Developments in researches on acute exacerbation of idiopathic pulmonary fibrosis_West China Medical Journal

Authors：

ZHU Lili ¹ ,  DAI Huaping ² ,  WANG Chen ^1,2

1. Department of Respiratory Medicine, Xuanwu Hospital, Capital Medical University, Beijing 100053, P. R. China;
2. Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, Beijing 100029, P. R. China;

Corresponding author：

DAI Huaping, Email: daihuaping@ccmu.edu.cn; WANG Chen, Email: cyh-birm@263.net

Keywords：

Acute exacerbation of idiopathic pulmonary fibrosis; Etiology; Risk factor; Treatment; Prevention

DOI：

10.7507/1002-0179.201712028

Video：

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Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is defined as an acute and clinically significant respiratory deterioration characterized by evidence of new, widespread alveolar abnormality. In the past, AE-IPF was considered to be idiopathic, which was hard to be prevented and its prognosis was hard to be obviously improved; the latest researches have shown that AE-IPF can be triggered by known causes, including pulmonary infection, aspiration, etc. This review summarizes the etiology or risk factors, treatment and prevention of AE-IPF according to the latest researches.

Citation： ZHU Lili, DAI Huaping, WANG Chen. Developments in researches on acute exacerbation of idiopathic pulmonary fibrosis. West China Medical Journal, 2018, 33(1): 93-98. doi: 10.7507/1002-0179.201712028 Copy

