1. Assessment of Patients with IPF

2. Educational Activity Learning Objective
Describe the most appropriate lung function tests to assess and manage patients with IPF

3. US Demographics of IPF Prevalence Incidence50
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 a recent analysis using age, medical claim, and differential diagnosis criteria, Raghu and colleagues estimate 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. Hereditary factors may contribute, although no specific genetic markers have been identified. 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. 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. The diagnostic process will be addressed in more detail later in this section.
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.

6. Diagnosing Chronic Exertional Dyspnea
Differential Diagnosis
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
Basilar Velcro® crackles? no
yes
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.
Asthma, COPD
ILD
Typical HRCT scan
Confident diagnosis of IPF
Image courtesy of Steven A. Sahn, MD.

7. 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.
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:

8. 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
This slide illustrates the 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 (2009).
All major criteria and at least 3 minor criteria must be present to increase the likelihood of an IPF diagnosis
Criteria currently under revision (2009)
*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:

9. Role of Bronchoscopy in the Diagnosis of IPF
Updated
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 bronchoalveolar lavage (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/European Respiratory Society. International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med. 2002;165:
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:
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(11):
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(11): 9

10. Occurrence of Granulocytosis and Lymphocytosis
Updated
Occurrence of Granulocytosis and Lymphocytosis
G only: 59
IPF
Neither G nor L: 9
IPF
Occurrence of Granulocytosis and Lymphocytosis
This Venn diagram shows the distribution of granulocytosis (≥ 3% in BAL), lymphocytosis (≥ 30% in BAL), and the final diagnoses. 59 patients displayed granulocytosis only, 2 patients displayed lymphocytosis only, 4 patients displayed both conditions, and 9 patients displayed neither. The diagnosis of IPF in the 68 patients without lymphocytosis was unchanged after BAL.
Careful clinical histories of the 6 patients with lymphocytosis revealed that 3 had a history of exposure to birds and mold, humidifier water, or moldy hay. Two of the 3 individuals with granulocytosis and lymphocytosis had biopsy results suggesting NSIP and the third had a clinical course suggesting NSIP. Histologic results of UIP from the remaining patients with IPF would have supported the diagnosis of IPF.
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(11):
G&L: 4
EAA
L only: 2
3 NSIP
1 EAA
Ohshimo S, et al. Am J Respir Crit Care Med. 2009;179(11): 10

11. Usefulness of BAL in Diagnosis of IPF: Conclusions
Updated
Usefulness of BAL in Diagnosis of IPF: Conclusions
8% of IPF diagnoses were wrong
4% NSIP
4% EAA, 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 EAA 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.
Ohshimo S, et al. Am J Respir Crit Care Med. 2009;179(11):
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(11): 11

12. Serologic Tests Can Help Exclude Other Conditions
ESR
ANA
CCP (for RA) CK
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 Exclude Other Conditions
The routine laboratory evaluation of patients with suspected IPF is helpful to rule out other causes of clinical symptoms. These 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-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:

13. 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:

14. 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 Alternate 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 opacities 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:

15. 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.

16. Pathological Sections Demonstrating UIP
a. Peripheral accentuation of disease
b. Transition into uninvolved lung
Fibrosis
Normal lung
Fibroblast
focus
Normal lung
Normal lung
d. High power image of fibroblastic foci
c. Microscopic honeycombing
Myofibroblasts
Chronic inflammation
Pathological Sections Demonstrating UIP
UIP is the pathology 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
Mucus-filled cysts
Courtesy of Kevin O. Leslie, MD.
Courtesy of Kevin O. Leslie, MD.
Pleura
Images courtesy of Kevin O. Leslie, MD.

