idiopathic pulmonary fibrosis (IPF); usual interstitial pneumonitis (UIP)

Introduction

IPF is a highly variable, but progressive disease of unknown etiology.

Etiology

• pattern may be seen with:
  • connective tissue disease
    • rheumatoid arthritis
    • systemic sclerosis
    • Sjogren's syndrome
    • idiopathic inflammatory myopathy
  • pneumoconiosis (occupational lung disease)
    • asbestosis
    • coal workers pneumonoconosis
    • silicosis
    • beryliosis
    • organic dust exposure (carpenters)
  • smoking
  • hypersensitivity pneumonitis
    • molds
    • avian antigents
    • Mycobacteria
    • isocyanates
  • drug-induced interstitial lung disease
    • amiodarone
    • methotrexate
    • nitrofurantoin
    • chemotherapy
• idiopathic

Epidemiology

• onset most commonly between age 50-70 years
• most common interstitial lung disease in older adults

Pathology

• usual interstitial pneumonia (UIP)
  • varying degrees of patchy interstitial fibrosis & alveolitis interspersed with normal pulmonary parenchyma
  • distortion of pulmonary architecture with cystic spaces (honeycomb lung) in advanced disease
• organizing pneumonia has been reported

Genetics

• a subset of patients may have a familial form of IPF
• a polymorphism in the SFTPA1 gene influences susceptibility to idiopathic pulmonary fibrosis in non-smokers
• defects in TERT are associated with susceptibility to idiopathic pulmonary fibrosis

Clinical manifestations

• insidious onset of exertional dyspnea
• onset over 3-15 months
• relentlessly progressive disorder
• episodes of acute exacerbation may occur
• breathlessness (dyspnea) & cough (non-productive, dry)
• chest auscultation
  • bibasilar, end-expiratory (Velcro) crackles
  • bibasilar, fine inspiratory crepitant rales
  • bibasilar, inspiratory crackles
• clubbing of digits 40-80%
• no fever
• cor pulmonale (late manifestation)

Laboratory

• arterial blood gas
  • hypoxemia at rest (variable)
  • chronic respiratory alkalosis
  • respiratory acidosis in more severe cases
• serology
  • serology generally negative or low-titer
  • antinuclear antibody (ANA) positive in 35%
  • rheumatoid factor (RF) positive in 30%
  • anti-neutrophil cytoplasmic antibody (ANCA)
• serum angiotensin-converting enzyme (ACE) low
• serum protein electrophoresis (SPE)
  • polyclonal gammopathy in > 50%

Diagnostic procedures

• pulmonary function tests
  • restrictive patterns
    • decreased total lung capacity
    • FEV1/FVC >= 0.75
  • decreased DLCO
  • pulse oximetry: decreased oxygen saturation during exercise
  • increased alveolar-arterial oxygen gradient worsened or unmasked by exertion
• fiberoptic bronchoscopy with bronchoalveolar lavage if acutely worsening hypoxemia in patients with diagnosis of idiopathic pulmonary fibrosis
• fiberoptic bronchoscopy lung biopsy vs surgical lung biopsy to rule out other etiologies* (initial diagnosis)

* classic high-resolution CT pattern in conjunction with multidisciplinary team case review may preclude need for diagnostic lung biopsy

Radiology

• chest radiograph
  • diffuse bilateral peripheral reticular infiltrates (generally)
  • predominantly lower lobe infiltrates
    • honeycomb changes at the lung bases
  • normal (occasionally)
• computed tomography (high resolution) of thorax
  • septal line thickening with traction bronchiectasis
  • subpleural honeycombing (cystic changes)
  • interstitial process in basal areas
  • predominantly peripheral, subpleural & basilar reticular opacities
  • mild mediastinal & hilar adenopathy
  • no ground glass opacities or nodules
    • ground glass opacities typical of interstitial pneumonia
      • may appear during an acute exacerbation
  • obtain prior to biopsy to delineate distribution of disease & direct selection of site for biopsy*

* classic high-resolution CT pattern in conjunction with multidisciplinary team case review may preclude need for lung biopsy

Complications

• pulmonary hypertension (30-40%)
• acute exacerbations associated with high mortality
• acute respiratory failure
  • mechanical ventilation not recommended

