NEW CONCEPTS IN THE DIAGNOSIS AND TREATMENT OF IDIOPATHIC PULMONARY FIBROSIS
Abstract
NEW CONCEPTS IN THE DIAGNOSIS AND TREATMENT OF IDIOPATHIC PULMONARY FIBROSIS (Abstract): Idiopathic pulmonary fibrosis is a chronic, progressive form of diffuse parenchymal lung disease, leading to respiratory failure. It has unknown causes, affects older adults, with a predilection for men, cigarette smokers, and it has a poor prognosis with a median survival time of approximately 2-3 years from diagnosis. Considering the rapid decline in lung function, this review brings into attention the importance of a multidisciplinary team for an early diagnosis. The methods for the assessment include spirometry which identifies restricted lung volume and impaired gas exchange, and imaging procedures. High-resolution computed tomography is the gold standard for the early diagnosis of idiopathic pulmonary fibrosis, allowing treatment initiation on mild-to-moderate form. Surgical lung biopsy is required in about a third of cases, in the lack of definite usual interstitial pattern on high-resolution computed tomography. The procedure is limited by its complications and increase mortality rate. At present, there are two antifibrotic therapies available for a mild-to-moderate form of idiopathic pulmonary fibrosis with positive effects on lung function but are not a cure. Other treatment options are lung transplant, pulmonary rehabilitation, stem cell therapy, and biotechnology. Mesenchymal stem cells could have protective effects, reducing inflammation and slowing fibrotic process. The review aims to illustrate the management of this rare disease and future directions for treatment research.
References
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7. Fidler L, Sitzer M, Shapera S, Shah PS. Treatment of Gastroesophageal Reflux in Patients with Idio-pathic Pulmonary Fibrosis: A Systematic Review and Meta-Analysis. Chest 2018; 153(6): 1405-1415.
8. Raghu G, Meyer KC. Silent gastro-oesophageal reflux and micro aspiration in IPF: mounting evidence for anti-reflux therapy? Eur Respir J 2012; 39: 242-245.
9. Sgalla G, Iovene B, Calvello M, Ori M, Varone F, Richeldi L. Idiopathic pulmonary fibrosis: patho-genesis and management. Respir Res 2018; 19: 32
10. Raghu G, Amatto VC, Behr J, Stowasser S. Comorbidities in idiopathic pulmonary fibrosis patients: a systematic literature review. Eur Respir J 2015; 46(4): 1113-1130.
11. Kim JS, Podolanczuk AJ, Borker P, Kawut SM, Raghu G, Kaufman JD, et al. Obstructive Sleep Apnea and Subclinical Interstitial Lung Disease in the Multi-Ethnic Study of Atherosclerosis (MESA). Ann Am Thorac Soc 2017; 14(12): 1786-1795.
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13. Wuyts WA, Agostini C, Antoniou KA, Bouros D, Chambers RC, Cottin V, et al. The pathogenesis of pulmonary fibrosis: a moving target. Eur Respir J 2013; 41(5): 1207-1218.
14. Günther A, Korfei M, Mahavadi P, von der Beck D, Ruppert C, Markart P. Unravelling the progressive pathophysiology of idiopathic pulmonary fibrosis. Eur Respir Rev 2012; 21(124): 152-160.
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16. Plantier L, Cazes A, Dinh-Xuan AT, Bancal C, Marchand-Adam S, Crestani B. Physiology of the lung in idiopathic pulmonary fibrosis. Eur Respir Rev 2018; 27(147): 170062.
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19. du Bois RM, Weycker D, Albera C, Bradford WZ, Costabel U, Kartashov A, et al. Six-minute-walk test in idiopathic pulmonary fibrosis: test validaion and minimal clinically important difference. Am J Respir Crit Care Med 2011, 183(9): 1231-1237.
20. Schmidt SL, Nambiar AM, Tayob N, Sundaram B, Han MK, Gross BH, et al. Pulmonary function measures predict mortality differently in IPF versus combined pulmonary fibrosis and emphysema. Eur Respir J 2011; 38(1): 176-183.
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24. Kawano-Dourado L, Kairalla RA. Usual interstitial pneumonia: a pattern or a disease? A reflection upon the topic. J Bras Pneumol 2013; 39(1): 111-112.
