Pulmonary · PANCE / PANRE

Idiopathic Pulmonary Fibrosis (IPF)

Chronic progressive fibrosing interstitial pneumonia of unknown cause with UIP pattern.

Also known as: IPF, idiopathic pulmonary fibrosis, UIP, usual interstitial pneumonia

Overview

Specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause, occurring primarily in older adults, limited to the lungs, with the histologic and/or radiographic pattern of usual interstitial pneumonia (UIP).

Epidemiology

Incidence ~10 per 100,000; rises sharply with age (most diagnoses >60). Male predominance. Median survival from diagnosis 3-5 years without antifibrotic therapy, though highly variable.

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Risk factors

  • Age >60 years
  • Male sex
  • Cigarette smoking (most consistent risk factor)
  • Environmental/occupational exposures: metal/wood dust, stone dust, agriculture
  • Chronic microaspiration / GERD
  • Viral infections (EBV, hepatitis C — controversial associations)
  • Genetic: MUC5B promoter polymorphism (most common), surfactant gene mutations (SFTPC, SFTPA2), telomere-related genes (TERT, TERC) in familial cases

Pathophysiology

Repeated micro-injuries to alveolar epithelium in genetically susceptible individuals trigger aberrant wound healing — fibroblast/myofibroblast proliferation, excessive extracellular matrix deposition, and destruction of normal lung architecture. Honeycombing represents end-stage cystic remodeling. UIP pattern is the histopathologic hallmark.

Clinical presentation

Symptoms

  • Chronic progressive exertional dyspnea (months to years)
  • Persistent non-productive cough
  • Fatigue
  • Lack of constitutional or systemic symptoms (helps distinguish from CTD-ILD)

Signs / physical exam

  • Bibasilar, late inspiratory, fine 'Velcro' crackles (classic and persistent)
  • Digital clubbing (~25-50%)
  • Signs of pulmonary hypertension and right heart failure in advanced disease
  • Cyanosis with exertion or at rest in end-stage disease

Classic findings

Older man, smoker, with progressive dyspnea + 'Velcro' bibasilar crackles + clubbing + reticulonodular pattern on CXR — IPF until proven otherwise.

Differential diagnosis

  • Connective tissue disease-associated ILD — RA, scleroderma, polymyositis/dermatomyositis, Sjögren — ANA, RF, anti-CCP, myositis panel; younger, female predominance
  • Hypersensitivity pneumonitis (chronic/fibrotic) — Exposure history (birds, mold, hot tub), upper-lobe predominance, mosaic attenuation, BAL lymphocytosis
  • Nonspecific interstitial pneumonia (NSIP) — Younger patients, ground-glass predominant, more responsive to immunosuppression
  • Asbestosis — Asbestos exposure history (≥20 years prior), pleural plaques, basal-predominant fibrosis
  • Drug-induced fibrosis — Amiodarone, methotrexate, nitrofurantoin, bleomycin, immune checkpoint inhibitors
  • Sarcoidosis stage IV — Upper-lobe fibrosis, history of granulomatous disease
  • Combined pulmonary fibrosis and emphysema (CPFE) — Heavy smokers with upper-lobe emphysema and basal fibrosis; preserved volumes but reduced DLCO and severe PH

Diagnostic workup

Diagnostic criteria

ATS/ERS/JRS/ALAT 2018: (1) exclusion of other known causes of ILD AND (2) presence of UIP pattern on HRCT in appropriate clinical context OR (3) specific combinations of HRCT and histopathologic patterns in patients undergoing biopsy — synthesized by MDD.

Labs

  • Connective tissue disease screen: ANA, RF, anti-CCP, ENA panel, myositis panel — exclude CTD-ILD
  • Hypersensitivity pneumonitis panel (precipitins) if exposure history
  • BMP, CBC, LFTs (baseline for antifibrotic therapy)

Imaging

  • HRCT chest is central to diagnosis — UIP pattern: subpleural, basal-predominant reticulation + honeycombing ± traction bronchiectasis, with absence of inconsistent features (extensive GGO, mosaic attenuation, micronodules, consolidation, perilymphatic distribution)
  • Probable UIP, indeterminate UIP, and alternative diagnosis patterns help guide biopsy decision
  • PFTs: restrictive pattern (reduced TLC, FVC) with reduced DLCO; preserved FEV1/FVC ratio (often elevated)
  • 6-minute walk test with desaturation (prognostic)
  • Echocardiogram for pulmonary hypertension

