INTRODUCTION — Idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP), previously known as cryptogenic fibrosing alveolitis (CFA) in Europe, is the most common type of idiopathic interstitial pneumonia (IIP). IIPs are spontaneously occurring (ie, idiopathic) diffuse parenchymal lung diseases. IPF is defined as a spontaneously occurring (idiopathic) specific form of chronic fibrosing interstitial pneumonia limited to the lung and associated with a pattern of UIP on high resolution computed tomography or histologic appearance on surgical (thoracoscopic or open) lung biopsy [1-3].

The other IIPs include nonspecific interstitial pneumonia (NSIP), desquamative interstitial pneumonia (DIP), respiratory bronchiolitis associated interstitial lung disease (RB-ILD), acute interstitial pneumonia (AIP), lymphocytic interstitial pneumonia (LIP), and cryptogenic organizing pneumonia (COP).

The clinical manifestations, evaluation, and diagnosis of IPF will be reviewed here. The evaluation of interstitial lung disease in general; the diagnosis of the other IIPs; and the treatment, monitoring, and prognosis of IPF are discussed separately. (See "Approach to the adult with interstitial lung disease: Clinical evaluation" and "Approach to the adult with interstitial lung disease: Diagnostic testing" and "Idiopathic interstitial pneumonias: Classification and pathology" and "Treatment of idiopathic pulmonary fibrosis" and "Prognosis and monitoring of idiopathic pulmonary fibrosis".)

EPIDEMIOLOGY — Reported prevalence and incidence data for IPF vary and depend on ascertainment and reporting methods, and also the age and geographic location of the population. Both prevalence and incidence increase with advancing age, with presentation commonly occurring in the sixth and seventh decades; rarely is IPF seen in patients aged less than 50 years [1,2]. The prevalence and incidence are higher in men than women [4].

In a systematic review, the reported prevalence of IPF ranged from 0.5 to 27.9/100,000 and the incidence ranged from 0.22 to 8.8/100,000 [5]. In the United States, IPF incidence estimates range from 7 to 16 cases per 100,000 overall [6]. In contrast, among a random sample of Medicare beneficiaries (largely ≥65 years old), the prevalence of IPF was 494 cases per 100,000, and the incidence was 94 cases per 100,000 person years [7]. In the United Kingdom, the IPF incidence in 2008 was 7.4 per 100,000 person-years [8]. In Europe, IPF prevalence ranged from 1.25 to 23.4 cases per 100,000 population, and the annual incidence ranged between 0.22 and 7.4 per 100,000 population [9]. Overall, the incidence of IPF is increasing worldwide and conservative estimates of the incidence range from 3 to 9 cases per 100,000 per year for Europe and North America [10].

PATHOGENESIS AND GENETIC PREDISPOSITION — The pathogenesis of IPF/usual interstitial pneumonia (UIP) is complex and likely involves cycles of epithelial cell injury and dysregulated repair. The pathogenesis of IPF is discussed separately. (See "Pathogenesis of idiopathic pulmonary fibrosis".)

Most cases of IPF are sporadic, but familial cases have been described. Familial pulmonary fibrosis, Hermansky-Pudlak syndrome (HPS), and the short telomere syndromes usually present at a younger age than IPF. While a number of genetic polymorphisms have been reported among patients with sporadic cases of IPF, none are well-established [1]. (See "Pathogenesis of idiopathic pulmonary fibrosis", section on 'Genetic predisposition'.)

●Familial pulmonary fibrosis – Familial pulmonary fibrosis (FPF) accounts for less than 5 percent of patients with IPF. Inheritance appears to follow an autosomal dominant pattern with variable penetration. Within a family, affected patients may have different interstitial lung diseases [11]. FPF has no distinct distinguishing features and requires a thorough family history. A number of genetic variants have been associated with FPF, for example the genes for surfactant-associated proteins A (SFTPA2), surfactant protein C (SFTPC), and mucin 5B (MUC5B). (See "Pathogenesis of idiopathic pulmonary fibrosis", section on 'Genetic predisposition'.)

FPF appears to be associated with an increased incidence of bronchogenic carcinoma [12].

●Hermansky-Pudlak syndrome – HPS, an autosomal recessive disorder characterized by oculocutaneous albinism and platelet abnormalities, is a rare cause of UIP and presents at an earlier age (eg, thirties) than IPF [13,14]. These patients are often easily diagnosed by the presence of oculocutaneous albinism, although patients with HPS who are of Puerto Rican descent may have brown hair and varying amounts of skin melanin. Photophobia and nystagmus are common in HPS. (See "Pathogenesis of idiopathic pulmonary fibrosis", section on 'Genetic predisposition' and "Idiopathic interstitial pneumonias: Classification and pathology", section on 'Differential diagnosis' and "Congenital and acquired disorders of platelet function", section on 'Storage pool disorders'.)

