Ganesh Raghu, Harold R. Collard, Jim J. Egan, Fernando J. Martinez, Juergen Behr, Kevin K. Brown et al on behalf of the ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis Am J Respir Crit Care Med Vol 183, 2011

specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause occurring primarily in older adults limited to the lungs associated with the histopathologic and/or radiologic pattern of UIP the exclusion of other forms of interstitial pneumonia including other idiopathic interstitial pneumonias and ILD associated with environmental exposure, medication, or systemic disease

 HRCT Features essential component of the diagnostic pathway in IPF UIP reticular opacities, often associated with traction bronchiectasis Honeycombing : common, critical for making a definite diagnosis as clustered cystic airspaces, usually subpleural Ground glass opacities: common, but usually less extensive than the reticulation basal and peripheral, though often patchy

The presence of coexistent pleural abnormalities (e.g., pleural plaques, calcifications, significant pleural effusion) micronodules, air trapping, nonhoneycomb cysts, extensive ground glass opacities, consolidation, or a peribronchovascular-predominant distribution  alternative diagnosis the positive predictive value of a HRCT diagnosis of UIP : 90 ~ 100% honeycombing x, otherwise meet criteria for UIP  possible UIP  surgical lung biopsy is necessary to make a definitive diagnosis UIP pattern x  surgical lung biopsy

Figure 1. High-resolution computed tomography (HRCT) images demonstrating usual interstitial pneumonia (UIP) pattern and possible UIP pattern.

Figure 3. Diagnostic algorithm for idiopathic pulmonary fibrosis (IPF).

 Histopathology Features The histopathologic hallmark and chief diagnostic criterion : areas of fibrosis with scarring and honeycomb change alternate with areas of less affected or normal parenchyma  heterogeneous appearance often affect the subpleural and paraseptal parenchyma most severely patchy interstitial infiltrate of lymphocytes and plasma cells associated with hyperplasia of type 2 pneumocytes and bronchiolar epithelium

The fibrotic zones - composed mainly of dense collagen - scattered convex subepithelial foci of proliferating fibroblasts and myofibroblasts (so-called fibroblast foci) Areas of honeycomb change - composed of cystic fibrotic airspaces - frequently lined by bronchiolar epithelium and filled with mucus and inflammatory cells The major differential diagnostic considerations -UIP in other clinical settings such as connective tissue diseases, chronic hypersensitivity pneumonitis (extrinsic allergic alveolitis), pneumoconioses (especially asbestosis)

Figure 2. Surgical lung biopsy specimens demonstrating UIP pattern.

Figure 3. Diagnostic algorithm for idiopathic pulmonary fibrosis (IPF).

Bronchoalveolar Lavage Cellular Analysis useful in the diagnosis of certain forms of ILD lymphocytosis> 40%  occult hypersensitivity pneumonitis Transbronchial Lung Biopsy useful in the evaluation of selected conditions (e.g., granulomatous disorders such as sarcoidosis) the sensitivity and specificity  unknown how many and where  unknown Serological Testing for Connective Tissues Disease UIP pattern : described as the sole clinical manifestation of CTD even in the absence of signs or symptoms of connective tissue disease

1. Exclusion of other known causes of ILD (e.g., domestic and occupational environmental exposures, connective tissue disease, and drug toxicity) 2. The presence of a UIP pattern on HRCT in patients not subjected to surgical lung biopsy 3. Specific combinations of HRCT and surgical lung biopsy pattern in patients subjected to surgical lung biopsy

1. Exclusion of other known causes of interstitial lung disease such as drug toxi cities, environmental exposures, and collagen vascular diseases 2. Abnormal PFT restriction (VC↓, FEV 1 /FVC ratio↑) and/or impaired gas exchange (↑AaPO 2 with rest or exercise or DL CO ↓) 3. Abnormalities on conventional chest radiographs or HRCT ATS/ERS. Am J Respir Crit Care Med. 2000;161:

All major criteria and at least 3 minor criteria must be present to increase the likelihood of an IPF diagnosis

1. Strong, No a. Corticosteroid monotherapy (+ooo) b. Colchicine (+ooo) to inhibit fibroblast proliferation and collagen synthesis in vitro c. Cyclosporine A (+ooo) d. Combined corticosteroid and immune-modulator therapy (++oo)

e. Interferon-γ1b (++++) agent with antifibrotic and immunomodulatory properties f. Bosentan (+++o) Endothelin-1 (ET-1) powerful vasoconstrictor and growth factor involved in the pathogenesis of pulmonary HTN and potentially of IPF dual endothelin receptor A and B antagonist, in a phase II randomized controlled trial g. Etanercept (+++o) recombinant soluble human tumor necrosis factor (TNF) receptor that binds to TNF and neutralizes its activity in vitro implicated in the pathogenesis of pulmonary fibrosis

2. Weak, No a. Combined acetylcysteine and azathioprine and prednisone (++oo) b. Acetylcysteine monotherapy (++oo) precursor to the antioxidant glutathione reduced in the lungs of patients with IPF c. Anticoagulation (+ooo) d. Pirfenidone (++oo) pyridone compound with pleiotropic, anti-inflammatory, antifibrotic, and antioxidant properties, with antagonism of TGF-β1 effects Significant gastrointestinal adverse events, liver laboratory abnormalities, photosensitivity, and rash

Sildenafil oral phosphodiesterase 5 inhibitor safely reduce pulmonary vascular pressures in patients with IPF Imatinib tyrosine kinase inhibitor with activity against platelet-derived growth factor receptors

3. Strong, Yes long-term oxygen therapy in patients with IPF and clinically significant resting hypoxemia (+ooo) lung transplantation in appropriate patients with IPF (+ooo) 4. Weak, No mechanical ventilation in patients with respiratory failure (++oo) 6. Weak, Yes pulmonary rehabilitation in patients with IPF (++oo)

7. Weak, Yes corticosteroids in patients with acute exacerbation of IPF (+ooo) 8. Weak, No the treatment of pulmonary hypertension associated with IPF (+ooo) 9. Weak, Yes the treatment of asymptomatic gastroesophageal reflux in patients with IPF (+ooo)

Figure 5. Schematic pathway for clinical management of patients with IPF.