Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Treatment and prognosis
- Jay H Ryu, MD
Jay H Ryu, MD
- Professor of Medicine
- Mayo Clinic College of Medicine
- Robert P Frantz, MD
Robert P Frantz, MD
- Professor of Medicine
- Mayo Clinic College of Medicine
- Section Editors
- Talmadge E King, Jr, MD
Talmadge E King, Jr, MD
- Editor-in-Chief — Pulmonary and Critical Care Medicine
- Section Editor — Interstitial Lung Disease
- Dean, School of Medicine
- Vice Chancellor, Medical Affairs
- University of California San Francisco
- Jess Mandel, MD
Jess Mandel, MD
- Section Editor — Pulmonary Vascular Disease
- Professor of Medicine
- University of California, San Diego
Patients with pulmonary hypertension (PH) due to chronic lung disease (eg, chronic obstructive pulmonary disease, interstitial lung disease, or overlap syndromes) or conditions that cause hypoxemia (eg, obstructive sleep apnea, alveolar hypoventilation disorders) are classified as having group 3 PH (table 1).
The treatment and prognosis of patients with group 3 PH are reviewed here. The prevalence, pathogenesis, and diagnostic evaluation of patients with suspected group 3 PH are presented separately. (See "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Epidemiology, pathogenesis, and diagnostic evaluation in adults".)
The World Health Organization (WHO) classifies patients with PH into five groups based upon etiology . Patients in group 1 are considered to have pulmonary arterial hypertension (PAH; also sometimes referred to as precapillary pulmonary hypertension), whereas patients in group 2 (due to left-sided heart disease), group 3 (due to lung disorders and hypoxemia), group 4 (due to chronic thromboembolic disease), and group 5 (associated with a variety of conditions) are considered to have PH (table 1). When all five groups are discussed collectively, the term PH is generally used. Classification of PH is discussed in detail separately. (See "Classification and prognosis of pulmonary hypertension in adults", section on 'Classification'.)
Treatment of associated condition — Treatment of the associated condition (eg, chronic obstructive pulmonary disease [COPD], interstitial lung disease [ILD], sleep disordered breathing [SDB]) is indicated in all patients with group 3 PH. However, while some strategies (eg, continuous positive airway pressure) modestly reduce pulmonary artery pressures (PAP), evidence to suggest significant reductions in PH or improved clinically impactful outcomes (eg, reduced mortality, improved exercise capacity, delayed progression) is lacking [2,3]. Nonetheless, disease-specific therapies are assumed to result in improved alveolar hypoxia, which is thought to contribute to the pathogenesis of PH and to progression of pulmonary hypertension. (See "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Epidemiology, pathogenesis, and diagnostic evaluation in adults", section on 'Pathogenesis'.)
Treatment of the associated conditions are discussed separately. (See "Treatment of idiopathic pulmonary fibrosis" and "Management of stable chronic obstructive pulmonary disease" and "Management of obstructive sleep apnea in adults" and "Obstructive sleep apnea and cardiovascular disease in adults", section on 'Impact of treatment'.).To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2013; 62:D34.
- Castro-Añón O, Golpe R, Pérez-de-Llano LA, et al. Haemodynamic effects of non-invasive ventilation in patients with obesity-hypoventilation syndrome. Respirology 2012; 17:1269.
- Kauppert CA, Dvorak I, Kollert F, et al. Pulmonary hypertension in obesity-hypoventilation syndrome. Respir Med 2013; 107:2061.
- Hoeper MM, Andreas S, Bastian A, et al. Pulmonary hypertension due to chronic lung disease: updated Recommendations of the Cologne Consensus Conference 2011. Int J Cardiol 2011; 154 Suppl 1:S45.
- 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; 1:681.
- Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease: a clinical trial. Nocturnal Oxygen Therapy Trial Group. Ann Intern Med 1980; 93:391.
- Timms RM, Khaja FU, Williams GW. Hemodynamic response to oxygen therapy in chronic obstructive pulmonary disease. Ann Intern Med 1985; 102:29.
- Weitzenblum E, Sautegeau A, Ehrhart M, et al. Long-term oxygen therapy can reverse the progression of pulmonary hypertension in patients with chronic obstructive pulmonary disease. Am Rev Respir Dis 1985; 131:493.
