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Review article: Biomedical intelligence

Vol. 146 No. 3940 (2016)

Pulmonary hypertension associated with chronic lung diseases

  • Manuela Funke
  • Thomas Geiser
  • Otto D. Schoch
DOI
https://doi.org/10.4414/smw.2016.14363
Cite this as:
Swiss Med Wkly. 2016;146:w14363
Published
28.09.2016

Abstract

In 2015, the international guidelines for diagnosis and treatment of pulmonary hypertension were updated. Group 3 of the current classification includes pulmonary hypertension associated with chronic obstructive pulmonary disease (COPD), interstitial lung disease, other pulmonary diseases with restrictive and obstructive pattern, sleep-disordered breathing, alveolar hypoventilation disorders, chronic exposure to high altitude, and developmental lung diseases. Pulmonary hypertension associated with COPD and interstitial lung disease is common but difficult to manage, as no long-term randomised controlled trial has been conducted with specific pulmonary arterial hypertension drugs in pulmonary hypertension associated with COPD, and the one recent RCT in pulmonary hypertension associated with interstitial lung disease had to be stopped early due to a possible increased risk of death and side effects in the treatment group. Specific treatment may thus be harmful and may worsen gas exchange as a result of possible recruitment of less oxygenised areas, i.e. by increasing ventilation-perfusion mismatch. Management of pulmonary hypertension patients with chronic lung diseases requires careful evaluation and understanding of pathophysiological mechanisms. Interestingly, mediators in PAH and in fibrotic lung disease show some overlaps. Several drugs effective in pulmonary arterial hypertensio have been evaluated for anti-fibrotic treatment in interstitial lung disease, but until today without consistent success. While new drugs with anti-fibrotic effects are now accessible, a specific evidence-based treatment for pulmonary hypertension in interstitial lung disease or COPD with or without emphysema is not yet available.

