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Clinical manifestations and diagnosis of idiopathic pulmonary fibrosis

Clinical manifestations and diagnosis of idiopathic pulmonary fibrosis
Literature review current through: Sep 2023.
This topic last updated: Aug 30, 2023.

INTRODUCTION — Idiopathic pulmonary fibrosis (IPF) is the most common of the spontaneously occurring diffuse parenchymal lung diseases also known as idiopathic interstitial pneumonias (IIPs). 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).

IPF is defined as a spontaneously occurring (idiopathic) specific form of chronic fibrosing interstitial pneumonia limited to the lung and associated with characteristic usual interstitial pneumonia (UIP) patterns on high-resolution computed tomography (HRCT) and lung histology [1-3]. A radiographic or histologic finding of UIP may be found in nonidiopathic interstitial lung diseases (ILDs) and therefore is not synonymous with the clinical diagnosis of IPF. We will consistently use the term UIP to refer to radiographic and histologic patterns and the term IPF to connote the disease.

The clinical manifestations, evaluation, and diagnosis of IPF will be reviewed here. The evaluation of ILD 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 depend on ascertainment, reporting methods, and population evaluated. Both prevalence and incidence increase with advancing age, with presentation commonly occurring in the sixth and seventh decades; IPF is rare in patients less than 50 years of age [1,2]. The prevalence and incidence are higher in males than females [4].

Overall, the incidence of IPF is increasing worldwide and conservative estimates of the incidence range from three to nine cases per 100,000 per year for Europe and North America [5]. However, among an older population, the incidence is higher. Among a random sample of United States 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 persons per year [6].

PATHOGENESIS AND GENETIC PREDISPOSITION — The pathogenesis of IPF 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 (FPF), 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 – 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 (ILDs) [7]. 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 [8]. In patients with FPF, smoking contributes to shortened transplant-free survival and the development of more advanced radiographic disease (honeycombing) [9].

Hermansky-Pudlak syndrome – HPS, an autosomal recessive disorder characterized by oculocutaneous albinism and platelet abnormalities, is a rare cause of usual interstitial pneumonia (UIP) pathology and presents at an earlier age (eg, thirties) than IPF [10,11]. 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 "Inherited platelet function disorders (IPFDs)", section on 'Hermansky-Pudlak syndrome'.)

Telomeropathies – The short telomere syndromes are caused by mutations in the genes responsible for maintaining telomere length (eg, TERT, TERC, PARN, DKC1, TINF2, RTEL1) [12]. 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 graying, transaminitis or evidence of liver dysfunction, and cytopenias or an unexplained macrocytosis. The short telomere syndromes also include dyskeratosis congenita, bone marrow failure, and liver disease [13-15]. (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 FPF [16]. Exome-based surveys suggest that up to 11 percent of patients with sporadic IPF have short telomere-associated gene variants [17]. The prevalence of short telomere syndromes may be higher in IPF patients referred for lung transplantation (estimated 16 percent in one study) [14].

Patients with a young age of IPF onset (<50), with IPF and familial fibrotic lung disease, or with personal or familial features of fibrotic syndromes (ie, telomeropathies or Hermansky-Pudlak syndrome) should undergo genetic counseling and consideration of genetic testing for FPF [18].

POTENTIAL RISK FACTORS — While IPF, by definition, lacks a known cause, certain risk factors have been identified [1,19]. Cigarette smoking is most strongly associated with IPF. Exposures to stone, metal, wood, organic dusts, and air pollutants have been suggested as additional risk factors [20-23]. Military exposure to Agent Orange has also been associated with increased risk of chronic lung injury in one study [24].

Gastroesophageal reflux may result in lung injury via microaspiration, although the association with IPF has been difficult to interpret given the high frequency of gastroesophageal reflux in the general population [25,26]. Two genetic studies based on large genome-wide association data for both GERD and IPF cohorts demonstrated that lifetime risk of IPF is increased in the setting of genetically determined GERD, although the magnitude of this effect is uncertain [27,28]. These studies did not find any significant causal effect of IPF on the risk of GERD. By using genetic risk factors to reduce potential confounding, these data support the hypothesis that microaspiration injury may contribute to IPF pathogenesis and suggests that GERD could be a potential therapeutic target for IPF treatment.

CLINICAL MANIFESTATIONS — Patients with IPF typically present at age 60 years or older [29,30]. 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 (ILD), 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 [31].

INITIAL 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 (PFT).

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 to maximize accuracy of the final diagnosis [3,32-35].

Clinical assessment — Patients with newly diagnosed ILD should have a detailed assessment for potential causes of ILD (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, anticyclic 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 5 [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 usual interstitial pneumonia (UIP) on HRCT and no known rheumatic disease [36]. 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 five. 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 anticyclic 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 [37,38]. Weakly positive findings on these routinely performed tests should not decrease clinical suspicion for IPF.