- Sliwiński P, Hawrylkiewicz I, Górecka D, Zieliński J. Acute effect of oxygen on pulmonary arterial pressure does not predict survival on long-term oxygen therapy in patients with chronic obstructive pulmonary disease. Am Rev Respir Dis 1992; 146:665.
- Selinger SR, Kennedy TP, Buescher P, et al. Effects of removing oxygen from patients with chronic obstructive pulmonary disease. Am Rev Respir Dis 1987; 136:85.
- Long-Term Oxygen Treatment Trial Research Group, Albert RK, Au DH, et al. A Randomized Trial of Long-Term Oxygen for COPD with Moderate Desaturation. N Engl J Med 2016; 375:1617.
- Ashutosh K, Dunsky M. Noninvasive tests for responsiveness of pulmonary hypertension to oxygen. Prediction of survival in patients with chronic obstructive lung disease and cor pulmonale. Chest 1987; 92:393.
- Polić S, Rumboldt Z, Dujić Z, et al. Role of digoxin in right ventricular failure due to chronic cor pulmonale. Int J Clin Pharmacol Res 1990; 10:153.
- Mathur PN, Powles P, Pugsley SO, et al. Effect of digoxin on right ventricular function in severe chronic airflow obstruction. A controlled clinical trial. Ann Intern Med 1981; 95:283.
- McLaughlin VV, Shah SJ, Souza R, Humbert M. Management of pulmonary arterial hypertension. J Am Coll Cardiol 2015; 65:1976.
- Lee-Chiong TL, Matthay RA.. The heart in the stable COPD patient.. In: Clinical management of chronic obstructive pulmonary disease., Similowski T, Whitelaw WA, Derenne JP (Eds), Marcel Dekker, Inc., New York 2002. p.475.
- Seeger W, Adir Y, Barberà JA, et al. Pulmonary hypertension in chronic lung diseases. J Am Coll Cardiol 2013; 62:D109.
- Barnett CF, Bonura EJ, Nathan SD, et al. Treatment of sarcoidosis-associated pulmonary hypertension. A two-center experience. Chest 2009; 135:1455.
- Olschewski H, Ghofrani HA, Walmrath D, et al. Inhaled prostacyclin and iloprost in severe pulmonary hypertension secondary to lung fibrosis. Am J Respir Crit Care Med 1999; 160:600.
- Strange C, Bolster M, Mazur J, et al. Hemodynamic effects of epoprostenol in patients with systemic sclerosis and pulmonary hypertension. Chest 2000; 118:1077.
- Ghofrani HA, Wiedemann R, Rose F, et al. Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomised controlled trial. Lancet 2002; 360:895.
- Fisher KA, Serlin DM, Wilson KC, et al. Sarcoidosis-associated pulmonary hypertension: outcome with long-term epoprostenol treatment. Chest 2006; 130:1481.
- Rhee RL, Gabler NB, Praestgaard A, et al. Adverse Events in Connective Tissue Disease-Associated Pulmonary Arterial Hypertension. Arthritis Rheumatol 2015; 67:2457.
- Blanco I, Gimeno E, Munoz PA, 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; 181:270.
- Blanco I, Santos S, Gea J, et al. Sildenafil to improve respiratory rehabilitation outcomes in COPD: a controlled trial. Eur Respir J 2013; 42:982.
- Rietema H, Holverda S, Bogaard HJ, et al. Sildenafil treatment in COPD does not affect stroke volume or exercise capacity. Eur Respir J 2008; 31:759.
- Lederer DJ, Bartels MN, Schluger NW, et al. Sildenafil for chronic obstructive pulmonary disease: a randomized crossover trial. COPD 2012; 9:268.
- Holverda S, Rietema H, Bogaard HJ, et al. Acute effects of sildenafil on exercise pulmonary hemodynamics and capacity in patients with COPD. Pulm Pharmacol Ther 2008; 21:558.
- Stolz D, Rasch H, Linka A, et al. A randomised, controlled trial of bosentan in severe COPD. Eur Respir J 2008; 32:619.
- Badesch DB, Feldman J, Keogh A, et al. ARIES-3: ambrisentan therapy in a diverse population of patients with pulmonary hypertension. Cardiovasc Ther 2012; 30:93.
- Naeije R, Mélot C, Mols P, Hallemans R. Reduction in pulmonary hypertension by prostaglandin E1 in decompensated chronic obstructive pulmonary disease. Am Rev Respir Dis 1982; 125:1.
