Archives ofDtsease in Childhood 1993; 68: 97-100

Pulmonary veno-occlusive disease: diagnosis duringlife in four patients

R N Justo, A J Dare, C M Whight, D J Radford

AbstractPulmonary veno-occlusive disease is a rareform of primary pulmonary hypertension ofunknown aetiology. Four cases were diagnosedin young patients. The diagnosis was sus-pected on the basis of clinical, radiological,echocardiographic, and catheter evidence andconfirmed by taking a lung biopsy sample. Inall patients the histology showed obstructionof the pulmonary veins by intimal fibrosis.The clinical course of all patients has beenone of progressive deterioration. Althoughthere is no specific treatment for this disease,to establish the diagnosis during life is of greatimportance in overall clinical management,including counselling the patient and family.

(Arch Dis Child 1993;68:97-100)

Pulmonary veno-occlusive disease is an un-common disorder characterised by pulmonaryhypertension secondary to progressive obstruc-tion of the pulmonary veins and venules.'Approximately 100 cases have been reported indetail and the clinical diagnosis has not oftenbeen made during life.2 Four patients with thisdisease who were managed at our hospitalduring the past 18 years are presented inchronological order. They were all diagnosedduring life and illustrate varied presentations,use of investigative modalities, and naturalhistory.

Department of PaediatricCardiology,The Prince CharlesHospital,Brisbane, Queensland,AustraliaR N JustoA J DareC M WhightD J RadfordCorrespondence to:Dr D J Radford,Department of Cardiology,The Prince Charles Hospital,Rode Road, Chermside,Queensland, Australia 4032.Accepted 13 August 1992

Case reportsCASE 1A seven year old boy presented in 1973 with afour month history of increasingly frequentrecurrent episodes of acute dyspnoea, sweating,and abdominal pain. These episodes usuallylasted about one hour and settled spontaneously.He had mild asthma as an infant but waswithout symptoms for the previous three years.On clinical examination he was a healthy boy

without cyanosis who had neither tachycardianor tachypnoea at rest. He was hypertensivewith a blood pressure of 150/80 mm Hg. A rightventricular heave was present. Cardiac ausculta-tion showed an accentuated pulmonary com-ponent of the second heart sound but nomurmurs, and normal breath sounds wereheard on auscultation of his chest. Chest radio-graphy showed a normal cardiac outline butpulmonary changes were consistent with acutepulmonary oedema (fig 1).The patient underwent cardiac catheterisation.

These original records were not available forreview, but the haemodynamic findings wereinterpreted as being 'consistent with a left atriallesion', whereas angiography showed normalcardiac anatomy. As a result of these apparentinconsistencies, surgical exploration of the rightand left atria was performed. This showed thepresence of four normal pulmonary veins andconfirmed normal cardiac anatomy. During theoperation the pulmonary artery peak systolicpressure was 50mm Hg and the mean pulmonary

Figure I (A) Chest radiograph ofcase I taken at the age of8years, showing normal cardiothoracic ratio, prominent mainpulmonary artery, and pulmonary oedema. (B) Chest radiograph ofthe same patient taken 15 months later, showingprogresstve radiological changes.

97

on 9 June 2018 by guest. Protected by copyright.

http://adc.bmj.com

/A

rch Dis C

hild: first published as 10.1136/adc.68.1.97 on 1 January 1993. Dow

nloaded from

8Justo, Dare, Whight, Radford

venous pressure was 4 mm Hg. In view of thesefindings, a lung biopsy sample was taken andthe diagnosis of pulmonary veno-occlusivedisease confirmed histologically.He recovered well after the operation but the

subsequent course of his illness was progressivedeterioration with intermittent hospital admis-sions. He was treated with digoxin, frusemide,warfarin, and with oxygen at home. Thisregimen did not significantly alter the course ofhis illness, however, and he finally died 18months after the onset of symptoms. Permissionfor a necropsy was refused.

CASE 2A 17 year old presented in 1979 with an eightweek history of malaise and progressive exer-tional dyspnoea which followed an acute febrileillness. She was referred for further investigationas she was observed to become cyanosed anddyspnoeic after minimal exertion. The onlyrelevant past history was an episode of ence-phalitis following infectious mononucleosis atthe age of 9 years. She had not taken anydrugs.

