1. Early and Accurate Diagnosis of Idiopathic Pulmonary Fibrosis (IPF)
SECTION 2
Early and Accurate Diagnosis of Idiopathic Pulmonary Fibrosis (IPF)

2. Objective
Discuss the diagnostic strategies for facilitating early and accurate diagnosis for IPF (clinical, radiologic, and pathologic evaluations)

3. Approach to Diagnosis of IPF
Clinical evaluation
Radiologic evaluation
Pathologic evaluation
Approach to Diagnosis of IPF
The general approach to the diagnosis of IPF is multifactorial and multidisciplinary. It involves primary care physicians, pulmonologists, radiologists, and pathologists. This section of slides addresses the elements involved in this diagnostic process by focusing on the clinical evaluation (history, physical examination, laboratory studies, and pulmonary physiology), radiologic evaluation (chest radiograph and HRCT), and pathologic evaluation (surgical lung biopsy).

4. Clinical Evaluation Major criteria
Exclusion of other known causes of ILD
Abnormal pulmonary function tests that include
evidence of restriction and impaired gas exchange
Bibasilar reticular abnormalities with minimal ground
glass opacities on HRCT scan
Transbronchial lung biopsy or BAL without features
to support an alternative diagnosis
Clinical Evaluation
As is generally the case, the clinical evaluation of patients suspected of having IPF begins with a thorough medical history, and in the case of IPF, the history should focus not only on presenting symptoms (insidious onset of dry cough and dyspnea on exertion in patients typically older than 50 years), but on evidence that may suggest the presence of a disease that can mimic IPF. Among these factors are a history of exposure to substances known to cause lung disease, connective tissue disease, and certain drug toxicities.
The clinical evaluation then proceeds with a physical examination, laboratory studies, pulmonary physiologic testing, radiologic evaluation, and pathologic examination of lung tissue. On physical examination, patients with IPF usually have dry or “Velcro” crackles that occur at the end of inspiration and are most prevalent at the lung bases. When the disease progresses, patients may develop crackles in the upper lobes, clubbing, cyanosis, and evidence of cor pulmonale. In cases where surgical lung biopsy is unobtainable, the ATS/ERS devised criteria that increase the likelihood of a correct clinical (without pathologic evaluation) diagnosis of IPF. All 4 major criteria, as listed on the slide, are required to increase the likelihood of a correct diagnosis.
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 Consensus Statement. Am J Respir Crit Care Med. 2002;165:

5. Clinical Evaluation Minor criteria Age > 50 yr
Insidious onset of otherwise unexplained
dyspnea on exertion
Duration of illness > 3 mo
Bibasilar, inspiratory “Velcro-like” crackles
All major criteria and at least 3 of the minor criteria must be
present to increase the likelihood of an IPF diagnosis
Clinical Evaluation
At least 3 of the minor criteria shown here must be present with all 4 major criteria to increase the likelihood of a correct clinical diagnosis of IPF.
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 Consensus Statement. Am J Respir Crit Care Med. 2002;165:

6. Pulmonary Function Tests
Typical findings in IPF patients:
Restriction
Reduced FVC and TLC
Normal or increased FEV1/FVC ratio
Impaired gas exchange
Decreased DLco, PaO2
Desaturation on exercise oximetry
Increased A-a gradient
Normal resting PFTs do not exclude IPF
Pulmonary Function Tests
Pulmonary function tests in patients with IPF typically reveal evidence of restriction and impaired gas exchange.
Reduced lung volumes, decreased diffusing capacity and reduced O2 saturation represent the hallmark findings. Several patients, however, may exhibit normal lung function at rest, therefore, it is recommended that patients undergo exercise oximetry to identify patients with the earliest evidence of disease.
American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International Consensus Statement. Am J Respir Crit Care Med. 2000;161:
ATS/ERS Consensus Statement. Am J Respir Crit Care Med. 2000;161:

7. 6-Minute Walk Test for Interstitial Lung Disease
Baseline blood pressure, pulse, O2 saturation
Timed walk at any pace
As many stops as necessary
If oxygen saturation persistently less than
88%, repeat test with supplemental oxygen
Primary endpoint is walk distance
6-Minute Walk Test for Interstitial Lung Disease
The 6-minute walk test (6MWT) is useful in measuring functional capacity and demonstrating evidence of pulmonary disease that is not evident while at rest. Essentially, after baseline vitals (blood pressure, pulse, O2 saturation) are measured, patients are instructed to walk as far as they can in a 6-minute period. They can stop as often as necessary and use supplemental oxygen if needed to maintain oxygen saturation. The primary endpoint is walking distance, but other endpoints, such as oxygen saturation and level of dyspnea, are also very useful. It has been suggested that repeat measures using the 6MWT can provide information regarding response to therapeutic interventions and change in functional capacity.
Enright PL. The six-minute walk test. Respir Care. 2003;48:
American Thoracic Society. ATS Statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002;166:
Enright PL. Respir Care. 2003;48: ; ATS. Am J Respir Crit Care Med. 2002;166:

8. Desaturation on 6-Minute Walk Test
Desaturation may occur in several lung diseases
Interstitial lung diseases
Pulmonary hypertension
Severe obstructive lung disease
If desaturation occurs on 6MWT and an ILD is
suspected, then HRCT may be indicated
Desaturation on 6-Minute Walk Test
In cases where a primary pulmonary process is suspected, exercise desaturation can indicate the presence of different diseases, such as interstitial lung disease, pulmonary hypertension, and obstructive lung diseases. In other words, the specificity of 6MWT is low, but when taken together with other clinical data (history, physical, PFTs) an interstitial lung disease may be suspected and further testing, such as HRCT, may be indicated.
Enright PL. The six-minute walk test. Respir Care. 2003;48:
American Thoracic Society. ATS Statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002;166:
Enright PL. Respir Care. 2003;48: ; ATS. Am J Respir Crit Care Med. 2002;166:

9. Lama VN, et al. Am J Respir Crit Care Med. 2003;168:1084-1090.
Desaturation on 6MWT Predicts Decreased Survival in UIP (N = 83)
1.0
69%
0.8
0.6
35%
Survival Probability
0.4
P =
0.2
0.0
Desaturation on 6MWT Predicts Decreased Survival in UIP (N = 83)
The usefulness of a 6MWT goes beyond diagnosis and functional capacity. Exercise-induced hypoxia is also an index of the severity of interstitial lung disease and can define prognosis in terms of mortality. Lama and colleagues followed 83 consecutive patients with biopsy-proven UIP with a 6MWT and found that patients with oxygen desaturation (defined as SaO2  88%) had significantly reduced survival when compared to those who did not desaturate (P = ). UIP patients with a 6MWT desaturation had 4.2 times the risk of death when compared to the UIP patients who did not experience desaturation. The relative 4-year survival rates for patients with UIP in this study were 69% for those patients who did not experience desaturation during the 6MWT and 35% for those patient who did experience desaturation.
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: 1 2 3 4 5
Nondesaturators
Years
Desaturators
Lama VN, et al. Am J Respir Crit Care Med. 2003;168:

10. Desaturation on 6MWT Predicts Decreased Survival in NSIP (N = 22)
1.0
100%
0.8
66%
0.6
Survival Probability
0.4
P =
0.2
0.0
Desaturation on 6MWT Predicts Decreased Survival in NSIP (N = 22)
Lama and colleagues also followed 22 consecutive patients with biopsy proven NSIP with a 6MWT and found that patients with oxygen desaturation (defined as SaO  88%) during the test had significantly decreased survival when compared to those patients that did not experience desaturation (P = ). The relative 4-year survival rates for patients with NSIP in this study were 100% for those patients who did not experience desaturation during the 6MWT and 66% for those patient who did experience desaturation.
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: 1 2 3 4 5
Nondesaturators
Years
Desaturators
Lama VN, et al. Am J Respir Crit Care Med. 2003;168:

11. Differential Diagnosis
Other idiopathic interstitial pneumonias
NSIP
DIP
RBILD
AIP
COP
Connective tissue diseases
Scleroderma
Rheumatoid arthritis
Polymyositis/dermatomyositis
Asbestosis
Hypersensitivity pneumonitis
Sarcoidosis
Differential Diagnosis
The differential diagnosis for IPF is quite broad and encompasses all of the idiopathic interstitial pneumonias, as well as several connective tissue diseases, sarcoidosis, and a number of exposure-related lung diseases. Therefore, a thorough history and clinical exam aimed at identifying previous exposures (asbestos, silicon, birds, metal, and wood dusts, etc) and features that might suggest a connective tissue disease is essential.
American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. Am J Respir Crit Care Med. 2000;161:
ATS/ERS Consensus Statement. Am J Respir Crit Care Med. 2000;161:

12. Diseases That Mimic IPF
IPF is often misdiagnosed, or diagnosed at an advanced stage of the disease
Symptoms of other diseases that mimic IPF:
COPD
CHF
Connective tissue diseases (eg, RA, Sjögren’s, SLE)
Other lung diseases (asbestosis, hypersensitivity
pneumonitis)
Diseases That Mimic IPF
The clinical features of IPF are nonspecific and resemble those of other lung diseases, thus making the differential diagnosis difficult and often resulting in misdiagnosis or diagnosis at an advanced stage of the disease. Although IPF is a distinct entity, it may resemble other lung diseases, such as asbestosis and hypersensitivity pneumonitis. Therefore, a thorough patient and exposure history assist in the process of ruling out other diseases.
American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International Consensus Statement. Am J Respir Crit Care Med. 2000;161:
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 Consensus Statement. Am J Respir Crit Care Med. 2000;161:
ATS/ERS Consensus Statement. Am J Respir Crit Care Med. 2002;165:

13. Clinical Evaluation Useful serology to exclude/include other diseases
ESR
ANA RF
Scl-70
CPK and aldolase
Jo-1 antibody
ANCA
ACE
Hypersensitivity panel (follow-up with exposure history)
Clinical Evaluation
Another aspect of the clinical evaluation in patients suspected of having an interstitial lung disease is serologic testing to exclude certain diseases that may mimic IPF. The routine laboratory evaluation of patients suspected of having IPF is often not helpful except to eliminate other causes of diffuse parenchymal lung disease. These tests should be tailored appropriately to the clinical situation. For example, a patient presenting with myalgias with pulmonary symptoms should have CPK, aldolase, and anti-Jo-1 antibody testing to assist in identifying the possibility of coexisting dermatomyositis/polymyositis and interstitial lung disease. In addition, a hypersensitivity panel may be beneficial for patients with pets, especially birds. However, it is crucial to obtain a thorough exposure history from these patients.
American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International Consensus Statement. Am J Respir Crit Care Med. 2000;161:
Adapted from ATS/ERS Consensus Statement. Am J Respir Crit Care Med. 2000;161:

14. Idiopathic Pulmonary Fibrosis (IPF) Chest X-Ray Findings
Reduced lung volume
Reticular opacities
Honeycombing sometimes visible
Lower-lobe and peripheral predominance of
abnormalities
HRCT should be performed in all patients with
suspected IPF, even if CXR is typical
Idiopathic Pulmonary Fibrosis (IPF) Chest X-Ray Findings
Virtually all patients with IPF have an abnormal chest x-ray at the time of diagnosis. Some of the key findings on CXR in patients with IPF include reduced lung volumes (except in patients with IPF and coexistent emphysema, who may have preserved or increased lung volumes), reticular opacities, and honeycombing. These findings are usually bilateral, asymmetric, and concentrated in the periphery and bases. It is important to note that bibasilar reticular opacities are also seen in asbestosis and certain connective tissue diseases, such as scleroderma and rheumatoid arthritis. While features consistent with IPF can be identified on chest x-ray, a confident diagnosis generally cannot be made on the basis of a chest x-ray, therefore, HRCT is recommended in all patients with suspected IPF even if CXR is typical.

15. Typical Features of IPF on Chest X-Ray
This slide compares a normal CXR with one from a patient with IPF. As is clear, the IPF CXR shows reduced lung volumes with basilar and asymmetric reticular opacities. As the disease progresses these findings may spread to the upper lung zones and honeycomb changes may appear. The reticular opacities are felt to reflect areas of fibrosis. Again, there have been cases of biopsy-proven IPF that are associated with a normal chest x-ray. High-resolution CT is required for a more confident diagnosis of IPF.
Normal CXR
Abnormal CXR
Slide courtesy of Ganesh Raghu, MD.

