Autopsy and Case Reports
Autopsy and Case Reports
Article / Autopsy Case Report

Severe pulmonary hypertension due to combined pulmonary fibrosis and emphysema: another cause of death among smokers

André Carramenha de Góes Hirano; Eduardo Pelegrineti Targueta; Fernando Peixoto Ferraz de Campos; João Augusto dos Santos Martines; Dafne Andrade; Silvana Maria Lovisolo; Aloisio Felipe-Silva

Downloads: 3
Views: 1563


In 2005, the combined pulmonary fibrosis and emphysema (CPFE) was first defined as a distinct entity, which comprised centrilobular or paraseptal emphysema in the upper pulmonary lobes, and fibrosis in the lower lobes accompanied by reduced diffused capacity of the lungs for carbon monoxide (DLCO). Recently, the fibrosis associated with the connective tissue disease was also included in the diagnosis of CPFE, although the exposure to tobacco, coal, welding, agrochemical compounds, and tire manufacturing are the most frequent causative agents. This entity characteristically presents reduced DLCO with preserved lung volumes and severe pulmonary hypertension, which is not observed in emphysema and fibrosis alone. We present the case of a 63-year-old woman with a history of heavy tobacco smoking abuse, who developed progressive dyspnea, severe pulmonary hypertension, and cor pulmonale over a 2-year period. She attended the emergency facility several times complaining of worsening dyspnea that was treated as decompensate chronic obstructive pulmonary disease (COPD). The imaging examination showed paraseptal emphysema in the upper pulmonary lobes and fibrosis in the middle and lower lobes. The echo Doppler cardiogram revealed the dilation of the right cardiac chambers and pulmonary hypertension, which was confirmed by pulmonary trunk artery pressure measurement by catheterization. During this period, she was progressively restricted to the minimal activities of daily life and dependent on caregivers. She was brought to the hospital neurologically obtunded, presenting anasarca, and respiratory failure, which led her to death. The autopsy showed signs of pulmonary hypertension and findings of fibrosis and emphysema in the histological examination of the lungs. The authors highlight the importance of the recognition of this entity in case of COPD associated with severe pulmonary hypertension of unknown cause.


Pulmonary Emphysema; Pulmonary Fibrosis; Hypertension, Pulmonary; Pulmonary Heart Disease; Autopsy


1. Cottin V, Nunes H, Brillet P-Y, et al. Groupe d’Etude et de Recherche sur les Maladies Orphelines Pulmonaires (GERM O P). Combined pulmonary fibrosis and emphysema: a distinct underrecognised entity. Eur Respir J. 2005;26(4):586-93. PMid:16204587.

2. Snider GL, Kleinerman J, Thurlbeck WM, et al. The definition of emphysema. Report of a National Heart, Lung, and Blood Institute, Division of Lung Diseases workshop. Am Rev Respir Dis. 1985;132(1):182-5. PMid:4014865.

3. Auerbach O, Garfinkel L, Hammond EC. Relation of smoking and age to findings in lung parenchyma: a microscopic study. Chest. 1974;65(1):29-35. PMid:4809331.

4. Wiggins J, Strickland B, Turner-Warwick M. Combined cryptogenic fibrosing alveolitis and emphysema: the value of high resolution computed tomography in assessment. Respir Med. 1990;84(5):365-9. PMid:2247666.

5. Grubstein A, Bendayan D, Schactman I, et al. Concomitant upper-lobe bullous emphysema, lower-lobe interstitial fibrosis and pulmonary hypertension in heavy smokers: report of eight cases and review of the literature. Respir Med. 2005;99(8):948-54. PMID: 15950135.

6. Katzenstein AL. Republished: smoking-related interstitial fibrosis (SRIF): pathologic findings and distinction from other chronic fibrosing lung diseases. Postgrad Med J. 2014;90(1068):597-602. PMid:25230948.

7. Cottin V, Nunes H, Mouthon L, et al. Combined pulmonary fibrosis and emphysema syndrome in connective tissue disease. Arthritis Rheum. 2011;63(1):295-304. PMid:20936629.