25. Wuyts WA, Cavazza A, Rossi G, Bonella F, Sverzellati N, Spagnolo P. Differential diagnosis of usual interstitial pneumonia: when is it truly idiopathic? Eur Respir Rev 2014; 23(133): 308-319.
26. Wells AU. The revised ATS/ERS/JRS/ALAT diagnostic criteria for idiopathic pulmonary fibrosis (IPF) – practical implications. Respir Res 2013; 14(Suppl 1): S2.
27. Chung JH, Chawla A, Peljto AL, Cool CD, Groshong SD, Talbert JL, et al. CT Scan Findings of Probable Usual Interstitial Pneumonitis Have a High Predictive Value for Histologic Usual Interstitial Pneumonitis. Chest 2015; 147(2): 450-459.
28. Alhamad EH. Clinical characteristics and survival in idiopathic pulmonary fibrosis and connective tissue disease- associated usual interstitial pneumonia. J Thorac Dis 2015; 7(3): 386-393.
29. Raghu G, Nicholson AG, Lyunch D. The classification, natural history and radiological/ histological appearance of idiopathic pulmonary fibrosis and the other idiopathic interstitial pneumonias. Eur Respir Rev 2008; 17(109): 108-115.
30. Chae KJ, Jin GY, Jung HN, et al. Differentiating Smoking-Related Interstitial Fibrosis (SRIF) from Usual Interstitial Pneumonia (UIP) with Emphysema Using CT Features Based on Pathologically Proven Cases. PLoS One 2016; 11 (9): e0162231.
31. Brownell R, Moua T, Henry TS, Elicker BM, White D, Vittinghoff E, et al. The use of pretest proba-bility increases the value of high-resolution CT in diagnosing usual interstitial pneumonia. Thorax 2017; 72(5): 424-429.
32. Devaraj A. Imaging: how to recognize idiopathic pulmonary fibrosis. Eur Respir Rev 2014; 23(132): 215-219.
33. Arakawa H, Honma K. Honeycomb Lung: History and Current Concepts. AJR Am J Roentgenol 2011; 196(4): 773-782.
34. Inomata M, Ikushima S, Awano N, Kondoh K, Satake K, Masuo M, et al. An autopsy study of com-bined pulmonary fibrosis and emphysema: correlations among clinical, radiological, and pathological features. BMC Pulmonary Medicine 2014; 14: 104.
35. LinH, Jiang S. Combined pulmonary fibrosis and emphysema (CPFE): an entity different from em-physema or pulmonary fibrosis alone. J Thorac Dis 2015; 7(4): 767-779.
36. Salisbury ML, Tolle LB, Xia M, Murray S, Tayob N, Nambiar AM, et al. Possible UIP Pattern on High-Resolution Computed Tomography is Associated with Better Survival than Definite UIP in IPF Patients. Respir Med 2017; 131: 229-235.
37. Kalchiem-Dekel O, Galvin JR, Burke AP, Atamas SP, Todd NW. Interstitial Lung Disease and Pul-monary Fibrosis: A Practical Approach for General Medicine Physicians with Focus on the Medical History. J Clin Med 2018; 7(12): 476.
38. Kaarteenaho R. The current position of surgical lung biopsy in the diagnosis of idiopathic pulmonary fibrosis. Respir Res 2013; 14: 43.
39. Juarez MM, Chan AL, Norris AG, Morrissey BM, Albertson TE. Acute exacerbation of idiopathic pulmonary fibrosis- a review of current and novel pharmacotherapies. J Thorac Dis 2015; 7(3): 499-519.
40. Prasad R, Gupta N, Singh A, Gupta P. Diagnosis of idiopathic pulmonary fibrosis: Current issues. Intractable Rare Dis Res 2015; 4(2): 65-69.
41. Martinez FJ, Chisholm A, Collard HR, Flaherty KR, Myers J, Raghu G, et al. The diagnosis of idio-pathic pulmonary fibrosis: current and future approaches. Lancet Respir Med 2017; 5(1): 61-71.
42. Oldham JM, Noth I. Idiopathic pulmonary fibrosis: Early detection and referral. Respir Med. 2014; 108(6): 819-829.
43. Fala L. Ofev (Nintedanib): First Tyrosine Kinase Inhibitor Approved for the Treatment of Patients with Idiopathic Pulmonary Fibrosis. Am Health Drug Benefits 2015; 8: 101-104.