●Telomeropathies – The short telomere syndromes are caused by mutations in the genes responsible for maintaining telomere length (eg, TERT, TERC, PARN, DKC1, TINF2, RTEL1) [15]. The disorder is characterized by severely short telomeres (below the first percentile for age), combined with dysfunction of one or more target organs, including the bone marrow, liver, skin, and lung. Clinical features suggestive of short telomere syndromes include a family history of pulmonary fibrosis (in adulthood, short telomere syndromes most commonly present as an autosomal dominant trait), a personal or family history of premature greying, transaminitis or evidence of liver dysfunction, cytopenias or an unexplained macrocytosis. The short telomere syndromes also include dyskeratosis congenita, bone marrow failure, and liver disease [16-18]. (See "Pathogenesis of idiopathic pulmonary fibrosis", section on 'Genetic predisposition' and "Dyskeratosis congenita and other telomere biology disorders".)

Short telomeres have been identified in about 25 percent of sporadic IPF and in about 15 percent of families with familial pulmonary fibrosis [19]. Exome-based surveys suggest that up to 11 percent of patients with sporadic IPF have short telomere-associated gene variants [20]. The prevalence of short telomere syndromes may be higher in IPF patients referred for lung transplantation (estimated 16 percent in one study) [17].

POTENTIAL RISK FACTORS — While IPF, by definition, lacks a known cause, certain risk factors have been identified [1,21]. Cigarette smoking is most strongly associated with IPF. Exposure to stone, metal, wood, and organic dusts has also been suggested as a risk factor [22-24]. Gastroesophageal reflux may contribute to lung injury via microaspiration, although this association is more difficult to interpret given the high frequency of gastroesophageal reflux in the general population [25,26].

CLINICAL MANIFESTATIONS — Patients with IPF typically present at age 60 years or older [27,28]. The majority of patients have a history of cigarette smoking [1]. Patients commonly report a gradual onset of dyspnea on exertion and nonproductive cough over several months. Fatigue, fever, myalgias, and arthralgias are rarely reported.

As with all patients who present with interstitial lung disease, the history should include questions about any family history of lung disease; symptoms suggestive of rheumatic disease (eg, arthralgias, dry eyes, dry mouth, muscle weakness, numbness, Raynaud phenomenon, tingling); current and recent medications; and exposure to fumes, dusts (eg, asbestos, silica), or therapeutic irradiation. (See "Approach to the adult with interstitial lung disease: Clinical evaluation", section on 'History'.)

On physical examination bibasilar crackles are usually audible, but rarely they may be absent or only heard unilaterally in early disease. Patients with more advanced disease may have end-inspiratory "squeaks" due to traction bronchiectasis. While early reports describe finger clubbing in 45 to 75 percent of patients, our clinical impression is that clubbing is a manifestation of advanced IPF [29].

EVALUATION — The evaluation of a patient with suspected IPF requires a combination of steps and includes the following:

●Exclusion of identifiable causes of interstitial lung disease (ILD) based on the history, physical, and laboratory testing.

●An assessment of the pattern and severity of respiratory impairment on pulmonary function testing.

●High resolution computed tomography (HRCT) of the chest to confirm the presence of ILD and characterize the distribution and pattern of opacities.

●A multidisciplinary clinical, radiologic, and pathologic discussion is useful in arriving at the most accurate final diagnosis [3,30-33].

Clinical assessment — Patients with newly diagnosed ILD should have a detailed assessment for potential causes of interstitial lung disease (table 1):

●Medications (eg, amiodarone, bleomycin, long-term nitrofurantoin, biologic therapies)

●Exposure at home or at work to agents that cause hypersensitivity pneumonitis

●Work exposure to asbestos, silica, other fumes, vapors, dusts, or mold

●Signs or symptoms of rheumatic disease (eg, joint pain or inflammation, digital ulcers, dry eyes, dry mouth, fatigue, fever, hair loss, muscle weakness or pain, photosensitivity, Raynaud phenomenon, skin thickening, telangiectasia)

●Family history (eg, ILD, premature graying, cryptogenic cirrhosis, aplastic anemia, other bone marrow diseases)

Laboratory — No laboratory tests are specific for a diagnosis of IPF, so the role of laboratory testing in patients with newly identified ILD is to identify or exclude processes in the differential diagnosis. The role of laboratory testing in patients being evaluated for ILD is discussed separately. (See "Approach to the adult with interstitial lung disease: Diagnostic testing", section on 'Laboratory tests'.)