16. Typical Features of IPF on Chest X-Ray (cont.)
This CXR of a patient with IPF shows bilateral reticular opacities in the bases and periphery, with reduced lung volumes.

17. Typical Features of IPF on Chest X-Ray (cont.)
In this CXR from a patient with IPF, the extent of disease is greater than the previous CXR. The peripheral reticular opacities extend beyond the bases to the mid and upper lung zones.

18. Slide courtesy of W. Richard Webb, MD.
High-Resolution CT Technique
Thin collimation (eg, 1 mm)
Spaced images (1–2 cm) at full inspiration
Volumetric helical HRCT may be used but results in a greater radiation dose
Additional prone scans often best for showing early
abnormalities
Window mean -600 to -700 H
Window width 1000 to 1500 H
High-Resolution CT Technique
HRCT has emerged as a critical and indispensable technique in the diagnosis of interstitial lung disease and IPF, in particular. In the upcoming slides, we will review the typical findings on HRCT in patients with IPF and discuss the value of HRCT in the diagnosis of IPF.
This slide addresses the proper technique for performing a HRCT scan. This technique involves thin collimation (eg, 1 mm) and thinly spaced images (1–2 mm) at full inspiration. A volumetric helical HRCT may be used, but this method results in a higher radiation dose for the patient. Additionally, prone scans can be useful for showing early abnormalities. The window mean should be –600 to –700 H, and the window width 1000 to 1500 H.
Slide courtesy of W. Richard Webb, MD.

19. Idiopathic Pulmonary Fibrosis (IPF) HRCT Findings
Peripheral honeycombing
Irregular reticular opacities
Traction bronchiectasis
Minimal ground-glass opacity
Sub-pleural, posterior, lower-lobe predominance of
abnormalities
Idiopathic Pulmonary Fibrosis (IPF) HRCT Findings
The typical findings on HRCT in a patient with IPF are very similar to those found on CXR, just in greater detail and resolution. IPF patients will usually have peripheral honeycombing, irregular reticular opacities, and traction bronchiectasis on their HRCT scans. Ground-glass opacity is generally limited in extent in IPF, and all of these findings are concentrated in the posterior lower-lobes, bilaterally, and in a subpleural distribution.
American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International Consensus Statement. Am J Respir Crit Care Med. 2000;161:
ATS/ERS Consensus Statement. Am J Respir Crit Care Med. 2000;161:

20. Early HRCT Findings in IPF
This HRCT scan shows a reticular pattern with a predominantly subpleural distribution in a patient with IPF. Septal thickening is also seen.
Slide courtesy of Kevin O. Leslie, MD.

21. UIP: Honeycombing Slide courtesy of W. Richard Webb, MD.
This is a HRCT scan from a patient with IPF, which demonstrates honeycombing.
Slide courtesy of W. Richard Webb, MD.

22. UIP: Minimal Honeycombing
This is a HRCT scan from a patient with IPF, which demonstrates honeycombing to a lesser degree.
Slide courtesy of W. Richard Webb, MD.

23. UIP: Irregular Reticular Opacities
This is a HRCT scan from a patient with IPF, which demonstrates irregular reticular opacities.
Slide courtesy of W. Richard Webb, MD.

24. UIP: Traction Bronchiectasis
This is a HRCT scan from a patient with IPF, which demonstrates traction bronchiectasis.
Slide courtesy of W. Richard Webb, MD.

25. Subpleural and Basal Predominance
This is a HRCT scan from a patient with IPF, which demonstrates the subpleural and basal predominance of honeycombing and reticular opacities.
Slide courtesy of W. Richard Webb, MD.