References

  1. Galie N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Respir J. 2015;46(4):903–75.
  2. Ma KC, Berlin DA. Pathophysiology of pulmonary hypertension in chronic parenchymal lung disease. Am J Med. 2016;129(4):366-71.
  3. Sommer N, Dietrich A, Schermuly RT, Ghofrani HA, Gudermann T, Schulz R, et al. Regulation of hypoxic pulmonary vasoconstriction: basic mechanisms. Eur Respir J. 2008;32(6):1639–51.
  4. Ball MK, Waypa GB, Mungai PT, Nielsen JM, Czech L, Dudley VJ, et al., Regulation of hypoxia-induced pulmonary hypertension by vascular smooth muscle hypoxia-inducible factor-1alpha. Am J Respir Crit Care Med. 2014;189(3):314–24.
  5. Bryant AJ, Carrick RP, McConaha ME, Jones BR, Shay SD, Moore CS, et al. Endothelial Hif Signaling Regulates Pulmonary Fibrosis-Associated Pulmonary Hypertension. Am J Physiol Lung Cell Mol Physiol. 2016;310(3):L249-62.
  6. Marshall BE, Marshall C, Magno M, Lilagan P, Pietra GG. Influence of bronchial arterial PO2 on pulmonary vascular resistance. J Appl Physiol (1985). 1991;70(1):405–15.
  7. Malenfant S, Neyron AS, Paulin R, Potus F, Meloche J, Provencher S, et al. Signal transduction in the development of pulmonary arterial hypertension. Pulm Circ. 2013;3(2):278–93.
  8. Fonseca C, Abraham D, Renzoni EA. Endothelin in pulmonary fibrosis. Am J Respir Cell Mol Biol. 2011;44(1):1–10.
  9. Humbert M, Ghofrani HA. The molecular targets of approved treatments for pulmonary arterial hypertension. Thorax. 2016;71(1):73–83.
  10. King TE Jr, Behr J, Brown KK, du Bois RM, Lancaster L, de Andrade JA, et al. BUILD-1: a randomized placebo-controlled trial of bosentan in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2008;177(1):75–81.
  11. King TE Jr, Brown KK, Raghu G, du Bois RM, Lynch DA, Martinez F, et al. BUILD-3: a randomized, controlled trial of bosentan in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2011;184(1):92–9.
  12. Raghu G, Behr J, Brown KK, Egan JJ, Kawut SM, Flaherty KR, et al. Treatment of idiopathic pulmonary fibrosis with ambrisentan: a parallel, randomized trial. Ann Intern Med. 2013;158(9):641–9.
  13. Raghu G, Million-Rousseau R, Morganti A, Perchenet L, Behr J, Music Study Group. Macitentan for the treatment of idiopathic pulmonary fibrosis: the randomised controlled MUSIC trial. Eur Respir J. 2013;42(6):1622–32.
  14. Corte TJ, Keir GJ, Dimopoulos K, Howard L, Corris PA, Parfitt L, et al. Bosentan in pulmonary hypertension associated with fibrotic idiopathic interstitial pneumonia. Am J Respir Crit Care Med. 2014;190(2):208–17.
  15. Wollin L, Wex E, Pautsch A, Schnapp G, Hostettler KE, Stowasser S, et al., Mode of action of nintedanib in the treatment of idiopathic pulmonary fibrosis. Eur Respir J. 2015;45(5):1434–45.
  16. Hoeper MM, Barst RJ, Bourge RC, Feldman J, Frost AE, Galie N, et al. Imatinib mesylate as add-on therapy for pulmonary arterial hypertension: results of the randomized IMPRES study. Circulation. 2013;127(10):1128–38.
  17. Clark JG, Madtes DK, and Raghu G, Effects of platelet-derived growth factor isoforms on human lung fibroblast proliferation and procollagen gene expression. Exp Lung Res. 1993;19(3):327–44.
  18. Bonner JC. Regulation of PDGF and its receptors in fibrotic diseases. Cytokine Growth Factor Rev. 2004;15(4):255–73.
  19. Lakatos HF, Thatcher TH, Kottmann RM, Garcia TM, Phipps RP, Sime PJ. The Role of PPARs in Lung Fibrosis. PPAR Res. 2007. 2007: p. 71323.
  20. Scotton CJ, Chambers RC. Molecular targets in pulmonary fibrosis: the myofibroblast in focus. Chest. 2007;132(4):1311–21.
  21. Russi EW, Karrer W, Brutsche M, Eich C, Fitting JW, Frey M, et al. Diagnosis and management of chronic obstructive pulmonary disease: the Swiss guidelines. Official guidelines of the Swiss Respiratory Society. Respiration. 2013;85(2):160–74.
  22. Andersen KH, Iversen M, Kjaergaard J, Mortensen J, Nielsen-Kudsk JE, Bendstrup E, et al. Prevalence, predictors, and survival in pulmonary hypertension related to end-stage chronic obstructive pulmonary disease. J Heart Lung Transplant. 2012;31(4):373–80.
  23. Seeger W, Adir Y, Barbera JA, Champion H, Coghlan JG, Cottin V, et al. Pulmonary hypertension in chronic lung diseases. J Am Coll Cardiol. 2013;62(25 Suppl):D109–16.
  24. Weitzenblum E, Apprill M, Oswald M, Chaouat A, Imbs JL. Long-term course of pulmonary arterial pressure in chronic obstructive pulmonary disease. Am Rev Respir Dis. 1984;130(6):993–8.
  25. Zisman DA, Ross DJ, Belperio JA, Saggar R, Lynch JP 3rd, Ardehali A, et al. Prediction of pulmonary hypertension in idiopathic pulmonary fibrosis. Respir Med. 2007;101(10):2153–9.