For patients undergoing an initial evaluation for possible IPF, serologic studies may be of benefit in identifying subclinical rheumatic disease [3]. We typically obtain tests for antinuclear antibodies, anti-cyclic citrullinated peptide antibodies, and rheumatoid factor. C-reactive protein (CRP) and erythrocyte sedimentation rate are nonspecific measures of inflammation and are obtained by some experts. Other tests, such as antisynthetase and other myositis panel antibodies (eg, anti-Jo-1, anti-PL7, anti-melanoma differentiation associated gene [MDA]-5), creatine kinase, aldolase, Sjögren's antibodies (anti-SS-A, anti-SS-B), and scleroderma antibodies (anti-topoisomerase [scl-70], anti-PM-1), may be helpful in selected cases with suggestive symptoms or signs [3].

●Role of screening for myositis antibodies unclear – The possibility that screening tests for myositis antibodies might identify unsuspected inflammatory myositis was examined in a case series that included 45 patients with a pattern of UIP on high resolution computed tomography (HRCT) and no known rheumatic disease [34]. Myositis antibody testing (Jo-1, PL-7, PL-12, MDA-5, Ro52) was positive in 15 patients, although a change in diagnosis only occurred in 5. Anti-Ro52 was least likely to be associated with a change in diagnosis. In the larger group that included patients with other patterns of ILD, approximately 60 percent of patients with myositis antibodies had negative antinuclear antibody, rheumatoid factor, and anti-cyclic citrullinated peptide antibody testing. Further study is needed to determine the best panel for identifying underlying rheumatic disease.

●Antinuclear antibodies and rheumatoid factor – Among patients with IPF documented by surgical lung biopsy or HRCT with multidisciplinary review and no symptoms or signs of rheumatic disease, circulating antinuclear antibodies (≥1:40) are present in 17 to 25 percent and a positive rheumatoid factor in 5 to 18 percent, depending on the population studied [35,36].

●Hypersensitivity pneumonitis panels – For patients with suspected IPF, the utility of screening panels for hypersensitivity pneumonitis (HP) is unclear due to problems with specificity. We typically reserve serologic testing for HP for patients with a historical risk factor (eg, occupational or environmental exposures) or features that are atypical for IPF (eg, younger age, centrilobular nodules on HRCT imaging). (See "Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Clinical manifestations and diagnosis", section on 'Laboratory tests'.)

●Biomarkers – Measurement of biomarkers, such as serum matrix metalloproteinase (MMP)-7, surfactant protein-D (SPD), chemokine ligand (CCL)-18, and Krebs von den Lungen (KL)-6, has high rates of false positive and false negative results when differentiating IPF from other ILDs and is not advised [3].

Pulmonary function tests — Complete pulmonary function testing (PFT; spirometry, lung volumes, diffusing capacity for carbon monoxide [DLCO]) and resting and ambulatory pulse oximetry are obtained in virtually all patients with suspected ILD. These tests are helpful in establishing the pattern of lung involvement (eg, restrictive, obstructive, or mixed) and assessing the severity of impairment. In patients with IPF, PFTs typically demonstrate a restrictive pattern (eg, reduced forced vital capacity [FVC], but normal ratio of forced expiratory volume in one second [FEV₁]/FVC), a reduced DLCO, and, as the disease progresses, a decrease in the six-minute walk distance. (See "Approach to the adult with interstitial lung disease: Diagnostic testing", section on 'Pulmonary function testing' and "Overview of pulmonary function testing in adults", section on 'Restrictive ventilatory defect'.)

Chest imaging

●Chest radiograph – A chest radiograph is typically obtained in adults with cough and/or progressive shortness of breath. The most common findings in IPF are an increase in reticular markings, although this is a nonspecific finding that is also associated with other interstitial lung diseases and heart failure.

●High resolution computed tomography – HRCT should be obtained in all patients suspected of having IPF [3]. Technical requirements for HRCT scanning of patients with ILD are described in the 2018 American Thoracic Society (ATS), European Respiratory Society (ERS), Japanese Respiratory Society (JRS), and Latin American Thoracic Society (ALAT) guideline and include submillimetric collimation, reconstruction of thin-section (≤1.5 mm) images, supine inspiratory (full inspiration) and expiratory images, and reduced radiation dose (1 to 3 mSv, but not <1 MSv) [3]. The presence of certain specific HRCT features in the appropriate clinical setting, may be sufficient to establish the diagnosis of IPF (table 2) [28,37,38].

A diagnosis of IPF cannot be made based on HRCT appearance alone [39]. The characteristic HRCT features of IPF include peripheral, basilar predominant opacities associated with honeycombing and traction bronchiectasis-bronchiolectasis (image 1) [40-42]. Honeycombing refers to clusters of cystic airspaces approximately 3 to 10 mm in diameter, usually in a subpleural location (image 2). While honeycombing is essential to making a definite HRCT diagnosis of usual interstitial pneumonia (UIP), it is absent in probable and indeterminate UIP [27,43].

Up to 30 percent of cases with a histopathological diagnosis of UIP may have HRCT findings more consistent with an alternate diagnosis [44]. (See "High resolution computed tomography of the lungs", section on 'Idiopathic interstitial pneumonias' and "Approach to the adult with interstitial lung disease: Diagnostic testing", section on 'Imaging'.)