1.	Raghu G, Collard HR, Egan JJ, et al. An official ATS/ ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med, 2011, 183(6): 788-824.
2.	Kondo A, Saiki S. Acute exacerbation in idiopathic interst ital pneumonia (IIP)//Harasawa M, Fukuchi Y, Morinari H. Interstitial pneumonia of unkown etiology. Tokyo: University of Tokyo Press, 1989: 33-42.
3.	Kondoh Y, Taniguchi H, Kawabata Y, et al. Acute exacerbation in idiopathic pulmonary fibrosis. Analysis of clinical and pathologic findings in three cases. Chest, 1993, 103(6): 1808-1812.
4.	Collard HR, Moore BB, Flaherty KR, et al. Acute exacerbations of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med, 2007, 176(7): 636-643.
5.	Ryerson CJ, Cottin V, Brown KK. Acute exacerbation of idiopathic pulmonary fibrosis: shifting the paradigm. Eur Respir J, 2015, 46(2): 512-520.
6.	Al-Hameed FM. Sharma S. Outcome of patients admitted to the intensive care unit for acute exacerbation of idiopathic pulmonary fibrosis. Can Respir J, 2004, 11(2): 117-122.
7.	Huie TJ, Olson AL, Cosgrove GP, et al. A detailed evaluation of acute respiratory decline in patients with fibrotic lung disease: aetiology and outcomes. Respirology, 2010, 15(6): 909-917.
8.	Collard HR, Yow E, Richeldi L, et al. Suspected acute exacerbation of idiopathic pulmonary fibrosis as an outcome measure in clinical trials. Respir Res, 2013, 14: 73.
9.	Collard HR, Ryerson CJ, Corte TJ, et al. Acute exacerbation of idiopathic pulmonary fibrosis an international working group report. Am J Respir Crit Care Med, 2016, 194(3): 265-275.
10.	Ding J, Chen Z, Feng K. Procalcitonin-guided antibiotic use in acute exacerbations of idiopathic pulmonary fibrosis. Int J Med Sci, 2013, 10(7): 903-907.
11.	Ranieri VM, Rubenfeld GD, Thompson BT, et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA, 2012, 307(23): 2526-2533.
12.	Wootton SC, Kim DS, Kondoh Y, et al. Viral infection in acute exacerbation of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med, 2011, 183(12): 1698-1702.
13.	Bando M, Ohno S, Oshikawa K, et al. Infection of TT virus in patients with idiopathic pulmonary fibrosis. Respir Med, 2001, 95(12): 935-942.
14.	Molyneaux PL, Cox MJ, Cookson WO, et al. Changes in the respiratory microbiome during acute exacerbations of idiopathic pulmonary fibrosis. Respir Res, 2017, 18(1): 29.
15.	Lee JS, Song JW, Wolters PJ, et al. Bronchoalveolar lavage pepsin in acute exacerbation of idiopathic pulmonary fibrosis. Eur Respir J, 2012, 39(2): 352-358.
16.	Erb-Downward JR, Thompson DL, Han MK, et al. Analysis of the lung microbiome in the " healthy” smoker and in COPD. PLoS One, 2011, 6(2): e16384.
17.	Raghu G, Freudenberger TD, Yang S, et al. High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis. Eur Respir J, 2006, 27(1): 136-142.
18.	Pellegrini CA, Demeester TR, Johnson LF, et al. Gastroesophageal reflux and pulmonary aspiration: incidence, functional abnormality, and results of surgical therapy. Surgery, 1979, 86(1): 110-119.
19.	Raghu G, Yang ST, Spada C, et al. Sole treatment of acid gastroesophageal reflux in idiopathic pulmonary fibrosis - a case series. Chest, 2006, 129(3): 794-800.
