Idiopathic Pulmonary Fibrosis (IPF)


Idiopathic pulmonary fibrosis (IPF) is a rare, progressive interstitial lung disease (ILD). IPF is typically fatal, with a median life expectancy of 3-5 years after diagnosis if left untreated.1 The most common presenting symptoms found in patients with IPF, including chronic cough and dyspnea, are found in many other disorders, making differential diagnosis more difficult.

A set of international diagnostic guidelines for IPF were initially published in 2000 by the American Thoracic Society (ATS) and European Respiratory Society (ERS).2 The ATS and ERS in combination with the Japanese Respiratory Society (JRS) and Latin American Thoracic Society (ALAT) published a more detailed set of guidelines in 2011,3 with further revisions in 2018.4 The Fleischner Society also published diagnostic criteria for IPF in 2018.5 Based on these guidelines, the diagnosis of IPF requires: the exclusion of other causes of ILD such as connective tissue disease, drug toxicity, and environmental exposure to lung irritants; and either the presence of a usual interstitial pneumonia (UIP) pattern on high resolution computed tomography (HRCT) scans or a combination of patterns seen on HRCT scans as well as histological samples from lung biopsy.4 The combination of test results along with multidisciplinary discussions (MDD) between the pulmonary clinician, chest radiologist, and pathologist can help achieve a definitive diagnosis.6

Clinical Evaluation, Medical History, and Physical Examination

A diagnosis of IPF should be pursued in older patients (over 50) with a chronic, refractory cough, exertional dyspnea, and digital clubbing – swelling of the distal ends of the fingers.4 Dyspnea, especially exertional dyspnea, is the most commonly reported symptom among patients with IPF.7 Chronic cough is also very frequent, with presentation in as high as 80% of patients.8 An estimated 7% to 52% of patients with IPF report finger clubbing.9 IPF is more predominant in patients who are older and is very rare in patients under 50.4 Some studies have suggested that male patients are at a higher risk of IPF.4

A thorough medical history and physical examination should be done on patients suspected to have IPF. Medical history should investigate any potential occupational or environmental exposures that could indicate exposure-related ILDs such as hypersensitivity pneumonitis or pneumoconiosis. A family history of ILDs should also be reviewed to look for familial forms of ILD and possible genetic mutations that could increase the risk of IPF. Exploration of all medications used in the past should be performed as well to look for any that could have caused pulmonary toxicity.6

Physical examination may find the presence of bibasilar inspiratory fine crackles on lung auscultation.4 These crackles are often described as the sound made when separating velcro. Crackles, combined with dyspnea and gas exchange abnormalities, can indicate interstitial lung disease, and follow-up testing should be done to confirm the diagnosis of IPF versus other diseases such as asbestosis.10 One study found that all patients who had received a diagnosis of UIP had velcro crackles, indicating that their presence may be a useful tool in the diagnosis of IPF.11

IPF fibrosis right lung
X-ray film of a patient with fibrosis in the right upper lung.

Imaging

If examinations and medical history review did not point to another cause of lung dysfunction, chest HRCT should be performed. The HRCT images will be used to look for evidence of UIP including honeycombing (clustered cystic airspaces), reticular abnormalities, traction bronchiectasis or bronchiolectasis, and a subpleural, basal predominance of features. Other features that may be present on HRCT include mediastinal lymphadenopathy, ground-glass opacification, and small ossified nodules within fibrotic areas.4

The features found on HRCT are used to make a determination of 1 of 4 diagnostic categories, including “UIP,” “probable UIP,” “indeterminate for UIP,” or “alternative diagnosis” patterns. To be categorized as “UIP” pattern on HRCT, images must show honeycombing with subpleural and basal predominance along with the absence of features inconsistent for UIP. A “probable UIP” pattern categorization is made if honeycombing is not present but reticular patterns with peripheral traction bronchiectasis and bronchiolectasis are found and are predominantly subpleural and basal. Mild ground-glass opacities may also be present.4

The “indeterminate for UIP” pattern describes HRCT scans that still show fibrosis with subpleural and basal predominance but do not meet the criteria for “UIP” or “probable UIP” pattern designations. The scans must not indicate an alternative diagnosis. “Alternative diagnosis” pattern designation is given when HRCT scans have features indicative of other disorders. Such features might include cysts, predominant ground-glass opacification, marked mosaic attenuation, profuse micronodules, centrilobular nodules, nodules, consolidation, pleural plaques, dilated esophagus, distal clavicular erosions, extensive enlargement of lymph nodes, and pleural effusions. Scans showing features with predominant peribronchovascular, perilymphatic, or upper or mid-lung distributions would also indicate an “alternative diagnosis” pattern.4

