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Idiopathic Pulmonary Fibrosis Workup

  • Author: Amanda M K Godfrey, MD; Chief Editor: Ryland P Byrd, Jr, MD  more...
 
Updated: Aug 11, 2015
 

Laboratory Studies

Results from routine laboratory studies are nonspecific for the diagnosis of idiopathic pulmonary fibrosis; however, some laboratory studies may be helpful for ruling out other causes of interstitial lung disease. Reportedly, up to 30% of patients with idiopathic pulmonary fibrosis (IPF) have positive tests for antinuclear antibodies or rheumatoid factor; however, these titers are generally not high.[7] The presence of high titers of antinuclear antibodies or rheumatoid factor may suggest the presence of a connective-tissue disease. The C-reactive protein value and erythrocyte sedimentation rate can be elevated in patients with idiopathic pulmonary fibrosis; however, this finding is nondiagnostic. Although chronic hypoxemia is a common finding in patients with idiopathic pulmonary fibrosis, polycythemia is a rare finding on laboratory studies.

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Imaging Studies

Chest radiography

The chest radiograph lacks diagnostic specificity for idiopathic pulmonary fibrosis. Virtually all patients with idiopathic pulmonary fibrosis (IPF) have an abnormal chest radiograph at the time of diagnosis. The typical findings are peripheral reticular opacities (netlike linear and curvilinear densities) predominantly at the lung bases (see image below). Honeycombing (coarse reticular pattern) and lower lobe volume loss can also be seen.[10]

Chest radiograph of a patient with idiopathic pulm Chest radiograph of a patient with idiopathic pulmonary fibrosis showing bilateral lower lobe reticular opacities (red circles).

High-resolution computed tomography

High-resolution computed tomography (HRCT) findings are significantly more sensitive and specific for the diagnosis of idiopathic pulmonary fibrosis and are an essential component of the diagnostic pathway of idiopathic pulmonary fibrosis. On HRCT images, idiopathic pulmonary fibrosis is characterized by patchy, peripheral, subpleural, and bibasilar reticular opacities (see image below).

Classic subpleural honeycombing (red circle) in a Classic subpleural honeycombing (red circle) in a patient with a diagnosis of idiopathic pulmonary fibrosis.

Reticular opacities refer to the fine network of lines that sometimes include interlobular septal thickening and/or intralobular lines. Areas that are severely involved with reticular markings may also demonstrate traction bronchiectasis. Subpleural honeycombing (< 5-mm round translucencies with a density equal to that of air) is also a common finding (see image below).

A patient with IPF and a confirmed histologic diag A patient with IPF and a confirmed histologic diagnosis of usual interstitial pneumonia. Note the reticular opacities (red circle) distributed in both lung bases and the minimal ground-glass opacities (blue circle).

Ground-glass opacities can be found but are less extensive than reticular abnormalities.[10] Reticular opacities and honeycombing seen on HRCT imaging correlates histologically with fibrosis and honeycombing. The presence of subpleural honeycombing, traction bronchiectasis, and thickened interlobular septae increase the specificity of HRCT for diagnosing idiopathic pulmonary fibrosis.[10] Patients with typical changes of idiopathic pulmonary fibrosis on HRCT imaging have a worse prognosis compared with patients with biopsy-proven usual interstitial pneumonia and atypical changes of idiopathic pulmonary fibrosis on HRCT imaging.[30]

Multiple studies have documented that the accuracy of a confident diagnosis of usual interstitial pneumonia made on the basis of HRCT imaging findings by an experienced observer exceeds 90%.[10] However, several clinical conditions may be associated with the histologic pattern of usual interstitial pneumonia and must therefore be considered in the differential diagnosis of usual interstitial pneumonia diagnosed on the basis of HRCT imaging.

The differential diagnosis of ground-glass opacities on HRCT imaging include heart failure, nonspecific interstitial pneumonia (NSIP), desquamative interstitial pneumonia, respiratory bronchiolitis-associated interstitial lung disease, and hypersensitivity pneumonitis. Fine nodules are suggestive of hypersensitivity pneumonitis, granulomatous infection, or metastatic malignancy. Upper lobe disease is the predominant pattern in hypersensitivity pneumonitis, a variety of pneumoconioses, sarcoidosis, and eosinophilic pneumonia.[7] Lymphadenopathy is associated with sarcoidosis and other granulomatous disease. Idiopathic pulmonary fibrosis and NSIP can have indistinguishable clinical presentations, and understanding how HRCT imaging can help to distinguish between these two entities is important (see image below).

A patient with nonspecific interstitial pneumonia. A patient with nonspecific interstitial pneumonia. Note the predominance of ground-glass opacities (blue circles) and a few reticular lines (red arrow).