Ground glass opacities that are superimposed on a fine reticular pattern can be present in UIP [40], but ground glass opacities without an associated reticular pattern and extensive ground glass opacities that are more prominent than the reticular changes are inconsistent with UIP. However, in the setting of an acute exacerbation of IPF, bilateral ground glass opacities and/or consolidation can be present on a background of a UIP pattern. (See "Acute exacerbations of idiopathic pulmonary fibrosis".)

Pleural disease is uncommon in IPF, so its presence should raise the possibility of an alternate or comorbid diagnosis such as rheumatoid arthritis, systemic lupus erythematosus, asbestosis, heart failure, drug-induced lung disease, or lymphangitic carcinomatosis. Nodular pleural abnormalities affecting the upper lung zones may be caused by idiopathic pleuropulmonary fibroelastosis [45].

Flexible bronchoscopy

Bronchoalveolar lavage — Bronchoalveolar lavage (BAL) has a limited role in the evaluation of patients with an HRCT that suggests UIP, because broad and overlapping ranges of cell counts make differentiation among interstitial lung diseases difficult. The general role of BAL in the diagnosis of ILD is discussed separately. (See "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease".)

The ATS/ERS/JRS/ALAT guideline advises against BAL cellular analysis when the clinical impression is IPF and the HRCT pattern is UIP [3]. On the other hand, when the clinical impression suggests IPF, but the HRCT pattern is probable UIP, indeterminate for UIP, or an alternate diagnosis, cellular analysis of BAL fluid to exclude eosinophilic pneumonia, sarcoidosis, or infection is suggested. (See "Basic principles and technique of bronchoalveolar lavage".)

Transbronchial lung biopsy and transbronchial cryobiopsy

●Transbronchial lung biopsy (TBLB) – TBLB uses forceps to obtain tissue samples that are a few millimeters in size and generally too small to secure a definitive diagnosis of UIP. It is estimated that approximately one-third of TBLB performed for newly diagnosed ILD of unknown cause will provide a clear diagnosis, while two-thirds will be nondiagnostic and require a surgical lung biopsy. The decision to perform TBLB should be individualized and generally limited to patients with reasons to suspect a non-UIP diagnosis. The technique of transbronchial biopsy is discussed separately. (See "Role of lung biopsy in the diagnosis of interstitial lung disease", section on 'Transbronchial lung biopsy' and "Flexible bronchoscopy in adults: Associated diagnostic and therapeutic procedures", section on 'Transbronchial biopsy'.)

●Transbronchial cryobiopsy (TBCB) – TBCB shows promise as a diagnostic technique for ILD, but further work is needed to standardize the technique [3,46,47]. In a series of 21 patients in whom multidisciplinary assessment determined a need for histology, sequential TBCB and surgical biopsies from two lobes each had poor concordance and TBCB was nondiagnostic in four patients [48]. It is possible that the more proximal nature of TBCB compared with surgical biopsy contributes to the low concordance. The technique of TBCB and its general role in the diagnosis of ILD are discussed separately. (See "Role of lung biopsy in the diagnosis of interstitial lung disease", section on 'Transbronchial cryobiopsy' and "Bronchoscopic cryotechniques in adults", section on 'Cryobiopsy'.)

Lung biopsy — For patients who require histopathologic confirmation of suspected IPF, a surgical lung biopsy is preferred over the bronchoscopic procedures TBLB or TBCB described above [1,3]. (See 'Transbronchial lung biopsy and transbronchial cryobiopsy' above.)

Patient selection — When the results of the clinical evaluation, laboratory testing, and HRCT do not allow the clinician to make a confident diagnosis of IPF, surgical lung biopsy may be indicated [1,3]. The decision requires assessment of the benefits of having a definitive diagnosis relative to the risks of the surgical procedure. The ATS/ERS/JRS/ALAT guideline and Fleischner Society systematic review advise that the decision about lung biopsy be made in the context of a multidisciplinary discussion [3,39]. The ATS/ERS/JRS/ALAT guideline also suggests the following:

●For patients with newly detected ILD of uncertain etiology and an HRCT pattern of probable UIP, indeterminate UIP, or an alternate diagnosis, the benefits of surgical lung biopsy generally outweigh the risks (eg, mortality [<2 percent], bleeding, prolonged air leak, pain), unless the patient has severe physiologic impairment (eg, requires supplemental oxygen) or substantial comorbidity.

●For patients with newly detected ILD and an HRCT pattern of UIP, surgical lung biopsy is unlikely to identify an alternate diagnosis and thus is deemed not to be worth the risk.