44. Lederer DJ, Martinez FJ. Idiopathic Pulmonary Fibrosis. N Engl J Med 2018; 378(19): 1811-1823.
45. Raghu G, Anstrom KJ, King TE Jr, Lasky JA, Martinez FJ. Prednisone, Azathioprine and N-Acetylcysteine for Pulmonary Fibrosis. N Engl J Med 2012; 366(21): 1968-1977.
46. McGrath E, Millar AB. Hot off the breath: triple therapy for idiopathic pulmonary fibrosis- hear the PANTHER roar. Thorax 2012; 67: 97-98.
47. Margaritopoulos GA, Vasarmidi E, Antoniou KM. Pirfenidone in the treatment of idiopathic pulmonary fibrosis: an evidence-based review of its place in therapy. Core Evid 2016; 11: 11-22.
48. Correale M, Ferraretti A, Monaco I, Grazioli D, Di Biase M, Brunetti ND. Endothelin-receptor antag-onists in the management of pulmonary arterial hypertension: where do we stand? Vasc Health Risk Manag 2018; 14: 253-264.
49. Costabel U, Behr J, Crestani B, Stansen W, Schlenker-Herceg R, Stowasser S, et al. Anti-acid therapy in idiopathic pulmonary fibrosis: insights from the INPULSIS® trials. Respir Res 2018; 19(1): 167.
50. Richeldi L, Cottin V, du Bois RM, Selman M, Kimura T, Schlenker-Herceg R, et al. Nintedanib in patients with idiopathic pulmonary fibrosis: Combined evidence from the TOMORROW and IN-PULSIS® trials. Respir Med 2016; 113: 74-79.
51. Ley B, Swigris J, Day BM, Stauffer JL, Raimundo K, Chow W, et al. Pirfenidone Reduces Respirato-ry-related Hospitalizations in Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med 2017; 196(6): 756-761.
52. Flaherty KR, Fell CD, Huggins T, Nunes H, Sussman R, Valenzuela C, et al. Safety of nintedanib added to pirfenidone treatment for idiopathic pulmonary fibrosis. Eur Respir J 2018; 52(2): 1800230.
53. Lehtonen ST, Veijola A, Karvonen H, Lappi-Blanco E, Sormunen R, Korpela S, et al. Pirfenidone and nintedanib modulate properties of fibroblasts and myofibroblasts in idiopathic pulmonary fibrosis. Respir Res 2016; 17: 14.
54. Cottin V. The role of pirfenidone in the treatment of idiopathic pulmonary fibrosis. Respir Res 2013; 14 (Suppl 1): S5.
55. Richeldi L, Kreuter M, Selman M, Crestani B, Kirsten A-M, Wuyts WA et al. Long-term treatment of patients with idiopathic pulmonary fibrosis with nintedanib: results from the TOMORROW trial and its open-label extension. Thorax 2018; 73(6): 581-583.
56. Collard HR, Richeldi L, Kim DS, Taniguchi H, Tschoepe I, Luisetti M, et al. Acute exacerbations in the INPULSIS trials of nintedanib in idiopathic pulmonary fibrosis. Eur Respir J 2017; 49(5): 1601339.
57. Millan-Billi P, Serra C, Alonso-Leon A, Castillo D. Comorbidities, Complications and Non-Pharmacologic Treatment in Idiopathic Pulmonary Fibrosis. Med Sci 2018; 6(3): 59.
58. Kondoh Y, Cottin V, Brown K. Recent lessons learned in the management of acute exacerbation of idiopathic pulmonary fibrosis. Eur Respir Rev 2017; 26: 170050.
59. Kreuter M, Costabel U, Richeldi L, Cottin V, Wijsenbeek M, Bonella F, et al. Statin Therapy and Outcomes in Trials of Nintedanib in Idiopathic Pulmonary Fibrosis. Respiration 2018; 95: 317-326.
60. Lee JS, Collard HR, Anstrom KJ, Martinez FJ, Noth I, Roberts RS, et al. Anti-acid treatment and disease progression in idiopathic pulmonary fibrosis: An analysis of data from three randomized con-trolled trials. Lancet Respir Med 2013; 1(5): 369-376.
