Residency · Residency · Internal Medicine

Interstitial Lung Disease: Recognition and Initial Workup

Overview

Interstitial lung diseases (ILDs) constitute a heterogeneous group of more than 200 disorders characterized by inflammation and/or fibrosis of the lung parenchyma. While the interstitium (alveolar walls, perivascular and perilymphatic tissue) is the primary target, airways and pleura may also be involved. The typical presentation includes progressive dyspnea, non-productive cough, and bilateral infiltrates on imaging. Pulmonary function testing reveals restrictive physiology with decreased FVC, decreased TLC, decreased DLCO, and a preserved or elevated FEV1/FVC ratio.

Classification

Known Causes

Drug-induced ILD can result from amiodarone, methotrexate, nitrofurantoin, bleomycin, checkpoint inhibitors, and radiation therapy. Occupational and environmental exposures cause conditions such as asbestosis, silicosis, coal workers' pneumoconiosis, and hypersensitivity pneumonitis (bird fancier's lung, farmer's lung). Connective tissue disease-associated ILD (CTD-ILD) occurs in the context of rheumatoid arthritis, scleroderma, inflammatory myositis (anti-MDA5, anti-Jo1 antibodies), systemic lupus erythematosus, and Sjogren's syndrome. Infection-related ILD may follow chronic fungal or atypical mycobacterial disease.

Idiopathic Interstitial Pneumonias (IIPs)

Idiopathic pulmonary fibrosis (IPF) is the most common and most lethal IIP. Nonspecific interstitial pneumonia (NSIP) is often associated with connective tissue disease. Cryptogenic organizing pneumonia (COP), formerly called BOOP, presents with characteristic imaging findings. Acute interstitial pneumonia (AIP), also known as Hamman-Rich syndrome, has a rapid onset and high mortality. Desquamative interstitial pneumonia (DIP) and respiratory bronchiolitis-ILD (RB-ILD) are both associated with smoking. Lymphoid interstitial pneumonia (LIP) is linked to Sjogren's syndrome and HIV.

Granulomatous ILD

This category includes sarcoidosis, chronic hypersensitivity pneumonitis, and berylliosis.

Other

Pulmonary Langerhans cell histiocytosis is smoking-related. Lymphangioleiomyomatosis (LAM) presents in young women with cystic lung disease and is associated with tuberous sclerosis. Pulmonary alveolar proteinosis and eosinophilic pneumonias round out additional important entities.

Clinical Approach

History -- Key Questions

The onset and tempo of symptoms help narrow the differential: acute presentations (days to weeks) suggest COP, AIP, drug-induced disease, or eosinophilic pneumonia, while chronic courses (months to years) point toward IPF, CTD-ILD, or hypersensitivity pneumonitis. A detailed occupational and environmental exposure history is essential, including work history, hobbies such as bird keeping, hot tub use, mold exposure, and farming. Medication review should specifically address methotrexate, amiodarone, nitrofurantoin, biologics, and checkpoint inhibitors. Smoking history is relevant because IPF, DIP, RB-ILD, and pulmonary Langerhans cell histiocytosis are all smoking-associated, while hypersensitivity pneumonitis may be less common in smokers. Symptoms of connective tissue disease should be sought, including joint pain and swelling, Raynaud's phenomenon, skin changes, dysphagia, muscle weakness, and dry eyes or mouth. Family history is pertinent because familial pulmonary fibrosis can result from telomere-related mutations (TERT, TERC). Extrapulmonary features such as erythema nodosum (sarcoidosis), skin thickening (scleroderma), and mechanic's hands (antisynthetase syndrome) provide valuable diagnostic clues.

Physical Examination

Bibasilar inspiratory crackles, often described as "Velcro crackles," are the hallmark of IPF and fibrotic ILD. Digital clubbing is present in 25-50% of IPF patients but is rare in other ILDs. Skin examination may reveal rash (dermatomyositis), sclerodactyly, or calcinosis. Joint examination may show synovitis (rheumatoid arthritis) or proximal muscle weakness (myositis). Signs of pulmonary hypertension including a loud P2, RV heave, and peripheral edema represent late findings.

