al. Radiological versus histological diagnosis in UIP and NSIP: survival implications. Thorax. 2003;58:
Lynch DA, Godwin JD, Safrin S, et al. High-resolution computed tomography in idiopathic pulmonary fibrosis: diagnosis and prognosis. Am J Respir Crit Care Med. 2005;172:

21. Early/Low Burden IPF HRCT
Reticular opacities with a subpleural and basal predominance
Early/Low Burden IPF HRCT
Prone HRCT near the lung bases shows fine reticular opacities in the subpleural lung. There is no visible honeycombing or traction bronchiectasis. This appearance could represent early IPF or fibrotic NSIP.
No honeycombing or traction bronchiectasis
Image courtesy of W. Richard Webb, MD.

22. Baseline HRCT Findings
Sumikawa et al
98 cases of IPF
Quantified various HRCT findings
Traction bronchiectasis and “fibrosis score” associated with survival
Best et al
167 cases of IPF (Interferon beta trial)
Extent of fibrosis (combined reticulation and honeycombing) associated with survival
Baseline HRCT Findings
Sumikawa et al studied 98 patients with a histologic diagnosis of UIP and a clinical diagnosis of IPF to clarify the correlation between the CT findings and mortality. Thirty-three of the 98 CT scans were classified as definite UIP, 36 as consistent with UIP, and 29 as suggestive of an alternative diagnosis. The mean survival was 45.7, 57.9, and 76.9 months, respectively. There was no significant difference in survival among the three categories (all P > 0.05). On univariate Cox regression analysis, all abnormalities, including airspace consolidation, honeycombing, architectural distortion, traction bronchiectasis, fibrosis score, and heterogeneous overall impression, were significant predictors (hazard ratios: 1.05, 1.10, 1.05, 1.72, 1.31, 1.12, and 4.30, respectively). On multivariate analysis, only traction bronchiectasis and fibrosis score were significant predictors of mortality (hazard ratios: 1.30 and 1.10, respectively).
Best et al retrospectively evaluated quantitative CT indexes, pulmonary function test results, and visual CT scoring as predictors of mortality and described serial changes in quantitative CT indexes over 12 months in patients with IPF. Upon univariate analysis, baseline variables predictive of death included TLC and fibrosis. Upon multivariate analysis, FVC (P = 0.006) and fibrosis (P = 0.002) were predictors of short-term mortality. In 95 patients who had both baseline and follow-up CT scans, fibrosis (P = 0.030) and MLA (mean lung attenuation, P = 0.003) showed change indicating disease progression. Visually determined disease extent on CT images is a strong independent predictor of mortality in IPF. Serial evaluation of quantitative CT measures can show disease progression in these patients.
Sumikawa H, et al. Am J Respir Crit Care Med. 2008;177:
Best AC, et al. Radiology. 2008;246:
Sumikawa H, Johkoh T, Colby TV, et al. Computed tomography findings in pathological usual interstitial pneumonia; relationship to survival. Am J Respir Crit Care Med. 2008;177:
Best AC, Meng J, Lynch AM, et al. Idiopathic pulmonary fibrosis: physiologic tests, quantitative CT indexes, and CT visual scores as predictors of mortality. Radiology. 2008;246:

23. Nonspecific Interstitial Pneumonia “Classic”
Fine reticulation
Ground-glass opacities
Traction bronchiectasis
Subpleural sparing
Temporal uniformity on biopsy
No/few fibroblastic foci
Nonspecific Interstitial Pneumonia “Classic”
Supine HRCT in a patient with NSIP proven on lung biopsy. Ground-glass opacity is visible, with a basal predominance. Notice that reticular opacities and traction bronchiectasis (arrows) are associated with the ground-glass opacities. This latter finding indicates that fibrosis is likely present. Note that the immediate subpleural lung is relatively spared. Subpleural sparing strongly suggests NSIP, but is not always present.
The lung typically has uniform involvement on biopsy, but the distribution of the lesions is often patchy. Fibroblastic foci, the key lesion in UIP, are absent or inconspicuous.
American Thoracic Society. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med. 2002;165:
ATS/ERS. Am J Respir Crit Care Med. 2002;165:

24. Chronic Hypersensitivity Pneumonitis: HRCT
Contrast-enhanced thin-slice CT in a patient with chronic hypersensitivity pneumonitis (HP) and dyspnea. Reticulation, traction bronchiectasis, and honeycombing (red arrows) are visible, diffusely involving the central as well as peripheral lung regions. Note that the upper lobes (shown here) are extensively involved. This distribution (ie, central as well as peripheral lung, upper lobes) is often seen with chronic hypersensitivity pneumonitis, but would be unusual with IPF. Note that the main pulmonary artery (PA) is dilated as a result of associated pulmonary hypertension. Superimposed ground-glass opacity and air-trapping are also visible in the left lung. These findings are sometimes seen in chronic HP.
Image courtesy of W. Richard Webb, MD. 24

25. Distinguishing IPF From HP
A histologic pattern of UIP can be seen in both IPF and HP; however the UIP pattern produced by hypersensitivity can be distinguished from that associated with IPF based on the presence of interstitial granulomas (black arrows) with associated multinucleated giant cells. These may be infrequent in late hypersensitivity.
Image courtesy of Kevin O. Leslie, MD. 25

26. Research findings, pending clinical validation
Biomarkers for IPF
Research findings, pending clinical validation
Not widely available
Surfactant proteins A & D
KL-6
Serum CCL18
Matrix Metallo-Proteases (MMP1/MMP7)
Circulating fibrocytes
Biomarkers for IPF
Surfactant proteins-A (SP-A) and -D (SP-D) are produced and secreted by type II cells. Serum SP-A and SP-D levels were significantly elevated in patients with IPF and systemic sclerosis compared to sarcoidosis, beryllium disease and normal controls, and the level of SP-D correlated with radiographic abnormalities in patients with IPF.1 Serum SP-A and SP-D levels were highly predictive of survival in patients with IPF.
Circulating levels of glycoprotein KL-6 are elevated in a majority of patients with a number of ILDs, including IPF. Yokoyama et al2 retrospectively compared the serum KL-6 level at IPF diagnosis with prognosis. Variables such as age, FVC%, PaO2 at rest, initial LDH level, CRP and KL-6 were assessed. Multivariate analysis revealed that KL-6 was a predictor of prognosis. The median survival of patients with KL-6 < 1000 U/mL was more than 36 months, whereas that of patients with high KL-6 was only 18 months. The baseline level of the myeloid cell product CCL18 predicted changes in TLC and FVC at the 6-month follow-up.3
A search for plasma markers for IPF4 revealed a group of proteins that distinguish IPF. MMP7 and MMP1 concentrations were not increased in patients with COPD or sarcoidosis and were significantly (P < 0.01, P < 0.001, resp) higher in IPF compared to HP. MMP7 concentrations were significantly (P < ) higher in IPF patients compared to controls in an independent validation cohort. Furthermore, MMP7 concentrations were significantly (P < 0.02) elevated in patients with subclinical ILD and IPF (P < 0.02, P < , resp); both predicted FVC% and DLCO% were negatively correlated with MMP7 (P = 0.002).
Peripheral blood fibrocyte levels were higher in patients with IPF than in control subjects, and were highest in patients experiencing an exacerbation.5
These biomarkers are at the discovery phase and may become extremely useful after development and clinical validation.
Prasse A, et al. Respirology. 2009;14:
Rosas IO, et al. PLoS Med. 2008;5:e93.
Nakamura M, Ogura T, Miyazawa N, et al. Outcome of patients with acute exacerbation of idiopathic interstitial fibrosis (IPF) treated with sivelestat and the prognostic value of serum KL-6 and surfactant protein D. Nihon Kokyuki Gakkai Zasshi. 2007;45:
Yokoyama A, Kohno N, Hamada H, et al. Circulating KL-6 predicts the outcome of rapidly progressive idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 1998;158:
3. Prasse A, Probst C, Bargagli E, et al. Serum CC-chemokine ligand 18 concentration predicts outcome in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2009;179:
4. Rosas IO, Richards TJ, Konishi K, et al. MMP1 and MMP7 as potential peripheral blood biomarkers in idiopathic pulmonary fibrosis. PLoS Med. 2008;5:e93.
5. Moeller A, Gilpin SE, Ask K, et al. Circulating fibrocytes are an indicator of poor prognosis in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2009;179:

27. Elevated Baseline CCL18 Predicts Mortality
CCL18 < 150 ng/ml
P < 0.001
Cumulative Survival
CCL18 > 150 ng/ml
Time to Death (months)
Serum CC-Chemokine Ligand 18
Cut off = 150 ng/ml  HR = 7.63 (P < )
Baseline factors not different between groups (age, gender, smoking hx, spirometry, therapy hx, etc.)
Elevated Baseline CCL18 Predicts Mortality
CCL18 is a human chemokine produced by alveolar macrophages which stimulates collagen production by lung fibroblasts. This prospective study tests the value of serum CCL18 concentrations in predicting the course of IPF. 72 patients were followed for 24 months; pulmonary function tests were performed at least every 6 months.
Baseline serum CCL18 concentrations correlated with the change in TLC and FVC at the 6-month follow-up (r = 0.59 and 0.54, respectively; each P < ).
ROC analysis indicates that a cutoff of 150 ng/ml yields the highest diagnostic accuracy. Kaplan-Meier survival analysis shows that patients with elevated CCL18 have higher mortality (graph) and shorter progression-free survival (data not shown, both P < 0.001). The hazard proportional ratio adjusted for age, sex, and baseline pulmonary function data was 8.0.
These data suggest that serum CCL18 may be a useful biomarker for predicting the disease course of IPF.
Prasse A, Probst C, Bargagli E, et al. Serum CC-chemokine ligand 18 concentration predicts outcome in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2009;179:
Prasse A, et al. Am J Respir Crit Care Med. 2009;179:

28. Heart Rate Recovery After 6MWT Predicts Survival in IPF
Proportion of Subjects Alive
Days of Follow-Up
 HR 1 min after 6MWT > 13bpm
HR 1 min after 6MWT ≤ 13bpm
P = (log rank test)
Heart Rate Recovery (HRR) after 6MWT Predicts Survival in IPF This study investigated HRR after a 6MWT. HRR impairment was defined as a failure of the heart rate to drop by 13 beats at 1 minute and 22 beats at 2 minutes after exercise termination in a 6MWT.
Evaluation of data from 76 subjects with IPF showed that abnormal HRR at 1 min was predicted by DLCO% (OR = 0.4 per 10% predicted, P = 0.003) and a right ventricular systolic pressure (RVSP) > 35 mm Hg by echocardiogram (OR = 12.7, P = 0.01). Subjects with an abnormal HRR at 1 min had worse survival than subjects with a normal HRR (log-rank P-value = ). This finding held true in subjects without elevated RVSP. In a multivariable model including several prognostic variables, abnormal HRR at 1 min was a significant predictor of mortality (HR = 5.2, 95% confidence interval , P = 0.004). With clinical validation in a larger patient population, HRR after 6MWT could be a simple and useful prognostic indicator in IPF.
Conclusions
Elevated RVSP and DLCO% predict abnormal HRR
Abnormal HRR is a significant predictor of mortality, even without elevated RVSP
Swigris JJ, et al. Chest. 2009;136:
Swigris JJ, Swick J, Wamboldt FS, et al. Heart rate recovery (HRR) after 6-Min walk test predicts survival in patients with idiopathic pulmonary fibrosis. Chest. 2009;136:

29. Predictors of Disease Severity and Progression in IPF
TESTS/CLINICAL FACTORS
PREDICTIVE VALUE
DLCO
< 35% predicted associated with worse survival
6MWT
O2 sat  88% increased mortality risk for IPF & NSIP
Walk distance correlates with mortality
FVC
Initial value correlates with mortality
Change over time correlates with progression
Pulmonary hypertension
Associated with higher mortality
Dyspnea score
Correlates with disease progression
Respiratory event
Predicts worse survival
Predictors of Disease Severity and Progression in IPF
This slide summarizes the predictive value of various clinical factors in the progression of IPF. Patients with compromised lung function or respiratory events have worse outcomes.