IPF is rare among patients <50 years of age, so a lung biopsy may be useful in the evaluation of such patients. On the other hand, in patients with severe physiologic impairment or substantial comorbidity, the risks of surgical lung biopsy may outweigh the benefits of establishing a secure diagnosis of IPF [3,49]. (See "Role of lung biopsy in the diagnosis of interstitial lung disease".)

Procedure — Surgical lung biopsy may be done via a video-assisted thoracoscopic approach (VATS, also called minimally-invasive thoracic surgery) or thoracotomy, depending on the expertise and preference of the surgeon [3]. Ideally, biopsies are obtained from more than one lobe of the lung and from areas of varying severity. Lung biopsy samples are ideally greater than 4 cm in the greatest dimension when inflated and include a depth from the pleural surface of 3 to 5 cm. Surgical lung biopsy virtually always yields an adequate specimen, and a definitive diagnosis (in combination with clinical assessment and HRCT) is made in approximately 89 percent of patients [3]. The technique and general role in the diagnosis of ILD are discussed separately. (See "Role of lung biopsy in the diagnosis of interstitial lung disease" and "Overview of minimally invasive thoracic surgery".)

Complications — While data are not available for suspected IPF in specific, the risk of mortality following surgical lung biopsy for ILD depends on several factors. As examples, nonelective procedures are associated with higher mortality than elective procedures (20 versus 2 percent), and older age, male sex, higher comorbidity, long-term oxygen therapy, and open thoracotomy are associated with greater mortality [49,50].

Complications of surgical lung biopsy and video-assisted lung biopsy are discussed separately. (See "Role of lung biopsy in the diagnosis of interstitial lung disease", section on 'Morbidity and mortality' and "Overview of minimally invasive thoracic surgery", section on 'Complications'.)

Histopathology — UIP is the histopathologic pattern associated with the clinical diagnosis of IPF. A UIP-like pattern of injury can also be seen in other fibrotic lung diseases, eg, associated with rheumatic diseases, chronic hypersensitivity pneumonitis, drug-toxicity, and pneumoconioses (eg, asbestosis) (table 3).

The histologic hallmark and chief diagnostic criterion for UIP is a heterogeneous appearance with alternating areas of normal lung, fibrosis, fibroblast foci, and honeycomb change [3]. The peripheral subpleural parenchyma is most severely affected. Fibroblastic foci, which are areas of active fibroproliferation characterized by clusters of fibroblasts and myofibroblasts that lie in continuity with the established fibrosis, are a hallmark feature of IPF. Features to suggest an alternate diagnosis (eg, granulomas, prominent airway-centered changes, inflammation separate from areas of honeycombing) should be absent.

The pathology of IPF/UIP is described in detail separately. (See "Idiopathic interstitial pneumonias: Classification and pathology", section on 'Pathology'.)

DIAGNOSIS — The diagnosis of IPF requires exclusion of other known causes of interstitial lung disease (ILD) and either definite features of usual interstitial pneumonia (UIP) on high resolution computed tomography (HRCT) or certain combinations of HRCT and histopathologic features of UIP [3]. Multidisciplinary discussion including specialists from pulmonary, pathology, radiology, and sometimes rheumatology can help improve diagnostic accuracy [3,30-33]. The following sections describe the diagnostic criteria.

Diagnosis without lung biopsy — The diagnosis of IPF/UIP can be made on the basis of a characteristic presentation (eg, insidious onset of dyspnea in a patient over age 60) in combination with definite features of UIP on HRCT (table 2), and exclusion of other known causes of UIP, including environmental exposure (eg asbestos, causes of hypersensitivity pneumonitis), medications, and rheumatic disease (table 4) [3]. The Fleischner Society white paper suggests that a lung biopsy is not necessary in patients with an HRCT pattern considered probable for UIP when a multidisciplinary discussion yields a confident diagnosis of IPF. In contrast, the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society (ATS/ERS/JRS/ALAT) guideline favors histopathologic confirmation [3]. (See 'Diagnosis with lung biopsy' below.)

Prediction rules are being developed to help diagnose IPF in patients without definite UIP on HRCT (ie, no honeycombing) in the absence of lung biopsy. In such patients, it has been suggested that clinical variables of increasing age and higher total HRCT interstitial score can predict a biopsy confirmation of IPF [28]. A further analysis has shown that for patients with an HRCT classified as possible UIP (2011 criteria with basilar predominant reticular opacities, traction bronchiectasis, but no honeycombing) [1], demographic information (eg, age, sex) and other radiographic features (eg, extent of reticular versus ground glass opacities) can help predict the presence of UIP [51]. In this analysis, age ≥60 years and extent of reticular density one-third or more of total lung volume had high specificity for IPF (80 percent probability). In an exploratory study, a clinical prediction rule (age, sex, total traction bronchiectasis score) improved the positive predictive value to >90 percent for a UIP pattern on surgical biopsy [27]. With further validation, the prediction tool may enable a confident diagnosis of UIP for those with an HRCT classified as possible UIP, without surgical lung biopsy. However, the prediction rule is not useful for those with an HRCT pattern considered inconsistent with UIP.

