Interstitial Lung Disease

Etiology

The classification system used to describe ILD categorizes conditions based on clinical, histopathological, or radiologic parameters.[2] Clinical classification groups ILD by its causes to help differentiate exogenous or endogenous factors.[3] ILD of unknown origin is classified as idiopathic (primary) based on histopathological and radiological assessments. This classification encompasses conditions such as sarcoidosis, cryptogenic organizing pneumonia, and idiopathic interstitial pneumonia, which includes desquamative interstitial pneumonia (or newly named alveolar macrophage pneumonia [AMP]), idiopathic pulmonary fibrosis (IPF), nonspecific interstitial pneumonitis, acute interstitial pneumonia, and idiopathic interstitial pneumonia with autoimmune features.[4] Please see StatPearls' companion references, "Desquamative Interstitial Pneumonia," "Idiopathic Interstitial Pneumonia With Autoimmune Features," "Idiopathic Pulmonary Fibrosis," and "Acute Interstitial Pneumonia," for further information. Among these, idiopathic interstitial pneumonia is the most common, characterized by a combination of inflammation and fibrosis, which distinguishes it from infectious pneumonia.[5]

Several distinct types exist, each identified by specific histopathological features and clear clinical distinctions. Although most cases occur sporadically, genetic factors may play a role in their development. Identified etiological factors include environmental and occupational exposures. Prolonged exposure to occupational or environmental agents can exert toxic effects on the pulmonary system, with common agents including mineral dust, organic dust, and toxic gases. Various types of mineral dust are associated with ILD, with silica, asbestos, coal mine dust, beryllium, and hard metal being frequently implicated. Organic dust sources include mold spores and aerosolized bird droppings.

Inhaled toxic gases, such as methane and cyanide, affect the airways either directly or through reactive oxygen species. The extent of exposure-related injuries is challenging to quantify and likely occurs more frequently than estimated. Therefore, clinicians must conduct a comprehensive review of a patient's complete employment history and home environment to identify any potential agent-disease relationships (see Image. Etiologies of Interstitial Lung Disease).

Hypersensitivity pneumonitis results from immune-mediated lung injury following repeated inhalation of organic antigens, including avian proteins (bird fancier lung), fungal spores (farmer lung, mold-related hypersensitivity pneumonitis), and occupational agents. Identification and avoidance of the causative antigen are cornerstones of management and may halt disease progression.[6][7] Another recognized etiology of ILD is linked to connective tissue diseases, including rheumatoid arthritis, polymyositis/dermatomyositis, systemic lupus erythematosus, scleroderma, and mixed connective tissue disease. Connective tissue diseases and vasculitides impact all regions of the lungs, including the bronchioles, parenchyma, and alveoli. Consequently, ILD is a prevalent characteristic of rheumatologic conditions.[8][9]

Drug-induced ILD is a crucial factor to consider during the initial assessment of any patient with ILD. More than 350 pharmaceutical agents have been identified as potential contributors to pulmonary complications, either through the generation of reactive metabolites or as part of a broader physiological response.[10][11] Furthermore, genetic predisposition plays a role in a subset of ILD cases. Familial pulmonary fibrosis, defined as IPF in 2 or more first-degree relatives, accounts for up to 20% of IPF cases, with mutations in telomere-related genes (TERT, TERC) and surfactant protein genes (SFTPC, SFTPA2) being most commonly implicated.[12]

Epidemiology

ILD incidence rates in the United States have been difficult to determine. The reported prevalence may be low because the disease may not be recognized. ILD is a diagnosis of exclusion that requires extensive investigation.[13] ILD affects over half a million individuals and results in approximately 25,000 to 30,000 deaths annually. IPF is the most prevalent form of ILD, accounting for roughly one-third of all ILD cases, followed by connective tissue disease-related ILD, which affects approximately 1 in 4 individuals with ILD (25%). Hypersensitivity pneumonitis constitutes 15% of ILD cases.[14]

The global age-standardized prevalence of ILD is approximately 58 cases per 100,000 population, reflecting a substantial health concern worldwide.[15] Marked geographic variation exists in both the incidence of ILD and the dominant subtypes observed, influenced by regional environmental exposures, genetic predispositions, and differences in healthcare infrastructure. Enhanced recognition of ILD has been driven by advances in imaging technologies and the demographic shift toward aging populations, who are more susceptible to these conditions.

Common ILD subtypes include IPF, connective tissue disease-associated ILD (CTD-ILD), hypersensitivity pneumonitis, and sarcoidosis, each contributing to significant morbidity, mortality, and economic burden globally. However, data remain limited from resource-limited countries, where diagnostic challenges and resource constraints hinder accurate assessment and management. Results from research conducted in the United States indicate that the estimated annual incidence of IPF ranges from 6.8 to 8.8 per 100,000 individuals and from 16.3 to 17.4 per 100,000 individuals.

Additionally, the prevalence is reported to be between 14 and 27.9 cases per 100,000 individuals, and between 42.7 and 63 cases per 100,000 individuals, respectively.[16] For non-IPF ILD subtypes, an even wider range of estimated incidence and prevalence exists across regions.[17] This variation is likely due to the absence of standardized diagnostic criteria, the diverse clinical presentations and phenotypes, and differences in genetic, occupational, and other environmental factors. Sarcoidosis is the most common non-IPF ILD, particularly among those younger than 45 years of age. The estimated incidence of sarcoidosis ranges from 0.13 to 17.8 per 100,000 person-years, while its prevalence spans from 2 to 160 per 100,000 individuals. Table 1 summarizes the incidence and prevalence of the various subtypes.

Table 1. Epidemiology Estimates of Major ILD Subtypes

CTD, connective tissue disease; ILD, interstitial lung disease; IIM, idiopathic inflammatory myopathies; IPF, idiopathic pulmonary fibrosis; pSjD, primary Sjögren disease; RA, rheumatoid arthritis; SSc, systemic sclerosis; SLE, systemic lupus erythematosus

Systemic sclerosis ILD is the most clinically significant CTD-ILD subtype due to its high prevalence (up to 70% to 90% on high-resolution computed tomography), association with pulmonary hypertension, and poor prognosis. All patients with systemic sclerosis should undergo baseline high-resolution computed tomography and pulmonary function testing screening regardless of respiratory symptoms.[20] Moreover, the evolution and increasing standardization of diagnostic criteria over recent decades have markedly affected the reported prevalence and incidence rates.

Enhanced imaging techniques and improved clinical awareness have led to better detection and classification of ILD subtypes, which vary geographically and epidemiologically. These findings underscore the critical need for consistent and standardized diagnostic approaches to ensure accurate epidemiological assessments, facilitate comparability across studies, and guide effective public health interventions. Taken together, these factors highlight the multifaceted nature of ILD risk, emphasizing the importance of integrated strategies that address environmental control, genetic research, and diagnostic refinement to mitigate the disease's global impact.

Pathophysiology

Many subsets of ILD have an unknown etiology. Key risk factors and drivers of ILD development encompass a range of environmental, occupational, genetic, and demographic elements.[15] Notably, exposure to environmental and occupational agents, such as dusts, fumes, and other airborne irritants, significantly contributes to the disease burden. Smoking and ambient air pollution further amplify this risk, collectively accounting for a substantial portion of the attributable risk associated with ILD. Genetic susceptibility also plays a crucial role by influencing individual vulnerability to these external factors, while the natural aging of populations exacerbates disease pathogenesis, because older age is linked to increased incidence and severity of ILD.[15]

The morphological changes seen histologically result from a sequence of inflammatory events within the parenchyma, the portion of the lung involved in gas exchange (the alveoli, alveolar ducts, and bronchioles). This compartment is the habitat for various proteins and profibrotic elements. These proteins, after repeated cycles of activation, give rise to the accumulation of connective tissue.[21] The trigger can be a known agent deposited in the lung tissue. In some cases, the fibrosis arises spontaneously. Table 2 summarizes the key pathophysiological findings in classes of ILD.

Table 2. Key Pathophysiological Findings in Classes of Interstitial Lung Disease

Histopathology

Histopathological examination plays a central role in diagnosing ILD, particularly when high-resolution computed tomography findings are nondiagnostic or do not align with a specific pattern. Surgical lung biopsy (via video-assisted thoracoscopic surgery) remains the gold standard for tissue diagnosis, though transbronchial lung cryobiopsy is an emerging minimally invasive alternative that is increasingly used in experienced ILD centers.[23]

Usual Interstitial Pneumonia

Usual interstitial pneumonia (UIP) is the histological pattern of IPF and is the most important pattern to recognize (see Image. Pattern of Usual Interstitial Pneumonia/Idiopathic Pulmonary Fibrosis on Computed Tomography Scan). Key features include temporal and spatial heterogeneity (areas of normal lung adjacent to honeycombing and fibroblastic foci), subpleural and basal predominance, fibroblastic foci (active sites of fibrogenesis at the leading edge of fibrosis), honeycombing with or without peripheral traction bronchiectasis, and relative absence of significant granulomas or extensive ground-glass opacity (see Image. Histopathology of Usual Interstitial Pneumonia in Idiopathic Pulmonary Fibrosis). Hyaline membranes and diffuse alveolar damage are absent in UIP, distinguishing UIP from acute exacerbation histology (see Image. Computed Tomography of the Lungs in Usual Interstitial Pneumonia).[37] 

Nonspecific Interstitial Pneumonia 

NSIP is characterized by temporal homogeneity (all areas of the lung appear similar in age), bilateral symmetric interstitial inflammation and/or fibrosis, and relative subpleural sparing, in contrast to UIP. Two subtypes exist: cellular NSIP (predominantly lymphoplasmacytic infiltration, better prognosis) and fibrotic NSIP (collagen deposition, worse prognosis but better than UIP). NSIP is the most common pattern in CTD-ILD, particularly SSc-ILD and antisynthetase syndrome (see Image. Nonspecific Interstitial Pneumonia).[38]

Organizing Pneumonia

Organizing pneumonia demonstrates intraluminal granulation tissue (Masson bodies) within alveolar ducts and alveoli, while preserving the underlying lung architecture. The pattern is temporally homogeneous and patchy. Importantly, organizing pneumonia is characterized by its reversibility with corticosteroid treatment, a key distinguishing feature. Cryptogenic organizing pneumonia is the idiopathic form; secondary organizing pneumonia may be drug-induced, infection-related, or associated with CTD (see Image. Organizing Pneumonia).[39]

Diffuse Alveolar Damage

Diffuse alveolar damage is the histological correlate of acute respiratory distress syndrome and acute interstitial pneumonia, also known as Hamman-Rich syndrome. The exudative phase is characterized by hyaline membrane formation, edema, and inflammatory infiltrates. The organizing and proliferative phase shows type II pneumocyte hyperplasia, interstitial fibrosis, and squamous metaplasia. Diffuse alveolar damage in the context of established ILD (particularly IPF) defines an acute exacerbation, which carries a very poor prognosis with in-hospital mortality exceeding 50%.[40]

Hypersensitivity Pneumonitis 

Acute hypersensitivity pneumonitis shows bronchiolocentric lymphocytic infiltration with poorly formed granulomas and giant cells. Chronic fibrotic hypersensitivity pneumonitis demonstrates upper-lobe-predominant peribronchovascular fibrosis with bridging fibrosis, lymphocytic infiltration, and scattered poorly formed granulomas or giant cells. The presence of granulomas or giant cells adjacent to areas of fibrosis is the key feature distinguishing fibrotic hypersensitivity pneumonitis from UIP and IPF. This distinction is clinically important because it suggests a potentially treatable etiology through antigen identification and avoidance (see Image. Hypersensitivity Pneumonitis).

Desquamative Interstitial Pneumonia, Respiratory Bronchiolitis-ILD, and Alveolar Macrophage Pneumonia

These smoking-related ILDs share intraalveolar macrophage accumulation as their defining feature. Desquamative interstitial pneumonia (now relabeled alveolar macrophage pneumonia) shows diffuse, uniform accumulation of pigmented macrophages throughout alveolar spaces. Respiratory bronchiolitis-ILD shows bronchiolocentric macrophage accumulation in a more patchy distribution. Both are strongly associated with smoking and may stabilize or improve with smoking cessation alone.[41]

Lymphoid Interstitial Pneumonia

Lymphoid interstitial pneumonia (LIP) demonstrates dense polyclonal lymphocytic infiltration of the interstitium, with germinal center formation and cystic changes. LIP is associated with Sjögren disease, human immunodeficiency virus infection, and other autoimmune conditions. Distinction from lymphoma (monoclonal B-cell proliferation) requires immunohistochemistry and clonality studies (see Image. Lymphoid Interstitial Pneumonia).

Role of Transbronchial Lung Cryobiopsy 

Transbronchial lung cryobiopsy (TBLC) uses a cryoprobe to obtain larger, better-preserved biopsy samples compared to conventional forceps transbronchial biopsy, with a reported diagnostic yield of 70% to 80% in ILD, approaching that of surgical lung biopsy in experienced centers. American Thoracic Society and European Respiratory Society 2022 guidelines conditionally recommend TBLC as an alternative to surgical biopsy in patients with nondiagnostic high-resolution computed tomography findings in experienced ILD centers. Complications include pneumothorax (approximately 5% to 10%) and bleeding; the surgical procedure should be performed with fluoroscopic guidance and bronchial blocker occlusion.[42]

Toxicokinetics

Toxicokinetics in interstitial lung disease primarily relates to drug-induced ILD and inhaled toxin-mediated pulmonary injury. More than 350 pharmaceutical agents have been identified as potential causes of ILD, and the mechanisms by which they cause pulmonary toxicity are diverse (see Image. Drug-Induced Interstitial Lung Disease).[43][44][45]

Mechanisms of Drug-Induced ILD

• Direct cytotoxicity: Reactive oxygen species generation damages alveolar epithelial cells and endothelium. This is the primary mechanism for drugs such as bleomycin, amiodarone, and nitrofurantoin. Bleomycin accumulates in the lung due to low concentrations of bleomycin hydrolase (the inactivating enzyme) in pulmonary tissue, leading to iron-catalyzed generation of free radicals and DNA strand breaks.
• Immune-mediated hypersensitivity: T-cell–mediated (type IV) hypersensitivity reactions cause lymphocytic alveolitis and organizing pneumonia patterns. Methotrexate, nitrofurantoin, and checkpoint inhibitor immunotherapy (programmed death-1 and programmed death-ligand 1 [PD-1 and PD-L1] inhibitors) cause ILD predominantly through this mechanism. Immune checkpoint inhibitor-related pneumonitis has emerged as a clinically important drug-induced ILD subtype, occurring in 3% to 5% of patients receiving anti-PD-1 therapy.
• Phospholipidosis: Amiodarone accumulates in lysosomes of type II pneumocytes and alveolar macrophages, inhibiting phospholipase enzymes and causing accumulation of phospholipids. This mechanism is responsible for the characteristic foamy macrophage appearance on lung biopsy in amiodarone pulmonary toxicity. Amiodarone's very long half-life (40 to 55 days) means pulmonary toxicity may persist or progress even after drug discontinuation.
• Vascular toxicity: Some chemotherapeutic agents (cyclophosphamide, carmustine) and targeted therapies cause endothelial injury and vascular remodeling, leading to pulmonary hypertension and ILD.[10]

Inhaled Toxin Mechanisms

Occupational and environmental inhalation of mineral dusts and organic antigens leads to ILD through distinct toxicokinetic pathways:

• Silica: Crystalline silica particles (quartz, cristobalite) are incompletely cleared by alveolar macrophages, leading to inflammasome (NLRP3) activation, interleukin-1β (IL-1β) and TNF-α release, and progressive granulomatous and fibrotic reaction. Silica's durability in biological tissue underpins the progressive nature of silicosis even after exposure cessation.[46]
• Asbestos: Asbestos fibers (particularly long, thin amphibole fibers) resist phagocytic clearance, stimulate reactive oxygen species and inflammatory cytokines, and form asbestos bodies (iron-coated fibers) that are pathological markers of significant exposure. Long fibers penetrate to the pleura, causing mesothelioma in addition to asbestosis.
• Organic antigens: Inhaled organic antigens (avian proteins, fungal spores) are processed by antigen-presenting cells and activate both immune complex (type III) and T-cell–mediated (type IV) pathways. The dose, frequency, and duration of antigen exposure, as well as individual immune susceptibility, determine whether acute, subacute, or chronic hypersensitivity pneumonitis develops.

Clinically Important Drug-ILD Associations

Key drug-ILD associations to recognize are as follows:

• Amiodarone: Prevalence of pulmonary toxicity 5% to 10% with long-term use; insidious onset; bilateral opacities on CT; foamy macrophages on bronchoalveolar lavage; may progress despite discontinuation
• Methotrexate: Hypersensitivity pneumonitis pattern; occurs at any dose; rechallenge generally contraindicated
• Nitrofurantoin: Acute (within weeks) or chronic (>6 months) patterns; one of the most common drug-induced ILD causes in primary care
• Checkpoint inhibitors (anti-PD-1/PD-L1): Pneumonitis in 3% to 5% of patients; treated with corticosteroids and immune checkpoint inhibitor discontinuation; may be severe (grade 3 to 4) in up to 1% to 2% of cases [47]
• Bleomycin: Cumulative dose-dependent (highest risk >400 units); supplemental oxygen use and renal impairment increase risk

A comprehensive drug history, including over-the-counter and herbal medications, is essential in any ILD evaluation. The pneumotox.com database provides a regularly updated reference of drug-lung toxicity associations and their evidence levels.

History and Physical

The initial and most crucial step in evaluating a patient suspected of having ILD is to gather a comprehensive history. Thoroughly documenting the patient's past medical history is vital during the initial assessment, because the cause of the disease is often identified through the patient's history. Besides a detailed review of previous systemic conditions and human immunodeficiency virus risk factors, several other historical aspects are particularly significant and include age, onset of symptoms, family history, and social, environmental, and occupational history (such as exposure to fumes, dust, or toxic inhalation), in addition to medication and past medical history, such as radiation.[48]

Symptoms are often nonspecific, with the most frequently noted being a slow development of breathlessness, particularly in those with scleroderma ILD and chronic hypersensitivity pneumonitis. Approximately 30% of patients with ILD report a nonresolving cough as the initial symptom. Although pleuritic chest pain is rare, chest pain can be present in specific subtypes like sarcoidosis. Hemoptysis might result from diffuse alveolar hemorrhages. Conversely, a patient may be entirely symptom-free yet exhibit abnormal imaging findings. The patient's history should include information about potential environmental or occupational exposures, current and past medications, and any exposure to radiation, fumes, dust, or toxic inhalants.

A family history is crucial because genetics might play a part. Symptoms of rheumatologic diseases should be taken into account; however, clinicians should recognize that shortness of breath may be the sole symptom of rheumatological-associated ILD.[14] Certain ILD types are more prevalent in specific age groups or are predominant in one sex. For example, most patients with sarcoidosis, connective tissue disease-associated ILD, lymphangioleiomyomatosis, and pulmonary Langerhans cell histiocytosis are typically between the ages of 20 and 40 years. In contrast, most patients with IPF are older than 50 years.

On physical examination, bibasilar fine end-inspiratory crackles (described as Velcro-like crepitations) are characteristic but not consistently observed. Patients with advanced disease may exhibit physical signs of pulmonary hypertension, such as an increased intensity of P₂ of the second heart sound, elevated jugular venous pressure, and peripheral edema.[30] In patients with fibrotic ILD, digital clubbing is as common as nearly half of the cases, and could be a marker of poor prognosis (see Image. Clinical Examination Findings of Interstitial Lung Disease).[31]

Hypoxia at rest, cyanosis, and weight loss are common in advanced cases and may indicate a poor prognosis. In patients with suspected CTD-ILD, signs of active inflammatory arthritis, skin thickening, mechanic hands (cracked, hyperpigmented skin over lateral and dorsal digits), or Gottron papules (violaceous papules over dorsal metacarpophalangeal and interphalangeal joints) should be sought. In patients with suspected sarcoidosis, examination should include the skin for erythema nodosum and lupus pernio (violaceous plaques on the nose and cheeks) (see Image. Lupus Pernio), and the eyes for uveitis (see Image. Uveitis Associated with Interstitial Lung Disease).

Evaluation

The diagnosis of ILD can be established with appropriate history and exam, clinical findings, and, in most instances, should be confirmed after excluding other potential causes. ILD encompasses a broad spectrum of disorders, each requiring distinct management strategies and presenting varying prognoses, underscoring the importance of an accurate diagnosis. The diagnostic process commences with a comprehensive patient history and physical examination, supplemented by laboratory tests, imaging, physiological assessments, and potentially a biopsy (see Image. Diagnosis of Interstitial Lung Disease).[49] The initial routine laboratory evaluation includes a complete blood count to identify indicators such as hemolytic anemia, which may be associated with systemic lupus erythematosus, or eosinophilia, which could indicate drug-induced conditions.

A comprehensive CTD-ILD serology panel should include antinuclear antibody with reflex testing, rheumatoid factor, anti-cyclic citrullinated peptide, anti-Scl-70, anti-centromere, anti-RNA polymerase III (for SSc), myositis panel including anti-Jo-1, anti-melanoma differentiation-associated protein 5 (anti-MDA-5; associated with rapidly progressive ILD), and antisynthetase antibodies (anti-PL-7, PL-12, EJ, OJ), anti-Ro and anti-La (Sjögren disease), and antineutrophil cytoplasmic antibody (vasculitis-associated ILD). Anti-MDA5 antibody is of particular clinical urgency because it is associated with a rapidly progressive and often fatal ILD phenotype in dermatomyositis. In certain instances, evaluations for infectious diseases, such as HIV or hepatitis, may be warranted.[50]

The imaging workup begins with a standard chest radiograph, where the most common radiographic feature is a reticular pattern, although nodular or mixed patterns may also be observed (see Image. Diffuse Interstitial Lung Disease).[51] However, the sensitivity of a chest radiograph is lower than that of high-resolution computed tomography (HRCT), at approximately 60%.[52] In certain instances, specific patterns can narrow diagnostic possibilities. The presence of mediastinal lymphadenopathy on a chest radiograph may suggest lymphoma or sarcoidosis (see Image. Sarcoidosis Imaging). HRCT provides a more detailed characterization of the disease and can assist in diagnosis when chest radiograph results are negative; HRCT should be performed in the supine and prone positions.

HRCT should be performed in the supine and prone positions. In some cases, HRCT may reveal a classic radiological pattern of a disease such as UIP (see Images. Usual Interstitial Pneumonia on Axial High-Resolution Computed Tomography and Usual Interstitial Pneumonia). The typical radiological pattern of UIP on HRCT includes subpleural and basilar predominant changes, reticular patterns, and honeycomb changes, with or without traction bronchiectasis. Table 3 summarizes the radiologic changes in common types of ILD (see Image. High-Resolution Computed Tomography Patterns of Interstitial Lung Disease).

Table 3. Radiologic Changes in Common Types of Interstitial Lung Disease

Interdisciplinary discussion, involving pulmonologists, radiologists, and pathologists, is the diagnostic gold standard for ILD and is particularly essential when HRCT and histological findings are discordant or nondiagnostic. The American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Association (ATS/ERS/JRS/ALAT) guidelines recommend interdisciplinary discussion in all cases where the diagnosis remains uncertain after a comprehensive noninvasive workup.[23] Table 4 describes the monitoring required. 

If the diagnosis remains uncertain after evaluating the patient's history, laboratory results, and radiological findings, an invasive workup may be advantageous. Bronchoalveolar lavage (BAL) yields nonspecific results because no findings in a BAL are definitively pathognomonic for a specific type of ILD. However, BAL can be instrumental in narrowing down the options. For example, in patients thought to have hypersensitivity pneumonitis, BAL will demonstrate marked lymphocytosis. The decision to pursue a lung biopsy should be individualized, because not all cases necessitate one. Lung biopsy is most beneficial in diagnosing sarcoidosis and idiopathic interstitial pneumonia. Guidelines from the ATS suggest that a surgical lung biopsy should be considered when a diagnosis of IPF cannot be established noninvasively, particularly if clinical and radiological evidence does not align with UIP, unless the patient is at high risk of complications.[22]

TBLC is conditionally recommended by ATS/ERS 2022 guidelines as a less invasive alternative to surgical lung biopsy in experienced ILD centers, with a diagnostic yield of approximately 70% to 80% and a lower procedural risk profile than video-assisted thoracoscopic surgery. Complete pulmonary function tests (PFT), including assessment of forced vital capacity, diffusion capacity, and oxygenation, are important for assessing disease severity. Individuals with ILD often present with a restrictive ventilatory pattern on spirometry. Oximetry is essential for all patients with ILD for prognostication and disease monitoring. However, a complete functional assessment should include the 6-minute walk test (6MWT).[58] Results from an observational study found that the 6MWT correlates closely with PFTs in patients with ILD. These functional tests also help in monitoring the progression of ILD, not only in establishing the diagnosis.

When to Screen

• Perform screening in patients with systemic associated rheumatological disorders who have respiratory signs or symptoms suggestive of ILD
• Consider screening in asymptomatic patients with high-risk features listed above

Initial Screening Tests

• PFTs: spirometry, lung volumes, and diffusion capacity

If ILD is suspected or the risk is increased

• Repeat PFT• Ambulatory oxygen desaturation testing• HRCT of the chest as clinically indicated

Table 4. Monitoring After Initial Screening 

MCTD, mixed connective tissue disease; PFT, pulmonary function test

Other Tests

• Ambulatory desaturation testing: Every 3 to 12 months
• HRCT chest: As needed based on symptoms, PFT decline, or clinical concern

Treatment / Management

Pharmacological Therapy

Pharmacological therapy depends on the ILD class and on eliminating the specific cause. In most idiopathic cases, therapy is supportive. However, the mainstay therapy for the treatment of IPF is novel antifibrotic therapies.[60] Nintedanib and pirfenidone are tyrosine kinase inhibitors approved for the treatment of IPF.[61] Research results indicate that both drugs can slow disease progression. With progressive disease despite the elimination of the offending agent, corticosteroids are indicated. Patients with cryptogenic organizing pneumonia or hypersensitivity pneumonitis can demonstrate a rapid, dramatic improvement with corticosteroids. For patients who do not respond to corticosteroids, immunosuppressant therapy is commonly considered. Table 5 summarizes treatment options for ILD by subtype.

Table 5. Treatment Options for Interstitial Lung Disease by Subtype

ALAT, Latin American Thoracic Association; ATS, American Thoracic Society; COP, cryptogenic organizing pneumonia; CTD-ILD, connective tissue disease–associated interstitial lung disease; ERS, European Respiratory Society; FVC, forced vital capacity; GERD, gastroesophageal reflux disease; HP, hypersensitivity pneumonitis; ILD, interstitial lung disease; IPF, idiopathic pulmonary fibrosis; ISHLT, International Society for Heart and Lung Transplantation; JRS, Japanese Respiratory Society; MMF, mycophenolate mofetil; PPF, progressive pulmonary fibrosis; RA-ILD, rheumatoid arthritis–associated interstitial lung disease; RCT, randomized controlled trial; SSc-ILD, systemic sclerosis–associated interstitial lung disease; WHO, World Health Organization

ATS and International Society for Heart and Lung Transplantation guidelines recommend listing consideration when: FVC is less than 80% predicted and declining, diffusing capacity of the lung for carbon monoxide is less than 40% predicted, 6MWT distance is less than 250 m or declining, or there is an acute exacerbation of ILD. Early referral (at the time of IPF diagnosis) is recommended because waitlist times can be 2 to 4 years.[67] Newly developed drugs such as nerandomilast (BI 1015550) are orally administered and selectively inhibit phosphodiesterase 4B, providing antifibrotic and immunomodulatory effects.

In a phase 3 multicenter study of 1177 patients with IPF from more than 30 countries, participants were either receiving stable antifibrotic treatment (pirfenidone or nintedanib) or had been off treatment for 8 weeks.[68] Participants were 40 years of age or older, with an FVC of at least 45% and a diffusing capacity of the lung for carbon monoxide of at least 25% of predicted. Nerandomilast achieved its primary endpoint by showing a significantly smaller FVC reduction versus placebo, with only the 18-mg twice-daily dose proving effective. The drug showed no impact on the risk of acute exacerbation, respiratory-related hospitalization, or mortality. The main adverse effect was diarrhea, causing drug discontinuation in less than 4% of patients, and occurring more frequently when combined with nintedanib therapy.

Nonpharmacological Management Strategies for Interstitial Lung Disease 

Supportive care

• Providing supplemental oxygen to patients with hypoxemia at rest or during exertion if the arterial oxygen saturation is less than 88%
• Implementing pulmonary rehabilitation to improve exercise capacity, reduce dyspnea, and enhance quality of life

Management of comorbidities

• Treating pulmonary hypertension with targeted therapies when appropriate [69]
• Managing gastroesophageal reflux disease through lifestyle changes and medications [70]
• Assessing and treating obstructive sleep apnea with proper sleep studies and positive airway pressure therapy, because up to two-thirds of patients with ILD have comorbid obstructive sleep apnea [71]
• Following lung cancer screening guidelines and participating in interdisciplinary cancer care
(A1)

Symptom control and advanced care

• Offering palliative care for persistent symptoms like dyspnea, cough, fatigue, and emotional distress
• Integrating palliative services early to improve symptom management and facilitate end-of-life planning

Some studies' results have provided indirect evidence that early therapy during the course of the disease might correlate with therapeutic responsiveness, as the lung architecture has not suffered significant derangement. Once fibrosis initiates, there is no treatment to reverse it, but nintedanib can slow disease progression.[49] Transplantation is the only treatment that can restore physiologic function.

Results from some studies have provided indirect evidence that early therapy during the course of the disease might correlate with therapeutic responsiveness, as the lung architecture has not yet suffered significant derangement. Once fibrosis has initiated, no treatment has been shown to reverse it, but nintedanib can slow disease progression.[49]  A lung transplant is the only treatment modality that can restore physiological function in patients.

Differential Diagnosis

The differential diagnosis of ILD encompasses both conditions that mimic ILD radiographically and the critical distinction between ILD subtypes, which has direct therapeutic implications.

Conditions That Mimic ILD

• Pulmonary edema (cardiogenic): Bilateral interlobular septal thickening, ground-glass opacity, and Kerley B lines on HRCT may simulate ILD. Distinguishing features include cardiomegaly on chest radiograph, pleural effusions, improvement with diuresis, elevated B-type natriuretic peptide and N-terminal pro-B-type natriuretic peptide levels, and bilateral perihilar (butterfly) distribution. Echocardiography is essential when a cardiac cause is suspected.
• Infectious pneumonias (bacterial, viral, fungal): Consolidation, ground-glass opacity, and nodules can overlap with ILD on imaging. Key distinguishing features include acute onset, fever, elevated inflammatory markers, and response to antimicrobial therapy. Pneumocystis jirovecii pneumonia in patients who are immunocompromised can simulate NSIP with diffuse bilateral ground-glass opacity. Bronchoalveolar lavage with silver stain or polymerase chain reaction is diagnostic.[72]
• Acute respiratory distress syndrome and diffuse alveolar damage: Acute onset bilateral opacification overlaps with acute ILD presentations. Acute respiratory distress syndrome is defined by a fraction of inspired oxygen (PaO₂/FiO₂₎ ratio less than 300, bilateral infiltrates, absence of cardiogenic cause, and onset within 7 days of a precipitating event.
• Lymphoma (pulmonary): Primary pulmonary lymphoma or lymphomatoid granulomatosis may present with consolidation, nodules, or ground-glass opacity that overlap with those of hypersensitivity pneumonitis, sarcoidosis, or organizing pneumonia. Tissue biopsy with clonality studies is definitive.
• Pulmonary alveolar proteinosis: The crazy-paving pattern on HRCT (ground-glass opacity with superimposed interlobular septal thickening) is characteristic and can mimic certain ILD patterns. Bronchoalveolar lavage with milky and opaque appearance and periodic acid-Schiff–positive material is diagnostic.[73]

Critical Intra-ILD Differential: Patterns With Therapeutic Implications

• UIP (IPF) versus fibrotic NSIP versus fibrotic hypersensitivity pneumonitis: This is the most clinically important differential for ILD. UIP and IPF are characterized by subpleural honeycombing, basal predominance, minimal ground-glass opacity, no upper lobe predominance, and no granulomas. Fibrotic NSIP demonstrates subpleural sparing, temporal homogeneity, more ground-glass opacity, and CTD association. Fibrotic HP shows predominance of the upper and mid-lobes, lobular air trapping, a history of antigen exposure, and poorly formed granulomas on biopsy. Misclassification leads to incorrect treatment: antifibrotics for IPF and PPF versus immunosuppression for fibrotic HP.
• Sarcoidosis versus hypersensitivity pneumonitis versus lymphoma: All may present with bilateral hilar lymphadenopathy and upper- and mid-lung nodules. Sarcoidosis demonstrates perilymphatic nodules, bilateral symmetric hilar adenopathy, elevated angiotensin-converting enzyme levels, and noncaseating granulomas on biopsy. HP shows centrilobular nodules, air trapping, a history of antigen exposure, and BAL lymphocytosis. Lymphoma presents with constitutional symptoms and monoclonal proliferation on biopsy.
• CTD-ILD versus IPF: CTD-ILD should be specifically excluded before diagnosing IPF, because management differs significantly. Clinicians should perform a thorough CTD evaluation in younger women with NSIP pattern, autoimmune symptoms (dry eyes, Raynaud phenomenon, arthritis, skin changes), or elevated autoantibody levels. Interstitial pneumonia with autoimmune features is a research category for patients with autoimmune features not meeting full CTD diagnostic criteria.[74]
• Acute exacerbation of IPF versus infection versus pulmonary edema: New bilateral ground-glass opacity superimposed on an established fibrotic pattern in patients with IPF should prompt urgent workup to exclude infection and cardiac cause before diagnosing acute exacerbation of IPF. An acute exacerbation carries a greater than 50% in-hospital mortality and requires high-dose corticosteroids, but immunosuppression in the context of pneumonia can be fatal.

Pertinent Studies and Ongoing Trials

Landmark Completed Trials

• CAPACITY and ASCEND trials (pirfenidone, IPF): Results from 2 phase 3 trials (Clinical Assessment of Three Doses of Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis [CAPACITY]; Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis [ASCEND]) established pirfenidone as the first antifibrotic approved for IPF. Pirfenidone reduced annual FVC decline by 47.9% compared to placebo in ASCEND (mean difference 235 mL/year). Both trials demonstrated reduced disease progression without a survival benefit at the individual trial level.[23][75]
• INPULSIS trials (nintedanib, IPF): Results from INPULSIS-1 and INPULSIS-2 demonstrated that nintedanib reduced the annual decline in FVC by approximately 125 to 130 mL/year compared with placebo. INPULSIS-2 also showed reduced exacerbation risk. Nintedanib and pirfenidone are both strongly recommended by ATS, ERS, JRS, and ALAT guidelines as equivalent first-line antifibrotic options in IPF.[76]
• SENSCIS trial (nintedanib, SSc-ILD): Results from this phase 3 randomized controlled trial of 576 patients with SSc-ILD (Safety and Efficacy of Nintednib in Systemic Sclerosis [SENCIS] showed nintedanib reduced annual FVC decline by 44% versus placebo (-52.4 versus -93.3 mL/year; P < .04). This trial established nintedanib as the first pharmacological therapy with demonstrated benefit in SSc-ILD, leading to the United States Food and Drug Administration approval in 2019.[63]
• INBUILD trial (nintedanib, PPF): Results from this phase 3 RCT of 663 patients with progressive pulmonary fibrosis of diverse underlying etiologies (excluding IPF) showed that nintedanib reduced the annual decline in FVC compared with placebo (-80.8 versus -187.8 mL/year; P < .001), regardless of HRCT fibrosis pattern. This landmark trial established nintedanib as the first antifibrotic approved for PPF across multiple non-IPF fibrotic ILD subtypes, representing a major paradigm shift in the treatment of progressive fibrosis.[77]
• SLS II trial (mycophenolate vs cyclophosphamide, SSc-ILD): Results from this phase 3 randomized controlled trial of 142 patients with SSc-ILD showed that mycophenolate mofetil was noninferior to cyclophosphamide in improving FVC at 24 months, with a more favorable toxicity profile. This trial established mycophenolate mofetil as the preferred first-line immunosuppressive agent for SSc-ILD, replacing cyclophosphamide.[78]
• Idiopathic Pulmonary Fibrosis International Group Exploring N-Acetylcysteine (IFIGENIA) trial (N-acetylcysteine + prednisone + azathioprine vs prednisone + azathioprine, IPF): Demedts et al established the use of N-acetylcysteine in IPF. Subsequently, in the Prednisone, Azathioprine, and N-Acetylcysteine: A Study That Evaluates Response in Idiopathic Pulmonary Fibrosis (PANTHER-IPF) trial, Raghu et al discontinued triple therapy (prednisone + azathioprine + N-acetylcysteine) early due to increased mortality, fundamentally changing IPF management away from immunosuppression toward antifibrotic therapy.[79][80]
• FIBRONEER-IPF trial (nerandomilast [BI 1015550], IPF): Results from this phase 3 RCT of 1177 patients with IPF showed that nerandomilast (a phosphodiesterase 4B [PDE4B] inhibitor) demonstrated a significantly smaller FVC reduction than placebo at 52 weeks, with an acceptable safety profile. As of early 2026, nerandomilast is under regulatory review.[68][81]

Key Ongoing Trials

• BMS-986325 (TGF-β inhibitor, IPF): This phase 2 trial targets the central profibrotic cytokine TGF-β, which drives fibroblast activation and ECM accumulation across multiple ILD subtypes.
• ISABELA 1&2 trials (ziritaxestat, IPF): These phase 3 trials of an autotaxin inhibitor were discontinued due to an unfavorable benefit-to-risk profile, demonstrating the challenges of targeting the LPA pathway in IPF.
• Phase 3 trials of inhaled treprostinil (INCREASE trial expansion): Building on the INCREASE trial, inhaled treprostinil improved 6MWT in ILD-associated pulmonary hypertension. Trials are ongoing to define durability and optimal patient selection.
• Anti–connective tissue growth factor pamrevlumab: Phase 3 (ZEPHYRUS-1 and ZEPHYRUS-2) trials of pamrevlumab (anti-CTGF monoclonal antibody) in IPF, results pending.

Prognosis

Prognosis varies substantially across ILD subgroups and is determined by the underlying ILD subtype, histological pattern, functional parameters at diagnosis, the rate of physiological decline, and the presence of complications.

General Adverse Prognostic Indicators

Across all ILD subtypes, the following factors are associated with worse outcomes:

• Physiological parameters: Baseline FVC less than 70% to 75% of predicted; DLCO <40% predicted; resting hypoxia (SpO₂ <88%); 6MWT distance <250 m or >50m decline over 6 months; FVC decline >10% or DLCO decline >15% in the preceding year [82]
• Radiological: Extent of fibrosis on CT >20%; presence of honeycombing; UIP pattern (versus NSIP or organizing pneumonia)
• Demographic: Age >60 years; male sex; higher body mass index
• Clinical events: Acute exacerbations of ILD requiring hospitalization are associated with markedly reduced survival; a median posthospitalization survival of approximately 7 months in acute exacerbation of IPF

Subtype-Specific Prognosis

• IPF: Median survival 2 to 5 years from diagnosis without treatment. The introduction of antifibrotic therapy (nintedanib, pirfenidone) slows FVC decline but does not alter the underlying progressive natural history for most patients. Five-year survival is approximately 20% to 40%. Lung transplant offers a median posttransplant survival of 5 to 7 years and is the only treatment that alters the natural history.[83]
• SSc-ILD: The most clinically severe CTD-ILD subtype. Median survival from SSc diagnosis is 11 years, but ILD is the leading cause of SSc-related mortality. Fibrotic pattern (UIP on HRCT), male sex, anti-Scl-70 positivity, and diffuse cutaneous SSc subtype are associated with more severe ILD and worse prognosis.
• CTD-ILD (rheumatoid arthritis, polymyositis/dermatomyositis, Sjögren disease, mixed connective tissue disease): Generally, a better prognosis than IPF. The NSIP pattern (common in CTD-ILD) has a better prognosis than UIP. Antimelanoma differentiation–associated gene 5-positive dermatomyositis-ILD is a notable exception because it is a rapidly progressive ILD phenotype with high short-term mortality if untreated.
• Hypersensitivity pneumonitis: Prognosis depends critically on identification and avoidance of the causative antigen. Acute and subacute hypersensitivity pneumonitis with an identifiable antigen that is successfully eliminated carries an excellent prognosis with near-complete resolution. Chronic fibrotic HP with UIP pattern carries a prognosis similar to IPF.
• Sarcoidosis: Overall, good prognosis, and 60% of patients achieve spontaneous remission within 2 to 3 years. Approximately 20% develop chronic disease, and 5% progress to severe pulmonary fibrosis. Löfgren syndrome (acute sarcoidosis with erythema nodosum, bilateral hilar adenopathy, arthritis) has an excellent prognosis with near-universal spontaneous resolution.
• Organizing pneumonia (cryptogenic organizing pneumonia): Excellent response to corticosteroids (80% to 90% of patients respond). Relapses occur in approximately 50% of patients when corticosteroids are tapered too rapidly, but usually respond to retreatment. Progression to irreversible fibrosis is very rare.