61. Dima-Cozma C, Mitu F, Szalontay A, Cojocaru DC. Socioeconomic status and psychological factors in patients with essential hypertension. Rev Cercet Interv Soc 2014; 44: 147-159.
62. Li X, Yue S, Luo Z. Mesenchymal stem cells in idiopathic pulmonary fibrosis. Oncotarget 2017; 8(60): 102600-102616.
63. Schilders KAA, Eenjes E, van Riet S, Poot AA, Stamatialis D, Truckenmüller R, et al. Regeneration of the lung: Lung stem cells and the development of lung mimicking devices. Respir Res 2016; 17: 44.
64. Postolache P, Cojocaru DC. Pulmonary rehabilitation – from guidelines to practice. Rev Med Chir Soc med Nat Iasi 2013; 117 (2): 380-387.
65. Dima-Cozma C, Moisuc D, Arhire O, Cojocaru DC, Mitu F. Polycystic lung disease: case report. Rev Med Chir Soc med Nat Iasi 2017; 121 (1): 68-72.
66. Bajwah S, Ross JR, Wells AU, Mohammed K, Oyebode C, Birring SS, et al. Palliative care for patients with advanced fibrotic lung disease: a randomised controlled phase II and feasibility trial of a community case conference intervention. Thorax 2015; 70(9): 830–839.
67. Asmani M, Velumani S, Li Y, Wawrzyniak N, Hsia I, Chen Z, et al. Fibrotic microtissue array to predict anti-fibrosis drug efficacy. Nat Commun 2018; 9(1): 2066.
2. Collard HR, Bradford WZ, Cottin V, Flaherty KR, King TE Jr, Koch GG, et al. A new era in idiopathic pulmonary fibrosis: considerations for future clinical trials Eur Respir J 2015; 46: 243-249.
3. Swigris JJ, Esser D, Wilson H, Conoscenti CS, Schmidt H, Stansen NK, et al. Psychometric properties of the St George's Respiratory Questionnaire in patients with idiopathic pulmonary fibrosis. Eur Respir J 2017; 49: 1601788.
4. Lamas DJ, Kawut SM, Bagiella E, Philip N, Arcasoy SM, Lederer DJ. Delayed access and survival in idiopathic pulmonary fibrosis: a cohort study. Am J Respir Crit Care Med 2011; 184: 842-847.
5. Ley B, Collard HR, King TE Jr. Clinical course and prediction of survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2011; 183(4): 431-440.
6. Overgaard D, Kaldan G, Marsaa K, Nielsen TL, Shaker SB, Egerod I. The lived experience with idiopathic pulmonary fibrosis: a qualitative study. Eur Respir J 2016; 47(5): 1472-1480.
7. Fidler L, Sitzer M, Shapera S, Shah PS. Treatment of Gastroesophageal Reflux in Patients with Idio-pathic Pulmonary Fibrosis: A Systematic Review and Meta-Analysis. Chest 2018; 153(6): 1405-1415.
8. Raghu G, Meyer KC. Silent gastro-oesophageal reflux and micro aspiration in IPF: mounting evidence for anti-reflux therapy? Eur Respir J 2012; 39: 242-245.
9. Sgalla G, Iovene B, Calvello M, Ori M, Varone F, Richeldi L. Idiopathic pulmonary fibrosis: patho-genesis and management. Respir Res 2018; 19: 32
10. Raghu G, Amatto VC, Behr J, Stowasser S. Comorbidities in idiopathic pulmonary fibrosis patients: a systematic literature review. Eur Respir J 2015; 46(4): 1113-1130.
11. Kim JS, Podolanczuk AJ, Borker P, Kawut SM, Raghu G, Kaufman JD, et al. Obstructive Sleep Apnea and Subclinical Interstitial Lung Disease in the Multi-Ethnic Study of Atherosclerosis (MESA). Ann Am Thorac Soc 2017; 14(12): 1786-1795.
12. Maher TM, Wells AU, Laurent GJ. Idiopathic pulmonary fibrosis: multiple causes and multiple mechanisms? Eur Respir J 2017; 30(5): 835-839.
13. Wuyts WA, Agostini C, Antoniou KA, Bouros D, Chambers RC, Cottin V, et al. The pathogenesis of pulmonary fibrosis: a moving target. Eur Respir J 2013; 41(5): 1207-1218.
