Pulmonary hypertension associated with interstitial lung disease
- 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
Pulmonary hypertension (PH) is increasingly recognized as a complication of interstitial lung disease (ILD) [1-3]. It can exist when ILD is mild, but is more common when hypoxemia and severe pulmonary dysfunction exist. The definition, classification, prevalence, pathogenesis, and clinical manifestations of ILD-associated PH are reviewed here. In addition, diagnosis, treatment, and prognosis are discussed. A specific type of ILD-associated PH, PH associated with systemic sclerosis (formerly called scleroderma), and diagnosis of non-ILD-associated PH are presented separately. (See "Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Definition, classification, risk factors, screening, and prognosis" and "Clinical features and diagnosis of pulmonary hypertension in adults" and "Overview of pulmonary hypertension in adults" and "Treatment of pulmonary hypertension in adults".)
Interstitial lung disease (ILD)-associated pulmonary hypertension (PH) is considered present when PH exists in a patient who has ILD, and no alternative cause of the PH can be identified.
●PH is defined as a mean pulmonary artery pressure (mPAP) greater than 25 mmHg at rest, as measured by right heart catheterization . PH is considered severe if cardiac index is <2 L/min/m2 or if mPAP is ≥35 mmHg .
Previous definitions that are no longer used include an mPAP greater than 30 mmHg with exercise (measured by right heart catheterization)  and a systolic pulmonary artery pressure (sPAP) greater than 40 mmHg (measured by Doppler echocardiography) . (See "Clinical features and diagnosis of pulmonary hypertension in adults", section on 'Diagnostic criteria'.)
●ILD is inferred when the history, physical examination, imaging, and pathology suggest diffuse parenchymal lung disease. Common manifestations include dyspnea with exertion, cough, auscultatory crackles on chest examination, diffuse bilateral reticular or nodular opacities on chest imaging studies, and interstitial inflammation or fibrosis on lung biopsy. (See "Approach to the adult with interstitial lung disease: Clinical evaluation" and "Approach to the adult with interstitial lung disease: Diagnostic testing".)
- 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.
- Nathan SD, Hassoun PM. Pulmonary hypertension due to lung disease and/or hypoxia. Clin Chest Med 2013; 34:695.
- Ryu JH, Moua T, Daniels CE, et al. Idiopathic pulmonary fibrosis: evolving concepts. Mayo Clin Proc 2014; 89:1130.
- Badesch DB, Champion HC, Sanchez MA, et al. Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol 2009; 54:S55.
- Seeger W, Adir Y, Barberà JA, et al. Pulmonary hypertension in chronic lung diseases. J Am Coll Cardiol 2013; 62:D109.
- Barst RJ, McGoon M, Torbicki A, et al. Diagnosis and differential assessment of pulmonary arterial hypertension. J Am Coll Cardiol 2004; 43:40S.
- Executive summary from the World Symposium on Primary Pulmonary Hypertension. Co-sponsored by The World Health Organization, Rich S (Ed), Evian, France 1998.
- Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2013; 62:D34.
- Corte TJ, Wells AU, Nicholson AG, et al. Pulmonary hypertension in sarcoidosis: a review. Respirology 2011; 16:69.
- 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.
- Maloney JP. Advances in the treatment of secondary pulmonary hypertension. Curr Opin Pulm Med 2003; 9:139.
- Shapiro S. Management of pulmonary hypertension resulting from interstitial lung disease. Curr Opin Pulm Med 2003; 9:426.
- Chaowalit N, Pellikka PA, Decker PA, et al. Echocardiographic and clinical characteristics of pulmonary hypertension complicating pulmonary Langerhans cell histiocytosis. Mayo Clin Proc 2004; 79:1269.
- 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.
- McGoon M, Gutterman D, Steen V, et al. Screening, early detection, and diagnosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest 2004; 126:14S.
- Hoeper MM. Pulmonary hypertension in collagen vascular disease. Eur Respir J 2002; 19:571.
- Rayner CF, Grubnic S. Pulmonary manifestations of systemic autoimmune disease. Best Pract Res Clin Rheumatol 2004; 18:381.
- Battle RW, Davitt MA, Cooper SM, et al. Prevalence of pulmonary hypertension in limited and diffuse scleroderma. Chest 1996; 110:1515.