- Archer SL, Mike D, Crow J, et al. A placebo-controlled trial of prostacyclin in acute respiratory failure in COPD. Chest 1996; 109:750.
- Dernaika TA, Beavin M, Kinasewitz GT. Iloprost improves gas exchange and exercise tolerance in patients with pulmonary hypertension and chronic obstructive pulmonary disease. Respiration 2010; 79:377.
- Vonbank K, Ziesche R, Higenbottam TW, et al. Controlled prospective randomised trial on the effects on pulmonary haemodynamics of the ambulatory long term use of nitric oxide and oxygen in patients with severe COPD. Thorax 2003; 58:289.
- Ghofrani HA, Staehler G, Grünig E, et al. Acute effects of riociguat in borderline or manifest pulmonary hypertension associated with chronic obstructive pulmonary disease. Pulm Circ 2015; 5:296.
- Saggar R, Khanna D, Vaidya A, et al. Changes in right heart haemodynamics and echocardiographic function in an advanced phenotype of pulmonary hypertension and right heart dysfunction associated with pulmonary fibrosis. Thorax 2014; 69:123.
- Idiopathic Pulmonary Fibrosis Clinical Research Network, Zisman DA, Schwarz M, et al. A controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis. N Engl J Med 2010; 363:620.
- Jackson RM, Glassberg MK, Ramos CF, et al. Sildenafil therapy and exercise tolerance in idiopathic pulmonary fibrosis. Lung 2010; 188:115.
- Han MK, Bach DS, Hagan PG, et al. Sildenafil preserves exercise capacity in patients with idiopathic pulmonary fibrosis and right-sided ventricular dysfunction. Chest 2013; 143:1699.
- Zimmermann GS, von Wulffen W, Huppmann P, et al. Haemodynamic changes in pulmonary hypertension in patients with interstitial lung disease treated with PDE-5 inhibitors. Respirology 2014; 19:700.
- Raghu G, Nathan SD, Behr J, et al. Pulmonary hypertension in idiopathic pulmonary fibrosis with mild-to-moderate restriction. Eur Respir J 2015; 46:1370.
- Raghu G, Behr J, Brown KK, et al. Treatment of idiopathic pulmonary fibrosis with ambrisentan: a parallel, randomized trial. Ann Intern Med 2013; 158:641.
- King TE Jr, Behr J, Brown KK, et al. BUILD-1: a randomized placebo-controlled trial of bosentan in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2008; 177:75.
- King TE Jr, Brown KK, Raghu G, et al. BUILD-3: a randomized, controlled trial of bosentan in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2011; 184:92.
- Raghu G, Million-Rousseau R, Morganti A, et al. Macitentan for the treatment of idiopathic pulmonary fibrosis: the randomised controlled MUSIC trial. Eur Respir J 2013; 42:1622.
- Hoeper MM, Halank M, Wilkens H, et al. Riociguat for interstitial lung disease and pulmonary hypertension: a pilot trial. Eur Respir J 2013; 41:853.
- Humbert M, Coghlan JG, Ghofrani HA, et al. Riociguat for the treatment of pulmonary arterial hypertension associated with connective tissue disease: results from PATENT-1 and PATENT-2. Ann Rheum Dis 2017; 76:422.
- Ghofrani HA, Grimminger F, Grünig E, et al. Predictors of long-term outcomes in patients treated with riociguat for pulmonary arterial hypertension: data from the PATENT-2 open-label, randomised, long-term extension trial. Lancet Respir Med 2016; 4:361.
- https://clinicaltrials.gov/ct2/results?term=NCT02138825&Search=Search (Accessed on July 12, 2016).
- Le Pavec J, Lorillon G, Jaïs X, et al. Pulmonary Langerhans cell histiocytosis-associated pulmonary hypertension: clinical characteristics and impact of pulmonary arterial hypertension therapies. Chest 2012; 142:1150.
- Kiakouama L, Cottin V, Etienne-Mastroïanni B, et al. Severe pulmonary hypertension in histiocytosis X: long-term improvement with bosentan. Eur Respir J 2010; 36:202.
- Cottin V, Harari S, Humbert M, et al. Pulmonary hypertension in lymphangioleiomyomatosis: characteristics in 20 patients. Eur Respir J 2012; 40:630.
- Bonham CA, Oldham JM, Gomberg-Maitland M, Vij R. Prostacyclin and oral vasodilator therapy in sarcoidosis-associated pulmonary hypertension: a retrospective case series. Chest 2015; 148:1055.