Other studies

  • Multidisciplinary discussion (MDD) with pulmonologist, radiologist, pathologist — gold standard for diagnosis
  • Surgical lung biopsy (VATS) only if HRCT pattern is inconsistent with definite/probable UIP
  • Cryobiopsy (less invasive) — emerging alternative in experienced centers
  • Bronchoscopy with BAL primarily to exclude alternatives (infection, hypersensitivity)

Diagnostic algorithm

HRCT PatternKey Features
Definite UIPSubpleural, basal predominance; reticulation + honeycombing ± traction bronchiectasis; absence of inconsistent features
Probable UIPSubpleural, basal reticulation + traction bronchiectasis without honeycombing
IndeterminateSubpleural, basal reticulation with insufficient features for UIP, no features of alternative diagnosis
Alternative diagnosisFindings suggesting non-IPF ILD (e.g., extensive GGO, mosaic attenuation, perilymphatic nodules)
HRCT patterns in IPF (ATS/ERS 2018) — definite or probable UIP in proper clinical context allows diagnosis without biopsy.

Treatment

First-line

  • Antifibrotic therapy — slows FVC decline (does not reverse disease):
  • Pirfenidone 801 mg TID (CAPACITY, ASCEND trials) — side effects: GI, photosensitivity, hepatotoxicity
  • Nintedanib 150 mg BID (INPULSIS trials) — multitargeted tyrosine kinase inhibitor; side effects: diarrhea, hepatotoxicity
  • Smoking cessation, pulmonary rehabilitation
  • Supplemental oxygen for resting or exertional hypoxemia (SpO2 ≤88%)
  • Treat comorbidities aggressively: GERD (PPI), OSA (CPAP), PH, deconditioning
  • Vaccinations: annual influenza, pneumococcal, COVID-19, RSV (age ≥60), Tdap
  • Avoid systemic glucocorticoids and immunosuppressants (PANTHER-IPF showed harm from prednisone + azathioprine + N-acetylcysteine combination)

Second-line / adjunct

  • Lung transplantation — early referral when FVC <80% predicted or DLCO <40% predicted; only intervention proven to improve survival
  • Palliative care for symptom control (dyspnea, cough, fatigue) and advance care planning
  • Acute exacerbations (rapid worsening dyspnea, new GGO superimposed on UIP, no infection): high-dose corticosteroids commonly used but evidence is weak; mortality >50%
  • Management of pulmonary hypertension associated with IPF: PAH-targeted vasodilators generally not effective; inhaled treprostinil approved for PH-ILD per INCREASE

Complications

  • Acute exacerbations of IPF (rapid decline, high mortality)
  • Pulmonary hypertension, cor pulmonale
  • Lung cancer (4-5× increased risk)
  • Pulmonary infections (bacterial, viral)
  • Pneumothorax
  • Anxiety, depression, refractory dyspnea, cough

PANCE pearls

  • PANTHER-IPF demonstrated HARM from prednisone + azathioprine + N-acetylcysteine combination — IPF is no longer treated with immunosuppression.
  • Antifibrotics (pirfenidone, nintedanib) slow but do not reverse FVC decline — start early and continue indefinitely.
  • Multidisciplinary discussion (pulm + radiology + pathology) is the diagnostic gold standard — avoids unnecessary biopsy.
  • Definite UIP on HRCT in an appropriate clinical context obviates the need for surgical lung biopsy.
  • Refer for lung transplant evaluation early (FVC <80% or DLCO <40%) — IPF is the second most common indication for lung transplant in the US.

References

  • ATS/ERS 2022 — Idiopathic Pulmonary Fibrosis (an Update) and Progressive Pulmonary Fibrosis in Adults: An Official Clinical Practice Guideline (Raghu et al., Am J Respir Crit Care Med 2022)
  • ASCEND — A Phase 3 Trial of Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis (King et al., NEJM 2014)
  • INPULSIS — Efficacy and Safety of Nintedanib in Idiopathic Pulmonary Fibrosis (Richeldi et al., NEJM 2014)
  • PANTHER-IPF — Prednisone, Azathioprine, and N-Acetylcysteine for Pulmonary Fibrosis (Raghu et al., NEJM 2012)

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