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Pulmonary veno-occlusive disease in an adult following bone marrow transplantation: case report and review of the literature
From CHEST, 5/1/96 by Luke M. Williams

Pulmonary veno-occlusive disease (PVOD) was diagnosed in an adult following chemotherapy and bone marrow transplantation (BMT) for acute lymphoblastic leukemia. A medical literature review showed only three previous reports of PVOD following BMT occurring in children but no prior cases in adults.

Key words: acute lymphocytic leukemia; antineoplastic agents; bone marrow transplantation; corticosteroids; pulmonary hypertension; pulmonary veno-occlusive disease

Abbreviations: ALL=acute lymphoblastic leukemia; BMT=bone marrow transplantation; PVOD=pulmonary veno-occlusive disease

Pulmonary veno-occlusive disease (PVOD) is a rare cause of primary pulmonary hypertension pathologically characterized by obstruction of the pulmonary veins and venules by intimal fibrosis. Approximately 125 cases have been reported in the literature, with the diagnosis having been made most often at the time of autopsy.(1) Affecting both children and adults, the typical clinical course is rapidly progressive, and few patients survive 2 years beyond the time of diagnosis.(2) The cause remains unknown, though numerous conditions have been associated with its development.(1),(2),(3),(4),(5),(6),(7),(8),(9),(10) Twelve cases of PVOD occurring after chemotherapy have been reported,(3),(4),(5),(6),(7),(8),(9) including those of three children after bone marrow transplantation (BMT) for acute lymphoblastic leukemia (ALL).(7),(8) We present the first case of PVOD following BMT in an adult.


A 24-year-old man with a 7-year history of cigarette smoking was admitted to the hospital with extreme dyspnea on exertion. ALL was diagnosed 20 months prior to this admission. A prolonged chemotherapeutic induction course included multiple doses of cyclophosphamide, doxorubicin (Adriamycin), methotrexate, intrathecally administered methotrexate, arabinosylcytosine, and vincristine sulfate. Other intermittent chemotherapeutic agents included prednisone, cyclosporine, dactinomycin, vincristine, and carmustine, granulocyte colony-stimulating factor, and gamma-immunoglobulin. Remission was achieved, and maintenance therapy was initiated with mercaptopurine and methotrexate. ALL recurred, and a second chemotherapeutic course with asparaginase was started; the patient then underwent allogeneic marrow transplantation. Post-transplantation maintenance therapy consisted of prednisolone and cyclosporine, and the patient's clinical course remained stable for 6 months. He noted intermittent pedal edema 3 months prior to admission, but this resolved spontaneously. Two weeks prior to admission, he developed rapidly progressive dyspnea on exertion, moderate cough productive of occasional clear sputum, but no fever. Outpatient evaluation at our institution showed moderately elevated jugular venous pressure, rare inspiratory squeaks on lung auscultation, and a chest radiograph significant for cardiomegaly, pulmonary vascular prominence, a patchy left lower lobe infiltrate, and a blunted right costophrenic angle. Spirometric values demonstrated a minimally decreased forced expiratory flow, mid-expiratory flow rates, and a severely decreased carbon monoxide diffusion capacity (11 mL/min/mm Hg; 28% predicted). He was treated with amoxicillin/clavulanate potassium and albuterol, and a follow-up visit 1 week later showed little change in symptoms and spirometric values. Lower extremity sonographic studies did not disclose the presence of thrombi, and a ventilation perfusion scan was not indicative of pulmonary emboli. A skin biopsy revealed no evidence of graft-vs-host disease. He was admitted to the hospital for a full evaluation of pulmonary hypertension. At the time of admission, physical examination showed a BP of 120/70 mm Hg taken with the patient supine; heart rate, 120 beats per minute; oral temperature, 37.4[degrees]C. He was a thin male in no distress at rest, who became tachypneic with minimal exertion. In addition to a normal [S.sub.1] and [S.sub.2], a soft [S.sub.4] and a 2/6 systolic murmur were auscultated at the left lower sternal border. Pulmonary examination showed bibasilar crackles and inspiratory squeaks. A WBC count was within normal limits. With the patient breathing room air, arterial blood gas values were as follows: pH, 7.48; [Pco.sub.2], 25 mm Hg; 44 mm Hg; oxygen saturation, 85%. An ECG demonstrated right axis deviation and a right bundle branch block. A chest x-ray film showed cardiomegaly, prominent pulmonary arteries, and patchy infiltrative changes in both bases and midlung fields (Fig 1). The ventilation perfusion scan revealed mild to moderate perfusion inhomogeneity with normal ventilation. However, no obvious defects in perfusion were evident (Fig 2). An echocardiogram showed a markedly increased right ventricular size with moderately decreased function, paradoxical septal motion, estimated pulmonary artery systolic pressure of 60 mm Hg, moderate tricuspid regurgitation, and an enlarged right atrium. The pulmonary artery systolic pressure was estimated by the continuous Doppler technique since tricuspid regurgitation was present and there was no evidence of pulmonic stenosis. Under circumstances, the peak regurgitation flow velocity predicts right ventricular systolic and thus pulmonary systolic pressure. Left ventricular function appeared normal, and there was no evidence of mitral valve disease.