- Keir GJ, Walsh SL, Gatzoulis MA, et al. Treatment of sarcoidosis-associated pulmonary hypertension: A single centre retrospective experience using targeted therapies. Sarcoidosis Vasc Diffuse Lung Dis 2014; 31:82.
- Baughman RP. Pulmonary hypertension associated with sarcoidosis. Arthritis Res Ther 2007; 9 Suppl 2:S8.
- Baughman RP, Judson MA, Lower EE, et al. Inhaled iloprost for sarcoidosis associated pulmonary hypertension. Sarcoidosis Vasc Diffuse Lung Dis 2009; 26:110.
- Baughman RP, Culver DA, Cordova FC, et al. Bosentan for sarcoidosis-associated pulmonary hypertension: a double-blind placebo controlled randomized trial. Chest 2014; 145:810.
- Preston IR, Klinger JR, Landzberg MJ, et al. Vasoresponsiveness of sarcoidosis-associated pulmonary hypertension. Chest 2001; 120:866.
- Shapiro S, Pollock DM, Gillies H, et al. Frequency of edema in patients with pulmonary arterial hypertension receiving ambrisentan. Am J Cardiol 2012; 110:1373.
- Milman N, Burton CM, Iversen M, et al. Pulmonary hypertension in end-stage pulmonary sarcoidosis: therapeutic effect of sildenafil? J Heart Lung Transplant 2008; 27:329.
- Boucly A, Cottin V, Nunes H, et al. Management and long-term outcomes of sarcoidosis-associated pulmonary hypertension. Eur Respir J 2017; 50.
- Friedman SE, Andrus BW. Obesity and pulmonary hypertension: a review of pathophysiologic mechanisms. J Obes 2012; 2012:505274.
- Hosokawa Y, Yamamoto T, Yabuno Y, et al. Inhaled nitric oxide therapy for secondary pulmonary hypertension with hypertrophic obstructive cardiomyopathy and severe kyphoscoliosis. Int J Cardiol 2012; 158:e20.
- Weill D, Benden C, Corris PA, et al. A consensus document for the selection of lung transplant candidates: 2014--an update from the Pulmonary Transplantation Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 2015; 34:1.
- Harari S, Simonneau G, De Juli E, et al. Prognostic value of pulmonary hypertension in patients with chronic interstitial lung disease referred for lung or heart-lung transplantation. J Heart Lung Transplant 1997; 16:460.
- Huerd SS, Hodges TN, Grover FL, et al. Secondary pulmonary hypertension does not adversely affect outcome after single lung transplantation. J Thorac Cardiovasc Surg 2000; 119:458.
- Fitton TP, Kosowski TR, Barreiro CJ, et al. Impact of secondary pulmonary hypertension on lung transplant outcome. J Heart Lung Transplant 2005; 24:1254.
- Bando K, Keenan RJ, Paradis IL, et al. Impact of pulmonary hypertension on outcome after single-lung transplantation. Ann Thorac Surg 1994; 58:1336.
- Whelan TP, Dunitz JM, Kelly RF, et al. Effect of preoperative pulmonary artery pressure on early survival after lung transplantation for idiopathic pulmonary fibrosis. J Heart Lung Transplant 2005; 24:1269.
- Hayes D Jr, Higgins RS, Black SM, 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; 34:430.
- Fang A, Studer S, Kawut SM, et al. Elevated pulmonary artery pressure is a risk factor for primary graft dysfunction following lung transplantation for idiopathic pulmonary fibrosis. Chest 2011; 139:782.
- Alalawi R, Whelan T, Bajwa RS, Hodges TN. Lung transplantation and interstitial lung disease. Curr Opin Pulm Med 2005; 11:461.
- Conte JV, Borja MJ, Patel CB, et al. Lung transplantation for primary and secondary pulmonary hypertension. Ann Thorac Surg 2001; 72:1673.
- Christie JD, Edwards LB, Kucheryavaya AY, et al. The Registry of the International Society for Heart and Lung Transplantation: 29th adult lung and heart-lung transplant report-2012. J Heart Lung Transplant 2012; 31:1073.
- Gottlieb J. Lung transplantation for interstitial lung diseases and pulmonary hypertension. Semin Respir Crit Care Med 2013; 34:281.