The abnormalities in NSIP usually predominate in the middle and lower lungs. NSIP is less likely to have a subpleural distribution compared with usual interstitial pneumonia. Ground-glass opacities are a frequent feature of NSIP and are reported to be found in 76-100% of cases.[10] Finally, honeycombing is less common than in usual interstitial pneumonia, with the prevalence ranging from 0-30% in different series.[10] Honeycombing is mainly seen in patients with purely fibrotic NSIP.

The following are HRCT Criteria for UIP Pattern:[1]

UIP pattern requires all 4 features below.

  • Subpleural, basal predominance
  • Reticular abnormality
  • Honeycombing with or without traction bronchiectasis
  • Absence of features listed as inconsistent with UIP pattern

Possible UIP pattern requires all 3 features below.

  • Subpleural, basal predominance
  • Reticular abnormality
  • Absence of features listed as inconsistent with UIP pattern

Inconsistent with UIP pattern requires any of the 7 features below.

  • Upper or mid-lung predominance
  • Peribronchovascular predominance
  • Extensive ground-glass abnormality (extent greater than reticular abnormality)
  • Profuse micronodules (bilateral, predominantly upper lobes)
  • Discrete cysts (multiple, bilateral, away from areas of honeycombing)
  • Diffuse mosaic attenuation/air-trapping (bilaterally, in 3 or more lobes)
  • Consolidation in bronchopulmonary segment(s)/lobe(s)
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Other Tests

Pulmonary function testing

The typical findings on pulmonary function tests in patients with idiopathic pulmonary fibrosis are a restrictive ventilatory defect and a reduced diffusion capacity for carbon monoxide.[8] These findings are nonspecific and should be used in conjunction with clinical, radiologic, and pathologic information to ensure an accurate diagnosis of idiopathic pulmonary fibrosis (IPF).

In patients with idiopathic pulmonary fibrosis, a restrictive ventilatory defect is typically present. Vital capacity, functional residual capacity, total lung capacity, and forced vital capacity (FVC) all are reduced. Additionally, the static pressure-volume curve is shifted downward and to the right as a result of decreased lung compliance.[8] Obstructive ventilatory defects are not common. However, if present, they may suggest the coexistence of chronic obstructive pulmonary disease.

Prognostication in idiopathic pulmonary fibrosis relies on serial assessments of FVC. Patients who have a greater than 10% decline in FVC (percent predicted) over 6 months, have a 2.4-fold increased risk of death. Additionally, in patients who do not desaturate to less than 88% during a 6-minute walk test (6MWT), the only strong predictor of mortality is a progressive decline in FVC (>10% after 6 mo).[31] As a result of these findings, change in FVC is being used more frequently as a primary end point in clinical trials.

A large study was completed in 2012 to estimate the minimal clinically important difference (MCID) of FVC in patients with IPF. In this study, data was used from 1,156 patients included in two clinical trials investigating IFN-γ1β. This study found that the hazard ratio for the one-year risk of death was 2.14 (1.43-3.20) in patients with a 24-week decline in FVC between 5% and 10%. The estimated MCID was 2-6%.[32]

Impaired gas exchange is demonstrated by the decreased diffusion capacity of carbon monoxide (DLCO). In idiopathic pulmonary fibrosis, the reduced DLCO may precede the development of abnormal lung volumes. Additionally, DLCO is reduced to a greater extent in idiopathic pulmonary fibrosis compared with other idiopathic interstitial pneumonias.[8] Prognostication in idiopathic pulmonary fibrosis also relies on serial assessments of DLCO. A baseline DLCO below 35% is correlated with increased mortality. Additionally, a decline in DLCO greater than 15% over 1 year is also associated with increased mortality.[31]

6-Minute walk testing

The 6MWT is a marker of functional exercise capacity that is being increasingly used in the initial and longitudinal clinical assessment of patients with idiopathic pulmonary fibrosis. Desaturation below the threshold of 88% during the 6MWT has been associated with an increased mortality.[31] Additionally, in patients with idiopathic pulmonary fibrosis who desaturate to less than 88% during a 6MWT, a progressive decline in DLCO (>15% after 6 mo) is a strong predictor of increased mortality.[9]

Heart rate recovery (HRR), specifically the failure of the heart rate to decline at 1 or 2 minutes postexercise, is associated with increased mortality. A 2009 retrospective analysis found that the failure of the heart rate to decline after exertion (by >13 beats at 1 min or by >22 beats at 2 min) is a strong predictor of increased mortality.[33]