Clinically, she was a healthy girl withoutresting cyanosis. On palpation there was a rightventricular heave. Cardiac auscultation showedan accentuated pulmonary second heart sound,tricuspid regurgitation, and pulmonary regur-gitation. Her breath sounds were vesicular andthe remainder of the physical examination wasnormal. The electrocardiograph showed sinusrhythm, right atrial, and right ventricularhypertrophy, and chest radiography showedprominant pulmonary arteries, increased reti-cular markings, and Kerly B lines, with anormal cardiac outline.

Arterial blood gas analysis confirmed thepresence of hypoxaemia (oxygen partial pressure52 mm Hg) and respiratory function testingshowed the presence of a restrictive defect.Echocardiography showed right ventricularhypertrophy but no other cardiac disease.At cardiac catheterisation there was severepulmonary hypertension (pulmonary arteryphasic pressure of 65/40 mm Hg with a mean of50 mm Hg) and the pulmonary arterial wedgedpressure was 15 mm Hg. Angiography showeddilated pulmonary arteries with normal venousreturn to the left atrium, though blood flow inthe pulmonary circulation was considered to beslow. All other investigations including viralserology, rheumatoid factor, and antinuclearfactors were normal.On the basis of this information the diagnosis

of pulmonary veno-occlusive disease was sug-gested and an open lung biopsy sample wastaken. At the operation the lung appearedmacroscopically normal, but the histology oftissue from the right middle lobe confirmed thediagnosis of pulmonary veno-occlusive disease.

After the operation she was treated withoxygen, a heparin infusion, prednisone, aza-thioprine, digoxin, and frusemide (Lasix,Hoechst). Her respiratory function deterioratedrapidly despite this treatment and she died threemonths after the onset of symptoms. Permissionfor necropsy was refused.

CASE 3An 11 year old girl with dysmorphic features,developmental delay, and cardiac abnormalitieswas admitted in early 1991 for investigation ofincreasing dyspnoea. She had developed asthmaat the age of 5 years and, apart from intermittentexacerbations of her asthma, remained welluntil the age of 9 years. At this time shedeveloped exertional dyspnoea which progressedslowly over the next two years, by which timeshe became dyspnoeic at rest.

She had congenital heart disease consisting ofcoarctation of the aorta, bicuspid aortic valve,and subaortic membrane. The coarctation wasoriginally repaired at the age of 6 months. Atthe age of 5 years, the coarctation was revisedand a subaortic membrane was resected. Shealso had some dysmorphic features includingshort stature, mid facial hypoplasia, prominantnasal bridge, deep set eyes, small hands, andclinodactyly of the fifth finger, which had notbeen classified into any syndrome. Chromo-somal analysis was normal.On examination she was not cyanosed at rest.

Her respiratory rate was 50 per minute. Thepulmonary component of the second heartsound was loud and there was a grade 2/6ejection murmur in the pulmonary area. Aus-cultation of the chegt showed fine basal inspira-tory crackles. The electrocardiogram showedsinus rhythm and RSR in lead VI, whereas onchest radiography there was mild cardiomegaly,bilateral perihilar changes, and diffusely in-creased reticular markings.

Echocardiography excluded left sided cardiaclesions and pulmonary vein ostial stenosis as acause for the respiratory symptoms. She hadhad a recent left heart catheter study, but not aright heart study because of venous accessproblems. As no important cardiac diseasecould be shown it was felt that a lung biopsysample should be taken to exclude interstitiallung disease. At the operation the right middleand lower lobes were grossly abnormal withscarring and reddened discoloration. Pulmonaryveno-occlusive disease was diagnosed histo-logically. The findings were typical of thedisease with the small veins affected by 'fluffy'myxomatous intimal proliferation. There wasno evidence of thrombosis.On review nine months later, the child was

tachypnoeic at rest and becoming increasinglytired and dyspnoeic with exertion. She requiredoxygen treatment and drug treatment withfrusemide, nifedipine, salbutamol (Ventolin,Allen and Hanburys), and beclomethasonedipropionate (Becotide, Allen and Hanburys).

CASE 4A 5 month old baby presented in 1991 with atwo day history of irritability, poor feeding, andtachypnoea. He had been previously well withno past history of cardiac or respiratory symp-toms, though there have been a history of poorweight gain.The child was peripherally shut down on

admission. He had small volume peripheralpulses and a right ventricular heave. His heartsounds were normal and a soft systolic murmurwas audible at the lower right sternal edge. Fine

98

on 9 June 2018 by guest. Protected by copyright.

http://adc.bmj.com

/A

rch Dis C

hild: first published as 10.1136/adc.68.1.97 on 1 January 1993. Dow

nloaded from

Pulmonary veno-occlusive disease

inspiratory crackles were heard throughoutboth lung fields. He had marked hepatomegaly.The electrocardiograph showed sinus rhythm, anormal axis, right atrial hypertrophy, and rightventricular hypertrophy, whereas severe pul-monary oedema with a normal sized heart wasseen on chest radiography.

Echocardiography showed a grossly dilatedhypertrophied right ventricle with flattening ofthe left ventricle. On Doppler examinationthere was marked tricuspid regurgitation with acalculated right ventricular systolic pressure ofapproximately 150 mm Hg. There was no rightventricular outflow tract or pulmonary arterialobstruction. Careful Doppler interrogation ofthe left atrium detected turbulent flow whichcould be traced into the pulmonary veins,suggesting obstruction within the pulmonaryvenous tree. After being ventilated he underwentcardiac catheterisation to distinguish betweenpulmonary vein ostial stenosis and pulmonaryveno-occlusive disease. The pulmonary arterypressure was 120/70 mm Hg (mean 95 mm Hg)and the mean right and left pulmonary arterialwedged pressures were 23 and 17 mm Hgrespectively. Directly measured peripheralpulmonary venous mean pressures measured indifferent areas of the right and left lungs rangedfrom 36 to 46 mm Hg. The left atrial pressurewas normal. Angiography by direct injection ofcontrast into pulmonary veins showed multipleareas of narrowing within both lungs. The veinsin their extrapulmonary course were angio-graphically normal. The areas of pulmonaryvenous obstruction so defined correspondedwith the sites of marked stasis of antegradeflow.Pulmonary veno-occlusive disease was diag-

nosed on the basis of these findings. Aftercareful discussion of the prognosis of thisdisease with the parents, ventilatory supportwas withdrawn and the child died shortlyafterwards. Necropsy was performed and thisconfirmed the diagnosis of pulmonary veno-occlusive disease with multiple acute pulmonaryinfarcts.

HistologyThe histopathological changes common to allfour patients consisted of patchy eccentricmyxomatous intimal fibrosis of small pulmonaryveins (fig 2). There was also dilatation of septal

}'.

'$t:

fi f

V~~~~~~~~~*¢. . 4 '. E A

,,.,, 1 :

Figure 2 Histology ofpulmonary veno-occlusive disease incase 1. An irregular proliferation ofintimalfibrous tissue (F)partially occludes the lumen ofthis venule (elastin VanGreson stain x300).

Figure 3 Histology ofbiopsy samplefrom case 3.Pulmonary lobules (L) are separated by widened interlobularsepta (S) producing a 'jigsaw puzzle' appearance ofthe lung.Septal.lymphatics (arrow)heads) appear dilated(haematoxylin and eosin stain x 70).

lymphatics and variable haemosiderin accumu-lation in the alveolar septa.The first three patients showed fibrosis of

alveolar and interlobular septa giving a 'jig-saw puzzle' appearance to histological sections(fig 3).

Cases 1, 2, and 4 showed multiple lumina insmall pulmonary veins, suggesting recanalisationfollowing organisation ofthrombi. Actual venousthrombus was only seen in case 4. Small veins incase 3 showed 'arterialisation' with twin elasticlamellae seen on elastin stains. Small pulmonaryarteries were normal in this patient but showedgrade 1 pulmonary hypertensive changes in theothers.