8. Ye Q, Huang K, Ding Y, et al. Cigarette smoking contributes to idiopathic pulmonary fibrosis associated with emphysema. Chin Med J. 2014;127(3):469-74. PMid:24451952.

9. Ryerson CJ, Hartman T, Elicker BM, et al. Clinical features and outcomes in combined pulmonary fibrosis and emphysema in idiopathic pulmonary fibrosis. Chest. 2013;144(1):234-40. PMid:23370641.

10. Washko GR, Hunninghake GM, Fernandez IE, et al. Lung volumes and emphysema in smokers with interstitial lung abnormalities. N Engl J Med. 2011;364(10):897-906. PMid:21388308.

11. Sakai F, Tominaga J, Kaga A, et al. Imaging diagnosis of interstitial pneumonia with emphysema (combined pulmonary fibrosis and emphysema). Pulm Med. 2012;2012:816541.

12. Fujimoto K, Kitaguchi Y, Kubo K, Honda T. Clinical analysis of chronic obstructive pulmonary disease phenotypes classified using high-resolution computed tomography. Respirology. 2006;11(6):731-40. PMid:17052301.

13. Papiris SA, Triantafillidou C, Manali ED, et al. Combined pulmonary fibrosis and emphysema. Expert Rev Respir Med. 2013;7(1):19-31, quiz 32. PMid:23362797.

14. Inomata M, Ikushima S, Awano N, et al. An autopsy study of combined pulmonary fibrosis and emphysema: correlations among clinical, radiological, and pathological features. BMC Pulm Med. 2014;14(1):104. PMid:24972672.

15. Sugino K, Ishida F, Kikuchi N, et al. Comparison of clinical characteristics and prognostic factors of combined pulmonary fibrosis and emphysema versus idiopathic pulmonary fibrosis alone. Respirology. 2014;19(2):239-45. PMid:25198924.

16. Kim YJ, Shin SH, Park JW, et al. Annual change in pulmonary function and clinical characteristics of combined pulmonary fibrosis and emphysema and idiopathic pulmonary fibrosis: over a 3-year follow-up. Tuberc Respir Dis. 2014;77(1):18-23. PMid:25114699.

17. Lin H, Jiang S. Combined pulmonary fibrosis and emphysema (CPFE): an entity different from emphysema or pulmonary fibrosis alone. J Thorac Dis. 2015;7(4):767-79. PMID: 25973246.

18. MacNee W. Oxidants/antioxidants and COPD. Chest. 2000;(5 Suppl 1):303S-17S. PMID: 10843965.

19. Chapman HA. Epithelial-mesenchymal interactions in pulmonary fibrosis. Annu Rev Physiol. 2011;73:413-35. PMID: 21054168.

20. Barnes PJ, Adcock IM, Ito K. Histone acetylation and deacetylation: importance in inflammatory lung diseases. Eur Respir J. 2005;25(3):552-63. PMid:15738302.

21. Hoyle GW, Li J, Finkelstein JB, et al. Emphysematous lesions, inflammation, and fibrosis in the lungs of transgenic mice overexpressing plateletderived growth factor. Am J Pathol. 1999;154(6):1763-75. PMid:10362801.

22. Lundblad LK, Thompson-Figueroa J, Leclair T, et al. Tumor necrosis factor alpha overexpression in lung disease: a single cause behind a complex phenotype. Am J Respir Crit Care Med. 2005;171(12):1363-70. PMid:15805183.

23. Lee CG, Cho S, Homer RJ, Elias JA. Genetic control of transforming growth factor-beta1-induced emphysema and fibrosis in the murine lung. Proc Am Thorac Soc. 2006;3(6):476-7. PMid:16921114.

24. Tasaka S, Mizoguchi K, Funatsu Y, et al. Cytokine profile of bronchoalveolar lavage fluid in patients with combined pulmonary fibrosis and emphysema. Respirology. 2012;17(5):814-20. PMid:22515655.

25. Heppleston AG. The pathological recognition and pathogenesis of emphysema and fi brocystic disease of the lung with special reference to coal workers. Ann N Y Acad Sci. 1972;200:347-69. PMid:4513322.

