Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic, interstitial pneumonia. The histological and/or chest HRCT characteristic manifestations are usual interstitial pneumonia (UIP). The etiology is unclear，and it is more common in older adults.
Pathology
Usual interstitial pneumonia (UIP) is the characteristic pathological change of idiopathic pulmonary fibrosis (IPF). The histological feature of UIP is dense fibrosis and patchy distribution, mainly involving the subpleural area or interlobular septa. In low-power microscopy, the lesion has different phases, and is manifested by fibrotic lesions adjacent to normal lung tissue, and the formation of dense fibrous scar areas with scattered focal fibroblasts.
Etiology and pathogenesis
The etiology of IPF is still unclear, but it is believed that genetic susceptibility, aging, cigarette smoking, environmental exposure, pathogenic microorganisms, and chronic inhalation can increase the risk.
The pathogenesis of IPF is not yet fully understood. Currently, it is believed that IPF originates from abnormal repair after repeated minor injuries to the alveolar epithelium. The main mechanisms include telomerase gene mutations and shortened telomere leading to accelerated aging; alveolar epithelial injury and abnormal activation, reduced autophagy of cells, and production of pro-fibrotic factors such as transforming growth factor β (TGF-β) and platelet-derived growth factor (PDGF), forming a local pro-fibrotic microenvironment and interfering with epithelial regeneration; transformation of activated and proliferated fibroblasts to myofibroblasts, resulting in excessive extracellular matrix deposition, thereby leading to the formation of fibrous scars and honeycomb cysts, destruction of lung structure, and dysfunction. The transformation of lung macrophages from type M1 to type M2, variations in MUC5B and TOLLIP genes, microecological changes, and responses to microorganisms play an important role in the formation of pulmonary fibrosis.
Clinical manifestations
The disease usually occurs in adults over age 50, with insidious onset, and is mainly manifested by exertional dyspnea and progressive exacerbation, often accompanied by dry cough. Systemic symptoms are not obvious, and may be malaise, fatigue, and emaciation, but fever is less common. 75% of patients have a history of cigarette smoking. About half of patients have clubbed fingers. In 90% of patients, Velcro crackles can be heard at the end of inspiration at the basal lungs. In the late stage, cyanosis, pulmonary hypertension, and right heart failure may occur.
Auxiliary examination
Chest x-ray usually shows obvious reticular or reticulonodular hazy opacities in the peripheral and basal lungs and subpleural area, accompanied by honeycomb changes and decreased lung volume in the lower lobe.
Figure 1 IPF on x-ray
Chest x-ray shows diffuse reticular opacities on both lungs, particularly under the pleura and at the base.
Chest HRCT can show the characteristic changes of UIP. The typical UIP manifestations on HRCT are reticular and honeycomb changes with or without traction bronchiectasis, mainly subpleural and basal lesions, and the concordance rate between HRCT and pathological diagnosis of UIP greater than 90%. Conclusive UIP is manifested by reticular changes with traction bronchiectasis, absence of honeycomb changes, mainly subpleural and basal lesions, and the concordance rate between HRCT and pathological diagnosis of UIP up to 70% - 89%. Therefore, HRCT has become an important method for diagnosis of IPF, and can replace surgical lung biopsy. If there are not characteristic distributions and manifestations of UIP, the disease can be inconclusive UIP or non-UIP, and biopsy and pathological diagnosis are required.
Figure 2 IPF on CT
Chest HRCT shows patchy reticular hazy opacities, mainly under the pleura in the outer zone of both lungs, accompanied by honeycomb changes.
Pulmonary function is mainly manifested by restrictive ventilation dysfunction, and reduced diffusion capacity, with hypoxemia or type 1 respiratory failure. In the early stage, resting pulmonary function can be normal or nearly normal, but cardiopulmonary exercise test shows increased P(A-a)O2 and decreased oxygen partial pressure.
Serum Krebs von den Lungen-6 (KL-6) is increased; ESR, antinuclear antibodies, and rheumatoid factor can be slightly abnormal, but there is no specificity. Connective tissue disease-related autoantibody examination is helpful in the identification of IPF.
BALF/TBLB BALF cell analysis often shows an increase in neutrophils and/or eosinophils. TBLB has no diagnostic significance for IPF. With the increased application of TBLC, it is currently believed that surgical lung biopsy (SLB) can be replaced by TBLC.
In patients with inconclusive UIP or non-UIP changes on HRCT, unclear diagnosis, and no contraindications to surgery, surgical lung biopsy should be considered. The histopathological type of IPF is UIP, and the pathological diagnostic criteria for UIP are dense fibrosis with lung structure destruction such as destructive scar tissue and/or honeycomb, mainly subpleural and/or paraseptal fibrosis, patchy parenchymal fibrosis, and focal fibroblasts.