30. Monitoring Patients with IPF
Every 3 to 6 months:
Spirometry
Diffusion
6MWT
QOL (patient questionnaire to assess dyspnea)
O2 requirement
Comorbidities
HRCT should be done only with clinical change
Monitoring Patients with IPF
It is recommended that patients with IPF be routinely evaluated every 3 to 6 months. The evaluation should comprise: spirometry, diffusion testing, a 6MWT, a patient questionnaire to assess dyspnea and QOL, determination of the patient’s O2 requirement, and review of comorbidities. An HRCT is recommended only with a clinical change.

31. Evaluation for Lung Transplantation
Early referral
SpO2 ≤ 88%1
Defines desaturation on 6MWT
Calls for O2 supplemented 6MWT
Distinguishes early/advanced disease
Lung Allocation Score (LAS) used to prioritize candidates2
Survival on list (urgency)
Survival posttransplant (benefit)
Evaluation for Lung Transplantation
It is strongly recommended that evaluation for lung transplantation is initiated at the time of diagnosis of IPF. A DLCO ≤ 88% predicted on 6MWT is a useful definition of desaturation and is recommended as a criterion for distinguishing early and advanced disease. The lung allocation score (LAS) is used to rank transplant recipient candidates, and is composed of survival likelihoods before and after transplantation.
Lama VN, Flaherty KR, Toews GB, et al. Prognostic value of desaturation during a 6-minute walk test in idiopathic interstitial pneumonia. Am J Respir Crit Care Med. 2003;168:
A Guide to Calculating the Lung Allocation Score.
Accessed August 2010.
1. Lama VN, Flaherty KR, Toews GB, et al. Prognostic value of desaturation during a 6-minute walk test in idiopathic interstitial pneumonia. Am J Respir Crit Care Med. 2003;168:
2. A Guide to Calculating the Lung Allocation Score.
score_updated_ pdf. Accessed August 2010.

32. Diagnosis Take Home Messages
Typical clinical features include age > 50 years, gender (male > female), insidious onset of dyspnea, nonproductive cough, and bibasilar Velcro® crackles
Atypical clinical or HRCT findings in a patient with suspected IPF should prompt consideration of a surgical lung biopsy. With a confident clinical and HRCT diagnosis, a biopsy is not recommended
IPF has characteristic UIP histopathologic features that enable definitive diagnosis when clinical and HRCT findings are inconclusive
Diagnosis Take Home Messages
Though IPF is a common interstitial lung disease, accurate diagnosis is important for prognosis and management. Some genetic and environmental factors have been identified which increase the risk of IPF.
None of the individual features of IPF are unique; all findings, including clinical presentation, lung function tests, serology, radiology, and sometimes histology must be considered in the differential diagnosis.
Typical clinical features include age > 50 years, gender (male > female), insidious onset of dyspnea, nonproductive cough, and bibasilar inspiratory crackles
Atypical clinical or radiologic findings in a patient with suspected IPF should prompt consideration of a surgical lung biopsy for staining and microscopic examination. With a confident clinical and HRCT diagnosis, a biopsy is not recommended
IPF has characteristic UIP histologic features that enable definitive diagnosis when clinical and radiologic findings are inconclusive
Revised ATS/ERS guidelines for diagnosis of IPF are expected in 2010.

33. Monitoring Take Home Messages
Both baseline and dynamic factors measured during monitoring of IPF are associated with an increased risk of mortality
Prognostic indicators do not fully predict the course of disease for an individual patient
Patients should be monitored every 3 to 6 months for comorbidities and progression of IPF
Monitoring Take Home Messages
There are a number of baseline predictors associated with an increased risk of mortality:
Low DLCO
A-a gradient
Desaturation during a 6MWT (SaO2 < 88%)
Pulmonary arterial hypertension (mPAP > 25 mm Hg)
Honeycombing on HRCT
The best dynamic predictors of prognosis are:
Change in FVC % predicted
Change in DLCO % predicted
Dyspnea
Despite the usefulness of these prognostic indicators, disease progression is not always linear. Patients can have relatively stable lung function or rapid decline in lung function. Prognostic indicators do not predict the course of disease for an individual patient.
Patients should be monitored every 3 to 6 months for spirometry, diffusion testing, a 6MWT, a patient questionnaire to assess dyspnea and QOL, determination of the patient’s O2 requirement, and review of comorbidities. Follow-up HRCT is not recommended except with significant clinical change.