Idiopathic Pulmonary Fibrosis (IPF)


Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial lung disease of unknown cause.1 It primarily affects older adults and is characterized by progressive worsening of lung function and dyspnea. It has a poor prognosis, with a median untreated survival of 3-5 years after diagnosis.2 The major clinical manifestations of IPF include exertional dyspnea, chronic cough, bibasilar inspiratory “velcro” crackles, and finger clubbing – swelling of the distal phalanges.1 The 2 most common features, dyspnea and cough, are not exclusive to IPF and many different forms of testing are required for definitive diagnosis. Several tests may also be used to monitor symptoms and responses to treatment over time.

Imaging

Imaging is a critical tool in the diagnosis of IPF. Chest radiographs or computed tomography scans can be used initially to look for evidence of bilateral pulmonary fibrosis. For patients over 60 years of age showing evidence of fibrosis along with bibasilar inspiratory crackles, high-resolution computed tomography (HRCT) is recommended.1

High-Resolution Computed Tomography

The use of HRCT can be critical to the imaging of several IPF features that indicate usual interstitial pneumonia (UIP), including honeycombing (consistent-diameter, clustered, cystic airspaces), traction bronchiectasis/bronchiolectasis, ground-glass opacifications, and fine reticulation. The presence of these features, along with the absence of features that would indicate other diseases, are used to categorize the scans into 1 of 4 patterns: “UIP,” “Probable UIP,” “Indeterminate for UIP,” or “Alternative Diagnosis.” Guidelines from the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society (ATS/ERS/JRS/ALAT) recommend that HRCT scans utilize the thinnest collimation, shortest rotation time, and highest pitch possible to create motion-free images along with techniques to minimize radiation exposure.1 Acquisitions should be performed of volumetric end-inspiration in the supine position, end-expiration in the supine position, and sequential or volumetric scans during inspiration while in the prone position.

Procedures

A number of procedures may be helpful in the diagnosis of IPF as well, including bronchoalveolar lavage (BAL) and tissue biopsies.

Bronchoalveolar Lavage

Bronchoalveolar lavage is typically performed during bronchoscopy and can be a useful tool for the collection of cells inside of the lungs. Cellular analysis of BAL fluid, discussed below in the Lab Work section, can be used for differential diagnosis of IPF and other interstitial lung diseases. Analysis of BAL fluid may also help indicate infection, malignancy, or the presence of irritating dust or asbestos.3

Biopsy

Tissue biopsies may also be needed to aid in diagnosis for patients who do not meet the requirements for the “UIP” pattern of HRCT. The 2018 ATS/ERS/JRS/ALAT guidelines recommend surgical lung biopsy via video-assisted thoracoscopic surgery in patients who can handle the procedure. Samples should be taken from 2 or 3 lobes. The guidelines acknowledged 2 other methods of collecting samples, transbronchial lung biopsy and lung cryobiopsy, but did not make recommendations for or against their uses.2

Tissue samples collected by biopsy may be processed in a number of different ways to check for differential diagnosis. Iron stains can be useful to check for asbestos bodies. Elastic tissue stains and connective tissue stains may also be helpful for differential diagnosis. Standard staining such as hematoxylin and eosin is also of use. Analysis of samples can be performed to look for signs of UIP, including dense fibrosis with architectural distortions such as honeycombing or scarring, patchy involvement of the lung parenchyma in fibrosis, fibroblast foci, and predominant subpleural or paraseptal spatial distributions of fibrosis.1

Lab Work

A number of serological tests may be performed during differential diagnosis to eliminate connective tissue diseases. These tests include C-reactive protein, erythrocyte sedimentation rate, antinuclear antibodies, rheumatoid factor, myositis panel, and anti-cyclic citrullinated peptide. Additional testing may be warranted on a case-by-case basis depending on presenting symptoms.1

These additional tests may include: muscle enzymes such as creatine phosphokinase, myoglobin, and/or aldolase; antisynthetase antibodies such as Jo-1; anti-melanoma differentiation-associated protein 5 (anti-MDA5); anti-Mi 2; anti-nuclear matrix protein 2 (anti-NXP2); anti-transcriptional intermediary factor 1-gamma (anti-TIF1-γ); anti-signal recognition particle (anti-SRP); anti-3-hydroxy-3-methylglutaryl-CoA reductase (anti-HMGCR); anti-small ubiquitin-related modifier-activating enzyme (anti-SAE); anti-U1 ribonucleoprotein (anti-U1RNP); anti-polymyositis/scleroderma 75 (anti-PM/Scl75); anti-polymyositis/scleroderma 100 (anti-PM/Scl100); and anti-Ku.1