14. Günther A, Korfei M, Mahavadi P, von der Beck D, Ruppert C, Markart P. Unravelling the progressive pathophysiology of idiopathic pulmonary fibrosis. Eur Respir Rev 2012; 21(124): 152-160.
15. Thannickal VJ, Henke CA, Horowitz JC, Noble PW, Roman J, Sime PJ et al. Matrix biology of idio-pathic pulmonary fibrosis: a workshop report of the national heart, lung, and blood institute. Am J Pathol 2014; 184(6): 1643-1651.
16. Plantier L, Cazes A, Dinh-Xuan AT, Bancal C, Marchand-Adam S, Crestani B. Physiology of the lung in idiopathic pulmonary fibrosis. Eur Respir Rev 2018; 27(147): 170062.
17. Schoenheit G, Becattelli I, Cohen AH. Living with idiopathic pulmonary fibrosis: an in-depth qualitative survey of European patients. Chron Respir Dis 2011; 8(4): 225-231.
18. Behr J. The diagnosis and treatment of idiopathic pulmonary fibrosis. Dtsch Arztebl Int 2013; 110(51-52): 875-881.
19. du Bois RM, Weycker D, Albera C, Bradford WZ, Costabel U, Kartashov A, et al. Six-minute-walk test in idiopathic pulmonary fibrosis: test validaion and minimal clinically important difference. Am J Respir Crit Care Med 2011, 183(9): 1231-1237.
20. Schmidt SL, Nambiar AM, Tayob N, Sundaram B, Han MK, Gross BH, et al. Pulmonary function measures predict mortality differently in IPF versus combined pulmonary fibrosis and emphysema. Eur Respir J 2011; 38(1): 176-183.
21. Raghu G. Diagnostic criteria for idiopathic pulmonary fibrosis (IPF). Am J Respir Crit Care Med 2011; 183: 788-824.
22. Bonella F, Stowasser S, Wolling L. Idiopathic pulmonary fibrosis: current treatment options and critical appraisal of nintedanib. Drug Des Devel Ther 2015; 9: 6407-6419.
23. Chung JH, Cox CW, Montner SM, Adegunsoye A, Oldham JM, Husain AN, et al. CT Features of the Usual Interstitial Pneumonia Pattern: Differentiating Connective Tissue Disease- Associated Interstitial Lung Disease from Idiopathic Pulmonary Fibrosis. AJR Am J Roentgenol 2018; 210(2): 307-313.
24. Kawano-Dourado L, Kairalla RA. Usual interstitial pneumonia: a pattern or a disease? A reflection upon the topic. J Bras Pneumol 2013; 39(1): 111-112.
25. Wuyts WA, Cavazza A, Rossi G, Bonella F, Sverzellati N, Spagnolo P. Differential diagnosis of usual interstitial pneumonia: when is it truly idiopathic? Eur Respir Rev 2014; 23(133): 308-319.
26. Wells AU. The revised ATS/ERS/JRS/ALAT diagnostic criteria for idiopathic pulmonary fibrosis (IPF) – practical implications. Respir Res 2013; 14(Suppl 1): S2.
27. Chung JH, Chawla A, Peljto AL, Cool CD, Groshong SD, Talbert JL, et al. CT Scan Findings of Probable Usual Interstitial Pneumonitis Have a High Predictive Value for Histologic Usual Interstitial Pneumonitis. Chest 2015; 147(2): 450-459.
28. Alhamad EH. Clinical characteristics and survival in idiopathic pulmonary fibrosis and connective tissue disease- associated usual interstitial pneumonia. J Thorac Dis 2015; 7(3): 386-393.
29. Raghu G, Nicholson AG, Lyunch D. The classification, natural history and radiological/ histological appearance of idiopathic pulmonary fibrosis and the other idiopathic interstitial pneumonias. Eur Respir Rev 2008; 17(109): 108-115.
30. Chae KJ, Jin GY, Jung HN, et al. Differentiating Smoking-Related Interstitial Fibrosis (SRIF) from Usual Interstitial Pneumonia (UIP) with Emphysema Using CT Features Based on Pathologically Proven Cases. PLoS One 2016; 11 (9): e0162231.
