Idiopathic Pulmonary Fibrosis (IPF)

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease (ILD). The prognosis of IPF is generally poor, with a median survival of 3 to 5 years post-diagnosis without treatment.¹ A diagnosis has become more necessary with the approval of 2 antifibrotic drugs, pirfenidone and nintedanib, which have been shown to slow the decline in forced vital capacity and possibly reduce the risk of acute exacerbations-rapid deteriorations in lung function.² Correct differential diagnosis is also important because immunosuppressive drugs used to treat other ILDs are harmful to patients with IPF.³ Differential diagnosis remains difficult and time-consuming, however, since the main IPF symptoms of chronic cough and exertional dyspnea are nonspecific and overlap with a number of other pulmonary and cardiovascular diseases.⁴

Diagnosis of IPF involves the exclusion of other ILDs and either a pattern of usual interstitial pneumonia (UIP) on high-resolution computed tomography (HRCT) or certain features on HRCT in combination with certain histological patterns on lung biopsy.^5,6 

Read more about IPF diagnosis.

Differential diagnosis between IPF and other diseases is further complicated by the overlap in common risk factors including history of smoking, age, and male sex.⁷ A number of methods including clinical assessments, review of medical history, radiologic imaging, histology of biopsy samples, bronchoalveolar lavage (BAL), and serology are used to exclude similar diseases in the differential diagnosis. Results of these tests should be reviewed and discussed with a multidisciplinary team in order to make a diagnosis.⁴

Heart Failure

One disease that IPF is commonly misdiagnosed as is heart failure (HF) due to their overlap in symptoms, such as dyspnea and reduced exercise tolerance. Medical history review and physical examination can be used to differentiate these diseases, with HF patients displaying other symptoms such as bilateral edema, orthopnea, displaced apical beat, increased jugular vein pressure, and bilateral posterior smooth crackles. Patients displaying these symptoms who have a history of hypertension, coronary artery disease, or diuretic use should be referred for further diagnosis of HF. Patients with IPF, on the other hand, frequently have crackles on lung auscultation at the posterior lung bases that have been described as the sound of separating velcro and are bibasilar and present during the entire inspiration (pan-inspiratory), even after deep breaths and coughing. Patients with IPF may also present with finger clubbing, where the distal phalanges are enlarged.⁷ 

Interstitial Idiopathic Pneumonias

It is also critical to differentiate IPF from a number of other interstitial idiopathic pneumonias (IIPs), as the disease course and treatment options differ between diseases. The differential diagnosis of these diseases from IPF is described below.

Desquamative interstitial pneumonia (DIP) is an uncommon form of IIP that is most common in smokers but may be seen in non-smokers related to other causes of fibrosis, such as connective tissue diseases, viral infections, or drug toxicities. DIP can be differentiated from IPF through imaging that shows ground-glass opacities without certain reticular features found in patients with IPF such as reticulonodular opacities. Numerous mononuclear cells in the distal airspaces are also characteristic features seen on histology.⁴

Respiratory bronchiolitis-interstitial lung disease is another form of IIP found in current smokers that may be a direct reaction to smoking. Radiologic findings show ground-glass opacities and centrilobular nodules. Histologic analysis shows the presence of pigmented macrophages in the lumen of bronchioles, as well as the infiltration of lymphocytes and histiocytes into submucosal and peribronchiolar areas.⁴

Another IIP, acute interstitial pneumonia (AIP), is a rapidly progressing form with a high short-term mortality rate (50% or more). As opposed to IPF, which progresses insidiously, AIP usually affects previously healthy individuals with rapid deterioration in lung function. Imaging shows patchy, ground-glass opacities with consolidation, while histology shows features of a diffuse distribution, thickening of alveolar walls due to connective tissue organization, and pneumocyte hyperplasia.⁴

Cryptogenic organizing pneumonia (COP) usually affects patients in the fifth or sixth decade, is a subacute IIP that commonly presents with symptoms of cough, weight loss, dyspnea, and fever. Histology usually shows a growth of granulation tissue in the alveoli or alveolar ducts. High-resolution CT imaging shows ground-glass opacities with consolidation.⁴

Two rare forms of IIP that may also need to be differentiated are idiopathic lymphoid interstitial pneumonia (ILIP) and idiopathic pleuroparenchymal fibroelastosis (IPPFE). ILIP is usually secondary to other diseases and displays ground-glass attenuation, interstitial thickening, centrilobular nodules, and lung cysts on HRCT. Infiltration of lymphocytes, plasma cells, and histiocytes into the alveolar septum are common histological findings in patients with ILIP. IPPFE usually results in upper lobe fibrosis, which can differentiate it from IPF. Histologic analysis shows septal elastosis and pleural fibrosis along with lymphoid follicle formation related to nonspecific inflammation.⁴

A group of IIPs that do not fit into the above categories is often collected into idiopathic nonspecific interstitial pneumonia (NSIP). The clinical characteristics that distinguish this group from IPF are that it has subacute symptoms and a lack of predominance in male patients. NSIP also does not typically have patchy involvement resulting in the patchwork pattern, fibroblastic foci, and architectural distortions common in IPF.⁴

