idiopathic%20pulmonary%20fibrosis
IDIOPATHIC PULMONARY FIBROSIS

Idiopathic pulmonary fibrosis is the progressive parenchymal scarring & loss of pulmonary function due to unidentifiable cause of lung injury.

It is a specific form of chronic fibrosing interstitial pneumonia with the histopathologic characteristics of usual interstitial pneumonia.

Approximately 5% of patients are asymptomatic. Common signs and symptoms are exertional dyspnea, nonproductive cough, finger clubbing and bilateral inspiratory crackles.

Diagnosis

Diagnostic Criteria for Idiopathic Pulmonary Fibrosis

  • Establishing diagnosis involves clinical, radiological, & pathological correlation
  • Includes the following:
    • Other causes of interstitial lung disease have been excluded
    • Usual interstitial pneumonia pattern confirmed with high-resolution computed tomography (HRCT) without biopsy (see HRCT criteria on Imaging section)
    • HRCT & histopathologic criteria confirms usual interstitial pneumonia pattern after surgical lung biopsy (see histopathological criteria on Screening section)

Classification

Classification of Idiopathic Interstitial Pneumonia (IIP)

  • Based on the consensus statement of the American Thoracic Society (ATS) & European Respiratory Society (ERS)
  • Major idiopathic interstitial pneumonia:
    • Idiopathic pulmonary fibrosis - most common
    • Idiopathic nonspecific interstitial pneumonia
    • Respiratory bronchiolitis-associated interstitial pneumonia
    • Desquamative interstitial pneumonia
    • Cryptogenic organizing pneumonia
    • Acute interstitial pneumonia 
  • Rare idiopathic interstitial pneumonia:
    • Idiopathic lymphoid interstitial pneumonia
    • Idiopathic pleuroparenchymal fibroelastosis 
  • Unclassifiable idiopathic interstitial pneumonia

History

  • Since symptoms of idiopathic pulmonary fibrosis are nonspecific, having a complete history is essential as it excludes other causes of interstitial lung diseases
  • A complete history should include:
    • Medications like Amiodarone, Bleomycin, Nitrofurantoin are associated with pulmonary fibrosis
    • Recreational or drug use
    • Occupational exposure (eg asbestos, silica, heavy metals, contaminated ventilation systems, moldy foliage, &/or pigeon droppings)
    • Environmental respiratory exposure
    • Human immunodeficiency (HIV) infection
    • Review of systems - presence of arthralgia, photosensitivity, arthritis, dry eyes &/or mouth, Raynaud phenomenon must be checked to ensure that other causes of interstitial lung diseases (ILD) are excluded
    • Current smoker
    • Social 
  • Patients should also be asked for the presence of obstructive sleep apnea (OSA)

Physical Examination

  • Prominent findings in patients with idiopathic pulmonary fibrosis :
    • Fine bibasilar inspiratory crackles (known as Velcro crackles)
    • Digital clubbing
    • 20-40% of patients have pulmonary hypertension at rest & is a common comorbidity
      • Loud P2 component of the 2nd heart sound, fixed split S2, holosystolic tricuspid regurgitation murmur & pedal edema are present
    • Right ventricular hypertrophy may be observed
      • Right ventricular heave is palpated at the lower left sternal border
      • Right atrial pressure is increased & causes an increase in jugular venous pressure

Laboratory Tests

  • Routine laboratory studies are nonspecific in diagnosing idiopathic pulmonary fibrosis
  • The following are some tests that excludes other interstitial lung diseases:
    • Antinuclear antibodies (ANA) or rheumatoid factor titers are not that high & are positive in about 30% of patients with idiopathic pulmonary fibrosis
      • High titers are suggestive of connective tissue diseases
    • Elevated C-reactive protein level & erythrocyte sedimentation rate (ESR)
      • May be elevated but is nondiagnostic of idiopathic pulmonary fibrosis
    • Complete blood count (CBC) may reveal polycythemia & is rare in patients with idiopathic pulmonary fibrosis
    • Chronic hypoxemia is a common finding in arterial blood gas (ABG)
  • 6-minute walk test (6MWT)
    • A marker of functional exercise capacity
    • Used as an initial & longitudinal clinical assessment for patients with idiopathic pulmonary fibrosis