31. Brownell R, Moua T, Henry TS, Elicker BM, White D, Vittinghoff E, et al. The use of pretest proba-bility increases the value of high-resolution CT in diagnosing usual interstitial pneumonia. Thorax 2017; 72(5): 424-429.
32. Devaraj A. Imaging: how to recognize idiopathic pulmonary fibrosis. Eur Respir Rev 2014; 23(132): 215-219.
33. Arakawa H, Honma K. Honeycomb Lung: History and Current Concepts. AJR Am J Roentgenol 2011; 196(4): 773-782.
34. Inomata M, Ikushima S, Awano N, Kondoh K, Satake K, Masuo M, et al. An autopsy study of com-bined pulmonary fibrosis and emphysema: correlations among clinical, radiological, and pathological features. BMC Pulmonary Medicine 2014; 14: 104.
35. LinH, Jiang S. Combined pulmonary fibrosis and emphysema (CPFE): an entity different from em-physema or pulmonary fibrosis alone. J Thorac Dis 2015; 7(4): 767-779.
36. Salisbury ML, Tolle LB, Xia M, Murray S, Tayob N, Nambiar AM, et al. Possible UIP Pattern on High-Resolution Computed Tomography is Associated with Better Survival than Definite UIP in IPF Patients. Respir Med 2017; 131: 229-235.
37. Kalchiem-Dekel O, Galvin JR, Burke AP, Atamas SP, Todd NW. Interstitial Lung Disease and Pul-monary Fibrosis: A Practical Approach for General Medicine Physicians with Focus on the Medical History. J Clin Med 2018; 7(12): 476.
38. Kaarteenaho R. The current position of surgical lung biopsy in the diagnosis of idiopathic pulmonary fibrosis. Respir Res 2013; 14: 43.
39. Juarez MM, Chan AL, Norris AG, Morrissey BM, Albertson TE. Acute exacerbation of idiopathic pulmonary fibrosis- a review of current and novel pharmacotherapies. J Thorac Dis 2015; 7(3): 499-519.
40. Prasad R, Gupta N, Singh A, Gupta P. Diagnosis of idiopathic pulmonary fibrosis: Current issues. Intractable Rare Dis Res 2015; 4(2): 65-69.
41. Martinez FJ, Chisholm A, Collard HR, Flaherty KR, Myers J, Raghu G, et al. The diagnosis of idio-pathic pulmonary fibrosis: current and future approaches. Lancet Respir Med 2017; 5(1): 61-71.
42. Oldham JM, Noth I. Idiopathic pulmonary fibrosis: Early detection and referral. Respir Med. 2014; 108(6): 819-829.
43. Fala L. Ofev (Nintedanib): First Tyrosine Kinase Inhibitor Approved for the Treatment of Patients with Idiopathic Pulmonary Fibrosis. Am Health Drug Benefits 2015; 8: 101-104.
44. Lederer DJ, Martinez FJ. Idiopathic Pulmonary Fibrosis. N Engl J Med 2018; 378(19): 1811-1823.
45. Raghu G, Anstrom KJ, King TE Jr, Lasky JA, Martinez FJ. Prednisone, Azathioprine and N-Acetylcysteine for Pulmonary Fibrosis. N Engl J Med 2012; 366(21): 1968-1977.
46. McGrath E, Millar AB. Hot off the breath: triple therapy for idiopathic pulmonary fibrosis- hear the PANTHER roar. Thorax 2012; 67: 97-98.
47. Margaritopoulos GA, Vasarmidi E, Antoniou KM. Pirfenidone in the treatment of idiopathic pulmonary fibrosis: an evidence-based review of its place in therapy. Core Evid 2016; 11: 11-22.
48. Correale M, Ferraretti A, Monaco I, Grazioli D, Di Biase M, Brunetti ND. Endothelin-receptor antag-onists in the management of pulmonary arterial hypertension: where do we stand? Vasc Health Risk Manag 2018; 14: 253-264.
49. Costabel U, Behr J, Crestani B, Stansen W, Schlenker-Herceg R, Stowasser S, et al. Anti-acid therapy in idiopathic pulmonary fibrosis: insights from the INPULSIS® trials. Respir Res 2018; 19(1): 167.