- Badesch DB, Tapson VF, McGoon MD, et al. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial. Ann Intern Med 2000; 132:425.
- MacGregor AJ, Canavan R, Knight C, et al. Pulmonary hypertension in systemic sclerosis: risk factors for progression and consequences for survival. Rheumatology (Oxford) 2001; 40:453.
- Fagan KA, Badesch DB. Pulmonary hypertension associated with connective tissue disease. Prog Cardiovasc Dis 2002; 45:225.
- Hesselstrand R, Ekman R, Eskilsson J, et al. Screening for pulmonary hypertension in systemic sclerosis: the longitudinal development of tricuspid gradient in 227 consecutive patients, 1992-2001. Rheumatology (Oxford) 2005; 44:366.
- Chang B, Wigley FM, White B, Wise RA. Scleroderma patients with combined pulmonary hypertension and interstitial lung disease. J Rheumatol 2003; 30:2398.
- Rhee RL, Gabler NB, Sangani S, et al. Comparison of Treatment Response in Idiopathic and Connective Tissue Disease-associated Pulmonary Arterial Hypertension. Am J Respir Crit Care Med 2015; 192:1111.
- Wigley FM, Lima JA, Mayes M, et al. The prevalence of undiagnosed pulmonary arterial hypertension in subjects with connective tissue disease at the secondary health care level of community-based rheumatologists (the UNCOVER study). Arthritis Rheum 2005; 52:2125.
- Shorr AF, Davies DB, Nathan SD. Outcomes for patients with sarcoidosis awaiting lung transplantation. Chest 2002; 122:233.
- Handa T, Nagai S, Miki S, et al. Incidence of pulmonary hypertension and its clinical relevance in patients with sarcoidosis. Chest 2006; 129:1246.
- Shorr AF, Helman DL, Davies DB, Nathan SD. Pulmonary hypertension in advanced sarcoidosis: epidemiology and clinical characteristics. Eur Respir J 2005; 25:783.
- Dobarro D, Schreiber BE, Handler C, et al. Clinical characteristics, haemodynamics and treatment of pulmonary hypertension in sarcoidosis in a single centre, and meta-analysis of the published data. Am J Cardiol 2013; 111:278.
- Rapti A, Kouranos V, Gialafos E, et al. Elevated pulmonary arterial systolic pressure in patients with sarcoidosis: prevalence and risk factors. Lung 2013; 191:61.
- Nadrous HF, Pellikka PA, Krowka MJ, et al. Pulmonary hypertension in patients with idiopathic pulmonary fibrosis. Chest 2005; 128:2393.
- Leuchte HH, Neurohr C, Baumgartner R, et al. Brain natriuretic peptide and exercise capacity in lung fibrosis and pulmonary hypertension. Am J Respir Crit Care Med 2004; 170:360.
- Rosenman KD, Zhu Z. Pneumoconiosis and associated medical conditions. Am J Ind Med 1995; 27:107.
- Tomasini M, Chiappino G. Hemodynamics of pulmonary circulation in asbestosis: study of 16 cases. Am J Ind Med 1981; 2:167.
- Scano G, Garcia-Herreros P, Stendardi D, et al. Cardiopulmonary adaptation to exercise in coal miners. Arch Environ Health 1980; 35:360.
- Hopkins N, McLoughlin P. The structural basis of pulmonary hypertension in chronic lung disease: remodelling, rarefaction or angiogenesis? J Anat 2002; 201:335.
- Strange C, Highland KB. Pulmonary hypertension in interstitial lung disease. Curr Opin Pulm Med 2005; 11:452.
- Mura M, Anraku M, Yun Z, et al. Gene expression profiling in the lungs of patients with pulmonary hypertension associated with pulmonary fibrosis. Chest 2012; 141:661.
- MacLean MR. Endothelin-1 and serotonin: mediators of primary and secondary pulmonary hypertension? J Lab Clin Med 1999; 134:105.
- Cella G, Bellotto F, Tona F, et al. Plasma markers of endothelial dysfunction in pulmonary hypertension. Chest 2001; 120:1226.