20.	Lee JS, Collard HR, Anstrom KJ, et al. Anti-acid treatment and disease progression in idiopathic pulmonary fibrosis: an analysis of data from three randomised controlled trials. Lancet Respir Med, 2013, 1(5): 369-376.
21.	Linden PA, Gilbert RJ, Yeap BY, et al. Laparoscopic fundoplication in patients with end-stage lung disease awaiting transplantation. J Thorac Cardiovasc Surg, 2006, 131(2): 438-446.
22.	Macnee W, Donaldson K. Exacerbations of COPD: environmental mechanisms. Chest, 2000, 117(5 Suppl 2): 390S-397S.
23.	Andersen ZJ, Bonnelykke K, Hvidberg M, et al. Long-term exposure to air pollution and asthma hospitalisations in older adults: a cohort study. Thorax, 2012, 67(1): 6-11.
24.	Schikowski T, Sugiri D, Ranft U, et al. Long-term air pollution exposure and living close to busy roads are associated with COPD in women. Respir Res, 2005, 6: 152.
25.	Johannson KA, Vittinghoff E, Lee K, et al. Acute exacerbation of idiopathic pulmonary fibrosis associated with air pollution exposure. Eur Respir J, 2014, 43(4): 1124-1131.
26.	Kondoh Y, Taniguchi H, Kitaichi MA, et al. Acute exacerbation of interstitial pneumonia following surgical lung biopsy. Respir Med, 2006, 100(10): 1753-1759.
27.	Sakamoto S, Homma S, Mun M, et al. Acute exacerbation of idiopathic interstitial pneumonia following lung surgery in 3 of 68 consecutive patients: a retrospective study. Intern Med, 2011, 50(2): 77-85.
28.	Sakamoto K, Taniguchi H, Kondoh Y, et al. Acute exacerbation of IPF following diagnostic bronchoalveolar lavage procedures. Respir Med, 2012, 106(3): 436-442.
29.	Meduri GU, Headley AS, Golden E, et al. Effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome: a randomized controlled trial. JAMA, 1998, 280(2): 159-165.
30.	Steinberg KP, Hudson LD, Goodman RB, et al. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med, 2006, 354(16): 1671-1684.
31.	Boyle AJ, Mac Sweeney R, Mcauley DF. Pharmacological treatments in ARDS; a state-of-the-art update. BMC Med, 2013, 11: 166.
32.	Song JW, Hong SB, Lim CM, et al. Acute exacerbation of idiopathic pulmonary fibrosis: incidence, risk factors and outcome. Eur Respir J, 2011, 37(2): 356-363.
33.	Horita N, Akahane M, Okada Y, et al. Tacrolimus and steroid treatment for acute exacerbation of idiopathic pulmonary fibrosis. Intern Med, 2011, 50(3): 189-195.
34.	Sakamoto S, Homma S, Miyamoto A, et al. Cyclosporin a in the treatment of acute exacerbation of idiopathic pulmonary fibrosis. Intern Med, 2010, 49(2): 109-115.
35.	Homma S, Sakamoto S, Kawabata M, et al. Cyclosporin treatment in steroid-resistant and acutely exacerbated interstitial pneumonia. Intern Med, 2005, 44(11): 1144-1150.
36.	Morawiec E, Tillie-Leblond I, Pansini V, et al. Exacerbations of idiopathic pulmonary fibrosis treated with corticosteroids and cyclophosphamide pulses. Eur Respir J, 2011, 38(6): 1487-1489.
37.	Nakamura M, Ogura T, Miyazawa N, et al. Outcome of patients with acute exacerbation of idiopathic interstitial fibrosis (IPF) treated with sivelestat and the prognostic value of serum KL-6 and surfactant protein D. Nihon Kokyuki Gakkai Zasshi, 2007, 45(6): 455-459.
38.	Shishido M, Ichiki H, Yano M, et al. A case of idiopathic pulmonary fibrosis with histology of usual interstitial pneumonia that responded to pulse therapy followed by combined immunosuppression with prednisolone and azathioprine. Nihon Kyobu Shikkan Gakkai Zasshi, 1992, 30(12): 2139-2145.