- Puri V, Patterson GA, Meyers BF. Single versus bilateral lung transplantation: do guidelines exist? Thorac Surg Clin 2015; 25:47.
- Gottlieb J. Lung transplantation for interstitial lung diseases. Curr Opin Pulm Med 2014; 20:457.
- Lu BS, Bhorade SM. Lung transplantation for interstitial lung disease. Clin Chest Med 2004; 25:773.
- Yildiz OA, Onen ZP, Sen E, et al. Predictors of long-term survival in patients with chronic obstructive pulmonary disease. Saudi Med J 2006; 27:1866.
- Budev MM, Arroliga AC, Wiedemann HP, Matthay RA. Cor pulmonale: an overview. Semin Respir Crit Care Med 2003; 24:233.
- MacNee W. Pathophysiology of cor pulmonale in chronic obstructive pulmonary disease. Part One. Am J Respir Crit Care Med 1994; 150:833.
- Hurdman J, Condliffe R, Elliot CA, et al. Pulmonary hypertension in COPD: results from the ASPIRE registry. Eur Respir J 2013; 41:1292.
- Oswald-Mammosser M, Weitzenblum E, Quoix E, et al. Prognostic factors in COPD patients receiving long-term oxygen therapy. Importance of pulmonary artery pressure. Chest 1995; 107:1193.
- Stone AC, Machan JT, Mazer J, et al. Echocardiographic evidence of pulmonary hypertension is associated with increased 1-year mortality in patients admitted with chronic obstructive pulmonary disease. Lung 2011; 189:207.
- Kessler R, Faller M, Fourgaut G, et al. Predictive factors of hospitalization for acute exacerbation in a series of 64 patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999; 159:158.
- Leuchte HH, Baumgartner RA, Nounou ME, et al. Brain natriuretic peptide is a prognostic parameter in chronic lung disease. Am J Respir Crit Care Med 2006; 173:744.
- Shorr AF, Davies DB, Nathan SD. Outcomes for patients with sarcoidosis awaiting lung transplantation. Chest 2002; 122:233.
- Nadrous HF, Pellikka PA, Krowka MJ, et al. Pulmonary hypertension in patients with idiopathic pulmonary fibrosis. Chest 2005; 128:2393.
- Strange C, Highland KB. Pulmonary hypertension in interstitial lung disease. Curr Opin Pulm Med 2005; 11:452.
- Nunes H, Humbert M, Capron F, et al. Pulmonary hypertension associated with sarcoidosis: mechanisms, haemodynamics and prognosis. Thorax 2006; 61:68.
- King TE Jr, Tooze JA, Schwarz MI, et al. Predicting survival in idiopathic pulmonary fibrosis: scoring system and survival model. Am J Respir Crit Care Med 2001; 164:1171.
- McLaughlin VV, Presberg KW, Doyle RL, et al. Prognosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest 2004; 126:78S.
- Kimura M, Taniguchi H, Kondoh Y, et al. Pulmonary hypertension as a prognostic indicator at the initial evaluation in idiopathic pulmonary fibrosis. Respiration 2013; 85:456.
- Hamada K, Nagai S, Tanaka S, et al. Significance of pulmonary arterial pressure and diffusion capacity of the lung as prognosticator in patients with idiopathic pulmonary fibrosis. Chest 2007; 131:650.
- Song JW, Song JK, Kim DS. Echocardiography and brain natriuretic peptide as prognostic indicators in idiopathic pulmonary fibrosis. Respir Med 2009; 103:180.
- Baughman RP, Engel PJ, Taylor L, Lower EE. Survival in sarcoidosis-associated pulmonary hypertension: the importance of hemodynamic evaluation. Chest 2010; 138:1078.
- Held M, Walthelm J, Baron S, et al. Functional impact of pulmonary hypertension due to hypoventilation and changes under noninvasive ventilation. Eur Respir J 2014; 43:156.
- GENERAL MEASURES
- Treatment of associated condition
- Conventional and supportive therapies
- OUR APPROACH
- Mild to moderate pulmonary hypertension
- - Observation
- Severe pulmonary hypertension
- - Pulmonary arterial hypertension-directed therapy
- Chronic obstructive disease
- Interstitial lung disease
- Sleep disordered breathing and hypoxia
- Overlap syndromes
- Patients who fail therapy
- - Lung transplantation
- SOCIETY GUIDELINE LINKS
- SUMMARY AND RECOMMENDATIONS