26. Roshan R, Guptal M, Kulshrestha R, Menon B, Chhabra SK. Combined pulmonary fibrosis and emphysema in a welder. Monaldi Arch Chest Dis. 2012;77(1):26-8. PMid:22662643.

27. Daniil Z, Koutsokera A, Gourgoulianis K. Combined pulmonary fibrosis and emphysema in patients exposed to agrochemical compounds. Eur Respir J. 2006;27(2):434. PMid:16452604.

28. Karkhanis VS, Joshi JM. Combined pulmonary fibrosis and emphysema in a tyre industry worker. Lung India. 2012;29(3):273-6. PMid:22919169.

29. Kawabata Y, Hoshi E, Murai K, et al. Smoking-related changes in the background lung of specimens resected for lung cancer: a semiquantitative study with correlation to postoperative course. Histopathology. 2008;53(6):707-14. PMid:19102010.

30. Yousem SA. Respiratory bronchiolitis-associated interstitial lung disease with fi brosis is a lesion distinct from fibrotic nonspecific interstitial pneumonia: a proposal. Mod Pathol. 2006;19(11):1474-9. PMid:16951670.

31. Jankowich MD, Polsky M, Klein M, Rounds S. Heterogeneity in combined pulmonary fibrosis and emphysema. Respiration. 2008;75(4):411-7. PMid:17684315.

32. Katzenstein AL, Mukhopadhyay S, Zanardi C, Dexter E. Clinically occult interstitial fi brosis in smokers: classification and significance of a surprisingly common finding in lobectomy specimens. Hum Pathol. 2010;41(3):316-25. PMid:20004953.

33. Hanaoka M, Ito M, Droma Y, et al. Comparison of gene expression profiling between lung fibrotic and emphysematous tissues sampled from patients with combined pulmonary fibrosis and emphysema. Fibrogenesis Tissue Repair. 2012;5(1):17. PMid:23025845.

34. Cottin V, Reix P, Khouatra C, Thivolet-Béjui F, Feldmann D, Cordier JF. Combined pulmonary fibrosis and emphysema syndrome associated with familial SFTPC mutation. Thorax. 2011;66(10):918-9. PMid:21248320.

35. Epaud R, Delestrain C, Louha M, Simon S, Fanen P, Tazi A. Combined pulmonary fibrosis and emphysema syndrome associated with ABCA3 mutations. Eur Respir J. 2014;43(2):638-41. PMid:24136335.

36. Armanios M. Telomerase and idiopathic pulmonary fibrosis. Mutat Res. 2012;730(1-2):52-8. PMid:22079513.

37. Armanios MY, Chen JJ, Cogan JD, et al. Telomerase mutations in families with idiopathic pulmonary fibrosis. N Engl J Med. 2007;356(13):1317-26. PMid:17392301.

38. Alder JK, Guo N, Kembou F, et al. Telomere length is a determinant of emphysema susceptibility. Am J Respir Crit Care Med. 2011;184(8):904-12. PMid:21757622.

39. Price DB, Baker CL, Zou KH, Higgins VS, Bailey JT, Pike JS. Real-world characterization and differentiation of the Global Initiative for Chronic Obstructive Lung Disease strategy classification. Int J Chron Obstruct Pulmon Dis. 2014;9:551-61. PMid:24920893.

40. Lee AS, Mira-Avendano I, Ryu JH, Daniels CE. The burden of idiopathic pulmonary fibrosis: an unmet public health need. Respir Med. 2014;108(7):955-67. PMid:24780718.

41. Cottin V. The impact of emphysema in pulmonary fibrosis. Eur Respir Rev. 2013;22(128):153-7. PMid:23728869.

42. Seeger W, Adir Y, Barberà JA, et al. Pulmonary hypertension in chronic lung diseases. J Am Coll Cardiol. 2013;62(25, Suppl):D109-16. PMid:24355635.

43. Cottin V, Le Pavec J, Prévot G, et al. Pulmonary hypertension in patients with combined pulmonary fibrosis and emphysema syndrome. Eur Respir J. 2010;35(1):105-11. PMid:19643948.