26. HRCT Diagnosis of IPF
Prospective study of 91 patients with suspected IIP
54 (59%) had IPF
37 (41%) had other diseases
On HRCT, radiologists “certain” of dx in 52 (57%) of 91
“Certain” IPF: diagnosis correct in 26 (96%) of 27
“Certain” non-IPF: correct in 21 (84%) of 25
Confident clinical/HRCT diagnosis of IPF: SLB probably
unnecessary
Confident clinical/HRCT not IPF and diagnosis uncertain:
SLB indicated
HRCT Diagnosis of IPF
Research suggests that certain HRCT findings are highly specific for IPF and can be used to make a diagnosis in the absence of surgical lung biopsy. Hunninghake and colleagues conducted a double-blind, prospective study to assess the accuracy of a correct diagnosis on IPF by HRCT and found that a confident diagnosis of IPF made by an experienced pulmonologist or radiologist based on clinical and radiologic data alone is sufficient to obviate the need for surgical lung biopsy.
These investigators analyzed the data from 91 patients suspected of having an idiopathic interstitial pneumonia. They found 54 (59%) had IPF, based on a surgical lung biopsy showing UIP and 37 (41%) had a variety of other diseases (silicosis, respiratory bronchiolitis, hypersensitivity pneumonitis, sarcoidosis, histiocytosis-X, emphysema, BOOP, NSIP, bronchoalveolar carcinoma, pulmonary hypertension, and eosinophilic pneumonia).
A core group of 4 chest radiologists independently evaluated the HRCT scans from 8 referral centers and provided an overall clinical diagnosis with a rating of certainty (certain, uncertain, unlikely). When the core radiologists provided a rating of “certain” to a diagnosis of IPF, they were correct in 26/27 cases for a positive predictive value of 96%. When the core radiologists provided a rating of “certain” to a diagnosis other than IPF, they were correct in 21/25 cases for a positive predictive value of 84%.
Again, the study investigators concluded that a confident clinical and radiological diagnosis of IPF may make a surgical lung biopsy unnecessary, and lung biopsy may be most helpful when clinical and radiologic data result in an uncertain diagnosis or when patients are thought not to have IPF.
Hunninghake GW, Zimmerman MB, Schwartz DA, et al. Utility of a lung biopsy for the diagnosis of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2001;164:
Hunninghake et al. Am J Respir Crit Care Med 2001; 164:

27. HRCT Diagnosis of IPF Independent predictors of IPF
Lower-lobe honeycombing (odds ratio 5.36; P = 0.007)
Upper-lobe reticular opacities (odds ratio 6.28; P = )
In patients presenting with a clinical syndrome suggestive of IIP, CT findings of lower-lung honeycombing and upper-lung irregular lines are most closely associated with a pathologic diagnosis of UIP
HRCT Diagnosis of IPF
In a further evaluation of their data on the 91 patients suspected of having idiopathic interstitial pneumonia, Hunninghake and colleagues sought to determine which clinical and radiologic findings are independently associated with a pathologic diagnosis of UIP. Again, 54/91 (59%) patients received a pathologic diagnosis of UIP, and on multivariate analysis of specific HRCT features identified by 4 experienced chest radiologists, lower-lobe honeycombing (odds ratio 5.36; P = 0.007) and upper-lobe irregular lines (odds ratio 6.28; P = 0.004) were the only predictors of UIP. With these two findings alone, the radiologist could correctly identify IPF with a sensitivity of 74%, a specificity of 81%, and positive predictive value of 85%.
The investigators concluded that in patients presenting with a clinical syndrome suggestive of IIP, CT findings of lower-lung honeycombing and upper-lung irregular lines are most closely associated with a pathologic diagnosis of UIP.
Hunninghake GW, Lynch DA, Galvin JR, et al. Radiologic findings are strongly associated with a pathologic diagnosis of usual interstitial pneumonia. Chest. 2003;124:
Hunninghake et al. Chest 2003; 124:

28. HRCT Diagnosis of IPF Diagnosis Sensitivity Specificity
HRCT consistent with IPF
80%
84%
Radiograph consistent with IPF
89%
75%
HRCT or radiograph consistent with IPF
91%
72%
HRCT and radiograph consistent with IPF
78%
87%
HRCT Diagnosis of IPF
Hunninghake and colleagues also evaluated factors that were associated with a pathologic diagnosis of UIP. Evaluations were recorded by a clinical core of 3 pulmonologists. The only two observations (symptoms, signs, smoking status, PFT results and radiologic evaluations) from this core group of pulmonologists that reliably predicted UIP on surgical lung biopsy were HRCT consistent with IPF and chest radiograph consistent with IPF. This slide shows the sensitivities and specificities of these observations in predicting a correct pathologic diagnosis of UIP. One important point is that when either HRCT or CXR consistent with IPF was used for diagnosis, the sensitivity rose to 91%, but the specificity fell to 72%.
Hunninghake GW, Lynch DA, Galvin JR, et al. Radiologic findings are strongly associated with a pathologic diagnosis of usual interstitial pneumonia. Chest. 2003;124:
Hunninghake et al. Chest 2003; 124:

29. HRCT Diagnosis of IPF 73 patients with UIP; 23 with NSIP
Honeycombing on HRCT = definite or probable UIP
All 27 patients with a HRCT diagnosis of definite or probable UIP had UIP on biopsy
Patients with HRCT diagnosed definite or probable UIP had shortest survival
HRCT Diagnosis of IPF
Flaherty and colleagues hypothesized that the HRCT appearance of idiopathic interstitial pneumonias would have an impact on the survival of patients with these diseases. Two thoracic radiologists independently reviewed the HRCT scans from 96 patients—73 with a histological diagnosis of UIP and 23 with a histological diagnosis of NSIP. The radiologists recorded each case as definite UIP, probable UIP, indeterminate (equal probability of UIP or NSIP), probable NSIP, or definite NSIP, based on widely accepted criteria for diagnosing these diseases. The one finding on HRCT that the radiologist consistently felt indicated definite or probable UIP was honeycombing, for this abnormality correlates strongly with pathological fibrosis and impaired survival. The investigators identified 27 of the 96 patients as having definite or probable UIP, and all 27 patients were found to have UIP on pathological examination. Furthermore, the group of patients found to have the worst overall survival was those 27 patients with a diagnosis of definite or probable UIP by HRCT scan. With a median follow-up of 3.1 years, 17 deaths occurred with a median survival of only 2.08 years in this group.
Flaherty KR, Thwaite EL, Kazerooni EA, et al. Radiological versus histological diagnosis in UIP and NSIP: survival implications. Thorax. 2003;58:
Flaherty et al. Thorax. 2003;58:

30. Survival in Relation to HRCT and Histology
Diagnostic Category
Deaths/Patients (%)
Median Survival (yrs)
Histological Diagnosis
UIP
NSIP
34/73 (47)
2/23 (9)
3.98
> 9
HRCT Diagnosis
Definite/probable UIP
Indeterminate
Definite/probable NSIP
17/27 (63)
9/25 (36)
10/44 (23)
2.08
5.76
5.81
Histological HRCT
UIP
NSIP
17/27 (63)
17/46 (37)
2/18 (11)
0/5 (0)
2.08
5.76
> 9
> 6.6
Def/Prob UIP
Def/Prob NSIP
Indeterminate
Survival in Relation to HRCT and Histology
Looking at Flaherty’s data more closely, a few important points begin to emerge. As is well known, patients with a histological diagnosis of UIP have a much worse prognosis that those with a histological diagnosis of NSIP (in this study, median survival of 3.98 years and > 9 years, respectively). Moreover, HRCT features add prognostic information to the histological diagnosis of UIP. Patients with both a histological and HRCT diagnosis of UIP had a significantly decreased rate of survival compared to patients with a histological diagnosis of UIP and an atypical HRCT for UIP (median survival of 2.08 years and 5.76 years, respectively). As a result, the investigators concluded that patients with HRCT features typical for UIP are likely to have UIP on histological examination. When UIP is not suggested by HRCT, a surgical lung biopsy is indicated to distinguish between UIP and NSIP, and thus provide accurate prognostic information.
Flaherty KR, Thwaite EL, Kazerooni EA, et al. Radiological versus histological diagnosis in UIP and NSIP: survival implications. Thorax. 2003;58:
Table adapted from Flaherty KR, et al. Thorax. 2003;58(2):