39.	Raghu G, Rochwerg B, Zhang Y, et al. An official ATS/ERS/JRS/ALAT clinical practice guideline: treatment of idiopathic pulmonary fibrosis. An update of the 2011 clinical practice guideline. Am J Respir Crit Care Med, 2015, 192(2): e3-e19.
40.	Richeldi L, Costabel U, Selman M, et al. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med, 2011, 365(12): 1079-1087.
41.	Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med, 2014, 370(22): 2071-2082.
42.	Azuma A, Nukiwa T, Tsuboi E, et al. Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med, 2005, 171(9): 1040-1047.
43.	Iwata T, Yoshino I, Yoshida S, et al. A phase Ⅱ trial evaluating the efficacy and safety of perioperative pirfenidone for prevention of acute exacerbation of idiopathic pulmonary fibrosis in lung cancer patients undergoing pulmonary resection: West Japan Oncology Group 6711 L (People Study). Respir Res, 2016, 17(1): 90.
44.	Tomioka H, Takada H. Treatment with nintedanib for acute exacerbation of idiopathic pulmonary fibrosis. Respirol Case Rep, 2017, 5(2): e215.
45.	Oishi K, Aoe K, Mimura Y, et al. Survival from an acute exacerbation of idiopathic pulmonary fibrosis with or without direct hemoperfusion with a polymyxin B-immobilized fiber column: a retrospective analysis. Intern Med, 2016, 55(24): 3551-3559.
46.	Enomoto N, Mikamo M, Oyama Y, et al. Treatment of acute exacerbation of idiopathic pulmonary fibrosis with direct hemoperfusion using a polymyxin B-immobilized fiber column improves survival. BMC Pulm Med, 2015, 15: 15.
47.	Abe S, Azuma A, Mukae H, et al. Polymyxin B-immobilized fiber column (PMX) treatment for idiopathic pulmonary fibrosis with acute exacerbation: a multicenter retrospective analysis. Intern Med, 2012, 51(12): 1487-1491.
48.	Donahoe M, Chien N, Raval JS, et al. Autoantibody-targeted treatments for acute exacerbations of idiopathic pulmonary fibrosis. PLoS One, 2013, 187(6): e127771.
49.	Kim DS, Park JH, Park BK, et al. Acute exacerbation of idiopathic pulmonary fibrosis: frequency and clinical features. Eur Respir J, 2006, 27(1): 143-150.
50.	Kawamura K, Ichikado K, Yasuda Y, et al. Azithromycin for idiopathic acute exacerbation of idiopathic pulmonary fibrosis: a retrospective single-center study. BMC Pulm Med, 2017, 17(1): 23-30.
51.	Idiopathic Pulmonary Fibrosis Clinical Research Network, Martinez FJ, de Andrade JA, et al. Randomized trial of acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med, 2014, 370(22): 2093-2101.
52.	Abe M, Tsushima K, Matsumura T, et al. Efficacy of thrombomodulin for acute exacerbation of idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia: a nonrandomized prospective study. Drug Des Devel Ther, 2015, 9: 5755-5762.
53.	Yokoyama T, Kondoh Y, Taniguchi HA, et al. Noninvasive ventilation in acute exacerbation of idiopathic pulmonary fibrosis. Intern Med, 2010, 49(15): 1509-1514.
54.	Johannson KA, Collard HR. Acute exacerbation of idiopathic pulmonary fibrosis: a proposal. Curr Respir Care Rep, 2013, 2(4): 233-240.
55.	Vogelmeier CF, Criner GJ, Martinez FJ, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease 2017 report. Gold executive summary. Am J Respir Crit Care Med, 2017, 195(5): 557-582.