Diagnosis with lung biopsy — When performed, surgical lung biopsy results need to be correlated with the HRCT findings, preferably in the context of a multidisciplinary discussion (MDD) (table 3) [3,33,52]. (See 'Chest imaging' above and 'Histopathology' above.)

●HRCT shows UIP – If the HRCT shows a UIP pattern and the lung histopathology pattern is UIP, probable UIP, or indeterminate for UIP, then the diagnosis is IPF, unless the histopathology demonstrates a definite alternate diagnosis (eg, poorly formed granulomas indicating chronic hypersensitivity pneumonitis).

●HRCT shows probable UIP – If the HRCT shows probable UIP and the histopathology shows UIP or probable UIP, then the diagnosis is IPF; and if the lung histopathology pattern is indeterminate for UIP, the diagnosis is likely IPF.

●HRCT is indeterminate for UIP – If the HRCT is indeterminate for UIP (eg, mild ground glass opacities or distortion, distribution of fibrosis that is not typical for a specific ILD), but the histopathology shows definite or probable UIP, then the diagnosis is IPF or likely IPF, respectively. If the histopathology is also indeterminate for UIP, the diagnosis remains indeterminate unless MDD reclassifies to a more specific diagnosis.

●HRCT suggests an alternate diagnosis – If the HRCT demonstrates features suggestive of an alternate diagnosis, but the histopathology shows UIP, MDD may determine that the diagnosis is likely IPF. Otherwise, for histopathology findings that are probable, indeterminate, or suggest an alternate diagnosis, the final diagnosis would be not IPF.

In all of the various HRCT scenarios, the histopathology may identify a specific non-IPF diagnosis that becomes the final diagnosis.

Discordant findings have been described among samples from different lobes in a single patient. When lung biopsy findings are discordant among lobes, for example UIP in one lobe and nonspecific interstitial pneumonia (NSIP) in another lobe, the convention is to classify and manage that patient as IPF because the disease trajectory tends to follow that of patients with UIP in all lobes.

Post-diagnostic evaluation — The possibility of short telomere syndrome (STS) should be explored in patients with a diagnosis of IPF who have premature graying, cytopenias, unexplained macrocytosis, or a family history of interstitial lung disease. The diagnosis is based on the combination of clinical manifestations and telomere length analysis of peripheral blood leukocytes. Identification of pathogenic variants in known STS-causing genes (in adults, typically TERT, PARN, TERC, and RTEL1) provides corroborative evidence, but is not essential for establishing a diagnosis. The diagnosis of STS is discussed separately. (See 'Pathogenesis and genetic predisposition' above and "Dyskeratosis congenita and other telomere biology disorders", section on 'Laboratory testing and bone marrow'.)

Patients who are found to have STS need to be screened for bone marrow and liver dysfunction; at-risk family members may need screening with telomere length analysis. Patients with bone marrow dysfunction may require treatment (eg, danazol, hematopoietic cell transplantation). (See "Dyskeratosis congenita and other telomere biology disorders", section on 'Screening of family members and relatives' and "Dyskeratosis congenita and other telomere biology disorders", section on 'Management'.)

Patients with IPF and STS have a poorer prognosis following lung transplantation and may benefit from modified anti-rejection treatment plans to prevent myelotoxicity and hepatotoxicity. (See "Treatment of idiopathic pulmonary fibrosis", section on 'Telomerase complex mutations'.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of IPF includes other diseases with histopathologic features of usual interstitial pneumonia (UIP), such as rheumatic diseases (eg, rheumatoid arthritis, systemic sclerosis), chronic hypersensitivity pneumonitis [53], asbestosis, and certain drug-induced lung diseases (table 4) [54,55]. In addition, the differential diagnosis of IPF includes the other idiopathic interstitial pneumonias, pulmonary Langerhans' cell histiocytosis, combined pulmonary fibrosis and emphysema, and pleuropulmonary elastosis. The interpretation of lung biopsy results in interstitial pneumonitis is discussed separately. (See "Interpretation of lung biopsy results in interstitial lung disease" and "Idiopathic interstitial pneumonias: Classification and pathology".)

●Nonspecific interstitial pneumonitis – Nonspecific interstitial pneumonia (NSIP) is a type of idiopathic interstitial pneumonia that is frequently in the differential diagnosis of IPF. Characteristic features include diffuse ground glass opacities on high resolution computed tomography (HRCT), a reticular pattern, and traction bronchiectasis; honeycombing is generally absent. The diagnosis generally requires histopathologic confirmation by lung biopsy, either via thoracoscopic surgery or thoracotomy. (See "Causes, clinical manifestations, evaluation, and diagnosis of nonspecific interstitial pneumonia", section on 'Diagnosis'.)