High-resolution computed tomography scans of the chest of a patient with IPF. IPFeditor, CC BY-SA 3.0, used with permission via Wikimedia Commons

Histopathology

If HRCT scans do not indicate a “UIP” pattern, further testing should be performed for diagnosis, including surgical lung biopsies taken from 2 to 3 lobes in patients healthy enough where the risks do not outweigh the benefits. Histopathology of these samples should be performed to look for patterns and features of “UIP,” “probable UIP,” “indeterminate for UIP,” and “alternative diagnosis” categorizations. A “UIP” pattern should include dense fibrosis with architectural distortion such as honeycombing, predominant subpleural and/or paraseptal distribution, patchy involvement of the lung parenchyma, fibroblast foci, and an absence of alternative diagnosis features. Histopathology showing honeycombing only or only some of the features for a “UIP” pattern and an absence of alternative diagnosis features would indicate a “probable UIP” pattern. Fibrosis indicating another primary cause or a pattern other than UIP in combination with other “UIP” pattern features along with features suggestive of an alternative diagnosis should be categorized as “indeterminate for UIP.” An “alternative diagnosis” pattern is indicated when histological patterns of other idiopathic interstitial pneumonias are present along with findings of other diseases.4

Transbronchial lung biopsy or lung cryobiopsy may be alternative techniques for tissue collection in some patients where surgical lung biopsy is not recommended. The 2018 guidelines made no recommendations for or against their uses in diagnosis. After analysis, the categorization of patterns from HRCT and histopathology should be discussed between the MDD to determine a diagnosis of IPF or other.4

Laboratory Testing

If results of HRCT and histopathology are still inconclusive, laboratory testing of fluids may also be considered. Bronchoalveolar lavage (BAL) fluid may be collected and tested for eosinophil and lymphocyte levels along with CD4/CD8 ratio for patients with suspected differential diagnosis of eosinophilic pneumonia or sarcoidosis. Eosinophil levels in patients with IPF are slightly elevated compared to those of the general population but markedly lower than those of patients with eosinophilic pneumonia. Lymphocyte and CD4/CD8 ratio levels are also slightly higher in IPF patients compared to those of the general population but lower than those of patients with sarcoidosis.4

Several serum biomarkers have also been investigated as diagnostic tools for IPF including MMP-7, SPD, CCL-18, and KL-6. Due to high false-positive and false-negative rates found in their literature review, the ATS/ERS/JRS/ALAT recommend against the use of these serological tests for IPF diagnosis in their 2018 guidelines.4

The 2018 guidelines did recommend serological testing to exclude connective tissue disease. The ATS/ERS/JRS/ALAT panel suggests tests for C-reactive protein, erythrocyte sedimentation rate, antinuclear antibodies through immunofluorescence, rheumatoid factor, myositis panel, and anti-cyclic citrullinated peptide. Other tests may be utilized on a case-by-case basis for further differentiation.4

References

  1. 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
  2. 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
  3. Raghu G, Collard HR, Egan JJ, et al.; ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011;183(6):788-824. doi:10.1164/rccm.2009-040GL
  4. Raghu G, Remy-Jardin M, Myers JL, et al. 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
  5. Lynch DA, Sverzellati N, Travis WD, et al. Diagnostic criteria for idiopathic pulmonary fibrosis: a Fleischner Society White Paper. Lancet Respir Med. 2018;6(2):138-153. doi:10.1016/S2213-2600(17)30433-2
  6. Wakwaya Y, Brown KK. Idiopathic pulmonary fibrosis: epidemiology, diagnosis andoutcomes. Am J Med Sci. 2019;357(5):359-369. doi:10.1016/j.amjms.2019.02.013
  7. Nakamura Y, Suda T. Idiopathic pulmonary fibrosis: diagnosis and clinical manifestations. Clin Med Insights Circ Respir Pulm Med. 2016;9(Suppl 1):163-171. doi:10.4137/CCRPM.S39897
  8. van Manen MJG, Birring SS, Vancheri C, et al. Cough in idiopathic pulmonary fibrosis. Eur Respir Rev. 2016;25(141):278-286. doi:10.1183/16000617.0090-2015
  9. van Manen MJG, Vermeer LC, Moor CC, et al. Clubbing in patients with fibrotic interstitial lung diseases. Respir Med. 2017;132:226-231. doi:10.1016/j.rmed.2017.10.021
  10. 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
  11. Sellarés J, Hernández-González F, Lucena CM, et al. Auscultation of velcro crackles is associated with usual interstitial pneumonia. Medicine (Baltimore). 2016;95(5):e2573. doi:10.1097/MD.0000000000002573

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

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