For patients suspected of scleroderma, lab tests for anti-topoisomerase-1 (anti-Scl-70), anti-centromere antibodies (ACA), anti-RNA polymerase III (anti-RNAP III), anti-PMScl, and U3 RNP (fibrillarin), as well as the previously mentioned tests for anti-U1RNP and anti-Ku, may also be warranted. Other potential differential diagnostic serological tests could include anti-Sjögren-specific antibody A (anti-SSA/anti-Ro) and anti-Sjögren-specific antibody B (anti-SSB/anti-La) for Sjögren syndrome or anti-cytoplasmic antibodies for vasculitis.1

Cellular analysis of BAL fluid may also be helpful in the differential diagnosis of IPF in some patients without an HRCT “UIP” pattern. The 2018 guidelines conditionally recommend BAL fluid collection in patients whose radiologic results indicate the possibility of eosinophilic pneumonia, sarcoidosis, cryptogenic organizing pneumonia (also known as bronchiolitis obliterans organizing pneumonia), or infection.1 Evidence suggests that eosinophil proportion is slightly elevated in patients with IPF compared to that of the the general population but is much lower than that of patients with eosinophilic pneumonia. Lymphocyte proportion and CD4/CD8 ratio are also elevated in IPF patients but are much less than those of patients with sarcoidosis.1

Lung Auscultation

Patients suspected of IPF should also be examined using lung auscultation to check for the presence of inspiratory fine crackles. These crackles are usually bibasilar with a distinctive sound described as the separation of velcro, such as opening a blood pressure cuff. It is recommended that all patients with velcro crackles receive further diagnostic testing for UIP.4

Pulmonary Function Testing

Another tool for the diagnosis and monitoring of the progression of IPF includes pulmonary function testing. Fibrosis can affect lung volume, airway mechanics, gas exchange, and sleep disturbances. As the disease progresses and fibrosis increases, the lungs become stiffer and less compliant, leading to reduced lung volume and worsened gas exchange. Testing for sleep disturbances may also be warranted in patients.5

6MWT IPF
Advanced Six Minute Walk Test (6MWT) with ventilation measurement by COSMED

Six-Minute Walk Test

The 6-minute walk test (6MWT) is another test that may be useful for monitoring disease progression. During the test, the primary measurement of 6-minute walk distance (6MWD), how far the patient can travel in 6 minutes, can be useful to determine the patient’s overall cardiopulmonary reserve and to observe changes over time. This data may also have some prognostic value to determine risk of mortality for patients. The 6MWD has been used as a clinical endpoint to show treatment effects in clinical trials.6

References

  1. Raghu G, Remy-Jardin M, Myers JL, et al.; American Thoracic Society; European Respiratory Society; Japanese Respiratory Society; Latin American Thoracic Society. Diagnosis of idiopathic pulmonary fibrosis. An official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med. 2018;198(5):e44-e68. doi:10.1164/rccm.201807-1255ST
  2. Quinn C, Wisse A, Manns ST. Clinical course and management of idiopathic pulmonary fibrosis. Multidiscip Respir Med. 2019;14:35. doi:10.1186/s40248-019-0197-0.
  3. Meyer KC, Raghu G. Bronchoalveolar lavage for the evaluation of interstitial lung disease: is it clinically useful? Eur Respir J. 2011;38(4):761-769. doi:10.1183/09031936.00069509
  4. Cottin V, Cordier JF. Velcro crackles: the key for early diagnosis of idiopathic pulmonary fibrosis? Eur Respir J. 2012;40(3):519-521. doi:10.1183/09031936.00001612
  5. 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(2 Pt 1):646-664. doi:10.1164/ajrccm.161.2.ats3-00
  6. Lancaster LH. Utility of the six-minute walk test in patients with idiopathic pulmonary fibrosis. Multidiscip Respir Med. 2018;13:45. doi:10.1186/s40248-018-0158-z

Reviewed by Harshi Dhingra, MD, on 7/1/2021.