Pulmonary Function Tests

A restrictive pattern with decreased FVC, decreased TLC, and normal or elevated FEV1/FVC is characteristic. Decreased DLCO is often the earliest abnormality, reflecting alveolar-capillary membrane damage. The 6-minute walk test with desaturation (greater than 4% drop to below 88%) indicates significant disease and is useful for monitoring and prognosis. An obstructive or mixed pattern may occur in sarcoidosis (airway granulomas), hypersensitivity pneumonitis, LAM, and pulmonary Langerhans cell histiocytosis.

HRCT Patterns -- The Cornerstone of ILD Diagnosis

Usual Interstitial Pneumonia (UIP) Pattern

The hallmarks of UIP are a basal-predominant, subpleural, heterogeneous distribution with honeycombing (the key finding), traction bronchiectasis, reticulation, and temporal heterogeneity (fibrosis of varying ages). Ground-glass opacity is minimal or absent; if present, an alternate or superimposed diagnosis should be considered. A definite UIP pattern on HRCT in the right clinical context establishes the diagnosis of IPF without biopsy, per the ATS/ERS 2018 guidelines. This pattern is also seen in RA-ILD, chronic hypersensitivity pneumonitis, asbestosis, and familial pulmonary fibrosis.

NSIP Pattern

NSIP is characterized by basal-predominant ground-glass opacity and reticulation with relative subpleural sparing and a homogeneous appearance reflecting the same temporal stage of disease. Honeycombing is absent; if present, UIP should be reconsidered. NSIP is the most common ILD pattern in CTD-ILD, particularly scleroderma and myositis.

Organizing Pneumonia (OP) Pattern

The organizing pneumonia pattern features patchy bilateral consolidation, often peripheral and migratory, with perilobular distribution and the "reverse halo" or "atoll sign." It often responds dramatically to corticosteroids and is seen in COP, drug-induced disease, infection-related processes, post-radiation changes, and CTD.

Diffuse Ground-Glass Opacity

In acute or subacute settings, diffuse ground-glass opacity suggests hypersensitivity pneumonitis, drug reaction, acute eosinophilic pneumonia, PCP pneumonia, alveolar hemorrhage, or AIP. The key distinction is between active inflammation (potentially treatable) and fine fibrosis.

Cystic Lung Disease

LAM presents with thin-walled cysts diffusely distributed without zonal predominance. Pulmonary Langerhans cell histiocytosis shows upper and mid zone cysts and nodules that spare the costophrenic angles. LIP features scattered thin-walled cysts with ground-glass opacity.

Upper Lobe-Predominant Fibrosis

Upper lobe-predominant fibrosis is seen in chronic hypersensitivity pneumonitis, sarcoidosis (stage IV), ankylosing spondylitis, and radiation.

Diagnostic Workup

Serologic Studies

ANA, RF, and anti-CCP screen for connective tissue disease. Myositis-specific antibodies (anti-Jo-1, anti-MDA5, anti-Mi-2, anti-PL-7/PL-12) identify antisynthetase syndrome. Scl-70 (anti-topoisomerase I) is associated with scleroderma and SSc-ILD, while anti-centromere antibody is seen in limited scleroderma, which less commonly causes ILD. ANCA should be checked if vasculitis or diffuse alveolar hemorrhage is suspected. Hypersensitivity pneumonitis panels testing serum precipitins (IgG) to common antigens have limited sensitivity and specificity. ACE level and lysozyme are used for sarcoidosis but have low sensitivity. KL-6 and SP-D are ILD biomarkers used in some centers but not widely adopted.