50. Richeldi L, Cottin V, du Bois RM, Selman M, Kimura T, Schlenker-Herceg R, et al. Nintedanib in patients with idiopathic pulmonary fibrosis: Combined evidence from the TOMORROW and IN-PULSIS® trials. Respir Med 2016; 113: 74-79.
51. Ley B, Swigris J, Day BM, Stauffer JL, Raimundo K, Chow W, et al. Pirfenidone Reduces Respirato-ry-related Hospitalizations in Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med 2017; 196(6): 756-761.
52. Flaherty KR, Fell CD, Huggins T, Nunes H, Sussman R, Valenzuela C, et al. Safety of nintedanib added to pirfenidone treatment for idiopathic pulmonary fibrosis. Eur Respir J 2018; 52(2): 1800230.
53. Lehtonen ST, Veijola A, Karvonen H, Lappi-Blanco E, Sormunen R, Korpela S, et al. Pirfenidone and nintedanib modulate properties of fibroblasts and myofibroblasts in idiopathic pulmonary fibrosis. Respir Res 2016; 17: 14.
54. Cottin V. The role of pirfenidone in the treatment of idiopathic pulmonary fibrosis. Respir Res 2013; 14 (Suppl 1): S5.
55. Richeldi L, Kreuter M, Selman M, Crestani B, Kirsten A-M, Wuyts WA et al. Long-term treatment of patients with idiopathic pulmonary fibrosis with nintedanib: results from the TOMORROW trial and its open-label extension. Thorax 2018; 73(6): 581-583.
56. Collard HR, Richeldi L, Kim DS, Taniguchi H, Tschoepe I, Luisetti M, et al. Acute exacerbations in the INPULSIS trials of nintedanib in idiopathic pulmonary fibrosis. Eur Respir J 2017; 49(5): 1601339.
57. Millan-Billi P, Serra C, Alonso-Leon A, Castillo D. Comorbidities, Complications and Non-Pharmacologic Treatment in Idiopathic Pulmonary Fibrosis. Med Sci 2018; 6(3): 59.
58. Kondoh Y, Cottin V, Brown K. Recent lessons learned in the management of acute exacerbation of idiopathic pulmonary fibrosis. Eur Respir Rev 2017; 26: 170050.
59. Kreuter M, Costabel U, Richeldi L, Cottin V, Wijsenbeek M, Bonella F, et al. Statin Therapy and Outcomes in Trials of Nintedanib in Idiopathic Pulmonary Fibrosis. Respiration 2018; 95: 317-326.
60. Lee JS, Collard HR, Anstrom KJ, Martinez FJ, Noth I, Roberts RS, et al. Anti-acid treatment and disease progression in idiopathic pulmonary fibrosis: An analysis of data from three randomized con-trolled trials. Lancet Respir Med 2013; 1(5): 369-376.
61. Dima-Cozma C, Mitu F, Szalontay A, Cojocaru DC. Socioeconomic status and psychological factors in patients with essential hypertension. Rev Cercet Interv Soc 2014; 44: 147-159.
62. Li X, Yue S, Luo Z. Mesenchymal stem cells in idiopathic pulmonary fibrosis. Oncotarget 2017; 8(60): 102600-102616.
63. Schilders KAA, Eenjes E, van Riet S, Poot AA, Stamatialis D, Truckenmüller R, et al. Regeneration of the lung: Lung stem cells and the development of lung mimicking devices. Respir Res 2016; 17: 44.
64. Postolache P, Cojocaru DC. Pulmonary rehabilitation – from guidelines to practice. Rev Med Chir Soc med Nat Iasi 2013; 117 (2): 380-387.
65. Dima-Cozma C, Moisuc D, Arhire O, Cojocaru DC, Mitu F. Polycystic lung disease: case report. Rev Med Chir Soc med Nat Iasi 2017; 121 (1): 68-72.
66. Bajwah S, Ross JR, Wells AU, Mohammed K, Oyebode C, Birring SS, et al. Palliative care for patients with advanced fibrotic lung disease: a randomised controlled phase II and feasibility trial of a community case conference intervention. Thorax 2015; 70(9): 830–839.
67. Asmani M, Velumani S, Li Y, Wawrzyniak N, Hsia I, Chen Z, et al. Fibrotic microtissue array to predict anti-fibrosis drug efficacy. Nat Commun 2018; 9(1): 2066.
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