1. THE DIAGNOSIS OF IPF Steven A. Sahn, MD
Professor of Medicine and Director
Division of Pulmonary, Critical Care,
Allergy and Sleep Medicine
Medical University of South Carolina
IPF Diagnosis: A Practical, Multidisciplinary Approach
The learning objective of this slide section is to adopt into clinical practice a multidisciplinary approach to diagnose patients with IPF.

2. 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 which are often present. The histolopathologic 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:

3. Demographics and Risk Factors for IPF
US Demographics
Incidence: > 30,000 patients/year
Prevalence: > 80,000 current patients
Age of onset: 40–70 years
Two-thirds > 60 years old at presentation
Males > females
Risk Factors
Familial
Smoking
Environment (eg, wood or metal dust)
Gastroesophageal reflux disease (GERD)
Infectious agents
Demographics and Risk Factors for IPF
Currently, more than 80,000 adults have IPF in the US, 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.
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 area 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. American Thoracic Society/European Respiratory Society International Consensus Classification of the Idiopathic Interstitial Pneumonias. 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. 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
Desaturation on exercise oximetry
Increased P(A-a)O2 gradient
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 gradient (P(A-a)O2). 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:

5. Diagnosing Chronic Exertional Dyspnea
Differential Diagnosis
Others
Neuromuscular
Pulmonary
Cardiac
Vascular
Anemia,
Anxiety, Obesity, Deconditioning, hyperthyroidism
Pulmonary Hypertension
AVM
NM disease, malnutrition, diaphragm dysfunction
COPD, ILD, Asthma
Cardiomyopathy, R-to-L Shunt
YES No
Basilar Velcro Crackles
HRCT SCAN
IPF
Image courtesy of Steven A. Sahn, MD.

6. Serologic Tests Can Help Exclude Other Conditions
ESR
ANA RF CK
Aldolase
Anti-myositis panel with Jo-1 antibody
ENA panel
p-ANCA
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:
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) and rheumatoid factor (RF) elevations occur in 10% to 20% of IPF patients but titers are rarely high. High titers suggest a connective tissue disease.
Creatinine kinase (CK) and aldolase are muscle injury markers. Elevation of these enzymes in serum suggests myocardial infarction.
An anti-myositis panel with Jo-1 antibody is useful for detecting systemic autoimmune diseases. Anti-Jo 1 is an antibody to histidyl-t RNA synthase commonly found in polymyositis and dermatomyositis patients.
An Anti-ENA panel is a screen for autoimmune diseases, especially collagen vascular diseases.
Perinuclear ANCA (p-ANCA) is commonly seen in microscopic polyangiitis.
Angiotensin Converting Enzyme (ACE): An elevated ACE level suggests sarcoidosis, but may be present with IPF, tuberculosis, pulmonary embolism or asbestosis.
The hypersensitivity panel is a collection of tests for antibodies to common antigens from microbial, fungal, and animal sources. Typically 10 antigens are tested.
Sarcoid
ACE
Hypersensitivity pneumonitis
Hypersensitivity panel
(exposure history)
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:

7. Chest Radiograph in IPF
These chest radiographs show peripheral reticular opacities that predominate at the lung bases, but also involve the mid-lung zones. Lung volume is reduced.
Reduced lung volume
Basal and peripheral reticulation
Images courtesy of W. Richard Webb, MD.

8. 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 UIP/IPF or fibrotic NSIP.
No honeycombing or traction bronchiectasis
Image courtesy of W. Richard Webb, MD.

9. Classic IPF HRCT Basal and subpleural predominance Reticular opacities
HRCT near the lung bases shows subpleural reticulation with traction bronchiectasis. Subpleural honeycombing is also present. Honeycombing can be confidently diagnosed if air-filled cysts are visible in a subpleural location.
Reticular opacities
Traction
bronchiectasis
Honeycombing
Image courtesy of W. Richard Webb, MD.

10. 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 UIP/IPF.
Basal and subpleural predominance
Image courtesy of W. Richard Webb, MD.

11. 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 characteristic1)
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 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)
All major criteria and at least 3 minor criteria must be present to increase the likelihood of an IPF diagnosis
1. Not included in current guidelines
ATS/ERS. Am J Respir Crit Care Med. 2000;161:
American Thoracic Society. American Thoracic Society/European Respiratory Society International Consensus Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med. 2000;161:

12. Radiologic Diagnosis Inconclusive
Subpleural reticular opacities
Radiologic Diagnosis Inconclusive
These prone HRCT images are from patients with early UIP/IPF (left) and fibrotic NSIP (right). The scans show subpleural reticulation without honeycombing or traction bronchiectasis. This appearance is nonspecific and may be seen with early UIP/IPF or fibrotic NSIP. In such cases a biopsy and histologic examination of the sections is necessary for diagnosis.
Both scans show subpleural reticulation. This appearance may represent early UIP/IPF or fibrotic NSIP.
Biopsy is needed for their differentiation.
Images courtesy of W. Richard Webb, MD.

13. Video-Assisted Thoracic Surgery (VATS)
High diagnostic accuracy
Less morbidity and mortality than open lung biopsy
Ideal biopsy
Two or more surgical wedge biopsies with areas of normal lung from different sites of the lung
Samples 3–5 cm in length and 2–3 cm in depth
Outpatient thoracoscopic lung biopsy in patients with interstitial or focal lung disease
Diagnosis in 61/62 patients
72% discharged within 8 hours
22% discharged within 23 hours
Video-Assisted Thoracic Surgery (VATS)
VATS is a less invasive method of lung biopsy than open lung biopsy. VATS is the preferred technique, providing good sample acquisition and high diagnostic accuracy. It is associated with less morbidity and mortality than open lung biopsy. The ideal biopsy should obtain 2 or more samples and should include normal adjacent tissue from different areas of the lung. Samples should measure 3 to 5 cm in length and 2 to 3 cm in depth.
In a study by Chang and colleagues, a definitive histologic diagnosis was obtained in 61 of 62 patients with a clinical diagnosis of either interstitial lung disease or indeterminant pulmonary nodules. Forty-five patients (72.5%) were discharged within 8 hours of observation on the day of the operation while another 14 (22.5%) were discharged within 23 hours. .
Rena O, et al. Eur J Cardiothorac Surg. 1999;16:
Chang AC, et al. Ann Thorac Surg. 2002;74:
American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International Consensus Statement. Am J Respir Crit Care Med. 2000;161:
Chang AC, Yee J, Orringer MB, Iannettoni MD. Diagnostic thoracoscopic lung biopsy: an outpatient experience. Ann Thorac Surg. 2002;74:
Rena O, Casadio C, Leo F, et al. Videothoracoscopic lung biopsy in the diagnosis of interstitial lung disease. Eur J Cardio-thorac Surg. 1999;16:

14. 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
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. Points to Remember
Typical clinical features: male > 50 years, smoker, insidious onset of dyspnea, non-productive cough and bibasilar Velcro crackles
Other diseases, such as CTD and sarcoidosis need to be excluded
Surgical lung biopsy necessary when typical clinical and HRCT findings of IPF not present
IPF: characteristic UIP histology enables definitive diagnosis when clinical/radiologic findings not conclusive
Take Home Messages
Typical clinical features include age > 50 years, male gender, smoker, insidious onset of dyspnea, non-productive cough and bibasilar Velcro crackles
A surgical lung biopsy is necessary when typical clinical and HRCT findings of IPF are not present
IPF has characteristic UIP histologic features that enable definitive diagnosis when clinical and radiologic findings are not conclusive