Bronchoalveolar Lavage (BAL)

BAL helps narrow the differential but is rarely diagnostic alone. A lymphocytic BAL (greater than 25%) suggests hypersensitivity pneumonitis, sarcoidosis, COP, drug reaction, or NSIP. Neutrophilic BAL is seen in IPF/UIP, acute exacerbations, and aspiration. Eosinophilic BAL (greater than 25%) points toward eosinophilic pneumonia. Bloody or hemorrhagic fluid indicates diffuse alveolar hemorrhage, confirmed by hemosiderin-laden macrophages. PAS-positive milky fluid is pathognomonic of pulmonary alveolar proteinosis.

Surgical Lung Biopsy

Surgical biopsy is the gold standard when clinical and radiologic findings are inconclusive. VATS is preferred, with open thoracotomy if needed. It is most useful for atypical HRCT patterns, suspected HP without exposure history, and unclassifiable ILD. Biopsy is not needed when a definite UIP pattern is present on HRCT with clinical features of IPF, and is contraindicated in severe disease. Transbronchial cryobiopsy is an emerging alternative with lower morbidity and a diagnostic yield of 70-80%.

Multidisciplinary Discussion (MDD)

The gold standard for ILD diagnosis involves collaborative discussion among a pulmonologist, radiologist, and pathologist. This approach improves diagnostic accuracy and interobserver agreement and is recommended by ATS/ERS guidelines for all ILD cases.

Idiopathic Pulmonary Fibrosis (IPF) -- In-Depth

Epidemiology and Prognosis

IPF is the most common idiopathic IIP with an incidence of 13 to 20 per 100,000 and a median survival of 3 to 5 years from diagnosis, which is worse than many cancers. Risk factors include age over 60, male sex, smoking, GERD, and family history. The GAP index (Gender, Age, Physiology) serves as a staging system for prognosis.

Diagnosis

A definite UIP pattern on HRCT in the appropriate clinical context establishes the diagnosis of IPF without biopsy. Probable UIP or indeterminate patterns may warrant biopsy or use of a genomic classifier (Envisia). Known causes such as CTD, drugs, and exposures must be excluded.

Antifibrotic Therapy

Pirfenidone reduces FVC decline by approximately 50% but causes gastrointestinal side effects (nausea, anorexia) and photosensitivity. Nintedanib, a tyrosine kinase inhibitor, also reduces FVC decline by about 50% with diarrhea as the main side effect. Nintedanib has been studied in the INPULSIS trials (IPF), SENSCIS trial (SSc-ILD), and INBUILD trial (progressive pulmonary fibrosis beyond IPF). Both agents are FDA-approved for IPF, but neither reverses established fibrosis. Antifibrotic therapy should be initiated at diagnosis without waiting for significant decline.

Treatments NOT Effective in IPF

Corticosteroids provide no benefit and may cause harm. The PANTHER trial demonstrated that the combination of azathioprine, prednisone, and N-acetylcysteine increased harm. Anticoagulation is not beneficial. Sildenafil shows no benefit except possibly in severe pulmonary hypertension.

Acute Exacerbation of IPF

Acute exacerbations present as respiratory worsening within 30 days with new bilateral ground-glass opacity on CT. Mortality is high at 50-80%. Infection, PE, and heart failure must be ruled out. Treatment relies on supportive care and often high-dose steroids (with limited evidence), with consideration of continuing antifibrotics.

Lung Transplant

Referral should occur early, ideally at diagnosis for IPF. Listing criteria include DLCO below 40%, FVC decline of 10% or more in 6 months, desaturation below 88% on 6-minute walk test, and pulmonary hypertension. IPF is the leading indication for lung transplant in many centers.

Progressive Pulmonary Fibrosis (PPF)

The concept of progressive pulmonary fibrosis was introduced in the ATS/ERS/JRS/ALAT 2022 guidelines. It is defined as non-IPF ILD with progressive fibrosis despite standard management. Criteria require (within one year of follow-up) worsening respiratory symptoms plus at least one of: FVC decline of 5% or more, DLCO decline of 10% or more, or progressive fibrosis on HRCT. Nintedanib is FDA-approved for PPF based on the INBUILD trial. This paradigm applies to chronic HP, CTD-ILD, unclassifiable ILD, and other conditions demonstrating progressive fibrotic behavior.