17. IPF Prognosis At Time of Diagnosis Follow Up (Baseline) (Dynamic)
Clinical
Dyspnea
Physiologic
DLCO
6MWT desaturation
A-a gradient
Pulmonary hypertension
Radiologic
HRCT pattern
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:

18. 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:

19. 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, 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:

20. Chronic Hypersensitivity Pneumonitis: HRCT
Updated
Chronic Hypersensitivity Pneumonitis: HRCT
Chronic Hypersensitivity Pneumonitis: HRCT
Contrast-enhanced thin-slice CT in a patient with chronic hypersensitivity pneumonitis 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. 20

21. Chronic Hypersensitivity Pneumonitis: Histopathology
Updated
Chronic Hypersensitivity Pneumonitis: Histopathology
Chronic Hypersensitivity Pneumonitis: Histopathology
This histopathology image from a biopsy of a patient with chronic hypersensitivity pneumonitis illustrates the occasional histopathologic similarity that can occur between chronic hypersensitivity reactions and usual interstitial pneumonia. Note the heterogeneity in this image with normal lung alternating with areas of fibrosis (f) and chronic inflammation (black arrows). A fibroblast focus can be seen here (green arrow).
Image courtesy of Kevin O. Leslie, MD. 21

22. Distinguishing IPF From HP
Updated
Distinguishing IPF From HP
A histologic pattern can be seen in both IPF and hypersensitivity pneumonitis; 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. 22

23. Subacute Hypersensitivity Pneumonitis: HRCT
Updated
Subacute Hypersensitivity Pneumonitis: HRCT
Subacute Hypersensitivity Pneumonitis: HRCT
HRCT in a patient with subacute hypersensitivity pneumonitis and progressive dyspnea shows a diffuse distribution of centrilobular nodules of ground-glass opacity. This finding is seen in some patients with subacute hypersensitivity pneumonitis and reflects the presence of peribronchiolar inflammation. This pattern would not be seen in IPF.
Image courtesy of W. Richard Webb, MD. 23

24. Subacute Hypersensitivity: Histopathology
Updated
Subacute Hypersensitivity: Histopathology
In subacute hypersensitivity pneumonitis the inflammatory reaction often has a centrilobular distribution (circle), consistent with the inhalational nature of the antigen exposure in this disease process. The interlobular septa (ILS) are clearly visible here because of edema. In the higher magnification on the right, interstitial granulomas (gr) are visible and help solidify the diagnosis.
Higher Magnification
Images courtesy of Kevin O. Leslie, MD. 24

25. Scleroderma: HRCT Updated Image courtesy of W. Richard Webb, MD. 25
HRCT in a 34-year-old woman with scleroderma shows reticulation, traction bronchiectasis, and ground-glass opacity with a posterior, subpleural, and lower lobe predominance. No definite honeycombing is present. The major fissures are displaced posteriorly (red arrows) as a result of fibrosis and volume loss. These findings are consistent with fibrotic NSIP associated with scleroderma. IPF without honeycombing could have a similar appearance. Note that the esophagus is dilated (blue arrow), a finding typical of scleroderma.
Image courtesy of W. Richard Webb, MD. 25

26. Scleroderma NSIP Updated Image A Image B
This image illustrates the inflammatory "alveolitis" of scleroderma lung. Note the irregular thickening of alveolar walls by inflammatory cells (arrows), sometimes making lymphoid aggregates (LA). Even the thinnest alveolar walls here are inflamed.
Image B
In another area from this patient's biopsy, the alveolar walls are distended by collagen (arrows), fibroblasts, and some chronic inflammation (blue cells here). This picture is one of classic "fibrotic NSIP," although in this case it is not idiopathic NSIP but NSIP related to scleroderma. This mild degree of microscopic fibrosis without confluence can produce ground glass attenuation on HRCT.
Image A
Image B
Images courtesy of Kevin O. Leslie, MD. 26

27. Conditions That Give a Pattern of UIP
Updated
Conditions That Give a Pattern of UIP
IPF
Asbestosis
Chronic hypersensitivity pneumonitis
Connective tissue diseases
Toxic drug reactions
Acute interstitial pneumonia
Conditions That Give a 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(7): 27