A study by du Bois and colleagues estimated the minimal clinically important difference in the 6MWT in 822 patients with idiopathic pulmonary fibrosis. For patients who had a decline in 6MWT of 26-50 meters at 24 weeks, the hazard ratio for death at 1 year was 3.59 (1.95-6.63). For patients who had a decline in the 6MWT of more than 50 meters at 24 weeks, the hazard ratio for death at 1 year was 4.27 (2.57-7.10). The minimal clinically important difference in 6MWT was distance is 24-45 meters.[34]

Bronchoalveolar lavage

Bronchoalveolar lavage (BAL) has been an immensely useful research tool in idiopathic pulmonary fibrosis. However, the role of BAL in the clinical diagnosis of idiopathic pulmonary fibrosis remains limited. Increased numbers of neutrophils in BAL fluid are found in 70-90% of all patients with idiopathic pulmonary fibrosis, and increased numbers of eosinophils in BAL fluid are found in 40-60% of all patients with idiopathic pulmonary fibrosis. Previous studies have demonstrated that the absence of BAL fluid lymphocytosis is important for the diagnosis of idiopathic pulmonary fibrosis. A 2009 study suggests that BAL fluid analysis has an additional benefit for the diagnosis of idiopathic pulmonary fibrosis. The study demonstrated the discriminating power of a cut-off level of less than 30% lymphocytosis in BAL fluid in distinguishing idiopathic pulmonary fibrosis from nonidiopathic pulmonary fibrosis diagnoses.[35]

BAL is not required for the diagnosis of idiopathic pulmonary fibrosis. However, BAL fluid analysis can be useful to exclude other alternative diagnoses. Appropriate analysis of BAL fluid may demonstrate the presence of infection, malignancy, alveolar proteinosis, eosinophilic pneumonia, or occupational dusts.

BAL fluid neutrophilia has been demonstrated to predict early mortality. One study demonstrated a linear relationship between increasing neutrophil percentage and the risk of mortality. Each doubling in baseline BAL fluid neutrophil percentage was associated with a 30% increased risk of death or transplantation in the first year after presentation.[36] Additionally, studies of BAL matrix metalloproteinase (MMP) levels suggest that MMP1 and MMP7 are increased in patients with idiopathic pulmonary fibrosis and that MMP7 levels may correlate with disease severity.[1]

Transthoracic echocardiography

Studies have demonstrated that pulmonary hypertension is present at rest in approximately 20-40% of idiopathic pulmonary fibrosis patients who are listed for lung transplantation.[6] The US National Institutes of Health (NIH) definition of pulmonary arterial hypertension is a mean pulmonary artery pressure greater than 25 mmHg at rest with a normal pulmonary capillary wedge pressure measured by right-sided heart catheterization. Generally, transthoracic echocardiography is an excellent modality to detect pulmonary hypertension. However, in patients with chronic lung disease, including idiopathic pulmonary fibrosis, studies have shown a variable performance for transthoracic echocardiography to detect pulmonary hypertension.[6]

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Procedures

Bronchoscopy

As previously stated, bronchoscopy with BAL and/or transbronchial biopsy is not required for the diagnosis of idiopathic pulmonary fibrosis. However, it can be used to ensure that alternative diagnoses are excluded. In cases requiring histopathology, the specificity and positive predictive value of UIP pattern identified by transbronchial biopsy has not been rigorously studied.[1]

Surgical lung biopsy

A surgical lung biopsy specimen can be obtained through either an open lung biopsy or video-assisted thoracoscopic surgery (VATS). A surgical lung biopsy provides the best sample for which to distinguish usual interstitial pneumonia from other idiopathic interstitial pneumonias. VATS is preferred because it is associated with less morbidity and a shorter hospital stay compared with open lung biopsy.

Given the high-quality evidence regarding HRCT specificity for the recognition of histopathologic UIP pattern, surgical lung biopsy is not essential in making the diagnosis.[1] In patients with UIP pattern on HRCT a surgical lung biopsy is not needed for the diagnosis of idiopathic pulmonary fibrosis. However, in patients with possible UIP pattern or inconsistent with UIP pattern on HRCT, a surgical lung biopsy is needed for the diagnosis of idiopathic pulmonary fibrosis.[1] The previously described major and minor criteria for the clinical diagnosis of idiopathic pulmonary fibrosis have been eliminated.[12]

The diagnosis of idiopathic pulmonary fibrosis now requires the following:[1]

  • The exclusion of other known causes of interstitial lung disease (ILD), including domestic and occupational environmental exposures, connective tissue disease, and drug toxicity
  • The presence of a UIP pattern on HRCT in patients not subjected to a surgical lung biopsy
  • Specific combinations of HRCT and surgical lung biopsy pattern in patients subjected to surgical lung biopsy
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Histologic Findings