ILD-Associated Pulmonary Hypertension as a Prognostic Modifier

Pulmonary hypertension complicates up to 30% to 40% of patients with advanced ILD and is an independent predictor of mortality. The development of ILD-associated pulmonary hypertension (World Health Organization Group 3) markedly worsens prognosis. The median survival is approximately 1 year from diagnosis in IPF-associated pulmonary hypertension without treatment. Inhaled treprostinil (INCREASE trial) improves 6MWT distance and reduces clinical worsening, and represents the first approved therapy for this complication

Complications

ILS is associated with a range of serious complications that contribute significantly to morbidity and mortality. Recognition and proactive treatment of these complications are essential to optimizing patient outcomes.

Progressive Respiratory Failure and Hypoxia

Progressive dyspnea and hypoxia are universal complications of advancing ILD. Resting hypoxia (oxygen saturation, SpO₂ < 88%) develops as fibrosis replaces functional parenchyma, leading to ventilation-perfusion mismatch and impaired gas transfer (DLCO decline). Supplemental oxygen is recommended when SpO₂ decreases below 88% at rest or with exertion, improving exercise tolerance, dyspnea, and quality of life, though the effect on survival in ILD has not been definitively established.

Acute Exacerbation of ILD

Acute exacerbation (AE)-ILD is defined as a new bilateral ground-glass opacity superimposed on a preexisting fibrotic pattern with no identifiable cause (excluding infection, cardiac failure, or volume overload) and is the most feared complication of IPF and other fibrotic ILDs. AE-IPF carries an in-hospital mortality exceeding 50%, with a median survival of less than 3 months from the event. High-dose corticosteroids (methylprednisolone 500 mg to 1000 mg/d for 3 days) are commonly prescribed, though evidence for this practice is limited. Mechanical ventilation provides only temporary stabilization; most patients do not recover to baseline function.

Pulmonary Hypertension (ILD-PH, WHO Group 3)

Pulmonary hypertension develops in 30% to 40% of patients with advanced interstitial lung disease due to hypoxic vasoconstriction, vascular remodeling, and fibrosis-induced compression of the pulmonary vasculature. ILD-PH is an independent predictor of mortality, with a median survival of approximately 1 year after diagnosis in IPF-PH. Clinical recognition, as suggested by progressive dyspnea disproportionate to lung function decline, syncope, and right heart strain on electrocardiography, should prompt echocardiography and right heart catheterization. Inhaled treprostinil (INCREASE trial) is the only United States Food and Drug Administration–approved therapy for ILD-PH, and results from the INCREASE trial demonstrated improvement in 6-minute walk test distance and reduction in clinical worsening.

Lung Cancer

Patients with IPF have a 5% to 10% prevalence of concurrent lung cancer, substantially higher than in the general population with a smoking history. The shared risk factors (smoking, age) and the fibrotic lung environment (which promotes epithelial-mesenchymal transition and DNA damage from oxidative stress) account for this association. Lung cancers in patients with IPF most commonly arise in the periphery and lower lobes, areas of maximal fibrosis, and are predominantly squamous cell carcinoma or adenocarcinoma. Treatment is complicated by the elevated surgical risk (AE-ILD triggered by resection) and the potential for worsening ILD with platinum-based chemotherapy. Annual low-dose CT should be performed in all patients with a smoking history and ILD for lung cancer screening.

Infections

Patients with ILD are at increased risk of respiratory infections due to impaired mucociliary clearance, structural lung abnormalities (particularly honeycombing), and immunosuppressive therapy. Key infection risks include the following:

• Bacterial pneumonia: Higher incidence in patients with ILD; bacterial pneumonia may precipitate AE-ILD and carries high mortality. Annual influenza and pneumococcal vaccination are recommended for all patients with ILD.
• Opportunistic infections: Patients receiving immunosuppressive therapy (corticosteroids, azathioprine, cyclophosphamide, rituximab) are at risk for Pneumocystis jirovecii pneumonia and fungal infections. Prophylaxis (trimethoprim-sulfamethoxazole) should be considered in patients receiving 20 mg/d or more of prednisolone equivalent for 4 weeks or more in combination with another immunosuppressant.

Venous Thromboembolism

Patients with ILD, particularly those with IPF, have an elevated risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism), likely driven by a chronic procoagulant state associated with progressive fibrosis and systemic inflammation. Pulmonary embolism can be clinically difficult to distinguish from AE-ILD and should be actively excluded in patients with acute deterioration. Appropriate prophylaxis during hospitalizations is essential.[84]

Gastroesophageal Reflux Disease and Aspiration

Gastroesophageal reflux disease is present in up to 90% of patients with IPF and may contribute to ILD pathogenesis and progression through chronic microaspiration of gastric acid contents. Aggressive treatment (proton pump inhibitors, head elevation, dietary modification) is recommended as part of IPF treatment. Antireflux surgery (fundoplication) may be considered in patients with IPF and severe refractory gastroesophageal reflux disease, though evidence for a direct ILD benefit is limited.

Obstructive Sleep Apnea

Obstructive sleep apnea complicates up to two-thirds of patients with ILD, contributing to nocturnal hypoxia, poor sleep quality, and exacerbation of pulmonary hypertension. Screening for obstructive sleep apnea should be performed in all patients with ILD, particularly those with unexplained nocturnal desaturation, daytime somnolence, or coexistent obesity. Positive airway pressure therapy improves oxygenation and quality of life in patients with ILD and concurrent obstructive sleep apnea.

Psychological Complications

Anxiety and depression are highly prevalent in patients with ILD (up to 30% to 40%), driven by progressive disability, oxygen dependence, and poor prognosis. These conditions are frequently underdiagnosed and undertreated. Psychological assessment should be part of routine ILD follow-up, and referral to psychological or palliative care services is appropriate.[85]