28. Biomarkers for IPF Matrix Metallo-Proteases (MMP1/MMP7)1
Research findings, pending clinical validation
Matrix Metallo-Proteases (MMP1/MMP7)1
Surfactant proteins A & D2
TGFb-13
KL-64
Collagen turnover products (PIIINP, ICTP, PYD/DYD)5
Emerging markers
Biomarkers for IPF
A recent search for plasma markers for IPF1 revealed a group of proteins that can be used to 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); we found that both predicted FVC% and DLCO% were negatively correlated with MMP7 (P = 0.002).
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.2 Serum SP-A and SP-D levels were highly predictive of survival in patients with IPF.
A 2008 ATS poster (919) investigated several markers in IPF, including TGFβ-1, KL-6 and SP-D.3 Analysis of plasma and lung tissue revealed that total TGFβ -1 was significantly higher in patients with severe disease vs controls (P = 0.006); the same was true for active TGF-1 (P = 0.01). SP-D and KL-6 were higher in disease vs controls (P = 0.002, P = 0.006). A combination of active TGF-1 and SP-D correlated with disease severity. Patients with pulmonary hypertension (PH) had higher active TGFβ -1 than those without PH (P = ).
Circulating levels of glycoprotein KL-6 are elevated in a majority of patients with a number of ILDs, including IPF. Yokoyama et al4 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.
Another ATS poster (907) analyzed serum from patients with UIP. Procollagen III N-propeptide (PIIINP), a marker of collagen synthesis, carboxy-terminal telopeptide of type I collagen (ICTP), marker for collagen breakdown, and serum as well as urinary pyridinoline/deoxypyridinoline (PYD/DYD) maturation products of collagen crosslinks, were all significantly increased (P < 0.05) in UIP patients with respect to volunteer controls. Collagen turnover marker levels were all positively correlated to 6 minute walk, VO2max, and lung volume results (r2 = 0.6).
These biomarkers are at the discovery phase and may become extremely useful after development and clinical validation.
Rosas IO, et al. PLoS Med. 2008;5:e93.
Nakamura M, et al. Nihon Kokyuki Gakkai Zasshi. 2007;45:
Greene KE, et al. Eur Respir J. 2002;19:
Allam JS, et al. ATS 2008 poster 919.
Yokoyama A, et al. Am J Respir Crit Care Med. 1998;158:
Schaberg T, et al. Eur Respir J. 1994;7: Hiwatari N, et al. Tohoku J Exp Med. 1997;181(2): Froese AR, et al. ATS 2008 poster 907.
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.
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: Greene KE, King TE Jr, Kuroki Y, et al. Serum surfactant proteins-A and -D as biomarkers in idiopathic pulmonary fibrosis. Eur Respir J. 2002;19:
Allam JS, Kootom TJ, Vuk-Pavlovic Z, Limper AH. Biomarkers in idiopathic pulmonary fibrosis: a lung tissue research consortium based study. Poster presented at: 2008 ATS Annual Meeting; May 18, 2008; Toronto, Canada.
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:
Schaberg T, Orzechowski K, Oesterling C, Lode H, Schuppan D. Simultaneous measurement of collagen type-VI-related antigen and procollagen type-III-N-propeptide levels in bronchoalveolar lavage. Eur Respir J.1994;7: Hiwatari N, Shimura S, Yamauchi K, Nara M, Hida W, Shirato K. Significance of elevated procollagen-III-peptide and transforming growth factor-beta levels of bronchoalveolar lavage fluids from idiopathic pulmonary fibrosis patients. Tohoku J Exp Med. 1997;181(2): Froese AR, Moeller A, Ask K, Gauldie J, Kolb M. Markers of disease activity and lung function in UIP: collagen turnover products. Poster presented at: 2008 ATS Annual Meeting; May 18, 2008; Toronto, Canada.

29. MMPs as Peripheral Biomarkers
Updated
MMPs as Peripheral Biomarkers
Are there peripheral biomarkers which enhance the sensitivity or specificity of diagnosing IPF?
49 candidate proteins individually and in combination
Patients
74 with IPF
47 with sarcoidosis
73 with COPD
41 with HP
53 controls
Validate results in separate cohort
MMPs as Peripheral Biomarkers
The plasma concentrations of 49 candidate proteins were assessed to identify a peripheral blood protein signature of IPF. The concentrations of candidate analytes were determined in plasma from patients with IPF, COPD, sarcoidosis, hypersensitivity pneumonitis (HP), and controls.
After candidates were identified, a separate validation cohort was assayed, which consisted of patients with sporadic IPF, subclinical ILD, familial IPF, and controls. Oligonucleotide arrays were used to probe gene expression levels in lung and BAL fluid was assayed for the presence of selected proteins (data not shown).
Rosas IO, Richards TJ, Konishi K, et al. MMP1 and MMP7 as potential peripheral blood biomarkers in idiopathic pulmonary fibrosis. PLoS Med. 2008;5(4):e93.
Rosas IO, et al. PLoS Med. 2008;5(4):e93. 29