Imaging

Chest Radiography

  • Typical findings are a net-like linear & curvilinear densities or peripheral reticular opacities that can be found at lung bases
  • May also reveal honeycombing or loss of lower lobe volume
  • Not a diagnostic test for patients with idiopathic pulmonary fibrosis as it lacks specificity
  • Usually, all patients who present with idiopathic pulmonary fibrosis at the time of diagnosis have an abnormal chest X-ray findings

High-Resolution Computed Tomography (HRCT) Scanning

  • Essential & more sensitive & specific
  • Reveals a patchy, peripheral, subpleural & bibasilar reticular opacities in patients with idiopathic pulmonary fibrosis
  • Criteria for usual interstitial pneumonia pattern (all 4 features should be present):
    • Subpleural, basal predominance is present
    • With reticular abnormality
    • Evidence of honeycombing with or without traction bronchiectasis
    • Absence of features listed as inconsistent with usual interstitial pneumonia pattern 
  • Possible usual interstitial pneumonia pattern (all 3 features should be present):
    • Subpleural, basal predominance is present
    • With reticular abnormality
    • Absence of features listed as inconsistent with usual interstitial pneumonia pattern 
  • Inconsistent usual interstitial pneumonia pattern (any of the 7 features should be present):
    • Upper or mid-lung predominance is present
    • Peribronchovascular predominance is present
    • With extensive ground-glass abnormality (extent greater than reticular abnormality)
    • Has profuse micronodules (bilateral, predominantly located in the upper lobes)
    • With discrete cysts (multiple, bilateral, away from areas of honeycombing)
    • Evidence of diffuse mosaic attenuation or air-tapping (bilaterally, in ≥3 lobes)
    • With consolidation in bronchopulmonary segments or lobes

Transthoracic Echocardiography

  • Used to detect pulmonary hypertension
    • Approximately 20-40% of idiopathic pulmonary fibrosis patients who are candidates for lung transplantation have pulmonary hypertension at rest 
  • Pulmonary hypertension is defined as the mean pulmonary artery pressure of >25 mmHg at rest with normal capillary wedge pressure
  • Measured by using a right-sided heart catheterization

Screening

Other Procedures

Bronchoalveolar Lavage (BAL)

  • Used to exclude other alternative diagnosis
  • Eosinophilia & lymphocytosis may be evident in bronchoalvelolar lavage fluid
  • Presence of neutrophilia in bronchoalveolar lavage fluid predicts early mortality
  • Appropriate analysis of bronchoalveolar lavage may reveal infection, malignancy, alveolar proteinosis, eosinophilic pneumonia, or occupational dusts
  • Based on the studies of bronchoalveolar lavage matrix metalloproteinase (MMP), both MMP 1 & MMP 7 are increased in patients with idiopathic pulmonary fibrosis, with MMP 7 is associated with disease severity

Bronchoscopy

  • Transbronchial biopsy &/or bronchoscopy with bronchoalveolar lavage are not required for the diagnosis of idiopathic pulmonary fibrosis
  • Ensures that alternative diagnosis are excluded

Histopathology

  • The associated histopathological lesion is usual interstitial pneumonia (UIP)
    • A heterogenous, variegated appearance with alternating areas of healthy lung, interstitial inflammation, fibrosis & honeycomb (patchwork appearance) on low magnification 
  • Specimens taken during an acute exacerbation of idiopathic pulmonary fibrosis revealed:
    • Combination of usual interstitial pneumonia with superimposed diffuse alveolar damage
    • Alveolar septa are expanded by more extensive fibroblast proliferation
    • Marked hyperplasia of type 2 pneumocytes
    • Remnants of hyaline membrane are present  
  • The usual interstitial pneumonia pattern may be associated with other diseases such as asbestosis, collagen-vascular disease, sarcoidosis, hypersensitivity pneumonitis, or toxic drug reactions (eg Amiodarone, Bleomycin, Nitrofurantoin)
  • Criteria for usual interstitial pneumonia pattern (all 4 features should be present):
    • Marked fibrosis or architectural distortion &/or honeycombing in predominantly subpleural or paraseptal distribution is evident
    • Patchy involvement of the lung parenchyma by fibrosis is present
    • Fibroblast foci is present
    • Features against a diagnosis of usual interstitial pneumonia suggesting an alternate diagnosis are absent 
  • Probable usual interstitial pneumonia pattern requires:
    • All 3 features:
      • Marked fibrosis or architectural distortion &/or honeycombing should be present
      • Either the patchy involvement or fibroplastic foci, but not both should be absent
      • The features against a diagnosis of usual interstitial pneumonia that suggests an alternate diagnosis should be absent
    • Or:
      • Only honeycombing changes 
  • Possible usual interstitial pneumonia pattern (all 3 criteria should be present):
    • Presence of patchy or diffuse involvement of lung parenchyma by fibrosis, with or without interstitial inflammation
    • Other criteria for an usual interstitial pneumonia are absent
    • The features against a diagnosis of usual interstitial pneumonia that suggests an alternate diagnosis is absent 
  • Non-UIP pattern (any of the 6 criteria may be present):
    • Hyaline membranes
    • Organizing pneumonias
    • Granulomas
    • Marked interstitial inflammatory cell infiltrate away from honeycombing
    • Predominant airway centered changes
    • Other features suggestive of an alternate diagnosis 