Known Causes of Usual Interstitial Pneumonia Patterns

While a UIP pattern on HRCT scans and/or histology are used for the diagnosis of IPF, several other diseases can also display these patterns. One disease, chronic hypersensitivity pneumonitis (CHP), can be very difficult to distinguish from IPF. CHP is caused by a reaction to a specific antigen, but many patients do not recall being exposed to specific antigens. CHP can be distinguished from IPF by its mid-upper lung zone predominance in many patients. A lower predominance of fibroblastic foci may also indicate CHP rather than IPF. Other features that may be present in CHP that would differentiate it include the presence of intraluminal fibrosis, isolated giant cells or granulomas, lymphoid aggregates, and centrilobular fibrosis. Bridging fibrosis is also an indicator of CHP, but it may be found in another disease with a UIP pattern, asbestosis.⁴

Asbestosis is a form of exposure-related lung disease caused by the inhalation of asbestos fibers. Asbestosis usually has a slow progression and its severity is typically dose-related, with its development requiring significant exposure over several months. Diagnosis can usually be made through exposure history and radiological findings, but histology may also be useful.⁴

Connective tissue diseases (CTDs) are other common diseases with UIP features that can make diagnosis more difficult.⁴ Patients with rheumatoid arthritis, systemic sclerosis, Sjögren syndrome, and antisynthetase syndrome are often at risk of developing ILDs.⁴ Diagnosis may be even more challenging as some patients may have both diseases, an ILD preceding a CTD, or an ILD that has CTD features that are insufficient to meet diagnostic criteria.⁴ A number of serological tests including C-reactive protein (CRP), erythrocyte sedimentation rate, antinuclear antibodies (by immunofluorescence), rheumatoid factor, myositis panel, and anti-cyclic citrullinated peptide may be helpful in the differentiation of CTDs.⁶

A number of lung diseases may also be due to damage caused by drugs or radiation treatment. Careful medical history review should be performed, as the link between these agents and lung disease may not occur for years after discontinuation, making diagnosis even harder. Patients with lung cancer may be at a higher risk for radiation-induced lung disease than other forms of cancer, such as breast cancer.⁴

A very rare autosomal recessive disease, Hermansky-Pudlak Syndrome (HPS), may also present with pulmonary fibrosis symptoms similar to IPF. HPS is characterized by oculocutaneous hypopigmentation, platelet dysfunction, and granulomatous colitis, which can be used for differentiation. HPS predominantly affects women and those of Puerto Rican descent in the third or fourth decade of life, adding further criteria for differentiation.⁴

Microaspirations from gastroesophageal reflux (GER) can also lead to lung fibrosis. Reflux may result in gastroesophageal reflux disease (GERD) or non-erosive gastroesophageal reflux disease (NERD) and could be silent aspirations. It is unclear whether the damage from microaspirations is a separate lung disease or merely a risk factor for IPF, however, and more research is needed.⁴

Other Diseases

A number of other diseases should also be included in differential diagnosis, including chronic obstructive pulmonary disease (COPD), sarcoidosis, eosinophilic pneumonia, lung cancer, and infections. COPD can commonly be differentiated from IPF through radiologic analyses.⁸ Sarcoidosis, eosinophilic pneumonia, lung cancer, and lung infections can typically be diagnosed through analysis of BAL fluid to look for signs of malignancy, infection, cell proportions, or CD4/CD8 ratios.⁶

References

1. Wakwaya Y, Brown KK. Idiopathic pulmonary fibrosis: Epidemiology, diagnosis and outcomes. Am J Med Sci. 2019;357(5):359-369.
2. Raghu G, Rochwerg B, Zhang Y, et al; American Thoracic Society; European Respiratory Society; Japanese Respiratory Society; Latin American Thoracic Association. An official ATS/ERS/JRS/ALAT clinical practice guideline: treatment of idiopathic pulmonary fibrosis. An update of the 2011 clinical practice guideline. Am J Respir Crit Care Med. 2015;192(2):e3-19. doi:10.1164/rccm.201506-1063ST
3. Mohning MP, Richards JC, Huie TJ. Idiopathic pulmonary fibrosis: the radiologist’s role in making the diagnosis. Br J Radiol. 2019;92(1099):20181003. doi:10.1259/bjr.20181003
4. Aburto M, Herráez I, Iturbe D, Jiménez-Romero A. Diagnosis of idiopathic pulmonary fibrosis: differential diagnosis. Med Sci (Basel). 2018;6(3):73. doi:10.3390/medsci6030073
5. Raghu G, Collard HR, Egan JJ, et al.; 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
6. 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
7. van Cleemput J, Sonaglioni A, Wuyts WA, Bengus M, Stauffer JL, Harari S. Idiopathic pulmonary fibrosis for cardiologists: differential diagnosis, cardiovascular comorbidities, and patient management. Adv Ther. 2019;36(2):298-317. doi:10.1007/s12325-018-0857-z
8. Chilosi M, Poletti V, Rossi A. The pathogenesis of COPD and IPF: distinct horns of the same devil? Respir Res. 2012;13(1):3. doi:10.1186/1465-9921-13-3

Reviewed by Debjyoti Talukdar, MD, on 7/2/2021.

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Brian Murphy, PhD

Brian Murphy, PhD, is a medical/science writer and educator who has written over 300 resource articles about rare diseases. He holds a BS from Georgia Institute of Technology and a PhD from Case Western Reserve University, both in Biomedical Engineering. After graduation, Brian worked as a clinical neural engineer to help restore movement in spinal cord injured patients by reconnecting their brain to their paralyzed muscles using experimental medical devices. In addition to resource pages, Brian has also authored/co-authored several research articles in journals including The Lancet, Journal of Neural Engineering, and PLOS ONE.