- Tuder RM, Cool CD, Yeager M, et al. The pathobiology of pulmonary hypertension. Endothelium. Clin Chest Med 2001; 22:405.
- Budhiraja R, Tuder RM, Hassoun PM. Endothelial dysfunction in pulmonary hypertension. Circulation 2004; 109:159.
- Kirchengast M, Luz M. Endothelin receptor antagonists: clinical realities and future directions. J Cardiovasc Pharmacol 2005; 45:182.
- Braun-Moscovici Y, Nahir AM, Balbir-Gurman A. Endothelin and pulmonary arterial hypertension. Semin Arthritis Rheum 2004; 34:442.
- Trakada G, Nikolaou E, Pouli A, et al. Endothelin-1 levels in interstitial lung disease patients during sleep. Sleep Breath 2003; 7:111.
- Yamakami T, Taguchi O, Gabazza EC, et al. Arterial endothelin-1 level in pulmonary emphysema and interstitial lung disease. Relation with pulmonary hypertension during exercise. Eur Respir J 1997; 10:2055.
- Harari S, Brenot F, Barberis M, Simmoneau G. Advanced pulmonary histiocytosis X is associated with severe pulmonary hypertension. Chest 1997; 111:1142.
- Fartoukh M, Humbert M, Capron F, et al. Severe pulmonary hypertension in histiocytosis X. Am J Respir Crit Care Med 2000; 161:216.
- Gagermeier J, Dauber J, Yousem S, et al. Abnormal vascular phenotypes in patients with idiopathic pulmonary fibrosis and secondary pulmonary hypertension. Chest 2005; 128:601S.
- Yousem SA. The pulmonary pathologic manifestations of the CREST syndrome. Hum Pathol 1990; 21:467.
- Tuder RM, Lee SD, Cool CC. Histopathology of pulmonary hypertension. Chest 1998; 114:1S.
- Rubin LJ, Badesch DB. Evaluation and management of the patient with pulmonary arterial hypertension. Ann Intern Med 2005; 143:282.
- Hoeper MM, Barberà JA, Channick RN, et al. Diagnosis, assessment, and treatment of non-pulmonary arterial hypertension pulmonary hypertension. J Am Coll Cardiol 2009; 54:S85.
- Wahidi MM, Rocha AT, Hollingsworth JW, et al. Contraindications and safety of transbronchial lung biopsy via flexible bronchoscopy. A survey of pulmonologists and review of the literature. Respiration 2005; 72:285.
- Bossone E, Bodini BD, Mazza A, Allegra L. Pulmonary arterial hypertension: the key role of echocardiography. Chest 2005; 127:1836.
- Rubin LJ, American College of Chest Physicians. Diagnosis and management of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest 2004; 126:4S.
- 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.
- Badesch DB, Abman SH, Ahearn GS, et al. Medical therapy for pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest 2004; 126:35S.
- Task Force for Diagnosis and Treatment of Pulmonary Hypertension of European Society of Cardiology (ESC), European Respiratory Society (ERS), International Society of Heart and Lung Transplantation (ISHLT), et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J 2009; 34:1219.
- Rhee RL, Gabler NB, Praestgaard A, et al. Adverse Events in Connective Tissue Disease-Associated Pulmonary Arterial Hypertension. Arthritis Rheumatol 2015; 67:2457.
- 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, Culver DA, Cordova FC, et al. Bosentan for sarcoidosis-associated pulmonary hypertension: a double-blind placebo controlled randomized trial. Chest 2014; 145:810.
- 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.
- 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.
- https://clinicaltrials.gov/ct2/results?term=NCT02138825&Search=Search (Accessed on July 12, 2016).
- 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.
- Barnett CF, Bonura EJ, Nathan SD, et al. Treatment of sarcoidosis-associated pulmonary hypertension. A two-center experience. Chest 2009; 135:1455.
- 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.
- 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.
- 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.
- Conte JV, Borja MJ, Patel CB, et al. Lung transplantation for primary and secondary pulmonary hypertension. Ann Thorac Surg 2001; 72:1673.
- Fitton TP, Kosowski TR, Barreiro CJ, et al. Impact of secondary pulmonary hypertension on lung transplant outcome. J Heart Lung Transplant 2005; 24:1254.
- 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.
- 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.
- 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.