Surgical Lung Biopsy

  • May be done via open lung biopsy (OLB) or video-assisted thoracoscopic surgery (VATS)
    • Video-assisted thoracoscopic surgery is more preferred because it is associated with less morbidity & shorter duration of stay in the hospital 
  • May be considered in patients with possible usual interstitial pneumonia or inconsistent with usual interstitial pneumonia pattern on high-resolution computed tomography

Other Tests

Pulmonary Function Tests (PFTs)

  • A noninvasive quantitative measurement
  • The keystone in the assessment of disease progression & its severity
  • Results of pulmonary function tests in patients with idiopathic pulmonary fibrosis:
    • Presence of restrictive ventilatory defect
    • Reduced diffusion capacity for carbon monoxide
    • Decreased functional residual capacity (FRC), vital capacity (VC), total lung capacity (TLC), & forced vital capacity (FVC) & forced expiratory volume in 1 second (FEV1)
      • Prognostication relies on the serial assessment of FVC
      • The risk of mortality increases if there is a decline of >10% in FVC over 6 months
    • Increased FEV1/FVC ratio associated with hypoxemia & dyspnea in patients 60-70 years old 
  • Obstructive ventilatory defects are uncommon
    • If present, it may coexist with chronic obstructive pulmonary disease (COPD) 
  • Impaired gas exchange is demonstrated by:
    • Decreased diffusion capacity for carbon monoxide (DLCO)
    • A decrease in DLCO may precede with the development of abnormal lung volumes
    • DLCO is greatly reduced in patients with idiopathic pulmonary fibrosis
  • Strong predictors of increased mortality:
    • Progressive decline in DLCO (>15% after 6 months)
    • Desaturation of <88% during a 6-minute walk test (6MWT)
    • Failure of the heart rate to decline in 1-2 minutes post-exercise

Acute Exacerbation of Idiopathic Pulmonary Fibrosis

Diagnostic Criteria

  • Confirmed diagnosis of idiopathic pulmonary fibrosis
  • Unexplained worsening of dyspnea within a month
  • Hypoxemia
  • New alveolar abnormality in imaging studies
  • Absence of other etiologies such as infection, pulmonary embolism, pneumothorax, cardiac failure

Pathophysiology

  • Clinical similarities with acute distress syndrome:
    • Need for increased oxygen
    • Presence of bilateral ground glass opacities &/or consolidation on imaging
    • Findings of diffuse alveolar damage on histopathology 
  • Lung injuries that would develop into an acute exacerbation of idiopathic pulmonary fibrosis:
    • Microaspiration of gastric contents
    • Surgery & other procedures (eg surgical lung biopsy, lung cancer resection & bronchoscopy)
    • With decreased FVC, DLCO & 6-minute walk test (6MWT)
  • Other potential contributors include evidence of pulmonary hypertension & coronary artery disease (CAD), higher body mass index (BMI), & treatment using immunosuppressive therapy

Signs & Symptoms

  • Shortness of breath
  • Exercise intolerance
    • May develop over days to weeks but not >1 month 
  • Cough with or without production of sputum (common)
  • Fever
  • Flu-like symptoms
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