The histopathological lesion associated with idiopathic pulmonary fibrosis is usual interstitial pneumonia. Usual interstitial pneumonia is characterized by a heterogeneous, variegated appearance with alternating areas of healthy lung, interstitial inflammation, fibrosis, and honeycomb change, which results in a patchwork appearance at low magnification (see image below).[15]

Patchwork distribution of abnormalities in a class Patchwork distribution of abnormalities in a classic example of usual interstitial pneumonia (low-magnification photomicrograph; hematoxylin and eosin stain; original magnification, X4). Courtesy of Chad Stone, MD.

Fibrosis predominates over inflammation in usual interstitial pneumonia. Fibroblastic foci represent microscopic zones of acute lung injury and are randomly distributed within areas of interstitial collagen deposition and consist of fibroblasts and myofibroblasts arranged in a linear fashion within a pale-staining matrix.[15] Although fibroblastic foci are not specific for usual interstitial pneumonia, they represent an important diagnostic criterion.

Another important diagnostic criterion for usual interstitial pneumonia is honeycomb change. Microscopically, honeycomb change is defined by cystically dilated bronchioles lined by columnar respiratory epithelium in scarred, fibrotic lung tissue.[15] Dense eosinophilic collagen without associated honeycomb change signifies fibrotic scars and is also characteristic of usual interstitial pneumonia. Interstitial inflammation, consisting of patchy alveolar septal infiltrates of mononuclear cells, is not predominant in usual interstitial pneumonia.

The usual interstitial pneumonia histologic pattern can be associated with other diseases besides idiopathic pulmonary fibrosis. These include asbestosis, collagen-vascular disease, fibronodular sarcoidosis, hypersensitivity pneumonitis, and toxic drug reactions (eg, to amiodarone, bleomycin, or nitrofurantoin). Correlation with clinical history is needed to identify these conditions.

In pathology specimens taken during acute exacerbations of idiopathic pulmonary fibrosis, microscopy reveals a combination of usual interstitial pneumonia with superimposed diffuse alveolar damage. Alveolar septa are expanded by more extensive fibroblast proliferation than is seen in conventional fibroblast foci. Additionally, marked hyperplasia of type 2 pneumocytes and hyaline membrane remnants is present.[15]

The following are histopathological criteria for UIP pattern:[1]

UIP pattern requires all 4 criteria below.

  • Evidence of marked fibrosis/architectural distortion and/or honeycombing in a predominantly subpleural/paraseptal distribution
  • Presence of patchy involvement of lung parenchyma by fibrosis
  • Presence of fibroblast foci
  • Absence of features against a diagnosis of UIP suggesting an alternate diagnosis

Probable UIP pattern requires the following:

  • Evidence of marked fibrosis/architectural distortion and/or honeycombing
  • Absence of either patchy involvement or fibroblastic foci, but not both
  • Absence of features against a diagnosis of UIP suggesting an alternate diagnosis

OR

  • Honeycombing changes only

Possible UIP pattern requires all 3 criteria below.

  • Patchy or diffuse involvement of lung parenchyma by fibrosis, with or without interstitial inflammation
  • Absence of other criteria for UIP
  • Absence of features against a diagnosis of UIP suggesting an alternate diagnosis

Not UIP pattern requires any of the 6 criteria below.

  • Hyaline membranes
  • Organizing pneumonia
  • Granulomas
  • Marked interstitial inflammatory cell infiltrate away from honeycombing
  • Predominant airway centered changes
  • Other features suggestive of an alternate diagnosis

A patient with possible UIP pattern on HRCT and UIP pattern or probable UIP pattern on surgical lung biopsy is consistent with the diagnosis of idiopathic pulmonary fibrosis. However, a patient with possible UIP pattern on HRCT and possible UIP pattern or nonclassifiable fibrosis on surgical lung biopsy is consistent with the diagnosis of probable idiopathic pulmonary fibrosis.[1]

A patient with a pattern inconsistent with UIP on HRCT and UIP pattern on surgical lung biopsy is consistent with the diagnosis of possible UIP. However, a patient with a pattern inconsistent with UIP on HRCT and probable UIP, possible UIP, or nonclassifiable fibrosis on surgical lung biopsy is not consistent with the diagnosis of idiopathic pulmonary fibrosis.[1]

Any pattern on HRCT associated with a surgical lung biopsy finding of not UIP is not consistent with the diagnosis of idiopathic pulmonary fibrosis.[1]

Multidisciplinary discussion amongst pulmonologists, radiologists, and pathologists experienced in the diagnosis of ILD is of the utmost importance to an accurate diagnosis.[1]

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Contributor Information and Disclosures
Author

Amanda M K Godfrey, MD Associate Staff, Department of Internal Medicine, IHA Pulmonary, Critical Care, and Sleep Consultants; Associate Staff, Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, St Joseph Mercy Ann Arbor

Amanda M K Godfrey, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American Medical Association, American Thoracic Society, Michigan State Medical Society

Disclosure: Nothing to disclose.