Diagnosis
The diagnostic criteria of IPF includes:
- Interstitial lung disease (ILD), with exclusion of other causes such as environment, drugs, and connective tissue disease (CTD)
- HRCT showing UIP or conclusive UIP
- UIP diagnosed by HRCT, pathological manifestations of SLB/TBLC, and multidisciplinary discussions
Acute exacerbation of IPF (AEIPF) is new diffuse alveolar damage in IPF patients, leading to acute or significant exacerbation of dyspnea.
The diagnostic criteria of AEIPF includes:
- Past or current diagnosis of IPF
- Significant exacerbation of dyspnea within 1 month
- CT showing new bilateral ground-glass opacities with or without consolidation on the background of UIP
- Lesions not fully explained by heart failure or fluid overload
Differential diagnosis
The diagnosis of IPF requires the exclusion of ILD resulting from other causes. UIP is the gold standard for diagnosis of IPF, but UIP can also be seen in fibrotic hypersensitivity pneumonitis, asbestosis, and connective tissue disease-related interstitial lung disease (CTD-ILD). Hypersensitivity pneumonitis often has a history of environmental antigen exposure, and BAL cell analysis shows an increased lymphocyte ratio. Asbestosis, silicosis, or other occupational pneumoconiosis often have a history of exposure to asbestos, silica, or other dusts. CTD-ILD often has rash, arthritis, multisystem involvement, and positive autoantibodies.
The differentiation between IPF and other IIPs is as follows.
Table 1 Comparation of clinical presentation, imaging, pathology, and prognosis in IPF and other IIPs
IPF, idiopathic pulmonary fibrosis; NSIP, nonspecific interstitial pneumonia; COP, cryptogenic organizing pneumonia; AIP, acute interstitial pneumonia; RB-ILD, respiratory bronchiolitis-interstitial lung disease; DIP, desquamative interstitial pneumonia; LIP, lymphoid interstitial pneumonia; UIP, usual interstitial pneumonia; DAD, diffuse alveolar damage; OP, organizing pneumonia
Treatment
IPF cannot be cured, and the goal of treatment is to delay disease progression, improve quality of life, and prolong survival, including anti-fibrotic treatment, non-drug treatment, treatment of complications, palliative treatment, disease monitoring, patient education, and self-management.
Evidence-based medicine shows that pirfenidone and nintedanib can slow down the decline of IPF lung function. Pirfenidone is a pleiotropic pyridine compound with anti-inflammatory, anti-fibrotic, and antioxidant properties. Nintedanib is a multi-target tyrosine kinase inhibitor that can inhibit platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor (VEGFR), and fibroblast growth factor receptor (FGFR). Acetylcysteine is an expectorant, has antioxidant and anti-fibrotic effects at high dose (1800 mg/d), and can be used in some IPF patients with TOLLIP gene.
IPF patients should undergo pulmonary rehabilitation training. Patients with significant hypoxemia (PaO2 < 55mmHg or SpO2 ＜ 88%) at rest should also receive long-term oxygen therapy, but mechanical ventilation is generally not recommended for the treatment of respiratory failure caused by IPF.
Lung transplantation is currently the most effective treatment for IPF, and suitable patients should be recommended for lung transplantation.
Gastroesophageal reflux and other complications should be properly treated, and inhaled sildenafil and treprostinil can be used for pulmonary hypertension in IPF patients.
Symptomatic treatment alleviates the pain caused by cough, dyspnea, and anxiety in patients and improves the quality of life.
Acute exacerbation of IPF is severe and has a high mortality, high-dose hormone therapy is still recommended clinically, although there is a lack of randomized controlled studies. Oxygen therapy, treatment of concurrent pulmonary infections, and symptomatic supportive treatment are the main treatment for patients with acute exacerbation of IPF. Mechanical ventilation is generally not recommended for the treatment of respiratory failure caused by IPF, but non-invasive mechanical ventilation can be used if needed.
Patient education and self-management should be strengthened. Smoking cessation and prevention of influenza and pneumonia should be conducted.
Prognosis
The median survival after IPF diagnosis is 2 - 3 years, but the natural course and outcome of IPF vary greatly in individuals. Most patients present a slow, gradual, and predictable decline in lung function, few patients have recurrent acute exacerbation, and very few patients have rapid progressive development. Factors affecting the prognosis of IPF patients include dyspnea, decline in lung function, fibrosis and honeycomb changes in HRCT, and 6-minute walk test (6MWT). DLCO < 40% predicted value at baseline and SpO2 < 88% during 6MWT, and a decrease of more than 10% in the absolute value of FVC or a decrease of more than 15% in the absolute value of DLCO within 6 - 12 months are all reliable indicators for predicting the risk of death.