44. Caminati A, Cassandro R, Harari S. Pulmonary hypertension in chronic interstitial lung diseases. Eur Respir Rev. 2013;22(129):292-301. PMid:23997057.

45. Mejía M, Carrillo G, Rojas-Serrano J, et al. Idiopathic pulmonary fibrosis and emphysema: decreased survival associated with severe pulmonary arterial hypertension. Chest. 2009;136(1):10-5. PMid:19225068.

46. Dias OM, Baldi BG, Costa AN, Carvalho CR. Combined pulmonary fibrosis and emphysema: an increasingly recognized condition. J Bras Pneumol. 2014;40(3):304-12.

47. Brillet PY, Cottin V, Letoumelin P, et al. Combined apical emphysema and basal fibrosis syndrome (emphysema/fibrosis syndrome): CT imaging features and pulmonary function tests. J Radiol. 2009;90(1 Pt 1):43-51. PMid:19182713.

48. Jankowich MD, Rounds S. Combined pulmonary fibrosis and emphysema alters physiology but has similar mortality to pulmonary fibrosis without emphysema. Lung. 2010;188(5):365-73. PMid:20614219.

49. Cottin V, Cordier JF. Combined pulmonary fibrosis and emphysema in connective tissue disease. Curr Opin Pulm Med. 2012;18(5):418-27. PMid:22781207.

50. Jankowich MD, Rounds SI. Combined pulmonary fibrosis and emphysema syndrome: a review. Chest. 2012;141(1):222-31. PMID: 22215830.

51. Ciccarese F, Attinà D, Zompatori M. Combined pulmonary fibrosis and emphysema (CPFE): what a radiologist should know. Radiol Med. 2016;121(7):564-72. PMid:26892068.

52. Cottin V, Cordier JF. The syndrome of combined pulmonary fibrosis and emphysema. Chest. 2009;136(1):1-2. PMid:19584202.

53. Schmidt SL, Nambiar AM, Tayob N, et al. Pulmonary function measures predict mortality differently in IPF versus combined pulmonary fibrosis and emphysema. Eur Respir J. 2011;38(1):176-83. PMid:21148225.

54. Akagi T, Matsumoto T, Harada T, et al. Coexistent emphy- sema delays the decrease of vital capacity in idiopathic pul- monary fibrosis. Respir Med. 2009;103(8):1209-15. PMid:19251407.

55. Tønnesen P, Carrozzi L. Fagerström KO, et al. Smoking cessation in patients with respiratory diseases: a high priority, integral component of therapy. Eur Respir J. 2007;29(2):390-417. PMID: 17264326.

56. Long term domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphysema. Report of the medical research council working party. Lancet. 1981;1(8222): 681-6. PMID: 6110912.

57. McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension. J Am Coll Cardiol. 2009;53(17): 1573-1619.

58. Oltmanns U, Kahn N, Palmowski K, et al. Pirfenidone in idiopathic pul- monary fibrosis: real-life experience from a German tertiary referral center for interstitial lung diseases. Respiration. 2014;88(3):199-207.

59. Papaioannou AI, Kostikas K, Manali ED, et al. Combined pulmonary fibrosis and emphysema: the many aspects of a cohabitation contract. Respir Med. 2016;(117): 14-26.

60. Kishaba T, Shimaoka Y, Fukuyama H, et al. A cohort study of mortality predictors and characteristics of patients with combined pulmonary fibrosis and emphysema. BMJ Open. 2012;2(3):e000988. PMid:22587885.

61. Kumagai S, Marumo S, Yamanashi K, et al. Prognostic significance of combined pulmonary fibrosis and emphysema in patients with resected non-small-cell lung cancer: a retrospective cohort study. Eur J Cardiothorac Surg. 2014;46(6): 113-9.

62. Todd NW, Jeudy J, Lavania S, et al. Centrilobular emphysema combined with pulmonary fibrosis results in improved survival, Fibrogenes. Tissue Repair. 2011;4(1):6.

Publication date:

59550d0e0e8825875124dc21 autopsy Articles
Links & Downloads

Autops Case Rep

Share this page
Page Sections