1. Raghu G, Collard HR, Egan JJ, et al. An official ATS/ ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med, 2011, 183(6): 788-824.
2. Kondo A, Saiki S. Acute exacerbation in idiopathic interst ital pneumonia (IIP)//Harasawa M, Fukuchi Y, Morinari H. Interstitial pneumonia of unkown etiology. Tokyo: University of Tokyo Press, 1989: 33-42.
3. Kondoh Y, Taniguchi H, Kawabata Y, et al. Acute exacerbation in idiopathic pulmonary fibrosis. Analysis of clinical and pathologic findings in three cases. Chest, 1993, 103(6): 1808-1812.
4. Collard HR, Moore BB, Flaherty KR, et al. Acute exacerbations of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med, 2007, 176(7): 636-643.
5. Ryerson CJ, Cottin V, Brown KK. Acute exacerbation of idiopathic pulmonary fibrosis: shifting the paradigm. Eur Respir J, 2015, 46(2): 512-520.
6. Al-Hameed FM. Sharma S. Outcome of patients admitted to the intensive care unit for acute exacerbation of idiopathic pulmonary fibrosis. Can Respir J, 2004, 11(2): 117-122.
7. Huie TJ, Olson AL, Cosgrove GP, et al. A detailed evaluation of acute respiratory decline in patients with fibrotic lung disease: aetiology and outcomes. Respirology, 2010, 15(6): 909-917.
8. Collard HR, Yow E, Richeldi L, et al. Suspected acute exacerbation of idiopathic pulmonary fibrosis as an outcome measure in clinical trials. Respir Res, 2013, 14: 73.
9. Collard HR, Ryerson CJ, Corte TJ, et al. Acute exacerbation of idiopathic pulmonary fibrosis an international working group report. Am J Respir Crit Care Med, 2016, 194(3): 265-275.
10. Ding J, Chen Z, Feng K. Procalcitonin-guided antibiotic use in acute exacerbations of idiopathic pulmonary fibrosis. Int J Med Sci, 2013, 10(7): 903-907.
11. Ranieri VM, Rubenfeld GD, Thompson BT, et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA, 2012, 307(23): 2526-2533.
12. Wootton SC, Kim DS, Kondoh Y, et al. Viral infection in acute exacerbation of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med, 2011, 183(12): 1698-1702.
13. Bando M, Ohno S, Oshikawa K, et al. Infection of TT virus in patients with idiopathic pulmonary fibrosis. Respir Med, 2001, 95(12): 935-942.
14. Molyneaux PL, Cox MJ, Cookson WO, et al. Changes in the respiratory microbiome during acute exacerbations of idiopathic pulmonary fibrosis. Respir Res, 2017, 18(1): 29.
15. Lee JS, Song JW, Wolters PJ, et al. Bronchoalveolar lavage pepsin in acute exacerbation of idiopathic pulmonary fibrosis. Eur Respir J, 2012, 39(2): 352-358.
16. Erb-Downward JR, Thompson DL, Han MK, et al. Analysis of the lung microbiome in the " healthy” smoker and in COPD. PLoS One, 2011, 6(2): e16384.
17. Raghu G, Freudenberger TD, Yang S, et al. High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis. Eur Respir J, 2006, 27(1): 136-142.
18. Pellegrini CA, Demeester TR, Johnson LF, et al. Gastroesophageal reflux and pulmonary aspiration: incidence, functional abnormality, and results of surgical therapy. Surgery, 1979, 86(1): 110-119.
19. Raghu G, Yang ST, Spada C, et al. Sole treatment of acid gastroesophageal reflux in idiopathic pulmonary fibrosis - a case series. Chest, 2006, 129(3): 794-800.
20. Lee JS, Collard HR, Anstrom KJ, et al. Anti-acid treatment and disease progression in idiopathic pulmonary fibrosis: an analysis of data from three randomised controlled trials. Lancet Respir Med, 2013, 1(5): 369-376.
21. Linden PA, Gilbert RJ, Yeap BY, et al. Laparoscopic fundoplication in patients with end-stage lung disease awaiting transplantation. J Thorac Cardiovasc Surg, 2006, 131(2): 438-446.
22. Macnee W, Donaldson K. Exacerbations of COPD: environmental mechanisms. Chest, 2000, 117(5 Suppl 2): 390S-397S.
23. Andersen ZJ, Bonnelykke K, Hvidberg M, et al. Long-term exposure to air pollution and asthma hospitalisations in older adults: a cohort study. Thorax, 2012, 67(1): 6-11.
24. Schikowski T, Sugiri D, Ranft U, et al. Long-term air pollution exposure and living close to busy roads are associated with COPD in women. Respir Res, 2005, 6: 152.
25. Johannson KA, Vittinghoff E, Lee K, et al. Acute exacerbation of idiopathic pulmonary fibrosis associated with air pollution exposure. Eur Respir J, 2014, 43(4): 1124-1131.
26. Kondoh Y, Taniguchi H, Kitaichi MA, et al. Acute exacerbation of interstitial pneumonia following surgical lung biopsy. Respir Med, 2006, 100(10): 1753-1759.
27. Sakamoto S, Homma S, Mun M, et al. Acute exacerbation of idiopathic interstitial pneumonia following lung surgery in 3 of 68 consecutive patients: a retrospective study. Intern Med, 2011, 50(2): 77-85.
28. Sakamoto K, Taniguchi H, Kondoh Y, et al. Acute exacerbation of IPF following diagnostic bronchoalveolar lavage procedures. Respir Med, 2012, 106(3): 436-442.
29. Meduri GU, Headley AS, Golden E, et al. Effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome: a randomized controlled trial. JAMA, 1998, 280(2): 159-165.