  26. Chaouat A, Bugnet AS, Kadaoui N, Schott R, Enache I, Ducolone A, et al. Severe pulmonary hypertension and chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2005;172(2):189–94.
  27. Abraham AS, Cole RB, Green ID, Hedworth-Whitty RB, Clarke, SW, Bishop JM. Factors contributing to the reversible pulmonary hypertension of patients with acute respiratory failure studies by serial observations during recovery. Circ Res. 1969;24(1):51–60.
  28. Chaouat A, Naeije R, Weitzenblum E. Pulmonary hypertension in COPD. Eur Respir J. 2008;32(5):1371–85.
  29. Weitzenblum E, Apprill M, Oswald M, Chaouat A, Imbs JL. Pulmonary hemodynamics in patients with chronic obstructive pulmonary disease before and during an episode of peripheral edema. Chest. 1994;105(5):1377–82.
  30. Wells JM, Washko GR, Han MK, Abbas N, Nath H, Mamary AJ, et al. Pulmonary arterial enlargement and acute exacerbations of COPD. N Engl J Med. 2012;367(10):913–21.
  31. Funke M, Geiser T. Idiopathic pulmonary fibrosis: the turning point is now! Swiss Med Wkly. 2015;145: p. w14139.
  32. Hamada K, Nagai S, Tanaka S, Handa T, Shigematsu M, Nagao T, et al. Significance of pulmonary arterial pressure and diffusion capacity of the lung as prognosticator in patients with idiopathic pulmonary fibrosis. Chest. 2007;131(3):650–6.
  33. Kimura M, Taniguchi H, Kondoh Y, Kimura T, Kataoka K, Nishiyama O, et al. Pulmonary hypertension as a prognostic indicator at the initial evaluation in idiopathic pulmonary fibrosis. Respiration. 2013;85(6):456–63.
  34. Nathan SD, Shlobin OA, Ahmad S, Koch J, Barnett SD, Ad N, et al. Serial development of pulmonary hypertension in patients with idiopathic pulmonary fibrosis. Respiration. 2008;76(3):288–94.
  35. Minai OA, Santacruz JF, Alster JM, Budev MM, McCarthy K, et al. Impact of pulmonary hemodynamics on 6-min walk test in idiopathic pulmonary fibrosis. Respir Med. 2012;106(11):1613–21.
  36. Raghu G, Nathan SD, Behr J, Brown KK, Egan JJ, Kawut SM, et al. Pulmonary hypertension in idiopathic pulmonary fibrosis with mild-to-moderate restriction. Eur Respir J. 2015;46(5):1370–7.
  37. Shorr AF, Wainright JL, Cors CS, Lettieri CJ, Nathan SD. Pulmonary hypertension in patients with pulmonary fibrosis awaiting lung transplant. Eur Respir J. 2007;30(4):715–21.
  38. Cottin V, Nunes H, Brillet PY, Delaval P, Devouassoux G, Tillie-Leblond I, et al. Combined pulmonary fibrosis and emphysema: a distinct underrecognised entity. Eur Respir J. 2005;26(4):586–93.
  39. Cottin V, Le Pavec J, Prevot G, Mal H, Humbert M, Simonneau G, et al. Pulmonary hypertension in patients with combined pulmonary fibrosis and emphysema syndrome. Eur Respir J. 2010;35(1):105–11.
  40. Puhan MA, Siebeling L, Zoller M, Muggensturm P, ter Riet G. Simple functional performance tests and mortality in COPD. Eur Respir J. 2013;42(4):956–63.
  41. Palazzuoli A, Ruocco G, Cekorja B, Pellegrini M, Del Castillo G, Nuti R. Combined BNP and Echocardiographic assessment in interstitial lung disease for pulmonary hypertension detection. Int J Cardiol. 2015;178:34–6.
  42. Arcasoy SM, Christie JD, Ferrari VA, Sutton MS, Zisman DA. Blumenthal NP et al., Echocardiographic assessment of pulmonary hypertension in patients with advanced lung disease. Am J Respir Crit Care Med. 2003;167(5):735–40.
  43. Caminati A, Cassandro R, Harari S. Pulmonary hypertension in chronic interstitial lung diseases. Eur Respir Rev. 2013;22(129):292–301.
  44. Brewis MJ, Church AC, Johnson MK, Peacock AJ. Severe pulmonary hypertension in lung disease: phenotypes and response to treatment. Eur Respir J. 2015;46(5):1378–89.
  45. Mueller-Mottet S, Stricker H, Domenighetti G, Azzola A, Geiser T, Schwerzmann M, et al. Long-term data from the Swiss pulmonary hypertension registry. Respiration. 2015;89(2):127–40.
  46. Maeder MT KR, Weilenmann D, Schoch OD. Pulmonary hypertension associated with left heart and lung diseases. Cardiovascular Medicine. 2014;17(11):320–7.
  47. Ehlken N, Lichtblau M, Klose H, Weidenhammer J, Fischer C, Nechwatal R, et al. Exercise training improves peak oxygen consumption and haemodynamics in patients with severe pulmonary arterial hypertension and inoperable chronic thrombo-embolic pulmonary hypertension: a prospective, randomized, controlled trial. Eur Heart J. 2016;37(1):35–44.
  48. Stone IS, Barnes NC, James WY, Midwinter D, Boubertakh R, Follows R et al. Lung deflation and cardiovascular structure and function in chronic obstructive pulmonary disease. A randomized controlled trial. Am J Respir Crit Care Med. 2016;193(7):717–26.