He was placed on oxygen, 5 L/min, delivered by nasal cannula, and oxygen saturation determined by pulse oximetry improved to 91 to 93%. In order to establish a diagnosis in this immunocompromised host, he underwent thoracoscopic biopsy of the right lower lobe without complications. Catheterization of the right side of the heart and pulmonary capillary wedge pressure measurements were not performed because a biopsy of the lung was to be performed. Pathologic appearance of the lung biopsy showed patchy interstitial fibrosis and veins with thickened, stenotic lumina (Fig 3). While minimal intimal proliferation was noted in the arterial walls, the primary pathologic finding was PVOD. Absence of accompanying airways supports the thesis that the involved vessels were veins. This diagnosis was confirmed in consultation with the Pulmonary Division of the Armed Forces Institute of Pathology after elastin, van Gieson's and MOVAT stains were performed (to confirm that the involved vessels were veins, not arteries). Intravenous corticosteroid and full-dose heparin anticoagulation therapy were instituted, and his dyspnea improved markedly for a period of 1 week. With the patient resting and breathing room air, oxygen saturation improved from 85% to 90%. A 6-min walk test showed oxygen desaturation to a low of 81% with exercise. He was discharged on a regimen of orally administered prednisone, 60 mg every day, warfarin to maintain an international normalized ratio (INR) of 2 to 3, and oxygen delivered by nasal cannula to be used during exertion. Follow-up has revealed continued symptomatic improvement, and currently, the dosage of prednisone is being tapered gradually. A chest radiograph 6 months later shows resolution of cardiomegaly and infiltrates, and another echocardiogram demonstrates resolution of right ventricular enlargement and no evidence of pulmonary hypertension.


Clinically described in 1934 and pathologically described and named in 1996,(11) PVOD is one of several unusual causes of pulmonary hypertension due to venous outflow obstruction. Most other venous causes of pulmonary hypertension are congenital or related to structural postoperative changes. Acquired causes of postcapillary pulmonary hypertension other than PVOD include venous compression by enlarged mediastinal structures, primary or metastatic tumor involving the pulmonary veins, atrial myxoma, fibrosing mediastinitis, and pulmonary venous phlebitis (as in tuberculosis).(12),(13)

Approximately 125 cases of PVOD are reported in the literature. About one third of these cases occur in children, but ages range from 8 weeks to 67 years.(14),(15),(16) While the male-female distribution is about equal for patients under the age of 16 years, it is 1.8:1.0 for adults.(14) Patients usually present with a history of progressive dyspnea on exertion. As the disease worsens, orthopnea, paroxysmal nocturnal dyspnea, and syncope may develop.(2) Physical signs are consistent with pulmonary hypertension and include a right ventricular heave and a loud pulmonic heart sound. In later stages, lower extremity edema and elevated jugular venous pressure may be noted. Bibasilar inspiratory crackles may result from increased pulmonary congestion.(17)

Radiographic findings include cardiomegaly and dilation of the central pulmonary arteries. Postcapillary pulmonary hypertension may produce patchy alveolar infiltrates, Kerley B lines, and small pleural effusions.(4),(18) A perfusion scan is usually normal but may exhibit patchy, nonsegmental abnormalities.(2),(19) Pulmonary function testing and blood gas value analysis demonstrate hypoxia, normal spirometric values, and normal or decreased diffusion capacity.(20) ECG abnormalities include right axis deviation and right ventricular hypertrophy. An echocardiogram shows right ventricular hypertrophy and may disclose tricuspid regurgitation in more advanced cases. An echocardiogram also helps exclude left ventricular failure and obstructive lesions of the left side of the heart, such as mitral stenosis, cor triatriatum, left atrial myxoma, and pulmonary vein stenosis.(17) Pulmonary artery catheterization generally shows the pulmonary capillary wedge pressure to be normal or slightly elevated. Because venules rather than the larger pulmonary veins are occluded, the static column of blood produced when the pulmonary artery catheter balloon is inflated reflects the normal pressure in the larger veins and left atrium, though the pressure in the proximal venules and capillaries may actually be elevated.(21) Pulmonary angiography typically reveals no arterial filling defects but delayed arterial runoff and venous filling.

It has been suggested that the triad of severe pulmonary hypertension, radiographic evidence of pulmonary edema, and a normal wedge pressure is diagnostic of PVOD. However, most investigators agree that the diagnosis of PVOD only can be made reliably by lung biopsy.(22) The prominent finding is obstruction of the pulmonary veins and venules by intimal fibrosis, usually of loose, myxoid, paucicellular connective tissue which is most reliably demonstrated by special elastic tissue stains.(1) Recanalization of venules with the formation of intravascular fibrous septae is also seen. Fibrosis of the pulmonary arteries, often as severe as that noted in veins, may be seen in about one half of patients with PVOD. In fact, it has been suggested that PVOD is infrequently diagnosed due to the underuse of elastic stains.(23) While it was previously suspected that the arterial involvement was due to prolonged pulmonary hypertension from venous occlusion, organization of thrombi is currently thought to be involved in a common pathogenesis affecting both veins and arteries.

No single cause can be implicated in the development of PVOD, making PVOD most likely a syndrome rather than a distinct clinical entity. Numerous factors have been associated with its pathogenesis. Several case reports have suggested a viral respiratory tract infection as a causal agent.(24) Others have proposed an immunologic cause.(25),(26) A genetic influence has been suggested by several cases involving siblings.(15),(22) More recently, chemotherapy has emerged as a potential toxic etiologic agent in the development of PVOD.(23) To our knowledge, 12 cases associated with chemotherapy have been reported in the literature.(3),(4),(5),(6),(7),(8),(9) Bleomycin sulfate, mitomycin, and carmustine have been most strongly implicated.(23) Most cases have been diagnosed at the time of autopsy and occurred in patients receiving multiple chemotherapeutic agents in multiple courses for varied types of malignant neoplasms.

Hepatic veno-occlusive disease is a well recognized complication of BMT,(23) but to our knowledge, only three cases of PVOD have been reported following BMT. Troussard et al(7) described a male child with ALL (the diagnosis was made when he was 7). This child was treated with total body irradiation and multiple chemotherapeutic agents, including cyclophosphamide, daunorubicin, arabinosylcytosine, and methotrexate. His clinical course was complicated by two relapses, graft-vs-host disease, and interstitial pneumonitis. He eventually died from respiratory failure, and a postmortem biopsy of the right lower lobe showed PVOD. Hackman et al(8) subsequently reported two cases of PVOD in children, ALL in both diagnosed when they were 4 years old; they were treated with BMT after therapy with high-dose carmustine, etoposide, and cyclophosphamide. Of interest is that hepatic veno-occlusive disease occurred and resolved in the second patient prior to the onset of pulmonary symptoms, suggesting that the course of PVOD does not parallel that of hepatic veno-occlusive disease. In one patient, a diagnosis of PVOD was made on the basis of open lung biopsy. The other patient was diagnosed clinically in view of signs and symptoms, an elevated pulmonary artery pressure, a normal wedge pressure, and a normal left ventricular function. Both responded favorably to steroid therapy.

Our case demonstrates the difficulty encountered when trying to implicate a specific chemotherapeutic agent in the development of this rarely diagnosed disease. Our patient received multiple agents. While carmustine has been linked to PVOD, our patient received a relatively low dose of this agent. We speculate that PVOD in this case was most likely secondary to toxicity due to multiple chemotherapeutic agents rather than a single offending drug. However, we cannot exclude the possibility of a complication due to the primary process, ALL.

In general, patients with PVOD respond poorly to therapy.(23) Death due to progressive pulmonary hypertension and right ventricular failure usually occurs within 2 years of symptom onset. Anticoagulants have been tried with very limited effect.(1) Response to vasodilators has been poor, though one patient treated with nifedipine survived greater than 6 years after onset.(14) One patient with a significant vasculitic component responded favorably to azathioprine.(25) Our patient has demonstrated remarkable improvement with corticosteroid and anticoagulant therapy, as evidenced by resolution of symptoms and pulmonary hypertension shown by echocardiography. Of the 12 reported patients with chemotherapy-associated PVOD, only 2 were treated with corticosteroids, and both showed significant clinical improvement.(8)

Our experience suggests that the diagnosis of PVOD should be entertained in adult patients following BMT and chemotherapy who present with signs or symptoms of pulmonary hypertension. Early diagnosis would seem to be advantageous, as available evidence in the literature and presented here suggests that chemotherapy-associated PVOD may respond favorably to corticosteroid therapy.


(1) Wagenvoort CA, Wagenvoort N, Takahashi T. Pulmonary veno-occlusive disease: involvement of pulmonary arteries and review of the literature. Hum Pathol 1985; 16:1033-41

(2) Thadani U, Burrow C, Whitaker W, et al. Pulmonary veno-occlusive disease. Quart J Med 1975; 44:133-59

(3) Rose AG. Pulmonary veno-occlusive disease due to bleomycin therapy for lymphoma. S Afr Med J 1983; 64:636-38

(4) Knight BK, Rose AG. Pulmonary veno-occlusive disease after chemotherapy. Thorax 1985; 40:874-75

(5) Lombard CM, Churg A, Winokur S. Pulmonary veno-occlusive disease following therapy for malignant neoplasms. Chest 1987; 92:871-76

(6) Joselson R, Warnock M. Pulmonary veno-occlusive disease after chemotherapy. Hum Pathol 1983; 14:88-91

(7) Troussard X, Bernaudin JF, Cordonnier C, et al. Pulmonary veno-occlusive disease after bone marrow transplantation. Thorax 1984; 39:956-57

(8) Hackman RC, Madtes DK, Peterson FB, et al. Pulmonary veno-occlusive disease following bone marrow transplantation. Transplantation 1989; 47:989-92

(9) Swift GL, Gibbs A, Campbell IA, et al. Pulmonary veno-occlusive disease and Hodgkin's lymphoma. Eur Respir J 1993; 6:596-98

(10) Townsend JN, Roberts DH, Jones EL, et al. Fatal pulmonary veno-occlusive disease after use of oral contraceptives. Am Heart J 1992; 124:1643-45

(11) Heath D, Segel N, Bishop J. Pulmonary veno-occlusive disease. Circulation 1966; 34:242-48

(12) Gaither NS, Hull RW, Wortham DC, et al. Pulmonary venous obstruction: utility of transesophageal echocardiography. Am Heart J 1991; 121:203-05

(13) Kim WS, Yean KM, Kim I, et al. Radiologic evaluation of pulmonary vein obstruction including two examination by magnetic resonance imaging. Pediatr Radiol 1993; 23:6-11

(14) Palevsky HI, Pietra GG, Fishman AP. Pulmonary veno-occlusive disease and its response to vasodilator agents. Am Rev Respir Dis 1990; 42:426-29

(15) Voordes CG, Kuipers G, lema JD. Familial pulmonary veno-occlusive disease: a case report. Thorax 1977; 32:763-66

(16) Scully RE, Mark EJ, McNeely BU. Case records of the Massachusetts General Hospital: case 17-1983. N Engl J Med 983; 308:823-33

(17) Justo RN, Dare AJ, Whight CM, et al. Pulmonary veno-occlusive disease: diagnosis during life in four patients. Arch Dis Child 1993; 68:97-100

(18) Cassart M, Gevenois PA, Kramer M, et al. Pulmonary veno-occlusive disease: CT findings before and after single lung transplantation. AJR 1993; 160:759-60

(19) Rich S. Primary pulmonary hypertension. Prog Cardiovasc Dis 1988; 31:205-31

(20) Cohn RC, Wong R, Spohn WA, et al. Death due to diffuse alveolar hemorrhage in a child with pulmonary veno-occlusive disease. Chest 199; 100:1456-58

(21) Weed HG. Pulmonary "capillary" wedge pressure not the pressure in the pulmonary capillaries. Chest 1991; 100:1138-40

(22) Hasleton PS, Ironside JW, Whittaker JS, et al. Pulmonary veno-occlusive disease: a report of four cases. Histopathology 1986; 10:933-44

(23) Doll DC, Yarbo JW. Vascular toxicity associated with antineoplastic agents. Semin Oncol 1992; 19:580-96

(24) McDonnell PJ, Summer WR, Hutchins GM. Pulmonary veno-occlusive disease: morphological changes suggesting a viral case. JAMA 1981; 246:667-71

(25) Sanderson JE, Spiro SG, Hendry AT, et al. A case of pulmonary veno-occlusive disease responding to treatment with azathioprine. Thorax 1977; 32:140-48

(26) Canny GJ, Arbus GS, Wilson GJ, et al. Fatal pulmonary hypertension following renal transplantation. Br J Dis Chest 1985; 79:191-95

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COPYRIGHT 2004 Gale Group

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