Interstitial Lung Disease

Inhalational / occupational (dose- and particle-dependent injury)

• Pneumoconioses: asbestos (lower-lobe fibrosis, pleural plaques), silica and coal dust (upper-lobe nodules, eggshell calcification of hilar nodes), beryllium (granulomatous disease mimicking sarcoidosis)
• Hypersensitivity pneumonitis: type III/IV immune response to inhaled organic antigen — thermophilic actinomycetes (farmer's lung), avian proteins (bird fancier's lung), Mycobacterium avium complex in aerosolized water (hot tub lung)

Immune-mediated

• Connective tissue disease–associated ILD: systemic sclerosis (most often NSIP), rheumatoid arthritis (often UIP pattern), antisynthetase syndrome, Sjögren, SLE, myositis; ILD may precede joint or skin disease
• Sarcoidosis: non-caseating granulomas from exaggerated Th1/CD4 response to an unidentified antigen

Iatrogenic

• Drugs: amiodarone, bleomycin (dose- and oxygen-potentiated), methotrexate, nitrofurantoin, and immune checkpoint inhibitors (pneumonitis)
• Radiation: fibrosis confined to the port, developing months after therapy

Non-modifiable risk factors

• Age and sex: IPF is a disease of adults over roughly 60, with male predominance
• Genetics: the MUC5B promoter polymorphism is the strongest known genetic risk allele for IPF; telomerase pathway mutations (TERT/TERC) and surfactant protein mutations underlie familial pulmonary fibrosis — look for a stem with premature graying, cytopenias, or cirrhosis
• Family history of pulmonary fibrosis

Modifiable risk factors

• Cigarette smoking: the dominant modifiable exposure for IPF and the required exposure for RB-ILD/DIP/PLCH
• Occupational and hobby exposures: metal and wood dust, mold, birds — ATS/ERS/JRS/ALAT guidance stresses a detailed exposure history, since antigen identification changes management
• Gastroesophageal reflux with microaspiration, viewed as a repetitive epithelial injury contributor
• Drug and radiation exposure, avoidable by substitution or dose limitation

• Initial insult and inflammation: Inhaled antigens, drugs, radiation, or autoimmune activation trigger alveolar epithelial cell injury and recruitment of inflammatory cells (macrophages, lymphocytes, neutrophils) to the interstitium, releasing pro-inflammatory cytokines (TNF-α, IL-1, IL-6)

• Aberrant wound healing and fibrosis: Rather than resolution, the inflammatory phase transitions to pathologic fibroproliferation driven by transforming growth factor-beta (TGF-β), leading to fibroblast activation, excessive collagen deposition (Types I and III), and myofibroblast differentiation; this results in progressive stiffness and architectural remodeling

• Epithelial-mesenchymal transition (EMT): Alveolar epithelial cells lose cell-cell adhesion and differentiate into fibroblasts via TGF-β signaling, contributing to fibroblast pool and perpetuating fibrosis

• Impaired gas exchange: Thickening of the alveolar-capillary membrane from interstitial fibrosis, edema, and inflammation causes diffusion limitation; ventilation-perfusion mismatch and shunting develop; loss of capillary bed worsens hypoxemia

• Progressive architectural destruction: Repeated cycles of injury and aberrant repair lead to honeycombing (cystic airspace formation), bronchiectasis, and loss of functional lung parenchyma, ultimately causing restrictive physiology

• Dyspnea on exertion (most common): Progressive, typically begins with moderate exertion and advances to dyspnea at rest; often precedes radiographic changes; worse in early morning or with positional changes; reflects reduced lung compliance and impaired diffusion capacity

• Dry, persistent, non-productive cough: Present in >90% of patients; often irritating; does NOT respond well to cough suppressants; may accompany dyspnea or precede it by months

• Chest pain or tightness: Pleuritic chest pain may occur with certain etiologies (connective tissue disease-associated ILD, hypersensitivity pneumonitis); substernal discomfort is less common

• Constitutional symptoms: Fatigue, malaise, low-grade fever (particularly in acute hypersensitivity pneumonitis or organizing pneumonia); weight loss suggests advanced disease or superimposed malignancy

• Physical examination findings: Bilateral basilar crackles (fine, "velcro-like," end-inspiratory) are classic and highly specific for usual interstitial pneumonia (UIP) pattern; clubbing suggests IPF, bronchiectasis, or lung cancer; cyanosis indicates advanced disease with severe hypoxemia; right heart strain signs (elevated JVP, edema) signal pulmonary hypertension/cor pulmonale