31. Role of BAL vs Biopsy in IPF
Procedure
Role
Brochoalveolar Lavage (BAL)
May rule out alternate diagnoses but
not diagnostic of IPF
Transbronchial Biopsy (TBB)
Often abnormal in IPF but does not
confirm diagnosis
Video-assisted Thoracoscopic Biopsy (VATS)
Preferred technique
Provides best tissue samples
Excludes other processes that mimic IPF
Biopsies should be obtained from more
than one lobe of the lung
Role of BAL vs Biopsy in IPF
With the knowledge that surgical lung biopsy is a critical element in the diagnosis of IPF, the question then becomes whether less invasive forms of obtaining tissue and cells are useful in this diagnostic process. This slide examines the relative utility of BAL, TBB, and surgical lung biopsy. BAL has limited utility in the diagnosis of IPF, but it may substantiate a variety of alternate diagnoses including malignancy, infection, and eosinophilic pneumonia, thereby excluding IPF as a primary diagnosis. In a similar manner to BAL, TBB is not helpful in making the diagnosis of IPF but certainly is acceptable as a diagnostic modality for many diseases that can mimic IPF (malignancy, infection, sarcoidosis, hypersensitivity pneumonitis, BOOP). Furthermore, the sample size provided by a TBB is inadequate to assess the degree of fibrosis or inflammation.
Surgical lung biopsy provides the best tissue samples to distinguish UIP from other idiopathic interstitial lung diseases and diseases that can mimic IPF. Video-assisted thoracoscopic surgical (VATS) lung biopsy is the preferred method of obtaining lung tissue. VATS is associated with less morbidity and decreased length of hospital stay when compared to open thoracotomy. When considering surgical lung biopsy, the risk and costs of such a procedure must be weighed against the benefits of accurately obtaining a clinical diagnosis and the potential efficacy of treatment. It is important to have the surgeon obtain samples from more than one lobe to increase the accuracy of histological examination.
American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International Consensus Statement. Am J Respir Crit Care Med. 2000;161:
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 Consensus Statement. Am J Respir Crit Care Med. 2000;161: ; ;165:

32. Diagnostic Pathologic Findings in UIP
UIP pattern
Fibroblastic foci
Temporal heterogeneity
Honeycombing
Minimal inflammation
Diagnostic Pathologic Findings in UIP
Usual interstitial pneumonia (UIP) is the histopathological pattern associated with clinical IPF. The key features of UIP have been well described and include a temporally heterogeneous appearance of alternating areas of normal lung, interstitial inflammation, fibrosis, and honeycomb change. These abnormalities are concentrated in the peripheral subpleural parenchyma. Examination at low power reveals fibrotic zones of dense collagen with fibroblastic foci, which are scattered areas of proliferating fibroblasts, and honeycomb change, which consists of cystic fibrotic air spaces filled with mucin. The inflammatory component of UIP is minimal in extent and is described as an alveolar septal infiltrate of lymphocytes and plasma cells.
American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International Consensus Statement. Am J Respir Crit Care Med. 2000;161:
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 Consensus Statement. Am J Respir Crit Care Med. 2000;161: ; 2002;165: .

33. Approach to Diagnosing IPF
Clinical Evaluation: History, PE, CXR, PFTs, 6MWT
Not IIP
Potential IIP
HRCT
Diagnostic of IPF or other diffuse lung disease
Diagnosis uncertain
Transbronchial Bx or BAL
Diagnostic
Nondiagnostic
Approach to Diagnosing IPF
In summary, the diagnostic approach to IPF is multidisciplinary, involving primary care physicians, pulmonologists, radiologists, and pathologists. It begins with a complete clinical evaluation, including history, physical examination, chest radiograph, laboratory studies, and pulmonary physiologic testing. After this thorough assessment, patients suspected of having an idiopathic interstitial pneumonia should undergo a HRCT scan of their lungs. In some instances—when an experienced chest radiologist can make a confident diagnosis—a diagnosis of IPF or other diffuse lung disease can be established without further diagnostic intervention. When the HRCT results are unclear, many patients will go directly to surgical lung biopsy, but others may have BAL and/or TBB, which can diagnose diseases that mimic IPF, and thus eliminate it as a primary diagnosis. Ultimately, surgical lung biopsy is the gold standard in diagnosis of IPF.
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:
Surgical lung biopsy
Not IPF
IPF
Adapted from ATS/ERS Consensus Statement. Am J Respir Crit Care Med. 2002;165: