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Epidemiology, pathogenesis, clinical evaluation, and diagnosis of pulmonary veno-occlusive disease in adults

Jess Mandel, MD
Barbara LeVarge, MD
Section Editor
Scott Manaker, MD, PhD
Deputy Editor
Geraldine Finlay, MD


Pulmonary veno-occlusive disease (PVOD) is a rare condition that represents a small subgroup of adult patients with pulmonary hypertension (PH) (table 1) [1-3]. The terms "isolated pulmonary venous sclerosis," "obstructive disease of the pulmonary veins," and "venous form of primary pulmonary hypertension" were previously used to describe the syndrome [4-7]. Compared with pulmonary arterial hypertension (eg, idiopathic or heritable PAH), PVOD-associated PH has a grim prognosis and serious adverse effects can occur when pulmonary hypertension-specific advanced therapy is administered. Thus, the suspicion for and early identification of PVOD is critical to its management.  

The epidemiology, pathogenesis, clinical features, and diagnosis of PVOD are reviewed here. The treatment of PVOD-associated PH as well as the clinical features and diagnosis of other forms of pulmonary hypertension are discussed separately. (See "Treatment and prognosis of pulmonary veno-occlusive disease in adults" and "Overview of pulmonary hypertension in adults" and "Clinical features and diagnosis of pulmonary hypertension in adults".)


The World Health Organization (WHO) has classified pulmonary hypertension (PH) based upon etiology and mechanism into the five groups listed below (table 1) [8,9]. Pulmonary arterial hypertension (PAH) refers to group 1 PAH. Pulmonary hypertension (PH) refers to any of group 2 through group 5 PH, and is also used when referring to all five groups collectively.

Group 1 – PAH (PVOD is a subgroup of this type of PAH)

Group 2 – PH due to left heart disease


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Literature review current through: Sep 2016. | This topic last updated: May 16, 2016.
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  1. Montani D, Price LC, Dorfmuller P, et al. Pulmonary veno-occlusive disease. Eur Respir J 2009; 33:189.
  2. Montani D, Achouh L, Dorfmüller P, et al. Pulmonary veno-occlusive disease: clinical, functional, radiologic, and hemodynamic characteristics and outcome of 24 cases confirmed by histology. Medicine (Baltimore) 2008; 87:220.
  3. O'Callaghan DS, Dorfmuller P, Jaïs X, et al. Pulmonary veno-occlusive disease: the bête noire of pulmonary hypertension in connective tissue diseases? Presse Med 2011; 40:e65.
  4. Brown CH, Harrison CV. Pulmonary veno-occlusive disease. Lancet 1966; 2:61.
  5. Heath D, Segel N, Bishop J. Pulmonary veno-occlusive disease. Circulation 1966; 34:242.
  6. Weisser K, Wyler F, Gloor F. Pulmonary veno-occlusive disease. Arch Dis Child 1967; 42:322.
  7. Rosenthal A, Vawter G, Wagenvoort CA. Intrapulmonary veno-occlusive disease. Am J Cardiol 1973; 31:78.
  8. Rich S (ed). Executive summary from the World Symposium on Primary Pulmonary Hypertension, Evian, France, September 6-10, 1998, co-sponsored by The World Health Organization.
  9. Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2013; 62:D34.
  10. Palazzini M, Manes A. Pulmonary veno-occlusive disease misdiagnosed as idiopathic pulmonary arterial hypertension. Eur Respir Rev 2009; 18:177.
  11. Balke L, Both M, Winkler C, et al. Scintigraphy Leading to the Misdiagnosis of Chronic Thromboembolic Disease in a Patient With Pulmonary Veno-Occlusive Disease. Circulation 2016; 133:1627.
  12. Pietra GG, Edwards WD, Kay JM, et al. Histopathology of primary pulmonary hypertension. A qualitative and quantitative study of pulmonary blood vessels from 58 patients in the National Heart, Lung, and Blood Institute, Primary Pulmonary Hypertension Registry. Circulation 1989; 80:1198.
  13. Palevsky HI, Schloo BL, Pietra GG, et al. Primary pulmonary hypertension. Vascular structure, morphometry, and responsiveness to vasodilator agents. Circulation 1989; 80:1207.
  14. Wagenvoort CA. Lung biopsy specimens in the evaluation of pulmonary vascular disease. Chest 1980; 77:614.
  15. Kinare SG, Deshpande J. Primary pulmonary hypertension in India (autopsy study of 26 cases). Indian Heart J 1987; 39:9.
  16. Burke AP, Farb A, Virmani R. The pathology of primary pulmonary hypertension. Mod Pathol 1991; 4:269.
  17. Pietra GG. The pathology of primary pulmonary hypertension. In: Primary pulmonary hypertension: lung biology in health and disease, Rubin LJ, Rich S (Eds), Marcel Dekker, Inc, New York 1997. p.19.
  18. Bjornsson J, Edwards WD. Primary pulmonary hypertension: a histopathologic study of 80 cases. Mayo Clin Proc 1985; 60:16.
  19. Wagenvoort, CA, Wagenvoort, N. Primary pulmonary hypertension: a pathologic study of the lung vessels in 156 clinically diagnosed cases. Circulation 1970; 42:1163.
  20. Rubin LJ. Primary pulmonary hypertension. N Engl J Med 1997; 336:111.
  21. Veeraraghavan S, Koss MN, Sharma OP. Pulmonary veno-occlusive disease. Curr Opin Pulm Med 1999; 5:310.
  22. Wagenvoort CA. Pulmonary veno-occlusive disease. Entity or syndrome? Chest 1976; 69:82.
  23. Thadani U, Burrow C, Whitaker W, Heath D. Pulmonary veno-occlusive disease. Q J Med 1975; 44:133.
  24. Bunte MC, Patnaik MM, Pritzker MR, Burns LJ. Pulmonary veno-occlusive disease following hematopoietic stem cell transplantation: a rare model of endothelial dysfunction. Bone Marrow Transplant 2008; 41:677.
  25. Davies P, Reid L. Pulmonary veno-occlusive disease in siblings: case reports and morphometric study. Hum Pathol 1982; 13:911.
  26. Voordes CG, Kuipers JR, Elema JD. Familial pulmonary veno-occlusive disease: a case report. Thorax 1977; 32:763.
  27. Eyries M, Montani D, Girerd B, et al. EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive form of pulmonary hypertension. Nat Genet 2014; 46:65.
  28. Runo JR, Vnencak-Jones CL, Prince M, et al. Pulmonary veno-occlusive disease caused by an inherited mutation in bone morphogenetic protein receptor II. Am J Respir Crit Care Med 2003; 167:889.
  29. Perros F, Cohen-Kaminsky S, Gambaryan N, et al. Cytotoxic cells and granulysin in pulmonary arterial hypertension and pulmonary veno-occlusive disease. Am J Respir Crit Care Med 2013; 187:189.
  30. Doll DC, Yarbro JW. Vascular toxicity associated with chemotherapy and hormonotherapy. Curr Opin Oncol 1994; 6:345.
  31. Gagnadoux F, Capron F, Lebeau B. Pulmonary veno-occlusive disease after neoadjuvant mitomycin chemotherapy and surgery for lung carcinoma. Lung Cancer 2002; 36:213.
  32. Perros F, Günther S, Ranchoux B, et al. Mitomycin-Induced Pulmonary Veno-Occlusive Disease: Evidence From Human Disease and Animal Models. Circulation 2015; 132:834.
  33. Lombard CM, Churg A, Winokur S. Pulmonary veno-occlusive disease following therapy for malignant neoplasms. Chest 1987; 92:871.
  34. Liu, L, Sackler, JP. A case of pulmonary veno-occlusive disease: etiological and therapeutic appraisal. Angiology 1973; 23:299.
  35. Montani D, Lau EM, Descatha A, et al. Occupational exposure to organic solvents: a risk factor for pulmonary veno-occlusive disease. Eur Respir J 2015; 46:1721.
  36. Rabiller A, Jaïs X, Hamid A, et al. Occult alveolar haemorrhage in pulmonary veno-occlusive disease. Eur Respir J 2006; 27:108.
  37. Abenhaim L, Moride Y, Brenot F, et al. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. International Primary Pulmonary Hypertension Study Group. N Engl J Med 1996; 335:609.
  38. Kumana CR, Ng M, Lin HJ, et al. Herbal tea induced hepatic veno-occlusive disease: quantification of toxic alkaloid exposure in adults. Gut 1985; 26:101.
  39. Tandon BN, Tandon HD, Tandon RK, et al. An epidemic of veno-occlusive disease of liver in central India. Lancet 1976; 2:271.
  40. Williams LM, Fussell S, Veith RW, et al. Pulmonary veno-occlusive disease in an adult following bone marrow transplantation. Case report and review of the literature. Chest 1996; 109:1388.
  41. Kramer MR, Estenne M, Berkman N, et al. Radiation-induced pulmonary veno-occlusive disease. Chest 1993; 104:1282.
  42. Gutman JA, Allen CT, Madtes DK, et al. Pulmonary veno-occlusive disease following reduced-intensity cord blood transplantation. Bone Marrow Transplant 2008; 42:559.
  43. Hackman RC, Madtes DK, Petersen FB, Clark JG. Pulmonary venoocclusive disease following bone marrow transplantation. Transplantation 1989; 47:989.
  44. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 14-1983. A 67-year-old woman with pulmonary hypertension. N Engl J Med 1983; 308:823.
  45. Hussein A, Trowitzsch E, Brockmann M. Pulmonary veno-occlusive disease, antiphospholipid antibody and pulmonary hypertension in an adolescent. Klin Padiatr 1999; 211:92.
  46. Kishida Y, Kanai Y, Kuramochi S, Hosoda Y. Pulmonary venoocclusive disease in a patient with systemic lupus erythematosus. J Rheumatol 1993; 20:2161.
  47. Hoffstein V, Ranganathan N, Mullen JB. Sarcoidosis simulating pulmonary veno-occlusive disease. Am Rev Respir Dis 1986; 134:809.
  48. Hamada K, Teramoto S, Narita N, et al. Pulmonary veno-occlusive disease in pulmonary Langerhans' cell granulomatosis. Eur Respir J 2000; 15:421.
  49. Morassut PA, Walley VM, Smith CD. Pulmonary veno-occlusive disease and the CREST variant of scleroderma. Can J Cardiol 1992; 8:1055.
  50. Saito A, Takizawa H, Ito K, et al. A case of pulmonary veno-occlusive disease associated with systemic sclerosis. Respirology 2003; 8:383.
  51. Zhang L, Visscher D, Rihal C, Aubry MC. Pulmonary veno-occlusive disease as a primary cause of pulmonary hypertension in a patient with mixed connective tissue disease. Rheumatol Int 2007; 27:1163.
  52. Johnson SR, Patsios D, Hwang DM, Granton JT. Pulmonary veno-occlusive disease and scleroderma associated pulmonary hypertension. J Rheumatol 2006; 33:2347.
  53. Crissman JD, Koss M, Carson RP. Pulmonary veno-occlusive disease secondary to granulomatous venulitis. Am J Surg Pathol 1980; 4:93.
  54. Liang MH, Stern S, Fortin PR, et al. Fatal pulmonary venoocclusive disease secondary to a generalized venulopathy: a new syndrome presenting with facial swelling and pericardial tamponade. Arthritis Rheum 1991; 34:228.
  55. Dwyer N, Smith R, Challis D, et al. Granulomatous angiitis leading to a pulmonary veno-occlusive disease-like picture. Eur Respir J 2009; 33:666.
  56. Günther S, Jaïs X, Maitre S, et al. Computed tomography findings of pulmonary venoocclusive disease in scleroderma patients presenting with precapillary pulmonary hypertension. Arthritis Rheum 2012; 64:2995.
  57. Hasleton PS, Ironside JW, Whittaker JS, et al. Pulmonary veno-occlusive disease. A report of four cases. Histopathology 1986; 10:933.
  58. Kokturk N, Demir N, Demircan S, et al. Pulmonary veno-occlusive disease in a patient with a history of Hashimoto's thyroiditis. Indian J Chest Dis Allied Sci 2005; 47:289.
  59. Naniwa T, Takeda Y. Long-term remission of pulmonary veno-occlusive disease associated with primary Sjögren's syndrome following immunosuppressive therapy. Mod Rheumatol 2011; 21:637.
  60. Devereux G, Evans MJ, Kerr KM, Legge JS. Pulmonary veno-occlusive disease complicating Felty's syndrome. Respir Med 1998; 92:1089.
  61. Höra, J. Zur Histologie der klinischen "primaren Pulmonalsklerose." Frankfurt Z Pathol 1934; 47:100.
  62. Pulmonary veno-occlusive disease. Br Med J 1972; 3:369.
  64. McDonnell PJ, Summer WR, Hutchins GM. Pulmonary veno-occlusive disease. Morphological changes suggesting a viral cause. JAMA 1981; 246:667.
  65. Ruchelli ED, Nojadera G, Rutstein RM, Rudy B. Pulmonary veno-occlusive disease. Another vascular disorder associated with human immunodeficiency virus infection? Arch Pathol Lab Med 1994; 118:664.
  66. Escamilla R, Hermant C, Berjaud J, et al. Pulmonary veno-occlusive disease in a HIV-infected intravenous drug abuser. Eur Respir J 1995; 8:1982.
  67. A case of veno-occlusive disease. Demonstrated at the Royal Postgraduate Medical School. Br Med J 1968; 1:818.
  68. Townend JN, Roberts DH, Jones EL, Davies MK. Fatal pulmonary venoocclusive disease after use of oral contraceptives. Am Heart J 1992; 124:1643.
  69. Tsou E, Waldhorn RE, Kerwin DM, et al. Pulmonary venoocclusive disease in pregnancy. Obstet Gynecol 1984; 64:281.
  70. Urisman A, Leard LE, Nathan M, et al. Rapidly progressive pulmonary venoocclusive disease in young women taking oral contraceptives. J Heart Lung Transplant 2012; 31:1031.
  71. Carrington CB, Liebow AA. Pulmonary veno-occlusive disease. Hum Pathol 1970; 1:322.
  72. D'Souza M, Vergales J, Jayakumar KA. Hypoplastic left heart syndrome and pulmonary veno-occlusive disease in an infant. Pediatr Cardiol 2013; 34:1949.
  73. Murakami T, Horigome H, Yamaki S, et al. Pulmonary veno-occlusive disease associated with partial anomalous pulmonary venous connection. Pediatr Int 2003; 45:747.
  74. Shrivastava S, Moller JH, Edwards JE. Congenital unilateral pulmonary venous atresia with pulmonary veno-occlusive disease in contralateral lung: an unusual association. Pediatr Cardiol 1986; 7:213.
  75. Güttinger E, Vrugt B, Speich R, et al. Reactive Pulmonary Capillary Hemangiomatosis and Pulmonary Veno-Occlusive Disease in a Patient with Repaired Scimitar Syndrome. Case Rep Cardiol 2016; 2016:9384126.
  76. Montani D, O'Callaghan DS, Savale L, et al. Pulmonary veno-occlusive disease: recent progress and current challenges. Respir Med 2010; 104 Suppl 1:S23.
  77. Montani D, Kemp K, Dorfmuller P, et al. Idiopathic pulmonary arterial hypertension and pulmonary veno-occlusive disease: similarities and differences. Semin Respir Crit Care Med 2009; 30:411.
  78. Dai Z, Matsui Y. Pulmonary veno-occlusive disease: an 80-year-old mystery. Respiration 2014; 88:148.
  79. Lantuéjoul S, Sheppard MN, Corrin B, et al. Pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis: a clinicopathologic study of 35 cases. Am J Surg Pathol 2006; 30:850.
  80. Holcomb BW Jr, Loyd JE, Ely EW, et al. Pulmonary veno-occlusive disease: a case series and new observations. Chest 2000; 118:1671.
  81. Resten A, Maitre S, Humbert M, et al. Pulmonary hypertension: CT of the chest in pulmonary venoocclusive disease. AJR Am J Roentgenol 2004; 183:65.
  82. Jones RM, Dawson A, Jenkins GH, et al. Sarcoidosis-related pulmonary veno-occlusive disease presenting with recurrent haemoptysis. Eur Respir J 2009; 34:517.
  83. Mandel J, Mark EJ, Hales CA. Pulmonary veno-occlusive disease. Am J Respir Crit Care Med 2000; 162:1964.
  84. Frazier AA, Franks TJ, Mohammed TL, et al. From the Archives of the AFIP: pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis. Radiographics 2007; 27:867.
  85. Leinonen H, Pohjola-Sintonen S, Krogerus L. Pulmonary veno-occlusive disease. Acta Med Scand 1987; 221:307.
  86. Elliott CG, Colby TV, Hill T, Crapo RO. Pulmonary veno-occlusive disease associated with severe reduction of single-breath carbon monoxide diffusing capacity. Respiration 1988; 53:262.
  87. Scheibel RL, Dedeker KL, Gleason DF, et al. Radiographic and angiographic characteristics of pulmonary veno-occlusive disease. Radiology 1972; 103:47.
  88. Swensen SJ, Tashjian JH, Myers JL, et al. Pulmonary venoocclusive disease: CT findings in eight patients. AJR Am J Roentgenol 1996; 167:937.
  89. Wiener-Kronish JP, Goldstein R, Matthay RA, et al. Lack of association of pleural effusion with chronic pulmonary arterial and right atrial hypertension. Chest 1987; 92:967.
  90. Resten A, Maître S, Humbert M, et al. Pulmonary arterial hypertension: thin-section CT predictors of epoprostenol therapy failure. Radiology 2002; 222:782.
  91. Cassart M, Gevenois PA, Kramer M, et al. Pulmonary venoocclusive disease: CT findings before and after single-lung transplantation. AJR Am J Roentgenol 1993; 160:759.
  92. Worthy SA, Müller NL, Hartman TE, et al. Mosaic attenuation pattern on thin-section CT scans of the lung: differentiation among infiltrative lung, airway, and vascular diseases as a cause. Radiology 1997; 205:465.
  93. Miura A, Akagi S, Nakamura K, et al. Different sizes of centrilobular ground-glass opacities in chest high-resolution computed tomography of patients with pulmonary veno-occlusive disease and patients with pulmonary capillary hemangiomatosis. Cardiovasc Pathol 2013; 22:287.
  94. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 48-1993. A 27-year-old woman with mediastinal lymphadenopathy and relentless cor pulmonale. N Engl J Med 1993; 329:1720.
  95. Dufour B, Maître S, Humbert M, et al. High-resolution CT of the chest in four patients with pulmonary capillary hemangiomatosis or pulmonary venoocclusive disease. AJR Am J Roentgenol 1998; 171:1321.
  96. Thomas de Montpréville V, Dulmet E, Fadel E, Dartevelle P. Lymph node pathology in pulmonary veno-occlusive disease and pulmonary capillary heamangiomatosis. Virchows Arch 2008; 453:171.
  97. Seferian A, Helal B, Jaïs X, et al. Ventilation/perfusion lung scan in pulmonary veno-occlusive disease. Eur Respir J 2012; 40:75.
  98. Rich S, Pietra GG, Kieras K, et al. Primary pulmonary hypertension: radiographic and scintigraphic patterns of histologic subtypes. Ann Intern Med 1986; 105:499.
  99. Bailey CL, Channick RN, Auger WR, et al. "High probability" perfusion lung scans in pulmonary venoocclusive disease. Am J Respir Crit Care Med 2000; 162:1974.
  100. Weed HG. Pulmonary "capillary" wedge pressure not the pressure in the pulmonary capillaries. Chest 1991; 100:1138.
  101. Rambihar VS, Fallen EL, Cairns JA. Pulmonary veno-occlusive disease: antemortem diagnosis from roentgenographic and hemodynamic findings. Can Med Assoc J 1979; 120:1519.
  102. Chawla SK, Kittle CF, Faber LP, Jensik RJ. Pulmonary venoocclusive disease. Ann Thorac Surg 1976; 22:249.
  103. Rapidly progressive dyspnea in a teenage boy. Clinical pathological conference. JAMA 1973; 223:1243.
  104. Masters K, Bennett S. Pulmonary veno-occlusive disease: an uncommon cause of pulmonary hypertension. BMJ Case Rep 2013; 2013.
  105. Palmer SM, Robinson LJ, Wang A, et al. Massive pulmonary edema and death after prostacyclin infusion in a patient with pulmonary veno-occlusive disease. Chest 1998; 113:237.
  106. Matthews AW, Buchanan R. A case of pulmonary veno-occlusive disease and a new bronchoscopic sign. Respir Med 1990; 84:503.
  107. Waldhorn RE, Tsou E, Smith FP, Kerwin DM. Pulmonary veno-occlusive disease associated with microangiopathic hemolytic anemia and chemotherapy of gastric adenocarcinoma. Med Pediatr Oncol 1984; 12:394.
  108. Sanderson JE, Spiro SG, Hendry AT, Turner-Warwick M. A case of pulmonary veno-occlusive disease respondong to treatment with azathioprine. Thorax 1977; 32:140.
  109. De Vries TW, Weening JJ, Roorda RJ. Pulmonary veno-occlusive disease: a case report and a review of therapeutic possibilities. Eur Respir J 1991; 4:1029.
  110. World Symposium on Primary Pulmonary Hypertension 1998. Evian, France, 1998.
  111. Rubin E, Farber JL. The respiratory system. In: Pathology, 2nd ed, Rubin E, Farber JL (Eds), J.B. Lippincott, Philadelphia 1994. p.557.
  112. Wagenvoort CA, Wagenvoort N. The pathology of pulmonary veno-occlusive disease. Virchows Arch A Pathol Anat Histol 1974; 364:69.
  113. Stewart S, Rassl D. Advances in the understanding and classification of pulmonary hypertension. Histopathology 2009; 54:104.
  114. Cortese DA. Pulmonary function in mitral stenosis. Mayo Clin Proc 1978; 53:321.
  115. Wagenvoort CA, Wagenvoort N, Takahashi T. Pulmonary veno-occlusive disease: involvement of pulmonary arteries and review of the literature. Hum Pathol 1985; 16:1033.
  116. Almagro P, Julià J, Sanjaume M, et al. Pulmonary capillary hemangiomatosis associated with primary pulmonary hypertension: report of 2 new cases and review of 35 cases from the literature. Medicine (Baltimore) 2002; 81:417.
  117. Ito K, Ichiki T, Ohi K, et al. Pulmonary capillary hemangiomatosis with severe pulmonary hypertension. Circ J 2003; 67:793.
  118. Fishman AP. Clinical classification of pulmonary hypertension. Clin Chest Med 2001; 22:385.
  119. Oviedo A, Abramson LP, Worthington R, et al. Congenital pulmonary capillary hemangiomatosis: Report of two cases and review of the literature. Pediatr Pulmonol 2003; 36:253.
  120. Matsukuma S, Sato K. Pulmonary capillary haemangiomatosis-like lesions in severely congested lungs. Histopathology 2011; 59:876.
  121. Glassroth J, Woodford DW, Carrington CB, Gaensler EA. Pulmonary veno-occlusive disease in the middle-aged. Respiration 1985; 47:309.