30. Steinberg KP, Hudson LD, Goodman RB, et al. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med, 2006, 354(16): 1671-1684.
31. Boyle AJ, Mac Sweeney R, Mcauley DF. Pharmacological treatments in ARDS; a state-of-the-art update. BMC Med, 2013, 11: 166.
32. Song JW, Hong SB, Lim CM, et al. Acute exacerbation of idiopathic pulmonary fibrosis: incidence, risk factors and outcome. Eur Respir J, 2011, 37(2): 356-363.
33. Horita N, Akahane M, Okada Y, et al. Tacrolimus and steroid treatment for acute exacerbation of idiopathic pulmonary fibrosis. Intern Med, 2011, 50(3): 189-195.
34. Sakamoto S, Homma S, Miyamoto A, et al. Cyclosporin a in the treatment of acute exacerbation of idiopathic pulmonary fibrosis. Intern Med, 2010, 49(2): 109-115.
35. Homma S, Sakamoto S, Kawabata M, et al. Cyclosporin treatment in steroid-resistant and acutely exacerbated interstitial pneumonia. Intern Med, 2005, 44(11): 1144-1150.
36. Morawiec E, Tillie-Leblond I, Pansini V, et al. Exacerbations of idiopathic pulmonary fibrosis treated with corticosteroids and cyclophosphamide pulses. Eur Respir J, 2011, 38(6): 1487-1489.
37. Nakamura M, Ogura T, Miyazawa N, et al. Outcome of patients with acute exacerbation of idiopathic interstitial fibrosis (IPF) treated with sivelestat and the prognostic value of serum KL-6 and surfactant protein D. Nihon Kokyuki Gakkai Zasshi, 2007, 45(6): 455-459.
38. Shishido M, Ichiki H, Yano M, et al. A case of idiopathic pulmonary fibrosis with histology of usual interstitial pneumonia that responded to pulse therapy followed by combined immunosuppression with prednisolone and azathioprine. Nihon Kyobu Shikkan Gakkai Zasshi, 1992, 30(12): 2139-2145.
39. Raghu G, Rochwerg B, Zhang Y, et al. An official ATS/ERS/JRS/ALAT clinical practice guideline: treatment of idiopathic pulmonary fibrosis. An update of the 2011 clinical practice guideline. Am J Respir Crit Care Med, 2015, 192(2): e3-e19.
40. Richeldi L, Costabel U, Selman M, et al. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med, 2011, 365(12): 1079-1087.
41. Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med, 2014, 370(22): 2071-2082.
42. Azuma A, Nukiwa T, Tsuboi E, et al. Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med, 2005, 171(9): 1040-1047.
43. Iwata T, Yoshino I, Yoshida S, et al. A phase Ⅱ trial evaluating the efficacy and safety of perioperative pirfenidone for prevention of acute exacerbation of idiopathic pulmonary fibrosis in lung cancer patients undergoing pulmonary resection: West Japan Oncology Group 6711 L (People Study). Respir Res, 2016, 17(1): 90.
44. Tomioka H, Takada H. Treatment with nintedanib for acute exacerbation of idiopathic pulmonary fibrosis. Respirol Case Rep, 2017, 5(2): e215.
45. Oishi K, Aoe K, Mimura Y, et al. Survival from an acute exacerbation of idiopathic pulmonary fibrosis with or without direct hemoperfusion with a polymyxin B-immobilized fiber column: a retrospective analysis. Intern Med, 2016, 55(24): 3551-3559.
46. Enomoto N, Mikamo M, Oyama Y, et al. Treatment of acute exacerbation of idiopathic pulmonary fibrosis with direct hemoperfusion using a polymyxin B-immobilized fiber column improves survival. BMC Pulm Med, 2015, 15: 15.
47. Abe S, Azuma A, Mukae H, et al. Polymyxin B-immobilized fiber column (PMX) treatment for idiopathic pulmonary fibrosis with acute exacerbation: a multicenter retrospective analysis. Intern Med, 2012, 51(12): 1487-1491.
48. Donahoe M, Chien N, Raval JS, et al. Autoantibody-targeted treatments for acute exacerbations of idiopathic pulmonary fibrosis. PLoS One, 2013, 187(6): e127771.
49. Kim DS, Park JH, Park BK, et al. Acute exacerbation of idiopathic pulmonary fibrosis: frequency and clinical features. Eur Respir J, 2006, 27(1): 143-150.
50. Kawamura K, Ichikado K, Yasuda Y, et al. Azithromycin for idiopathic acute exacerbation of idiopathic pulmonary fibrosis: a retrospective single-center study. BMC Pulm Med, 2017, 17(1): 23-30.
51. Idiopathic Pulmonary Fibrosis Clinical Research Network, Martinez FJ, de Andrade JA, et al. Randomized trial of acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med, 2014, 370(22): 2093-2101.
52. Abe M, Tsushima K, Matsumura T, et al. Efficacy of thrombomodulin for acute exacerbation of idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia: a nonrandomized prospective study. Drug Des Devel Ther, 2015, 9: 5755-5762.
53. Yokoyama T, Kondoh Y, Taniguchi HA, et al. Noninvasive ventilation in acute exacerbation of idiopathic pulmonary fibrosis. Intern Med, 2010, 49(15): 1509-1514.
54. Johannson KA, Collard HR. Acute exacerbation of idiopathic pulmonary fibrosis: a proposal. Curr Respir Care Rep, 2013, 2(4): 233-240.
55. Vogelmeier CF, Criner GJ, Martinez FJ, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease 2017 report. Gold executive summary. Am J Respir Crit Care Med, 2017, 195(5): 557-582.

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