●Rheumatic disease – Patients with rheumatic disease, most commonly rheumatoid arthritis (RA), can develop a UIP-like pattern of lung injury, although NSIP is the type of interstitial lung disease (ILD) among patients with rheumatic disease, including those with RA. Differentiating rheumatic disease-associated ILD from IPF is largely based on identifying clinical features that provide clues to the presence of rheumatic disease, such as arthritis, rheumatoid nodules, Raynaud phenomenon, skin changes (eg, sclerodactyly, increased skin thickness, digital ulcers), muscle weakness, and abnormal esophageal motility. On HRCT, features suggestive of rheumatic disease that would be atypical for IPF include pleural or pericardial effusion and esophageal abnormalities. (See "Interstitial lung disease in rheumatoid arthritis", section on 'Pathologic types of RA-ILD' and "Clinical manifestations, evaluation, and diagnosis of interstitial lung disease in systemic sclerosis (scleroderma)", section on 'Pathology'.)

●Drug and irradiation-induced UIP – Distinguishing the idiopathic form of UIP from drug-induced lung disease is largely a matter of correlation with the clinical information. Treatments associated with a UIP-like pattern of pulmonary toxicity include cyclophosphamide, bleomycin, nitrosoureas, methotrexate, nitrofurantoin, and irradiation, among others. Additional agents associated with pulmonary fibrosis are listed on the Pneumotox website [56]. (See "Cyclophosphamide pulmonary toxicity" and "Bleomycin-induced lung injury" and "Methotrexate-induced lung injury" and "Nitrosourea-induced pulmonary injury" and "Nitrofurantoin-induced pulmonary injury" and "Radiation-induced lung injury".)

●Asbestosis – Asbestosis is associated with occupational exposures such as mining of asbestos, shipbuilding, welding, and demolition. The HRCT pattern associated with asbestosis is similar to IPF, but pleural plaques, particularly with linear bands of calcification, are a clue to underlying asbestosis. A definitive diagnosis of asbestosis requires an appropriate occupational history and demonstration of asbestos fibers (usually in the form of ferruginated asbestos bodies) in the tissue specimen. (See "Asbestos-related pleuropulmonary disease".)

●Chronic hypersensitivity pneumonitis – Chronic hypersensitivity pneumonitis can present with imaging or histopathologic features similar to those found in IPF/UIP (image 3). The typical HRCT appearance is that of centrilobular nodules and lobular areas of decreased perfusion on HRCT, although these features are not always present (image 4). The histopathologic finding of poorly formed granulomas or giant cells in the interstitium, even if rare, should raise suspicion for chronic hypersensitivity pneumonitis. (See "Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Clinical manifestations and diagnosis", section on 'Diagnosis'.)

●Pulmonary Langerhans' cell histiocytosis – Pulmonary Langerhans' cell histiocytosis (also referred to as pulmonary eosinophilic granuloma or pulmonary histiocytosis X) is a disease of smokers aged 20 to 40 years with characteristic HRCT features including a mid to upper zone predominance, multiple cysts and nodules, and interstitial thickening. While lung biopsy is not always needed for the diagnosis, the histopathology typically shows cysts and aggregates of Langerhans-like dendritic cells (S-100 and CD1a positive on staining) surrounding smaller bronchioles. (See "Pulmonary Langerhans cell histiocytosis".)

●Airspace enlargement with fibrosis (AEF) – AEF is a pathologic entity seen in cigarette smokers that can mimic honeycomb cysts on HRCT [39,57,58]. However, AEF tends to predominate in the upper to mid lung zones, spare the most peripheral parts of the lung (subpleural but not abutting pleura), and be characterized by thinner walls than typical honeycomb cysts [39]. Areas of AEF can be seen in combination with combined pulmonary fibrosis and emphysema (CPFE) and UIP [59].

●Combined pulmonary fibrosis and emphysema – CPFE is most commonly seen in male smokers and is characterized by dyspnea, upper-lobe emphysema, lower-lobe fibrosis, and abnormalities of gas exchange [60]. In a case series, in addition to emphysematous changes, thick-walled cystic lesions with an internal diameter greater than the cysts of honeycombing, consistent with AEF noted above, were seen in 16 (73 percent) of the 22 patients with CPFE, but none of the eight patients with IPF [61]. (See "High resolution computed tomography of the lungs", section on 'Emphysema' and "Idiopathic interstitial pneumonias: Classification and pathology", section on 'Smoking-related interstitial abnormalities'.)

●Pleuropulmonary fibroelastosis – Pleuropulmonary fibroelastosis (PPFE), which can be idiopathic or chemotherapeutic drug-induced, is a rare process that is characterized by upper lobe pleural and subpleural lung parenchymal fibrosis. The pattern of pleural thickening and upper lobe predominance should raise suspicion for PPFE. (See "Interpretation of lung biopsy results in interstitial lung disease", section on 'Rare histopathologic interstitial pneumonia patterns'.)