Coauthor(s)

Daniel R Ouellette, MD, FCCP Associate Professor of Medicine, Wayne State University School of Medicine; Chair of the Clinical Competency Committee, Pulmonary and Critical Care Fellowship Program, Senior Staff and Attending Physician, Division of Pulmonary and Critical Care Medicine, Henry Ford Health System; Chair, Guideline Oversight Committee, American College of Chest Physicians

Daniel R Ouellette, MD, FCCP is a member of the following medical societies: American College of Chest Physicians, Society of Critical Care Medicine, American Thoracic Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Daniel R Ouellette, MD, FCCP Associate Professor of Medicine, Wayne State University School of Medicine; Chair of the Clinical Competency Committee, Pulmonary and Critical Care Fellowship Program, Senior Staff and Attending Physician, Division of Pulmonary and Critical Care Medicine, Henry Ford Health System; Chair, Guideline Oversight Committee, American College of Chest Physicians

Daniel R Ouellette, MD, FCCP is a member of the following medical societies: American College of Chest Physicians, Society of Critical Care Medicine, American Thoracic Society

Disclosure: Nothing to disclose.

Chief Editor

Ryland P Byrd, Jr, MD Professor of Medicine, Division of Pulmonary Disease and Critical Care Medicine, James H Quillen College of Medicine, East Tennessee State University

Ryland P Byrd, Jr, MD is a member of the following medical societies: American College of Chest Physicians, American Thoracic Society

Disclosure: Nothing to disclose.

Additional Contributors

Stephen P Peters, MD, PhD, FACP, FAAAAI, FCCP, FCPP Thomas H Davis Chair in Pulmonary Medicine, Chief, Section on Pulmonary, Critical Care, Allergy and Immunologic Diseases, Professor of Internal Medicine, Pediatrics, and Translational Science, Associate Director, Center for Genomics and Personalized Medicine Research, Wake Forest University School of Medicine; Executive Director of the Respiratory Service Line, Wake Forest Baptist Medical Center

Stephen P Peters, MD, PhD, FACP, FAAAAI, FCCP, FCPP is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Association of Immunologists, American College of Chest Physicians, American College of Physicians, American Federation for Medical Research, American Thoracic Society, Sigma Xi

Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Integrity CE, Merck<br/>Received income in an amount equal to or greater than $250 from: – Array Biopharma, AstraZeneca, Aerocrine, Airsonett AB, Boehringer-Ingelheim, Experts in Asthma, Gilead, GlaxoSmithKline, Merck, Novartis, Ono Pharmaceuticals, Pfizer, PPD Development, Quintiles, Sunovion, Saatchi & Saatichi, Targacept, TEVA, Theron.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous authors, Rajesh G. Patel, MD, and Javier I. Diaz, MD, to the development and writing of this article.

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Chest radiograph of a patient with idiopathic pulmonary fibrosis showing bilateral lower lobe reticular opacities (red circles).
Classic subpleural honeycombing (red circle) in a patient with a diagnosis of idiopathic pulmonary fibrosis.
A patient with IPF and a confirmed histologic diagnosis of usual interstitial pneumonia. Note the reticular opacities (red circle) distributed in both lung bases and the minimal ground-glass opacities (blue circle).
A patient with nonspecific interstitial pneumonia. Note the predominance of ground-glass opacities (blue circles) and a few reticular lines (red arrow).
Patchwork distribution of abnormalities in a classic example of usual interstitial pneumonia (low-magnification photomicrograph; hematoxylin and eosin stain; original magnification, X4). Courtesy of Chad Stone, MD.
Table 1. Scoring for mortality risk in IPF.
  Predictor Points
Sex Female 0
Male 1
Age (years) ≥60 0
61-65 1
>65 2
FVC (% predicted) >75 0
50-75 1
< 50 2
DLCO (% predicted) >55 0
36-55 1
≤35 2
Cannot perform 3
Table 2. Staging and mortality risk for IPF.
Stage I II III
Points 0-3 4-5 6-8
Mortality      
1-year 5.6 16.2 39.2
2-year 10.9 29.9 62.1
3-year 16.3 42.1 76.8
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