• Important variants: Acute presentations (acute interstitial pneumonia, acute hypersensitivity pneumonitis) present with fever, myalgias, and hypoxemia; subacute ILD (organizing pneumonia) may mimic pneumonia; asymptomatic ILD discovered incidentally on imaging is increasingly recognized with CT screening

• Temporal clues: Symptom onset within weeks of antigen exposure (birds, moldy hay, metal dust) suggests hypersensitivity pneumonitis; insidious onset over months/years suggests IPF or connective tissue disease-associated ILD

• High-resolution CT (HRCT) of the chest: Gold standard imaging; identifies pattern (UIP, non-specific interstitial pneumonia [NSIP], organizing pneumonia, hypersensitivity pneumonitis pattern); UIP pattern shows reticular opacities, traction bronchiectasis, basilar/peripheral predominance, and honeycombing; HRCT pattern alone can establish diagnosis in appropriate clinical context without biopsy (2018 Fleischner Society guidelines)

• Pulmonary function testing (PFT): Shows restrictive pattern (reduced FVC, preserved FEV1/FVC ratio >0.8); reduced DLCO (diffusion capacity for carbon monoxide) is often the most sensitive early finding; exercise-induced desaturation on 6-minute walk test (6MWT) with drops >4% is clinically significant; serial FVC decline >10% or DLCO decline >15% in 1 year indicates rapid progression

• Laboratory/serologic testing: ANA, rheumatoid factor, anti-CCP (detect connective tissue disease); specific antibodies for hypersensitivity pneumonitis (precipitins); ACE level and serum calcium (sarcoidosis); histology-specific markers (KL-6, SP-D) have research but limited clinical utility

• Bronchoalveolar lavage (BAL): Used selectively to rule out infection, malignancy, or sarcoidosis; differential cell count may support diagnosis (lymphocytosis in hypersensitivity pneumonitis, organizing pneumonia; neutrophilia in IPF); not diagnostic for IPF alone

• Lung biopsy (transbronchial or surgical): Surgical lung biopsy (VATS or open) remains gold standard for histologic diagnosis when HRCT pattern is indeterminate; shows UIP pattern (patchy fibrosis, fibroblast foci, preserved lung architecture in some areas) for IPF diagnosis; indicated when clinical-radiologic diagnosis uncertain and affects management

• Diagnostic criteria for IPF (per ATS/ERS/JRS/ALAT 2018): Clinical and radiologic diagnosis requires appropriate HRCT pattern (definite UIP or probable UIP) plus clinical context (>50 years, smoking history, dyspnea/cough >3 months, no alternative diagnosis); biopsy confirmation only if HRCT indeterminate

• Antifibrotic therapy (first-line for IPF): Pirfenidone (601 mg TID; three 200 mg tablets three times daily) or nintedanib (150 mg BID; inhibits tyrosine kinases); both slow FVC decline by ~50% (relative reduction ~45% over 52 weeks); start early in disease; nintedanib preferred if progressive fibrosis on prior therapy; monitor renal function (pirfenidone) and GI tolerance (nintedanib causes diarrhea); neither reverses existing fibrosis

• Corticosteroids and immunosuppression: Reserved for non-IPF ILD (connective tissue disease-associated, hypersensitivity pneumonitis, organizing pneumonia, acute interstitial pneumonia); prednisone 0.5-1 mg/kg daily (typical starting dose 40-60 mg) with taper over 3-6 months; add azathioprine 2-2.5 mg/kg daily or mycophenolate 1.5-3 g daily for steroid-sparing effect; NOT beneficial in IPF and may be harmful (triple therapy study showed increased mortality)

• Management of hypersensitivity pneumonitis: Antigen avoidance is primary intervention; corticosteroids (prednisone 0.5-1 mg/kg daily) for acute/subacute presentations with gradual taper; most recover with avoidance alone if caught early; chronic form may progress to pulmonary fibrosis despite steroids