FUTURE DIRECTIONS — An investigational technology has been developed that analyzes the RNA sequence data of 190 genes from transbronchial biopsy samples to classify patients as having a molecular pattern of usual interstitial pneumonia (UIP) or not [62,63]. In a validation cohort of 49 patients with new onset interstitial lung disease, three to five transbronchial biopsies were obtained from each participant for RNA molecular analysis [64]. The analysis demonstrated 70 percent sensitivity (95% CI 47-87) and 88 percent specificity (95% CI 70-98) for differentiating UIP from non UIP. Among patients with possible or inconsistent UIP on high resolution computed tomography (HRCT), the RNA molecular test showed a positive predictive value of 81 percent (95% CI 54–96) for biopsy-proven UIP. A subsequent validation cohort, which included 58 patients with UIP and 38 non-UIP, found a sensitivity of 60 percent (95% CI 47-73) and specificity of 92 percent (95% CI 79-98) [65]. Combining the two studies, the molecular classifier had a positive predictive value of 90 percent and a negative predictive value of 66 percent. Further study is needed to clarify whether the test can safely reduce the need for surgical biopsies in patients without a pattern of UIP on HRCT or aid in diagnosis when histopathology is not definitive. It is important to remember that UIP can be found in multiple settings (eg, hypersensitivity pneumonitis, rheumatoid arthritis, drug-induced lung toxicity), and this test does not distinguish among causes of UIP.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Interstitial lung disease".)

SUMMARY AND RECOMMENDATIONS

●Idiopathic pulmonary fibrosis (IPF) is an idiopathic chronic fibrosing interstitial pneumonia with a histopathologic or radiographic pattern of usual interstitial pneumonia (UIP) (table 5). (See 'Introduction' above.)

●On histopathologic examination, the hallmark and chief diagnostic criterion for UIP is a heterogeneous appearance with alternating areas of normal lung, interstitial inflammation, fibroblast foci, and honeycomb change, in a subpleural distribution. (See 'Histopathology' above.)

●The onset of IPF is typically in patients age 60 and older, except among patients with familial pulmonary fibrosis in whom disease presents earlier. Men appear to be affected more often than women, and the majority of patients have a history of cigarette smoking. (See 'Clinical manifestations' above.)

●Patients commonly report a gradual onset (over several months) of dyspnea on exertion and a nonproductive cough. Fatigue, fever, myalgias, and arthralgias are rarely reported. On physical examination bibasilar crackles are usually audible, but may be absent or heard unilaterally early in the disease. (See 'Clinical manifestations' above.)

●When IPF is suspected, the first step is clinical evaluation to identify features of rheumatic disease, familial pulmonary fibrosis, or exposures that can cause UIP (eg, medications, antigens associated with hypersensitivity pneumonitis, agents of pneumoconiosis) (table 1). Laboratory testing includes serologic tests for rheumatic disease and sometimes serology for hypersensitivity pneumonitis. (See 'Evaluation' above.)

●High resolution computed tomography (HRCT) should be obtained in all patients suspected of having IPF. The characteristic HRCT features of IPF/UIP include peripheral (subpleural), bibasilar reticular opacities associated with architectural distortion, including honeycomb changes and traction bronchiectasis or bronchiolectasis (table 2). Depending on the features in an individual patient, the pattern may be considered UIP, probable UIP, indeterminate for UIP, or suggestive of an alternate diagnosis. Ground glass opacities are occasionally present, but are less prominent than reticular changes, except in the setting of an acute exacerbation. (See 'Chest imaging' above.)

●Bronchoalveolar lavage (BAL) has a limited role in the evaluation of patients with suspected IPF, largely to identify alternate diagnoses, such as sarcoidosis. (See 'Bronchoalveolar lavage' above.)

●When the results of the clinical evaluation, laboratory testing, and HRCT do not allow the clinician to make a confident diagnosis of IPF, surgical lung biopsy may be indicated. The decision requires assessment of the benefits of having a definitive diagnosis relative to the risks of the surgical procedure. A surgical biopsy via video-assisted thoracoscopy or thoracotomy is preferred over a transbronchial lung biopsy, as the larger sample size is essential to a confident diagnosis. (See 'Lung biopsy' above.)

●The diagnosis of IPF requires exclusion of other known causes of interstitial lung disease AND either definite features of UIP on HRCT or certain combinations of HRCT and lung biopsy features of UIP (table 3). (See 'Diagnosis' above.)

●The differential diagnosis of IPF includes other diseases with histopathologic features of UIP, such as rheumatic diseases (eg, rheumatoid arthritis, systemic sclerosis), chronic hypersensitivity pneumonitis, asbestosis, and certain drug-induced lung diseases (table 4). (See 'Differential diagnosis' above.)