DiscussionPulmonary veno-occlusive disease is a rare formof primary pulmonary hypertension of unknownaetiology. Approximately 100 cases have beenreported and about one third have occurred inchildren with an equal distribution between thesexes.3 Most patients have been diagnosed atnecropsy on typical histological findings. Thedisease is now characterised well enough toallow an earlier diagnosis. Patients usuallypresent with a history of progressive dyspnoea.They have signs consistent with pulmonaryhypertension, including a right ventricular heaveand a loud pulmonary heart sound. Inspiratorycrackles which are a result of pulmonary con-gestion are often audible on auscultation of thechest. The chest radiographs shows a prominentright ventricle, dilated pulmonary arteries, andKerly B lines. Electrocardiographic abnor-malities include right axis deviation and rightventricular hypertrophy. Echocardiography willusually show evidence of increased right systolicheart pressure such as right ventricular hyper-trophy or systolic compression of the leftventricle, and will exclude left sided obstructivelesions such as pulmonary vein stenosis, cortriatriatum and mitral stenosis. The haemo-dynamic findings with cardiac catheterisationare pulmonary hypertension with increasedright ventricular and pulmonary artery pres-sures. In pulmonary veno-occlusive diseasepulmonary capillary wedge pressure has beenreported to be normal or increased.3 Wherethere is widespread disease of the pulmonaryveins, however, the wedge pressure may be

99

07W.

et

on 9 June 2018 by guest. Protected by copyright.

http://adc.bmj.com

/A

rch Dis C

hild: first published as 10.1136/adc.68.1.97 on 1 January 1993. Dow

nloaded from

0Justo, Dare, Whight, Radford

considerably increased, as in case 4, and selectivedirect measurement of pulmonary venous pres-sures will show high intrapulmonary venouspressures. The left atrial pressure is normal.Although this constellation of findings is highlysuggestive of pulmonary veno-occlusive disease,the definitive diagnosis can be made by takingan open lung biopsy specimen. The maindiagnostic microscopic feature of pulmonaryveno-occlusive disease is obstruction of thepulmonary veins and venules by intimal fibrosisconsisting of loose myxoid connective tissue,often with intravascular fibrous septa thought toresult from recanalisation of thrombi.2 4Lung histology in cases of primary pulmonary

hypertension has been classified into threepathological types.5 These are (a) plexogenicpulmonary arteriopathy, (b) recurrent pul-monary thromboemboli, and (c) pulmonaryveno-occlusive disease. The histology describedin our cases of pulmonary veno-occlusive diseaseare distinct from the other types. In plexogenicpulmonary arteriopathy the disease is in themuscular pulmonary arteries and arterioles withmedical hypertrophy and intimal cellularproliferation. In thromboembolic pulmonaryhypertension obstructive lesions of thrombi invarious stages of organisation are present in themuscular pulmonary arteries and arterioles.These were not the changes seen in our patients.

It is thought that pulmonary veno-occlusivedisease represents a syndrome rather than asingle aetiological entity, though a commonpathogenesis, probably thrombosis, is likely. Ithas been suggested that a primary disturbanceof the vascular wall of pulmonary veins andarteries may result in the formation of intra-vascular thrombi. Various aetiological agentshave been associated with this process. Res-piratory infections, usually viral in nature, havebeen implicated6 and some workers have shownimmune complexes resulting from such infec-tions in the vascular tissue.7 This suggests thepossibility of a pathological immune response toa viral infection. A genetic predisposition hasbeen proposed because of case reports of thedisease occurring in siblings.8 9 A toxic aetiologyhas been implicated with reports of veno-occlusive disease occurring following theadministration of chemotherapeutic drugsl'and inhalation of a toxic substance.'2

Cases 1 and 4 had no relevant past historywhich would suggest an aetiology for theirillness. The fact that case 4 occurred at such ayoung age, however, raises the question of acongenital pathological process. The onset ofpulmonary veno-occlusive disease in case 2followed an acute febrile illness and although noorganism was isolated, the possibility of a viralinfection remains. Case 3 developed this diseasein association with a history of congenital heartdisease and asthma. The latter was associatedwith genuine clinical bronchospasm and occurredintermittently before and after the other diag-nosis was made. In this instance (and in others)it was essential to exclude obstructive lesions ofthe left heart."' Having clearly done this, anopen lung biopsy sample was taken, allowingthe diagnosis of pulmonary veno-occlusivedisease to be made.