• Pulmonary hypertension management: Phosphodiesterase-5 inhibitors (sildenafil

Disease-related

• Acute exacerbation of IPF (emergency): acute diffuse alveolar damage superimposed on fibrosis; presents as dyspnea worsening over less than one month with new bilateral ground-glass opacities on HRCT superimposed on a UIP pattern, not explained by heart failure or fluid overload; mortality during hospitalization is very high. Infection and pulmonary embolism must be excluded first; supportive care and often corticosteroids are used, though evidence is weak
• Pulmonary hypertension and cor pulmonale: hypoxic vasoconstriction plus destruction of the capillary bed raises PVR; signaled by a DLCO that falls out of proportion to FVC, exertional syncope, loud P2, elevated JVP, and peripheral edema
• Chronic hypoxemic respiratory failure: driven by diffusion limitation and V/Q mismatch; exertional desaturation on the 6-minute walk precedes resting hypoxemia
• Lung cancer: fibrotic, repeatedly injured epithelium is a field defect; a new nodule or mass in peripheral fibrotic lung should not be dismissed as honeycombing
• Pneumothorax (tension pneumothorax is an emergency): rupture of subpleural honeycomb cysts; sudden pleuritic pain and desaturation in a patient already at ventilatory limit
• Venous thromboembolism, increased in IPF and in immobilized patients
• Sarcoidosis-specific: hypercalcemia and nephrolithiasis from macrophage 1α-hydroxylase activity; cardiac sarcoidosis with high-grade AV block or ventricular arrhythmia (emergency); uveitis threatening vision

Treatment-related

• Nintedanib: tyrosine kinase inhibition causes diarrhea, hepatotoxicity (monitor transaminases), and — via VEGFR blockade — impaired wound healing and bleeding risk; avoid in pregnancy
• Pirfenidone: nausea, anorexia with weight loss, transaminitis, and photosensitivity rash — counsel on sun protection
• Corticosteroids: hyperglycemia, osteoporosis, adrenal suppression, and opportunistic infection; per ATS/ERS/JRS/ALAT guidance, immunosuppression is harmful in IPF (PANTHER-IPF showed excess death and hospitalization with prednisone/azathioprine/N-acetylcysteine)
• Steroid-sparing agents: azathioprine myelosuppression (worse with TPMT/NUDT15 deficiency), mycophenolate cytopenias and teratogenicity, cyclophosphamide hemorrhagic cystitis and later bladder cancer; consider Pneumocystis prophylaxis with sustained high-dose steroids plus a second agent

• "Velcro" crackles plus clubbing in a man over 60: fine end-inspiratory basilar crackles with digital clubbing and a subpleural, basilar reticular/honeycomb pattern on HRCT is IPF until proven otherwise — the single best next step is HRCT, not biopsy, since a definite UIP pattern in the right clinical setting establishes the diagnosis under ATS/ERS/JRS/ALAT criteria
• Do not give steroids for IPF: the classic distractor. Immunosuppression increased mortality in PANTHER-IPF; the answer is an antifibrotic (pirfenidone or nintedanib) plus early lung transplant referral at diagnosis, supplemental oxygen for resting hypoxemia, and pulmonary rehabilitation
• Hypersensitivity pneumonitis is upper/mid-lobe, with centrilobular ground-glass nodules, mosaic attenuation/air trapping, and BAL lymphocytosis; the highest-yield intervention is antigen avoidance — steroids only buy time
• Sarcoidosis buzzwords: bilateral hilar lymphadenopathy with non-caseating granulomas, disproportionate involvement in Black patients, hypercalcemia from macrophage 1α-hydroxylase. Löfgren syndrome (erythema nodosum, hilar adenopathy, arthralgia/fever) has an excellent prognosis and is managed with NSAIDs, not steroids. Serum ACE is neither sensitive nor specific — do not pick it as the confirmatory test
• Match the dust to the lobe: silicosis and coal worker's pneumoconiosis are upper-lobe (silica also raises TB risk, and eggshell nodal calcification is the giveaway); asbestosis is lower-lobe with pleural plaques. Note the separate rule for emphysema — alpha-1 antitrypsin deficiency is basilar, smoking-related emphysema is upper-lobe
• Drug-induced ILD: amiodarone, bleomycin, methotrexate, nitrofurantoin, and checkpoint inhibitors; stopping the drug is the first step
• PFT pattern: reduced FVC with a preserved or elevated FEV1/FVC and a reduced DLCO; DLCO falling out of proportion to FVC points to superimposed pulmonary hypertension
• Progressive pulmonary fibrosis: non-IPF fibrotic ILD that keeps worsening on immunosuppression is an indication for nintedanib per ATS/ERS/JRS/ALAT guidance