<image> A grid of HRCT pattern illustrations for major ILD types. Four panels showing: (1) UIP pattern with subpleural honeycombing, traction bronchiectasis, and basal predominance; (2) NSIP pattern with ground-glass opacity and subpleural sparing; (3) Organizing pneumonia with peripheral consolidation and reverse halo sign; (4) Hypersensitivity pneumonitis with centrilobular nodules, mosaic attenuation, and air trapping. Each panel should be labeled with the pattern name, key features, and associated diagnoses. </image>

<image> A diagnostic algorithm flowchart for ILD evaluation. Start with "Progressive Dyspnea + Bilateral Infiltrates" leading to history (exposures, medications, CTD symptoms), PFTs (restrictive, decreased DLCO), and HRCT. Branch based on HRCT pattern: definite UIP (consider IPF), NSIP/OP/other patterns, and cystic disease. Show decision points for serologic workup, BAL, and surgical lung biopsy. End with multidisciplinary discussion as the gold standard for final diagnosis. </image>

<image> A comparison table infographic of IPF antifibrotic therapies. Two columns for pirfenidone and nintedanib showing: mechanism of action, key trials (ASCEND for pirfenidone, INPULSIS for nintedanib), efficacy data (FVC decline reduction), main side effects (GI, photosensitivity vs. diarrhea), and expanded indications beyond IPF (INBUILD for nintedanib in PPF, SENSCIS for SSc-ILD). Include lung transplant referral criteria as a sidebar. </image>

Clinical Pearls

Bibasilar Velcro crackles on lung auscultation should always prompt consideration of ILD, as this finding is frequently dismissed as atelectasis. A definite UIP pattern on HRCT in the appropriate clinical context is sufficient to diagnose IPF without surgical biopsy, and clinicians should know the UIP pattern hallmarks: honeycombing, basal and subpleural predominance, and traction bronchiectasis. Before diagnosing "idiopathic" pulmonary fibrosis, clinicians must always screen for CTD (ANA, RF, anti-CCP, myositis antibodies) and obtain a detailed exposure history, as CTD-ILD and chronic HP are treatable conditions. Antifibrotic therapy should be started at IPF diagnosis without waiting for significant decline, as both pirfenidone and nintedanib slow progression but do not reverse established fibrosis. The PANTHER trial demonstrated that immunosuppression (prednisone plus azathioprine plus NAC) is harmful in IPF, and steroids should never be used as primary therapy for this condition. Progressive pulmonary fibrosis represents a paradigm shift: any non-IPF ILD showing progressive fibrotic behavior can now be treated with nintedanib. Referral for lung transplant evaluation should occur early in IPF and should not be delayed until the patient is too sick, given significant median wait times and pre-transplant mortality.

References

• Raghu G, et al. 2018 ATS/ERS/JRS/ALAT Clinical Practice Guideline: Diagnosis of IPF. Am J Respir Crit Care Med. 2018.
• Raghu G, et al. 2022 ATS/ERS/JRS/ALAT Clinical Practice Guideline: Treatment of IPF. Am J Respir Crit Care Med. 2022.
• Flaherty KR, et al. INBUILD Trial: Nintedanib in Progressive Fibrosing ILD. NEJM. 2019.
• King TE, et al. ASCEND Trial: Pirfenidone for IPF. NEJM. 2014.
• Richeldi L, et al. INPULSIS Trials: Nintedanib for IPF. NEJM. 2014.
• Distler O, et al. SENSCIS Trial: Nintedanib in SSc-ILD. NEJM. 2019.
• Idiopathic Pulmonary Fibrosis Clinical Research Network. PANTHER Trial: Prednisone, Azathioprine, and NAC in IPF. NEJM. 2012.
• Travis WD, et al. ATS/ERS Classification of Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med. 2013.

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