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Pulmonary Vascular Disease: Specific Evaluation and Timing for Listing Eligible Patients to Receive Lung Transplantation and Management of the Pre-lung Transplant Patient

  • Alison S. Witkin
  • Richard N. Channick
Chapter

Abstract

Pulmonary arterial hypertension is characterized by progressive vasculopathy in the pulmonary arterial bed leading to right ventricular dysfunction and failure. Despite significant advances in medical therapy over the last several decades, lung transplantation remains a necessary treatment option for patients with severe and refractory disease. This chapter discusses the role of lung transplantation in the management of pulmonary hypertension as well as transplant-specific considerations, including the use of single versus dual lung transplant and the diminishing role of combined heart and lung transplantation.

Keywords

Pulmonary hypertension Pulmonary arterial hypertension Lung transplantation Heart transplantation Chronic thromboembolic pulmonary hypertension Pulmonary veno-occlusive disease Pulmonary capillary hemangiomatosis 

Abbreviations

6MWD

Six minute walk distance

APAH

Attributable pulmonary hypertension

CF

Cystic fibrosis

CHD

Congenital heart disease

COPD

Chronic obstructive pulmonary disease

DLT

Double-lung transplant

ECMO

Extracorporeal membrane oxygenation

FDA

Food and Drug Administration

IPF

Idiopathic pulmonary fibrosis

LAS

Lung allocation score

LT

Lung transplant

HLT

Heart/lung transplant

ILD

Interstitial lung disease

IPAH

Idiopathic pulmonary arterial hypertension

mPAP

Mean pulmonary artery pressure

NYHA

New York Heart Association

PAH

Pulmonary arterial hypertension

PASP

Pulmonary artery systolic pressure

PCH

Pulmonary capillary hemangiomatosis

PCWP

Pulmonary capillary wedge pressure

PH

Pulmonary hypertension

PPHN

Persistent pulmonary hypertension of the newborn

PTE

Pulmonary thromboendarterectomy

PVOD

Pulmonary veno-occlusive disease

PVR

Pulmonary vascular resistance

RHC

Right heart catheterization

SPH

Secondary pulmonary hypertension

TTE

Transthoracic echocardiogram

V/Q

Ventilation/perfusion

WHO

World Health Organization

WU

Woods units

References

  1. 1.
    Brown LM, Chen H, Halpern S, et al. Delay in recognition of pulmonary arterial hypertension: factors identified from the REVEAL Registry. Chest. 2011;140:19–26.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Galie N, Humbert M, Vachiery JL, 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 Heart J. 2016;37:67–119.CrossRefPubMedGoogle Scholar
  3. 3.
    Fisher MR, Forfia PR, Chamera E, et al. Accuracy of Doppler echocardiography in the hemodynamic assessment of pulmonary hypertension. Am J Respir Crit Care Med. 2009;179:615–21.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Rich JD, Shah SJ, Swamy RS, Kamp A, Rich S. Inaccuracy of Doppler echocardiographic estimates of pulmonary artery pressures in patients with pulmonary hypertension: implications for clinical practice. Chest. 2011;139:988–93.CrossRefPubMedGoogle Scholar
  5. 5.
    Hoeper MM, Bogaard HJ, Condliffe R, et al. Definitions and diagnosis of pulmonary hypertension. J Am Coll Cardiol. 2013;62:D42–50.CrossRefPubMedGoogle Scholar
  6. 6.
    Yusen RD, Edwards LB, Kucheryavaya AY, et al. The Registry of the International Society for Heart and Lung Transplantation: Thirty-second Official Adult Lung and Heart-Lung Transplantation Report—2015; Focus Theme: Early Graft Failure. J Heart Lung Transplant. 2015;34:1264–77.CrossRefPubMedGoogle Scholar
  7. 7.
    Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013;62:D34–41.CrossRefGoogle Scholar
  8. 8.
    Hoeper MM, Simon RGJ. The changing landscape of pulmonary arterial hypertension and implications for patient care. Eur Respiratory Rev. 2014;23:450–7.CrossRefGoogle Scholar
  9. 9.
    Badesch DB, Raskob GE, Elliott CG, et al. Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry. Chest. 2010;137:376–87.CrossRefGoogle Scholar
  10. 10.
    Vachiery JL, Adir Y, Barbera JA, et al. Pulmonary hypertension due to left heart diseases. J Am Coll Cardiol. 2013;62:D100–8.CrossRefPubMedGoogle Scholar
  11. 11.
    Strange G, Playford D, Stewart S, et al. Pulmonary hypertension: prevalence and mortality in the Armadale echocardiography cohort. Heart. 2012;98:1805–11.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Andersen KH, Iversen M, Kjaergaard J, et al. Prevalence, predictors, and survival in pulmonary hypertension related to end-stage chronic obstructive pulmonary disease. J Heart Lung Transplant. 2012;31:373–80.CrossRefGoogle Scholar
  13. 13.
    Hayes D Jr, Black SM, Tobias JD, Kirkby S, Mansour HM, Whitson BA. Influence of pulmonary hypertension on patients with idiopathic pulmonary fibrosis awaiting lung transplantation. Ann Thorac Surg. 2016;101:246–52.CrossRefPubMedGoogle Scholar
  14. 14.
    Hayes D Jr, Black SM, Tobias JD, Mansour HM, Whitson BA. Prevalence of pulmonary hypertension and its influence on survival in patients with advanced chronic obstructive pulmonary disease prior to lung transplantation. COPD. 2016;13:50–6.CrossRefPubMedGoogle Scholar
  15. 15.
    Solidoro P, Patrucco F, Bonato R, et al. Pulmonary hypertension in chronic obstructive pulmonary disease and pulmonary fibrosis: prevalence and hemodynamic differences in lung transplant recipients at transplant center’s referral time. Transplant Proc. 2015;47:2161–5.CrossRefPubMedGoogle Scholar
  16. 16.
    Seeger W, Adir Y, Barbera JA, et al. Pulmonary hypertension in chronic lung diseases. J Am Coll Cardiol. 2013;62:D109–16.CrossRefPubMedGoogle Scholar
  17. 17.
    Galiè N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J. 2009;34:1219–63.CrossRefPubMedGoogle Scholar
  18. 18.
    Tunariu N, Gibbs SJ, Win Z, et al. Ventilation-perfusion scintigraphy is more sensitive than multidetector CTPA in detecting chronic thromboembolic pulmonary disease as a treatable cause of pulmonary hypertension: official publication. J Nucl Med. 2007;48:680–4.CrossRefPubMedGoogle Scholar
  19. 19.
    Auger WR, Fedullo PF, Moser KM, Buchbinder M, Peterson KL. Chronic major-vessel thromboembolic pulmonary artery obstruction: appearance at angiography. Radiology. 1992;182:393–8.CrossRefPubMedGoogle Scholar
  20. 20.
    Galie N, Corris PA, Frost A, et al. Updated treatment algorithm of pulmonary arterial hypertension. J Am Coll Cardiol. 2013;62:D60–72.CrossRefPubMedGoogle Scholar
  21. 21.
    Galie N, Barbera JA, Frost AE, et al. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. N Engl J Med. 2015;373:834–44.CrossRefPubMedGoogle Scholar
  22. 22.
    Sitbon O, Channick R, Chin KM, et al. Selexipag for the treatment of pulmonary arterial hypertension. N Engl J Med. 2015;373:2522–33.CrossRefGoogle Scholar
  23. 23.
    Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013;369:809–18.CrossRefGoogle Scholar
  24. 24.
    Conte JV, Gaine SP, Orens JB, Harris T, Rubin LJ. The influence of continuous intravenous prostacyclin therapy for primary pulmonary hypertension on the timing and outcome of transplantation. J Heart Lung Transplant. 1998;17:679–85.PubMedPubMedCentralGoogle Scholar
  25. 25.
    LeVarge BL, Channick RN. The changing paradigm in pulmonary hypertension trials: longer duration, new endpoints. Curr Opin Pulm Med. 2015;21:438–45.CrossRefPubMedGoogle Scholar
  26. 26.
    Galie N, Manes A, Negro L, Palazzini M, Bacchi-Reggiani ML, Branzi A. A meta-analysis of randomized controlled trials in pulmonary arterial hypertension. Eur Heart J. 2009;30:394–403.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Benza RL, Miller DP, Barst RJ, Badesch DB, Frost AE, McGoon MD. An evaluation of long-term survival from time of diagnosis in pulmonary arterial hypertension from the REVEAL Registry. Chest. 2012;142:448–56.CrossRefPubMedGoogle Scholar
  28. 28.
    Sandoval J, Gaspar J, Pulido T, et al. Graded balloon dilation atrial septostomy in severe primary pulmonary hypertension. A therapeutic alternative for patients nonresponsive to vasodilator treatment. J Am Coll Cardiol. 1998;32:297–304.CrossRefPubMedGoogle Scholar
  29. 29.
    Doyle RL, McCrory D, Channick RN, Simonneau G, Conte J, American College of Chest Physicians. Surgical treatments/interventions for pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004;126:63S–71S.CrossRefPubMedGoogle Scholar
  30. 30.
    Kothari SS, Yusuf A, Juneja R, Yadav R, Naik N. Graded balloon atrial septostomy in severe pulmonary hypertension. Indian Heart J. 2002;54:164–9.PubMedGoogle Scholar
  31. 31.
    Rosenzweig EB, Brodie D, Abrams DC, Agerstrand CL, Bacchetta M. Extracorporeal membrane oxygenation as a novel bridging strategy for acute right heart failure in group 1 pulmonary arterial hypertension. ASAIO J. 2014;60:129–33.CrossRefPubMedGoogle Scholar
  32. 32.
    Mayes J, Niranjan G, Dark J, Clark S. Bridging to lung transplantation for severe pulmonary hypertension using dual central Novalung lung assist devicesdagger. Interact Cardiovasc Thorac Surg. 2016;22(5):677–8.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Patil NP, Mohite PN, Reed A, Popov AF, Simon AR. Modified technique using Novalung as bridge to transplant in pulmonary hypertension. Ann Thorac Surg. 2015;99:719–21.CrossRefPubMedGoogle Scholar
  34. 34.
    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;34:1–15.CrossRefPubMedGoogle Scholar
  35. 35.
    Toyoda Y, Thacker J, Santos R, et al. Long-term outcome of lung and heart-lung transplantation for idiopathic pulmonary arterial hypertension. Ann Thorac Surg. 2008;86:1116–22.CrossRefPubMedGoogle Scholar
  36. 36.
    de Perrot M, Granton JT, McRae K, et al. Outcome of patients with pulmonary arterial hypertension referred for lung transplantation: a 14-year single-center experience. J Thorac Cardiovasc Surg. 2012;143:910–8.CrossRefPubMedGoogle Scholar
  37. 37.
    Benza RL, Miller DP, Gomberg-Maitland M, et al. Predicting survival in pulmonary arterial hypertension: insights from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL). Circulation. 2010;122:164–72.CrossRefPubMedGoogle Scholar
  38. 38.
    Humbert M, Sitbon O, Chaouat A, et al. Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation. 2010;122:156–63.CrossRefPubMedGoogle Scholar
  39. 39.
    Miyamoto S, Nagaya N, Satoh T, et al. Clinical correlates and prognostic significance of six-minute walk test in patients with primary pulmonary hypertension. Comparison with cardiopulmonary exercise testing. Am J Respir Crit Care Med. 2000;161:487–92.CrossRefPubMedGoogle Scholar
  40. 40.
    Mandel J, Mark EJ, Hales CA. Pulmonary veno-occlusive disease. Am J Respir Crit Care Med. 2000;162:1964–73.CrossRefPubMedGoogle Scholar
  41. 41.
    Egan TM, Murray S, Bustami RT, et al. Development of the new lung allocation system in the United States. Am J Transplant. 2006;6:1212–27.CrossRefPubMedGoogle Scholar
  42. 42.
    McCurry KR, Shearon TH, Edwards LB, et al. Lung transplantation in the United States, 1998-2007. Am J Transplant. 2009;9:942–58.CrossRefPubMedGoogle Scholar
  43. 43.
    Chen H, Shiboski SC, Golden JA, et al. Impact of the lung allocation score on lung transplantation for pulmonary arterial hypertension. Am J Respir Crit Care Med. 2009;180:468–74.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Chan KM. Idiopathic pulmonary arterial hypertension and equity of donor lung allocation in the era of the lung allocation score: are we there yet? Am J Respir Crit Care Med. 2009;180:385–7.CrossRefPubMedGoogle Scholar
  45. 45.
    Miller DP, Farber HW. “Who’ll be the next in line?” The lung allocation score in patients with pulmonary arterial hypertension. J Heart Lung Transplant. 2013;32:1165–7.CrossRefPubMedGoogle Scholar
  46. 46.
    Gomberg-Maitland M, Glassner-Kolmin C, Watson S, et al. Survival in pulmonary arterial hypertension patients awaiting lung transplantation. J Heart Lung Transplant. 2013;32:1179–86.CrossRefPubMedGoogle Scholar
  47. 47.
    Schaffer JM, Singh SK, Joyce DL, et al. Transplantation for idiopathic pulmonary arterial hypertension: improvement in the lung allocation score era. Circulation. 2013;127:2503–13.CrossRefPubMedGoogle Scholar
  48. 48.
    Benza RL, Miller DP, Frost A, Barst RJ, Krichman AM, McGoon MD. Analysis of the lung allocation score estimation of risk of death in patients with pulmonary arterial hypertension using data from the REVEAL Registry. Transplantation. 2010;90:298–305.CrossRefPubMedGoogle Scholar
  49. 49.
  50. 50.
  51. 51.
  52. 52.
    Bando K, Armitage JM, Paradis IL, et al. Indications for and results of single, bilateral, and heart-lung transplantation for pulmonary hypertension. J Thorac Cardiovasc Surg. 1994;108:1056–65.PubMedGoogle Scholar
  53. 53.
    Pasque MK, Trulock EP, Cooper JD, et al. Single lung transplantation for pulmonary hypertension. Single institution experience in 34 patients. Circulation. 1995;92(8):2252.CrossRefPubMedGoogle Scholar
  54. 54.
    Gammie JS, Keenan RJ, Pham SM, et al. Single-versus double-lung transplantation for pulmonary hypertension. J Thorac Cardiovasc Surg. 1998;115:397–402; discussion 402–3.CrossRefPubMedGoogle Scholar
  55. 55.
    Levine SM, Gibbons WJ, Bryan CL, et al. Single lung transplantation for primary pulmonary hypertension. Chest. 1990;98:1107–15.CrossRefPubMedGoogle Scholar
  56. 56.
    Ritchie M, Waggoner AD, Davila-Roman VG, Barzilai B, Trulock EP, Eisenberg PR. Echocardiographic characterization of the improvement in right ventricular function in patients with severe pulmonary hypertension after single-lung transplantation. J Am Coll Cardiol. 1993;22(4):1170.CrossRefPubMedGoogle Scholar
  57. 57.
    Conte JV, Borja MJ, Patel CB, Yang SC, Jhaveri RM, Orens JB. Lung transplantation for primary and secondary pulmonary hypertension. Ann Thorac Surg. 2001;72:1673–9; discussion 1673–80.CrossRefPubMedGoogle Scholar
  58. 58.
    Boujoukos AJ, Martich GD, Vega JD, Keenan RJ, Griffith BP. Reperfusion injury in single-lung transplant recipients with pulmonary hypertension and emphysema. J Heart Lung Transplant. 1997;16:439–48.PubMedGoogle Scholar
  59. 59.
    Levine SM, Jenkinson SG, Bryan CL, et al. Ventilation-perfusion inequalities during graft rejection in patients undergoing single lung transplantation for primary pulmonary hypertension. Chest. 1992;101:401–5.CrossRefPubMedGoogle Scholar
  60. 60.
    Yusen RD, Edwards LB, Kucheryavaya AY, et al. The Registry of the International Society for Heart and Lung Transplantation: Thirty-second Official Adult Lung and Heart-Lung Transplantation Report—2015; Focus Theme: Early Graft Failure (Supplementary Online Slides). J Heart Lung Transplant. 2015;34:1264–77.CrossRefPubMedGoogle Scholar
  61. 61.
    Reitz BA, Wallwork JL, Hunt SA, et al. Heart-lung transplantation: successful therapy for patients with pulmonary vascular disease. N Engl J Med. 1982;306:557–64.CrossRefPubMedGoogle Scholar
  62. 62.
    Chapelier A, Vouhe P, Macchiarini P, et al. Comparative outcome of heart-lung and lung transplantation for pulmonary hypertension. J Thorac Cardiovasc Surg. 1993;106:299–307.PubMedGoogle Scholar
  63. 63.
    Ueno T, Smith JA, Snell GI, et al. Bilateral sequential single lung transplantation for pulmonary hypertension and Eisenmenger’s syndrome. Ann Thorac Surg. 2000;69:381–7.CrossRefPubMedGoogle Scholar
  64. 64.
    Olland A, Falcoz PE, Canuet M, Massard G. Should we perform bilateral-lung or heart-lung transplantation for patients with pulmonary hypertension? Interact Cardiovasc Thorac Surg. 2013;17:166–70.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Fadel E, Mercier O, Mussot S, et al. Long-term outcome of double-lung and heart-lung transplantation for pulmonary hypertension: a comparative retrospective study of 219 patients. Eur J Cardiothorac Surg. 2010;38:277–84.CrossRefPubMedGoogle Scholar
  66. 66.
    Pielsticker EJ, Martinez FJ, Rubenfire M. Lung and heart-lung transplant practice patterns in pulmonary hypertension centers. J Heart Lung Transplant. 2001;20:1297–304.CrossRefPubMedGoogle Scholar
  67. 67.
    Pereszlenyi A, Lang G, Steltzer H, et al. Bilateral lung transplantation with intra- and postoperatively prolonged ECMO support in patients with pulmonary hypertension. Eur J Cardiothorac Surg. 2002;21:858–63.CrossRefPubMedGoogle Scholar
  68. 68.
    Tudorache I, Sommer W, Kuhn C, et al. Lung transplantation for severe pulmonary hypertension—awake extracorporeal membrane oxygenation for postoperative left ventricular remodelling. Transplantation. 2015;99:451–8.CrossRefPubMedGoogle Scholar
  69. 69.
    Krishnamurthy Y, Cooper LB, Lu D, et al. Trends and outcomes of patients with adult congenital heart disease and pulmonary hypertension listed for orthotopic heart transplantation in the United States. J Heart Lung Transplant. 2016;35(5):619–24.CrossRefPubMedGoogle Scholar
  70. 70.
    Choong CK, Sweet SC, Guthrie TJ, et al. Repair of congenital heart lesions combined with lung transplantation for the treatment of severe pulmonary hypertension: a 13-year experience. J Thorac Cardiovasc Surg. 2005;129:661–9.CrossRefPubMedGoogle Scholar
  71. 71.
    Butler J, Stankewicz MA, Wu J, et al. Pre-transplant reversible pulmonary hypertension predicts higher risk for mortality after cardiac transplantation. J Heart Lung Transplant. 2005;24:170–7.CrossRefPubMedGoogle Scholar
  72. 72.
    Kirklin JK, Naftel DC, Kirklin JW, Blackstone EH, White-Williams C, Bourge RC. Pulmonary vascular resistance and the risk of heart transplantation. J Heart Transplant. 1988;7:331–6.PubMedGoogle Scholar
  73. 73.
    Vakil K, Duval S, Sharma A, et al. Impact of pre-transplant pulmonary hypertension on survival after heart transplantation: a UNOS registry analysis. Int J Cardiol. 2014;176:595–9.CrossRefPubMedGoogle Scholar
  74. 74.
    Hayes D Jr, Tumin D, Daniels CJ, et al. Pulmonary artery pressure and benefit of lung transplantation in adult cystic fibrosis patients. Ann Thorac Surg. 2016;101:1104–9.CrossRefPubMedGoogle Scholar
  75. 75.
    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;119:458–65.CrossRefPubMedGoogle Scholar
  76. 76.
    Julliard WA, Meyer KC, De Oliveira NC, et al. The presence or severity of pulmonary hypertension does not affect outcomes for single-lung transplantation. Thorax. 2016;71(5):478–80.CrossRefPubMedGoogle Scholar
  77. 77.
    Condliffe R, Kiely DG, Gibbs JS, et al. Improved outcomes in medically and surgically treated chronic thromboembolic pulmonary hypertension. Am J Respir Crit Care Med. 2008;177:1122–7.CrossRefPubMedGoogle Scholar
  78. 78.
    D’Armini AM, Cattadori B, Monterosso C, Emmi V, Piovella F, Vigano M. Surgical therapy for chronic thromboembolic pulmonary hypertension: criteria for choosing lung transplant vs thromboendarterectomy. J Heart Lung Transplant. 2001;20:218.CrossRefPubMedGoogle Scholar
  79. 79.
    Ghofrani HA, D’Armini AM, Grimminger F, et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med. 2013;369:319–29.CrossRefGoogle Scholar
  80. 80.
    Mizoguchi H, Ogawa A, Munemasa M, Mikouchi H, Ito H, Matsubara H. Refined balloon pulmonary angioplasty for inoperable patients with chronic thromboembolic pulmonary hypertension. Circ Cardiovasc Interv. 2012;5:748–55.CrossRefPubMedGoogle Scholar
  81. 81.
    Massad MG, Powell CR, Kpodonu J, et al. Outcomes of lung transplantation in patients with scleroderma. World J Surg. 2005;29:1510–5.CrossRefPubMedGoogle Scholar
  82. 82.
    Zhao YD, Peng J, Granton E, et al. Pulmonary vascular changes 22 years after single lung transplantation for pulmonary arterial hypertension: a case report with molecular and pathological analysis. Pulm Circulation. 2015;5:739–43.CrossRefGoogle Scholar
  83. 83.
    Soriano CM, Gaine SP, Conte JV, Fairman RP, White C, Rubin LJ. Anastomotic pulmonary hypertension after lung transplantation for primary pulmonary hypertension: report of surgical correction. Chest. 1999;116:564–6.CrossRefPubMedGoogle Scholar
  84. 84.
    Izbicki G, Shitrit D, Schechtman I, et al. Recurrence of pulmonary veno-occlusive disease after heart-lung transplantation. J Heart Lung Transplant. 2005;24:635–7.CrossRefPubMedGoogle Scholar
  85. 85.
    Lee C, Suh RD, Krishnam MS, et al. Recurrent pulmonary capillary hemangiomatosis after bilateral lung transplantation. J Thorac Imaging. 2010;25:W89–92.CrossRefPubMedGoogle Scholar

Copyright information

© The Author(s) 2018

Authors and Affiliations

  1. 1.Division of Pulmonary and Critical Care Medicine, Department of MedicineMassachusetts General HospitalBostonUSA

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