Regardless of the aetiology, pulmonary veno-occlusive disease is fatal in most patients withintwo years of the onset of symptoms due toprogressive pulmonary hypertension with rightventricular failure. Treatment with anti-coagulants has not been successful'4 but therehave been reports of patients responding toazathioprine. ' Similarly, there have beenisolated reports of prolonged survival with theuse of calcium antagonist' and vasodilators suchas prazosin.3 None of the three patients reportedin this paper who received treatment appearedto respond to the treatment. In particular, case 2followed a rapidly progressive course despitethe use of intravenous heparin anticoagulation,high doses of corticosteroids, and azathioprine.Treatment with nifedipine was started in case 3but no direct measurement of pulmonary resis-tance was performed to assess the effect. Nodrug treatment was started in case 4 because ofthe advanced stage of the disease process.The four cases reported here further show the

varied clinical course of this disease in children.These patients presented over a period of 18years, and all were diagnosed while still alive.As detailed in the case discussion, diagnosticmethods have evolved with progress in medicaltechnology. When investigative informationindicates obstruction within the lungs, probablyat the level of the pulmonary veins, a lungbiopsy sample will provide the definitive diag-nosis. This applied in the first three patients,but was not felt to be necessary in case 4 wherehaemodynamic and angiographic data wereconclusive in showing widespread intra-pulmonary venous disease. Although there hasbeen no effective treatment for pulmonaryveno-occlusive disease, to establish the diagnosisduring life is of great importance in overallclinical management, including counselling thepatient and family. Consideration can now begiven to heart-lung or lung transplantation.

I Salzman GA, Rose VW. Prolonged survival in pulmonaryveno-occlusive disease treated with nifedipine. Chest 1989;95:1154-6.

2 Wagenvoort CA, Wagenvoort N, Takahashi T. Pulmonaryveno-occlusive disease: involvement of pulmonary arteriesand review of the literature. Hum Pathol 1985;16:1033-41.

3 Palevsky HI, Pietra GG, Fishman AP. Pulmonary veno-occlusive disease and its response to vasodilator agents. AmRev Respir Dis 1990;142:426-9.

4 Wagenvoort CA. Pulmonary veno-occlusive disease; entity orsyndrome? Chest 1976;69:82-6.

5 Edwards WD, Edwards JE. Clinical primary pulmonaryhypertension. Three pathologic types. Circulation 1977;56:884-8.

6 McDonnell PJ, Summer WR, Hutchins GM. Pulmonaryveno-occlusive disease: morphological changes suggesting aviral cause. JAMA 1981;246:667-71.

7 Corrin B, Spencer H. Pulmonary veno-occlusion. An immunecomplex disease? Virchows Arch [Al 1974;364:81.

8 Voordes CG, Kuipers JRG, Elema JD. Familial pulmonaryveno-occusive disease: a case report. Thorax 1977;32-763-6.

9 Davies PP, Reid L. Pulmonary veno-occlusive disease insiblings: case reports and morphometric study. Hum Pathol1982;13:91 1-5.

10 Joelson R, Warnock M. Pulmonary veno-occlusive diseaseafter chemotherapy. Hum Pathol 1983;14:88-91.

11 Hackman RC, Madtes DK, Clark JG. Pulmonary veno-occlusive disease following bone marrow transplantation.Transplantation 1989;47:989-92.

12 Liu L, Sackler JP. A case of pulmonary veno-occlusivedisease. Aetiologic and therapeutic appraisal. Angiology1972;23:299-304.

13 Fong LV, Anderson RH, Zuberbuhler JR. Morphologicfeatures of stenosis of the pulmonary veins. Am J Cardiol1988;62:1 136-8.

14 Thadami U, Burrow C, Heath D. Pulmonary veno-occlusivedisease. Q J Med 1975;44:133-59.

15 Sanderson JE, Spro SG, Hendry PT, Turner-Warwick M. Acase of pulmonary veno-occlusive disease responding totreatment with azothioprine. Thorax 1977;32:140-8.

100

on 9 June 2018 by guest. Protected by copyright.

http://adc.bmj.com

/A

rch Dis C

hild: first published as 10.1136/adc.68.1.97 on 1 January 1993. Dow

nloaded from