Differential diagnosis

• connective tissue disease
• pulmonary-renal syndrome
  • Wegener's granulomatosis
  • Goodpasture's syndrome
• hypersensitivity pneumonitis
• drug-induced interstitial lung disease
• sarcoidosis
• chronic eosinophilic pneumonia
• Langerhan's cell granulomatosis
• bronchiolitis obliterans
• respiratory bronchiolitis interstitial lung disease
• acute interstitial pneumonia
• pulmonary alveolar proteinosis
• pulmonary emphysema (clubbing is rare)
  • obstructive airway disease

Management

• multidisciplinary team case review
  • classic high-resolution CT pattern in conjunction with multidisciplinary team case review may preclude need for diagnostic lung biopsy
• supportive
  • optimal physical fitness
    • pulmonary rehabilitation
  • oxygen as needed, SaO2 <= 88 mm Hg at rest or with exercise
• pirfenidone & nintedanib are the preferred agents
  • neither useful for acute exacerbation
• poor response to corticosteroids & other immunosuppressive agents
  • prednisone
    • 1.0-1.5 mg/kg PO QD early in the course of disease
    • 0.5-1.0 mg/kg PO QD 3-6 months if favorable initial response
    • 0.25 mg/kg PO QD for 6 months
    • taper to minimum dose that maintains clinical stability after 1 year
    • 50% of patients show subjective improvement
    • 25% show objective improvement
    • patients with organizing pneumonia may be more likely to respond to glucocorticoids
  • cyclophosphamide
    • 1-2 mg/kg/day
    • max dose 200 mg/day
    • adjust dose to keep WBC > 3000/mm3
  • azathiaprine plus prednisone
    • azathiaprine
      • 3 mg/kg/day
      • max dose 200 mg/day
    • prednisone (low dose)
  • combined use of corticosteroid + cyclophosphamide or azathioprine for young patients
• anti-fibrotic agents
  • colchicine 0.6 mg QD or BID
    • may be used in connection with prednisone &/or azathioprine
    • supresses release of fibroblast growth factors, fibronectin & alveolar macrophage-derived growth factor
    • inhibits fibroblast proliferation & total collagen synthesis
  • nintedanib (Ofev) & pirfenidone (Esbriet) FDA-approved
    • both slow progression of disease on pulmonary function tests
    • neither improves perceived quality of life
    • neither useful for acute exacerbation
  • recombinant human pentraxin 2 (presumptively anti-fibrotic) may slow decline in lung function over 28 weeks
• antineoplastic agents:
  • nintedanib may attenuate lung-function decline & acute exacerbations
    • adding sildenafil to nintedanib does not improve quality of life or reduce 24-week mortality
    • nintedanib + pirfenidone may attenuate disease progression
      • neither useful for acute exacerbation
• N-acetylcysteine 600 mg TID may slow progression
  • of no benefit
  • combination of prednisone, azathioprine & N-acetylcysteine not recommended
• not recommended
  • interferon gamma 1b subcutaneously of no benefit
  • trimethoprim-sulfamethoxazole of no benefit
  • imatinib, ambrisentan sildenafil, bosentan, macitentan
  • warfarin
  • mechanical ventilation if lung transplantation is not an option
    • mechanical ventilation not recommended (MKSAP19)
    • extracorporeal membrane oxygenation a better option than mechanical ventilation as a bridge for lung transplantation
• symptomatic
  • cough may respond to thalidomide
  • palliative treatment for acute respiratory failure
    • opiates to relieve dyspnea
  • multidisciplinary collaborative model to address the palliative care needs result in improved end-of-life care & decreased hospital deaths
• unilateral lung transplantation
  • indications:
    • young individuals
    • end-stage disease
    • free of infection
  • 5 year survival is 50%
  • only intervention that improves survival
  • older patient (72 years) with hypertension & type-2 diabetes not a candidate
• prognosis:
  • median survival is 3-6 years
  • poor outcomes with mechanical ventilation
  • mortality in patients hospitalized with acute respiratory failure 86-97%
  • good prognostic indicators
    • young age
    • less severe disease on presentation
      • breathlessness
      • infiltrates on chest radiographs
    • predominantly cellular versus fibrotic histology
    • initial response to glucocorticoids
  • no curative therapy
  • spontaneous remissions do NOT occur
  • acute deterioration occurs with 50% of deaths

More general terms

• pulmonary fibrosis

Patient information

idiopathic pulmonary fibrosis patient information

Database

• OMIM: https://mirror.omim.org/entry/178500