A multidisciplinary approach is an absolute requirement for the definitive identification of IPF ⁽⁹⁾. Because IPF's clinical and histopathologic features are found in a number of other disease states, accurate diagnosis is impossible without careful analysis of clinical and radiologic findings, serologic data, and lung biopsy specimens.

Patients diagnosed with IPF generally present with dyspnea and a dry cough. Chest x-rays and high-resolution computed tomography (HRCT) scans are abnormal, and a dry, "Velcro-like" crackling can be heard upon auscultation. Weight loss and fatigue may also occur over time. In late-stage IPF, clubbing may be observed.

An IPF workup usually requires:

• A complete patient history and thorough physical exam (including laboratory and serologic tests)
• Assessment of pulmonary function by spirometry, lung volumes, measurement of carbon monoxide diffusing capacity, and pulse oximetry at rest and exercise. If oxygen saturation is less than 89% at rest or exercise, an arterial blood gas test should be conducted to determine whether the patient needs supplemental oxygen.
• Chest x-ray and HRCT
• Lung biopsy. A surgical lung biopsy—open thoracotomy or, preferably, video—assisted thoracoscopy surgery (VATS)-should be conducted if not contraindicated, as surgical biopsies provide the best tissue samples for diagnosis. VATS is the preferred technique because it is associated with less morbidity, less prolonged chest tube drainage, and a reduced length of hospital stay vs. open-lung biopsy ⁽¹⁾. Bronchoalveolar lavage (BAL) should also be performed for cell count and flow cytometry.

In the absence of a definitive lung biopsy, the presence of all four major criteria and three minor criteria, as set forth in the current guidelines, increases the likelihood of a correct diagnosis of IPF. However, the guidelines strongly emphasize the need for a lung biopsy, because this procedure is the only way to obtain definitive evidence of UIP—the pathological hallmark essential to the diagnosis of IPF.

For the first 30 years of its use, the term IPF was applied liberally to several idiopathic interstitial pneumonias (IIPs). Today, however, IPF is recognized as a clinical syndrome with the distinct histopathology of usual interstitial pneumonia (UIP). UIP is a specific subset of the IIPs, characterized by a heterogeneous, predominantly subpleural distribution of involvement. Alternating areas of normal tissue, interstitial inflammation, fibrosis, and "honeycombing" (thickened collagenous septa surrounding airspaces lined by bronchial epithelium) are present. UIP is distinguished from other IIPs by the presence of fibroblastic foci at the junction of fibrotic and normal lung, subpleural "honeycomb" changes, and mild interstitial inflammation ⁽⁹⁾.Other IIPs include ⁽¹⁰⁾:

• Nonspecific interstitial pneumonia/fibrosis (NSIP/F)
• Desquamative interstitial pneumonia/respiratory bronchiolitis-associated interstitial lung disease (DIP/RBILD)
• Acute interstitial pneumonia (AIP)

IPF lung tissue showing microscopic honeycombing

IPF lung tissue showing peripheral accentuation of fibrosis with central sparing

These photomicrographs show areas of normal lung tissue with transition to the patchy interstitial inflammation, fibrosis, and "honeycombing" that characterize the temporal heterogeneity of UIP.

Courtesy of Kevin O. Leslie, MD

Differential Diagnoses Related to IPF

• Systemic/rheumatic abnormalities
  • Progressive systemic sclerosis (PSS)
  • Systemic lupus erythematosus (SLE)
  • Sjögren's syndrome (SS)
  • Ankylosing spondylitis (AS)
  • Rheumatoid arthritis (RA)
  • Mixed connective tissue disease (MCTD)
  • Polydermatomyositis
  • Chronic aspiration pneumonia
• Drug/radiation-induced
  • Antibiotics
  • Cardiovascular drugs
  • Chemotherapeutic agents
  • Radiation
• Malignancies
  • Lymphoma
  • Lymphangitic carcinoma
• Sarcoidosis
• Idiopathic interstitial pneumonias (IIPs)
  • Idiopathic pulmonary fibrosis (IPF)
  • Nonspecific interstitial pneumonia (NSIP)
  • Desquamative interstitial pneumonia (DIP)
  • Respiratory bronchiolitis-associated interstitial lung disease (RBILD)
  • Acute interstitial pneumonia (AIP)
• Occupational injuries
  • Inorganic fibrogenic disorders
  • Inorganic nonfibrogenic disorders
• Bronchiolitis obliterans organizing pneumonia (BOOP)
• Lymphangioleiomyomatosis (LAM)
• Eosinophilic granuloma (EG)
• Hypersensitivity pneumonitis
  • Organic dust
  • Bacteria
  • Animal protein
  • Fungi
• Lymphocytic interstitial pneumonitis (LIP)
  • Sjögren's syndrome (SS)
  • Lymphoma (low-grade)
  • HIV infection
• Giant cell interstitial pneumonitis (GIP)
  • Hard metal pneumoconiosis