30. MMPs as Peripheral Biomarkers
Updated
MMPs as Peripheral Biomarkers
MMP-7
MMP-1
MMPs as Peripheral Biomarkers
Plasma levels of twelve proteins were found to be different between IPF and controls, and a combination of 5 proteins (MMP7, MMP1, MMP8, IGFBP1, and TNFRSF1A) could distinguish these groups with a sensitivity of 98.6% and a specificity of 98.1%. Serum matrix metalloproteinase 1 (MMP1) and matrix metalloproteinase 7 (MMP7) were elevated in the plasma of patients with IPF; levels of these proteins discriminate between patients with IPF and controls, as well as patients with COPD, HP, and sarcoidosis. The combination of serum MMP1 and MMP7 had higher sensitivity and specificity than either marker alone. MMP7 levels correlate with disease severity and are significantly elevated in patients with subclinical interstitial lung disease (ILD).
Blood markers that sensitively and specifically define IPF would be a great advance in pulmonary medicine and could obviate the need for an open lung biopsy. Ideally, a profile of blood markers would give a definitive diagnosis of all ILDs. A limitation of this paper is that both the original study cohort and the validation cohort are small and do not include important idiopathic interstitial pneumonias such as non-specific interstitial pneumonitis (NSIP) that have a markedly different clinical course than IPF.
Rosas IO, Richards TJ, Konishi K, et al. MMP1 and MMP7 as potential peripheral blood biomarkers in idiopathic pulmonary fibrosis. PLoS Med. 2008;5(4):e93.
P <
P = 0.018
Rosas IO, et al. PLoS Med. 2008;5(4):e93. 30

31. KL-6 Predicts Survival in ILD
P = log-rank test
KL-6 Predicts Survival in IPF
KL-6, a high molecular weight glycoprotein, is a marker of type 2 alveolar epithelial cell injury and repair. Satoh et al studied 219 patients diagnosed with ILDs (152 with idiopathic interstitial pneumonia and 67 with collagen disease-associated pulmonary fibrosis). Patients who died of respiratory failure (58/219) during the follow-up period had higher levels of KL-6 than did those who did not (P = ).
The receiver operating characteristic curve analysis showed 1000 U/mL as the most suitable cut-off level to distinguish the two groups of patients. In univariate and multivariate analyses, elevated serum KL-6 (> 1000 U/mL) indicated poor prognosis (P = , log-rank test; P = , Cox proportional hazard model). Thus, elevated KL-6 level may be a way to identify patients with ILDs who are at increased risk for mortality. The KL-6 assay is not easily available in the US.
Satoh’s publication is consistent with other studies by Yokoyama and colleagues.
Total ILD n = 219
IPF n = 152
Satoh H, et al. J Intern Med. 2006;260:
Satoh H, Kurishima K, Ishikawa H, Ohtsuka M. Increased levels of KL-6 and subsequent mortality in patients with interstitial lung diseases. J Intern Med. 2006;260:429–434.
Yokiyama A, Kondo K, Nakajima M, et al. Prognostic value of circulating KL-6 in idiopathic pulmonary fibrosis. Respirology. 2006;11:
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:

32. Brain Natriuretic Peptide (BNP) Ratio and Survival
100 80 60
BNP ratio Normal
Percent Survival
BNP ratio High 40 20
N = 131 5 10 15 20 25
Time (months)
BNP Ratio
Mean Survival
1-year Mortality
Hazard Ratio
≥ 1
11 mo
70.5%
4.1
< 1
22.5 mo
23.7% 1
P-value
< 0.001
Brain Natriuretic Peptide (BNP) Ratio and Survival
Song and colleagues1 did a retrospective review of records of patients with IPF to evaluate the prognostic value of pulmonary hypertension (PH) assessed by echocardiography and brain natriuretic peptide (BNP) levels. BNP is a polypeptide secreted by the heart in response to excessive stretching of cardiomyocytes and has been used as a marker of right ventricular dysfunction and pulmonary arterial hypertension. A normalized BNP ratio was calculated by dividing the measured value by age- and gender-adjusted normal values.2 A ratio > 1 indicates an increase in plasma BNP concentration.
The prognosis of the subjects with increased BNP levels was poorer than those with normal BNP levels (1-year mortality rate: 70.5% vs. 23.7%, mean survival: 11.0 months vs months; P < 0.001). The hazard ratio for elevated BNP ratio was 4.1. Thus, the BNP level was an independent predictor of prognosis.
BNP ratio: measured value of BNP divided by age- and gender-adjusted normal values
Song JW, et al. Respir Med. 2009;103:
1. Song JW, Song JK, Kim DS. Echocardiography and brain natriuretic peptide as prognostic indicators in idiopathic pulmonary fibrosis. Respir Med. 2009;103(2):
2. Leuchte HH, El Nounou M, Tuerpe JC, et al. N-terminal pro-brain natriuretic peptide and renal insufficiency as predictors of mortality in pulmonary hypertension. Chest. 2007;131:

33. Song JW, et al. Respir Med. 2009;103:180-186.
sPAP, BNP, and Survival
sPAP < 40 mmHg + BNP ratio < 1
either sPAP ≥ 40 mmHg or BNP ratio ≥ 1
sPAP ≥ 40 mmHg + BNP ratio ≥ 1
vs P < 0.001
sPAP, BNP, and Survival
Although right heart catheterization is the definitive method for diagnosing PH, it is more invasive and difficult than echocardiography. The data in this figure are from the same observational study as the previous slide. Using systolic pulmonary arterial pressure of 40 mmHg as a threshold for PH, patients with PH had poorer survival (1-year mortality rate: 61.2%, mean survival: 10.8 months) than those without PH (19.9%, 23.7 months; p < 0.001). This figure shows the survival of patients stratified by PH:
On multivariate analysis, only the BNP level was an independent prognostic marker, leading the authors to suggest that BNP is a superior prognostic marker to sPAP for patients with IPF. The combination of the two indices provided a better prediction of prognosis than either alone.
Song JW, Song JK, Kim DS. Echocardiography and brain natriuretic peptide as prognostic indicators in idiopathic pulmonary fibrosis. Respir Med. 2009;103(2):
vs P < 0.009
Song JW, et al. Respir Med. 2009;103:

34. Albumin as a Predictor of Outcomes in IPF
Group
Serum Albumin, g/dL
Adjusted HR 1
1.7 to 3.3
5.8 2
3.4 to 3.7
2.3 3
3.8 to 4.1
1.9 4
4.2 to 4.5
1.8 5
4.6 – 5.3
1.0
Albumin as a Predictor of Outcomes in IPF
Hypoalbuminemia is a predictor of mortality in a variety of illnesses. The study presented on this slide evaluated the relationship of serum albumin level at the time of listing for lung transplantation and mortality during the wait in a cohort of patients with idiopathic interstitial pneumonia (IIP).
As seen in the figure, lower serum albumin was associated with increased mortality rate. The adjusted hazard ratio increases as the concentration of serum albumin decreases. Analysis with serum albumin as a continuous predictor indicated that the mortality rate increased by 54% with each 0.5 g/dL decrease in serum albumin concentration.
Zisman DA, Kawut SM, Lederer DJ, et al. Serum albumin concentration and waiting list mortality in idiopathic interstitial pneumonia. Chest. 2009;135(4):
P < (log-rank test)
Zisman DA, et al. Chest. 2009;135:

35. Baseline Serum SP-A Predicts Survival
Overall Survival (fraction)
Tertile
1st
2nd
3rd
Baseline Serum SP-A Predicts Survival
Serum surfactant protein (SP) A and SP-D have been shown to predict 1 year mortality in patients with IPF.1,2 This was prior to the reclassification of the idiopathic interstitial pneumonias; Kinder and colleagues3 evaluated the association between serum SP-A and SP-D concentrations and mortality in 82 patients with surgical lung biopsy-proven IPF.
The figure on this slide shows the Kaplan-Meier survival curves of patients with IPF based on serum SP-A level tertiles (≤ 80.4 ng/mL, 81 to 123 ng/mL, and > 123 ng/mL; P = [log rank test]; patients at risk: year 1, 68; year 2, 55; year 3, 43).
Follow-up Time (years)
P = (log rank test)
Kinder BW, et al. Chest. 2009;135(6):
1. Takahashi H, Fujishima T, Koba H, et al. Serum surfactant proteins A and D as prognostic factors in idiopathic pulmonary fibrosis and their relationship to disease extent. Am J Respir Crit Care Med. 2000;162:1109–1114.
2. Greene KE, King TE Jr, Kuroki Y, et al. Serum surfactant proteins-A and -D as biomarkers in idiopathic pulmonary fibrosis. Eur Respir J. 2002;19:439–446.
3. Kinder BW, Brown KK, McCormack FX, et al. Serum surfactant protein-A is a strong predictor of early mortality in idiopathic pulmonary fibrosis. Chest. 2009;135(6):

36. Baseline Serum SP-A Predicts Survival
Design
Serum surfactant proteins (SP-A and SP-D) assessed in 82 patients with IPF
Prospective observation (median follow-up 3.0 years)
Results
Mean SP-A at baseline = 106 ng/mL
Each increase of 49 ng/mL  3.3x increased risk of death or LT (P = 0.003)
Differences were attenuated in subsequent years
SP-D not a significant predictor of mortality
Levels of SP-A and SP-D together added value to clinical prediction (AROC = 0.83, P = 0.05)
Baseline Serum SP-A Predicts Survival
Analysis of patient survival showed that each increase of 49 ng/mL (1 SD) in baseline SP-A level was associated with a 3.3-fold increased risk of mortality (adjusted hazard ratio, 3.27; adjusted P = 0.003) in the first year after presentation. There was not significant association between serum SP-D and mortality (adjusted hazard ratio, 2.04; P = 0.053).
Area under the receiving operator curve analysis showed an improvement in the 1-year mortality prediction when both serum SP-A and SP-D were added to the clinical predictors (P = 0.03). Model 1 includes clinical parameters (age, gender, race, smoking status, FVC, DLCO, and alveolar-arterial oxygen gradient). Model 2 includes these clinical parameters, as well as serum SP-A and SP-D levels.
Kinder BW, Brown KK, McCormack FX, et al. Serum surfactant protein-A is a strong predictor of early mortality in idiopathic pulmonary fibrosis. Chest. 2009;135(6):
Kinder BW, et al. Chest. 2009;135(6):

37. Fibrocyte Level and Survival
Fibrocytes < 5%
(n = 48)
Percent Survival
P =
Fibrocytes > 5%
(n = 10)
Months
Conclusions
Fibrocyte levels did not correlate with clinical parameters
Fibrocyte levels were elevated in patients with IPF, and more elevated with AE
Predictive value yet to be determined in larger studies
Fibrocyte Level and Survival
Fibrocytes are circulating mesenchymal cell progenitors that are involved in tissue repair and fibrosis. The study on this slide investigated whether circulating fibrocytes are a marker for progression of IPF. Fibrocytes were defined as CD45+ collagen-1+ cells by flow cytometry. Peripheral blood fibrocytes were characterized in patients with stable IPF and with acute exacerbations (AEs). Fibrocyte counts were compared with clinical parameters and survival. Healthy age matched volunteers and patients with acute respiratory distress syndrome were controls.
Measurements and Main Results
Fibrocytes were significantly elevated in patients with stable IPF (N = 51), with a further increase during AEs (N = 7; P < vs. control subjects). Patients with acute respiratory distress syndrome (N = 10) were not different from healthy control subjects or stable patients with IPF. Fibrocyte levels were an independent predictor of mortality and were not correlated with PFTs or 6MWD. HRCT severity scores correlated with PFTs but not with fibrocyte levels. When patients were grouped by fibrocyte number, those with fibrocytes higher than 5% of total blood leukocytes had a mean survival of 7.5 months, compared with 27 months for patients with less than 5% (P < ).
The authors conclude that fibrocytes are an indicator for IPF disease activity and that measuring circulating fibrocytes may allow prediction of mortality in patients with IPF.
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:
Moeller A, et al. Am J Respir Crit Care Med. 2009;179:

38. 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 = 0.9 P = 0.004) and a right ventricular systolic pressure (RVSP) > 35 mmHg by echocardiogram (OR = 4.79, P = 0.03). 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 = , 95% confidence interval , P = 0.04). 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. Am J Respir Crit Care Med. 2009;179:A1122.
Swigris JJ, Swick J, Wamboldt FS, Kervitsky D, Brown KK. Heart rate recovery (HRR) after 6MWT predicts survival in IPF. Am J Respir Crit Care Med. 179;2009:A1122.

