Acute exacerbation of idiopathic pulmonary fibrosis (IPF) is an acute, clinically significant respiratory deterioration characterized by evidence of new widespread alveolar abnormality. Generally, it is fatal, not unusual complication occurred in advanced patients, there are no proven effective treatment despite current clinical practice such as oxygen therapy and high dose steroid therapy. 1) Definition of acute exacerbation of IPF Previous perspectives on the natural course of patients with idiopathic pulmonary fibrosis (IPF) were the patient died due to constant decline of lung function, lead to respiratory failure. However, according to the results of recent studies, natural course of IPF is not constant and variable1. Some patients experienced acute worsening while a gradual decline of pulmonary function, which are caused by infection, heart failure, pulmonary embolism, and pneumothorax. However, there are cases where the cause is unknown despite of precise examination2. Acute exacerbation is defined as acute and severe respiratory deterioration associated with new bilateral lung infiltration in IPF patients. Acute exacerbation can occur in patients with nonspecific interstitial pneumonia (NSIP), hypersensitivity pneumonitis, and connective tissue disease related interstitial pneumonia3. 2) Clinical manifestations of acute exacerbation The main symptom is the deterioration of dyspnea within one month. In some patients, fever, cough, increased sputum, elevated C-reactive protein elevation, hypoxemia, and neutrophilia in bronchoalveolar lavage fluid can be seen4. Diffuse bilateral pulmonary infiltration is shown at chest radiography, diffuse alveolar damage, multiple fibroblastic foci or organizing pneumonia can be seen at lung biopsy specimen. 3) Clinical impact of acute exacerbation Acute exacerbation has a fatal impact on the prognosis of the patient. The median survival time after acute exacerbation was 22 days to 4.2 months, and the hospital mortality rate was reported as 27-96%2. Acute exacerbation also affects prognosis after diagnosis, IPF patients who experienced acute exacerbation (median survival time 15.5 months, 5-years survival 18.4%) have worse outcome than others (median survival time 60.6 months, 5-years survival 50.0%)5. 4) Incidence of acute exacerbation The annual incidence of acute exacerbation is known as approximately 5 to 10%, but variable in many studies (18 to 61%)1,2. These results come from severity of the patient, definition of acute exacerbation, and difference in study design. Recently, a study on domestic population showed that the annual incidence rate was 14.2% and the 3-years incidence was 20.7%. 5) Risk factors of acute exacerbation Although the risk factors for acute exacerbation are not well known, several studies have shown that pulmonary function (forced vital capacity, diffusion capacity, total lung capacity), the severity of dyspnea (MMRC ≥ 2), the fibrosis extent on chest CT, forced vital capacity decline during six months are associated with acute exacerbation1,5- 7. It is believed that the more and faster disease progression might induce acute exacerbation. Also, bronchoscopy, bronchoalveolar lavage, thoracoscopic lung biopsy, pulmonary resection of lung cancer could develop acute exacerbation in patients with IPF2,5. 6) Etiologies of acute exacerbation The cause of acute exacerbations is not well known, but some studies have suggested possibility of deterioration of underlying disease characterized by acute lung injury8,9. Also, viral infection, aspiration and air pollution might contribute developing acute exacerbation in some patients10-12. Recent studies in domestic patients have shown that exposure to ozone (O3, HR 1.42-1.51) or nitrogen dioxide (NO2, HR 1.20-1.41) increases the risk of acute exacerbations11. 7) Diagnostic criteria of acute exacerbation According to international guidelines for the acute exacerbation of IPF in 2007, acute exacerbation was defined as 1) deterioriation of dyspnea within 30 days, 2) new bilateral pulmonary infiltration on chest HRCT, 3) excluding known causes of acute lung injury (i.e. infection, heart failure, and pulmonary embolism) even with detailed examinations such as bronchial aspiration or bronchoalveolar lavage analysis. If acute exacerbation is suspected, but all of the above conditions are not met, these conditions are defined as suspected acute exacerbation2. Revised diagnostic criteria of acute exacerbation was published in 201612. The revised definition is an acute, severe respiratory deterioration with new bilateral pulmonary infiltration 1) Previous or concurrent diagnosis of IPF, 2) Development or acute worsening of dyspnea typically less than 1 month duration, 3) Chest computed tomography with new bilateral ground-glass opacity and/or consolidation on a background pattern consistent with usual interstitial pneumonia pattern, 4) Deterioration not fully explained by heart failure or fluid overload. Like previously, events that are clinically considered acute exacerbation but fail to meet all four diagnostic criteria are termed as suspected acute exacerbations. In previous diagnostic criteria, acute exacerbation was diagnosed when the cause of acute lung injury such as infection or aspiration was excluded (idiopathic). However, in revised edition, bilateral pulmonary infiltration except pulmonary edema was classified as acute exacerbation regardless of etiology. Acute exacerbations are further categorized as triggered acute exacerbation (e.g., infection, aspiration, surgery, drug) or idiopathic acute exacerbation (no triggered identified, figure 1). In addition, although the period of occurrence was limited to [the development or deterioration of dyspnea within one month] in previous edition, revised criteria changed time interval from one moth to [typically less than 1 month] which make including cases that are suspected to be acute exacerbation but not previously classified owing to a period problem. 8) Prevention and treatment of acute exacerbation To date, the treatment of acute exacerbation has been largely lacking in evidence, only based on case reports or retrospective cohort studies. In the international recommendation for diagnosis and treatment of IPF published in 2011, the basis of acute exacerbation treatment is supportive treatment for acute lung injury. Although there is insufficient evidence for drug treatment, it is recommended to give priority to high dose steroid therapy1, cyclosporin A or warfarin, but afterwards warfarin has been shown to increase the mortality of patients with IPF13. Although there are not listed in the recommendation, in some reports, immunosuppresant such as cyclophosphamide or tacrolimus, and polymyxin B immobilized fiber column (PMX) hemoperfusion, recombinant human thrombomodulin and autoantibody reduction were reported to be helpful, prospective studies are need to confirm these results. Recently, nintedanib which has been shown to be effective in slowing the progress of IPF, has also been shown to reduce incidence of acute exacerbations in Phase II trials. Although two subsequent phase III studies showed conflicting results, nintedanib-treated group showed a significant decrease acute exacerbation than placebo group (1.9 vs. 5.7%, p = 0.01) in the analysis of centrally adjudicated confirmed or suspected acute exacerbation. In case of pirfenidone, phase II study in Japan showed a significant reduction in acute exacerbation compared with placebo, the clinical trials were early discontinued. However, there was no difference in subsequent phase III studies. In some patients, stopping of air pollution exposure, vaccination, and treatment of gastroesophageal reflux might be helpful in preventing acute exacerbation. Considering high mortality, mechanical ventilation is not recommended about severe respiratory failure in patients with acute exacerbation, unless lung transplantation is not considered.