  49. Ulrich S, Keusch S, Hildenbrand FF, Lo Cascio C, Huber LC, Tanner FC, et al. Effect of nocturnal oxygen and acetazolamide on exercise performance in patients with pre-capillary pulmonary hypertension and sleep-disturbed breathing: randomized, double-blind, cross-over trial. Eur Heart J. 2015;36(10):615–23.
  50. Singh VK, George MP, Gries CJ. Pulmonary hypertension is associated with increased post-lung transplant mortality risk in patients with chronic obstructive pulmonary disease. J Heart Lung Transplant. 2015;34(3):424–9.
  51. Boeck L, Tamm M, Grendelmeier P, Stolz D. Acute effects of aerosolized iloprost in COPD related pulmonary hypertension – a randomized controlled crossover trial. PLoS One. 2012;7(12):e52248.
  52. Stolz D, Rasch H, Linka A, Di Valentino M, Meyer A, Brutsche M, et al. A randomised, controlled trial of bosentan in severe COPD. Eur Respir J. 2008;32(3):619–28.
  53. Blanco I, Gimeno E, Munoz PA, Pizarro S, Gistau C, Rodriguez-Roisin R, et al. Hemodynamic and gas exchange effects of sildenafil in patients with chronic obstructive pulmonary disease and pulmonary hypertension. Am J Respir Crit Care Med. 2010;181(3):270–8.
  54. Girard A, Jouneau S, Chabanne C, Khouatra C, Lannes M, Traclet J, et al. Severe pulmonary hypertension associated with COPD: hemodynamic improvement with specific therapy. Respiration. 2015;90(3):220–8.
  55. Ghofrani HA, Staehler G, Grunig E, Halank M, Mitrovic V, Unger S, et al. Acute effects of riociguat in borderline or manifest pulmonary hypertension associated with chronic obstructive pulmonary disease. Pulm Circ. 2015;5(2):296–304.
  56. Fossati L, Muller-Mottet S, Hasler E, Speich R, Bloch KE, Huber LC, et al. Long-term effect of vasodilator therapy in pulmonary hypertension due to COPD: a retrospective analysis. Lung. 2014;192(6):987–95.
  57. Lange TJ, Baron M, Seiler I, Arzt M, Pfeifer M. Outcome of patients with severe PH due to lung disease with and without targeted therapy. Cardiovasc Ther. 2014;32(5):202–8.
  58. Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2071–82.
  59. Speich R, Ulrich S, Domenighetti G, Huber LC, Fischler M, Treder U, et al. Efficacy and Safety of Long-Term Imatinib Therapy for Pulmonary Arterial Hypertension. Respiration. 2015;89(6):515–24.
  60. Frost AE, Barst RJ, Hoeper MM, Chang HJ, Frantz RP, Fukumoto Y, et al. Long-term safety and efficacy of imatinib in pulmonary arterial hypertension. J Heart Lung Transplant. 2015;34(11):1366–75.
  61. Hayes D Jr, Higgins RS, Black SM, Wehr AM, Lehman AM, Kirkby S, et al. Effect of pulmonary hypertension on survival in patients with idiopathic pulmonary fibrosis after lung transplantation: an analysis of the United Network of Organ Sharing registry. J Heart Lung Transplant. 2015;34(3):430–7.
  62. Olschewski H, Ghofrani HA, Walmrath D, Schermuly R, Temmesfeld-Wollbruck, B, Grimminger F, et al. Inhaled prostacyclin and iloprost in severe pulmonary hypertension secondary to lung fibrosis. Am J Respir Crit Care Med. 1999;160(2):600–7.
  63. Blanco I, Ribas J, Xaubet A, Gomez FP, Roca J, Rodriguez-Roisin R, et al. Effects of inhaled nitric oxide at rest and during exercise in idiopathic pulmonary fibrosis. J Appl Physiol. (1985), 2011;110(3):638–45.
  64. Gunther A, Enke B, Markart P, Hammerl P, Morr H, Behr J, et al. Safety and tolerability of bosentan in idiopathic pulmonary fibrosis: an open label study. Eur Respir J. 2007;29(4):713–9.
  65. Raghu G, Rochwerg B, Zhang Y, Garcia CA, Azuma A, Behr J, 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):e3–19.
  66. Hoeper MM, Behr J, Held M, Grunig E, Vizza CD, Vonk-Noordegraaf A, et al. Pulmonary hypertension in patients with chronic fibrosing idiopathic interstitial pneumonias. PLoS One. 2015;10(12):e0141911.
  67. Idiopathic Pulmonary Fibrosis Clinical Research Network. Zisman DA, Schwarz M, Anstrom KJ, Collard HR, Flaherty KR, et al. A controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis. N Engl J Med. 2010;363(7):620–8.
  68. Ghofrani HA, Wiedemann R, Rose F, Schermuly RT, Olschewski H, Weissmann N, et al. Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomised controlled trial. Lancet. 2002;360(9337):895–900.
  69. Tanabe N, Taniguchi H, Tsujino I, Sakamaki F, Emoto, N, et al. Multi-institutional retrospective cohort study of patients with severe pulmonary hypertension associated with respiratory diseases. Respirology. 2015;20(5):805–12.
  70. Official press release. [updated 2016 May 12; cited 2016 Jul 4]. Accessed 4.6.2016 at: http://www.prnewswire.com/news-releases/bayer-terminates-phase-ii-study-with-riociguat-in-patients-with-pulmonary-hypertension-associated-with-idiopathic-interstitial-pneumonias-300267616.html.

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