39. Predictors of Disease Severity and Progression in IPF
ASSESSMENT
PREDICTIVE VALUE
DLCO % predicted
Worse survival if < 35% predicted
< 39% = breakpoint for advanced disease
6MWT
Desaturation to  88% correlates with increased mortality risk for IPF & NSIP
Walk distance is more reproducible than SpO2 desaturation and correlates with mortality risk
FVC
Initial value correlates with mortality risk but less reliably with disease severity
Changes over time correlate quite well with disease progression
Pulmonary hypertension
PH associated with higher mortality and lower DLCO
Dyspnea score
Increased dyspnea correlates directly with progression
Respiratory event
Predicts worse survival
Predictors of Disease Severity and Progression of IPF
This slide summarizes the established elements that can be used to help predict progression of IPF. Refinement of these tools depends on accurate diagnosis, as other ILDs may have different disease courses and predictors.

40. Emerging Baseline Markers of Mortality Risk
High BNP ratio
Low serum albumin
Elevated serum SP-A
Elevated peripheral fibrocytes
Abnormal heart rate recovery after 6MWT
Emerging Baseline Markers of Mortality Risk
The emerging markers listed on this slide have been identified as candidates for predicting mortality. They should be validated in larger studies but may be useful for managing patients with IPF.

41. 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.

42. Prevalence of GERD, Diabetes and Hypothyroidism in Patients with IPF
Updated
GERD and DM
16%
GERD
29%
GERD and HT HT
HT and DM
29%
HT, DM and GERD
11%
Prevalence of GERD, Diabetes, and Hypothyroidism in Patients with IPF
Gastroesophageal reflux disease (GERD) is a frequent comorbidity of IPF and acid reflux may contribute to its pathophysiology. This retrospective study investigated the prevalence of GERD in patients with IPF and its correlation with disease severity. Proton pump inhibitor and H2 blocker use were extracted from physician notes, and symptom information was collected with a questionnaire. Initial TLC, FVC, and DLCO were correlated with the incidence and treatment of GERD.
54% of the patients with IPF had either symptoms of GERD or were receiving medication for GERD. These patients had higher TLC % and higher DLCO % than patients with neither symptoms nor medication (P = and 0.005, respectively). 31% of the patients had diabetes mellitus and 15% had hypothyroidism.
The presence of GERD symptoms or medication use did not correlate with lower pulmonary function.
Patel S, Takahashi S, Demchuk C, Doeing D, Noth I, Strek ME. Gastroesophageal reflux disease in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 179;2009:A4063 3% DM 1%
(N = 140) 5% 6%
No comorbidity
DM = diabetes mellitus
HT = hypothyroidism
GERD = gastroesophageal reflux disease
Patel S, et al. Am J Respir Crit Care Med. 2009;179:A4063.

43. Evaluation for Lung Transplantation
Pre-LT HRCT to exclude lung cancer
Early referral
DLCO ≤ 88%
Defines desaturation on 6MWT
Calls for O2 supplemented 6MWT
Distinguishes early/advanced disease
Lung Allocation Score (LAS) used to prioritize candidates
Survival on list (urgency)
Survival posttransplant (benefit)
Evaluation for Lung Transplantation
It is strongly recommended that evaluation for LT is initiated at the time of diagnosis of IPF. An HRCT is useful to exclude lung cancer. 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:

44. Take Home Messages 1
Typical clinical features include age > 50 years, gender (male > female), insidious onset of dyspnea, nonproductive cough, and bibasilar Velcro® crackles
Atypical clinical or radiologic 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 histologic features that enable definitive diagnosis when clinical and radiologic findings are inconclusive
Take Home Messages
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 not conclusive

45. Take Home Messages 2
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 3-6 months for comorbidities and progression of IPF
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 mmHg)
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.