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 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 finding in IPF is an increase in reticular markings, although this is a nonspecific finding that is also associated with other ILDs 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 American Thoracic Society (ATS), European Respiratory Society (ERS), Japanese Respiratory Society (JRS), and Latin American Thoracic Society (ALAT) guidelines 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) [3,39]. The presence of certain specific HRCT features in the appropriate clinical setting may be sufficient to establish the diagnosis of IPF (table 2) [30,39-41].

The characteristic HRCT features of IPF include peripheral, basilar-predominant opacities associated with honeycombing and traction bronchiectasis-bronchiolectasis (image 1) [42-44]. Honeycombing refers to clusters of cystic airspaces approximately 3 to 10 mm in diameter, usually in a subpleural location (image 2). The histopathology of radiographic changes in IPF demonstrate progressive bronchiolar remodeling as a continuum that includes both honeycombing and traction bronchiectasis [45-47]. While honeycombing is essential to making a definite HRCT diagnosis of UIP, traction bronchiectasis alone indicates probable UIP. [29,48]. Both definite UIP and probable UIP patterns on HRCT show histopathologic confirmation of UIP greater than 80 percent of the time [49,50]. Following multidisciplinary discussion and in the appropriate clinical setting, the 2022 ATS, ERS, JRS, and ALAT guidelines endorse avoidance of additional histologic confirmation in patients with these radiographic patterns unless there is additional clinical concern for an alternative diagnosis [39].

Ground-glass opacities that are superimposed on a fine reticular pattern can be present in UIP [42], 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".)

HRCT patterns that are not suggestive of UIP do not rule out the diagnosis of IPF. Up to 30 percent of cases with a histopathologic diagnosis of UIP may have HRCT findings more consistent with an alternate diagnosis [51]. (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'.)

Pleural disease is uncommon in IPF, so its presence should raise the possibility of an alternate or comorbid diagnosis such as rheumatoid arthritis (RA), 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 [52].

MULTIDISCIPLINARY DISCUSSION AND NEXT STEPS — Following the initial evaluation, multidisciplinary discussion between clinicians and radiologists should guide further diagnostic work-up (algorithm 1) [3,53].

How to decide whether a biopsy is necessary — The diagnosis of IPF can frequently be made without biopsy on the basis of a characteristic presentation (eg, insidious onset of dyspnea in a patient over age 60) in combination with features of usual interstitial pneumonia (UIP) or probable UIP on high-resolution computed tomography (HRCT) (table 2). Clinical exclusion of other known causes of radiographic UIP is necessary, including environmental exposures (eg asbestos, causes of hypersensitivity pneumonitis), medications, and rheumatic disease (table 3) [3].

When the results of clinical evaluation, laboratory testing, and HRCT do not allow a confident diagnosis of IPF after multidisciplinary discussion, lung biopsy should be considered [1,3,39]. The decision for biopsy requires assessment of the benefits of having a definitive diagnosis relative to the risks of the invasive procedure (eg, mortality [<2 percent], bleeding, prolonged air leak, pain). (See 'Complications of lung biopsy' below.)

The 2022 American Thoracic Society (ATS), European Respiratory Society (ERS), Japanese Respiratory Society (JRS), and Latin American Thoracic Society (ALAT) guidelines suggest that a lung biopsy is not necessary in patients with an HRCT pattern considered definite or probable for UIP when a multidisciplinary discussion yields a confident diagnosis of IPF [39].

For patients with newly detected interstitial lung disease (ILD) of uncertain etiology, good physiologic reserve, and an HRCT pattern indeterminate for UIP or suggestive of an alternate diagnosis, the benefits of surgical lung biopsy generally outweigh the risks.

However, patients with severe pulmonary physiologic impairment (such as moderate to severe pulmonary hypertension or a supplemental oxygen requirement), substantial cardiovascular comorbidities, or frailty are at high risk for pulmonary and nonpulmonary complications of thoracic procedures, irrespective of the underlying diagnosis.

Lung biopsy is rarely helpful in the setting of an active ILD exacerbation, rapidly progressive ILD, or acute respiratory failure. In such cases, the acute process both decreases the chance of accurate diagnosis of the underlying disease and greatly increases morbidity and mortality of the procedure. (See "Role of lung biopsy in the diagnosis of interstitial lung disease", section on 'Interstitial lung disease presenting with acute respiratory failure' and "Role of lung biopsy in the diagnosis of interstitial lung disease", section on 'Morbidity and mortality'.)

Multiple groups are developing prediction rules for IPF incorporating clinical and radiographic features [29,30,54]. With further validation, these rules may increase concordance and confidence of diagnosis via multidisciplinary discussion in the absence of lung biopsy.

Obtaining an adequate biopsy — The histopathologic diagnosis of UIP requires a large enough sample to observe architectural features consistent with the disease (see 'Histopathology' below). Small sample size or peripheral sampling of honeycomb changes only are the most common reasons for inadequate specimens.

Surgical lung biopsy — Surgical lung biopsy is the traditional approach to tissue sampling for the diagnosis of IPF. The procedure may be performed 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 should be 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".)

Transbronchial cryobiopsy — Transbronchial cryobiopsy (TBCB) is an acceptable alternative to surgical lung biopsy in centers with expertise in this technique and multidisciplinary experience in diagnosis and management of ILD. The 2022 ATS/ERS/JRS/ALAT guidelines caution that this approach is most appropriate for high-volume centers with standardized protocols to minimize risk and maximize yield, as well as experienced personnel for performing biopsies and interpreting samples [39]. In this setting, TBCB offers a diagnostic yield of approximately 80 percent (compared with 90 percent on surgical lung biopsy). Sample number correlates most significantly with diagnostic yield, with three or more samples preferred [39]. Rates of pneumothorax are approximately 9 percent (compared with 6 percent prolonged air leak on surgical lung biopsy) [3,55]. Nonetheless, the procedure is less invasive than a surgical biopsy and can potentially be done as an outpatient procedure, unlike thoracotomy. Moreover, in high-volume centers, pulmonary infections, IPF exacerbation, severe bleeding, and periprocedural mortality are all rare with TBCB and less frequent compared with surgery [55]. (See 'Complications of lung biopsy' below.)

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'.)

Complications of lung biopsy — For patients with IPF, many thoracic procedures, including surgical lung biopsy, have been associated with the development of acute exacerbations [56-58]. (See 'How to decide whether a biopsy is necessary' above.)

For those in whom a lung biopsy is thought to be necessary, patients should be counseled regarding the risks of the procedure.

Surgical lung biopsy – Surgical lung biopsy in the setting of ILD has a peri-procedural mortality of 1.7 percent and a risk for subsequent respiratory infection of 6.5 percent, according to systematic reviews. Other complications include triggering of ILD exacerbations, bleeding, prolonged air leak, neuropathic pain, and delayed wound healing, most of which occur in 3 to 5 percent of patients [3].

Transbronchial cryobiopsy – A 2022 systematic review on TBCB complications suggests relatively frequent minor bleeding (30 percent) and pneumothorax (9 percent), but severe bleeding, pulmonary infections, ILD exacerbations, and mortality are rare (<1 percent) in high-volume centers with expertise in ILD diagnosis [39,55].

Patient-specific factors impacting the risk of poor outcomes following elective lung biopsy include older age, male sex, higher comorbidity, and long-term oxygen therapy [59,60].

General complications of transbronchial cryobiopsy, surgical lung biopsy, and video-assisted lung biopsy are discussed in more detail 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' and "Overview of minimally invasive thoracic surgery", section on 'Complications' and "Role of lung biopsy in the diagnosis of interstitial lung disease", section on 'Morbidity and mortality'.)

Procedures only used to rule-in alternative diagnoses

Bronchoalveolar lavage – Bronchoalveolar lavage (BAL) has a limited role in the evaluation of patients with an HRCT that suggests IPF. Fibrotic ILDs that comprise the radiographic differential in such patients share broad and overlapping ranges on BAL cell counts. Consequently, the ATS/ERS/JRS/ALAT guidelines advise against BAL cellular analysis when the clinical impression is IPF and the HRCT pattern is UIP [3], however, BAL cellular analysis may be used to suggest or exclude other diagnoses (chronic hypersensitivity pneumonitis, eosinophilic pneumonias, sarcoidosis, or infection) when imaging is indeterminate or suggests these entities alternative diagnoses [61]. (See "Basic principles and technique of bronchoalveolar lavage" and "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease".)

Transbronchial lung biopsy – Transbronchial lung biopsy (TBLB) uses forceps to obtain tissue samples that are a few millimeters in size, which are generally too small to secure a definitive histopathologic diagnosis of UIP. 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 an alternative diagnosis that can be obtained from a small sample (eg, sarcoidosis). 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'.)

DIAGNOSIS

Diagnosis without biopsy — Diagnosis can often be determined by clinical and radiographic features, without a biopsy, as discussed above. (See 'How to decide whether a biopsy is necessary' above.)

Diagnosis with biopsy

Histopathology — Usual interstitial pneumonia (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 4).

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

Correlation with imaging findings — When performed, lung biopsy results need to be correlated with the high-resolution computed tomography (HRCT) and clinical evidence, preferably in the context of a multidisciplinary discussion (MDD) (table 4 and algorithm 1) [3,35,62] (see 'Chest imaging' above and 'Histopathology' above). A histopathologic finding of UIP or probable UIP indicate a likely diagnosis of IPF unless the CT and clinical context strongly suggest an alternative diagnosis. A definitive alternative diagnosis on biopsy precludes the diagnosis of IPF. Indeterminate findings on histopathology often contribute little but can sometimes yield additional information in the context of MDD. Finally, longitudinal follow-up of patients with discordant findings among lobes (for example, UIP in one lobe and nonspecific interstitial pneumonia (NSIP) in another lobe) has shown that the disease trajectory is most consistent with IPF.

POSTDIAGNOSTIC 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 (ILD). 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 antirejection 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 radiographic and histopathologic features of usual interstitial pneumonia (UIP), such as rheumatic diseases (eg, rheumatoid arthritis [RA], systemic sclerosis), chronic hypersensitivity pneumonitis [63], asbestosis, and certain drug-induced lung diseases (table 3) [64,65]. 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. (See "Causes, clinical manifestations, evaluation, and diagnosis of nonspecific interstitial pneumonia", section on 'Diagnosis'.)

Rheumatic disease – Patients with rheumatic disease, most commonly RA, can develop a UIP-like pattern of lung injury, although NSIP is the most common type of interstitial lung disease (ILD) among patients with rheumatic diseases. 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 [66]. (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 UIP patterns on imaging or histopathology (image 3) [67]. The typical HRCT appearance also includes 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 (identified by CD207, S-100, and CD1a positivity on immunostaining) 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 [53,68,69]. 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 [53]. Areas of AEF can be seen in combination with combined pulmonary fibrosis and emphysema (CPFE) and UIP [70].

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 [71]. 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 [72]. (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 ribonucleic acid (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 [73,74]. In a validation cohort of 49 patients with new onset interstitial lung disease (ILD), three to five transbronchial biopsies were obtained from each participant for RNA molecular analysis [75]. 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) [76]. 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 [39]. It is important to remember that UIP can be found in multiple settings (eg, hypersensitivity pneumonitis, rheumatoid arthritis [RA], 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

Definition and genetic predisposition – IPF is an idiopathic chronic fibrosing interstitial pneumonia with a histopathologic or radiographic pattern of usual interstitial pneumonia (UIP) (table 5). Most cases are sporadic, but familial cases have been described. Familial pulmonary fibrosis (FPF), Hermansky-Pudlak syndrome (HPS), and the short telomere syndromes (STS) usually present at a younger age than IPF. (See 'Introduction' above and 'Pathogenesis and genetic predisposition' above.)

Clinical manifestations – The onset of IPF is typically in patients aged 60 years and older, except among patients with FPF, in whom disease presents earlier. Male patients appear to be at increased risk, 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. Clubbing is a manifestation of advanced IPF. (See 'Clinical manifestations' above.)

Evaluation

Clinical assessment – When IPF is suspected, the first step is clinical evaluation to identify any features of rheumatic disease, FPF, or exposures that can cause UIP (eg, medications, antigens associated with hypersensitivity pneumonitis, agents of pneumoconiosis) (table 1). (See 'Clinical assessment' above.)

Laboratory testing – The role of laboratory testing is to identify or exclude processes in the differential diagnosis. Selected serologic tests can help identify underlying rheumatic disease and hypersensitivity pneumonitis. (See 'Laboratory' above.)

High-resolution computed tomography (HRCT) – 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) – BAL has a limited role in the evaluation of patients with suspected IPF, largely to identify alternate diagnoses such as sarcoidosis. (See 'Procedures only used to rule-in alternative diagnoses' above.)

Diagnosis – The diagnosis of IPF requires exclusion of other known causes of interstitial lung disease (ILD) and either definite or probable features of UIP on HRCT (table 2) or certain combinations of HRCT and lung biopsy features of UIP (table 4). Multidisciplinary discussion (MDD) including specialists from pulmonary, pathology, radiology, and sometimes rheumatology improves diagnostic accuracy and is considered the gold standard for diagnosis. (See 'Diagnosis' 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 or transbronchial cryobiopsy may be indicated. The decision requires assessment of the benefits of having a definitive diagnosis relative to the risks of the procedure, including the possibility of precipitating an acute exacerbation. Transbronchial lung biopsies are not a preferred approach, as a larger sample size is essential to a confident diagnosis. (See 'Multidisciplinary discussion and next steps' above.)

When a lung biopsy is obtained, 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.)

Differential diagnosis – The differential diagnosis of IPF includes other diseases with histopathologic features of UIP, such as rheumatic diseases (eg, rheumatoid arthritis [RA], systemic sclerosis), chronic hypersensitivity pneumonitis, asbestosis, and certain drug-induced lung diseases (table 3). (See 'Differential diagnosis' above.)

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Topic 14870 Version 34.0

References

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