[

Original Research Pulmonary Vascular Disease

Pulmonary Venoocclusive Disease in Childhood

Cornelia Woerner, MD; Ernest Cutz, MD; Shi-Joon Yoo, MD, PhD; Hartmut Grasemann, MD;
and Tilman Humpl, MD, PhD

Pulmonary venoocclusive disease (PVOD) is a rare lung disease, diagnosed in

5% to 10% of patients with pulmonary hypertension (PH). The incidence, prevalence, and
etiology of PVOD in children are not well defined. The mortality remains high, related, at least
partly, to the limited treatment options.

BACKGROUND:

This retrospective analysis (1985-2011) summarizes symptoms, associated factors,

treatment, and outcomes of nine pediatric patients (five girls, four boys) with histologic confirmation of PVOD.
METHODS:

RESULTS: PH was diagnosed at a mean age of 13.5 years (range, 8-16 years), followed by the
definitive diagnosis of PVOD at a mean age of 14.3 years (range, 10-16 years). Symptoms such
as decreased exercise tolerance (n 5 6) and/or shortness of breath (n 5 9) preceded the diagnosis by 21 months on average; the mean survival time after diagnosis was 14 months (range,
0-47 months). CT scans of the lungs showed typical radiologic features. Treatment included
supplemental home oxygen (n 5 5), diuretics (n 5 9), warfarin (n 5 4), and pulmonary vasodilators (n 5 4). Four children were listed for lung transplantation, and three have undergone
transplantation. Eight patients died, including two after lung transplantation. One patient with
lung transplant survived with good quality of life.
CONCLUSIONS: PVOD is an important differential diagnosis for pediatric patients with PH.
CT scanning is a valuable tool to image lung abnormalities; the definitive diagnosis can only
be made by examination of lung biopsy specimens, which subjects the patient to additional
risk. Early listing for lung transplantation is essential, as the mean survival time is only
14 months.
CHEST 2014; 146(1):167-174

Manuscript received January 22, 2013; revision accepted January 2,

2014; originally published Online First February 6, 2014.
ABBREVIATIONS: NYHA 5 New York Heart Association; PAP 5 pulmonary artery pressure; PFT 5 pulmonary function test; PH 5 pulmonary hypertension; PVOD 5 pulmonary venoocclusive disease
AFFILIATIONS: From the Department of Pediatrics, Division of Cardiology (Drs Woerner, Yoo, and Humpl), Department of Laboratory
Medicine and Pathobiology (Dr Cutz), Department of Pediatrics, Division of Respiratory Medicine (Dr Grasemann), Department of Critical Care Medicine (Dr Humpl), and Department of Medical Imaging
(Dr Yoo), University of Toronto, Hospital for Sick Children, Toronto, ON,
Canada.

journal.publications.chestnet.org

FUNDING/SUPPORT: The authors have reported to CHEST that no

funding was received for this study.
CORRESPONDENCE TO: Tilman Humpl, MD, PhD, The Hospital for
Sick Children, Critical Care and Cardiology, 555 University Ave,
Toronto, ON, M5G 1X8, Canada; e-mail: tilman.humpl@sickkids.ca
2014 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of
this article is prohibited without written permission from the American
College of Chest Physicians. See online for more details.
DOI: 10.1378/chest.13-0172

167

Pulmonary venoocclusive disease (PVOD) is a rare

lung disease that affects the postcapillary venous pulmonary vasculature and accounts for 5% to 10% of cases
with idiopathic pulmonary arterial hypertension.1-5 It
carries a high risk of developing right-sided heart failure
secondary to elevated pulmonary artery pressure (PAP)
followed by death. Histopathologic findings in PVOD
have previously been well characterized.2 The main features include involvement of preseptal venules and
small septal veins with varying degree of luminal obliteration due to intimal fibrous proliferation that can be
loose initially and later becoming dense or sclerotic. The
media of the veins can become arterialized with an

increase in smooth muscle cells and elastic fibers in

their walls. Further progression may lead to pulmonary
arterioles with medial hypertrophy, capillary angiectasia, and even capillary proliferation. Parenchymal
changes begin with interstitial edema and can progress
to fibrosis.2 Incidence, prevalence, and etiology of
PVOD are not well defined, treatment is limited, and
the mortality remains high.

Materials and Methods

test, pulmonary function test (PFT), CT scan of the lung, cardiac catheterization, bronchoscopy, lung biopsy specimen examination, and
autopsy.

The cardiology, radiology, and pathology databases were searched for

patients with clinical suspicion of PVOD between 1985 and 2011. Final
patient selection for this study was based on histologic confirmation
of PVOD. Patients with clinical signs of PVOD but without histologic
findings were excluded.
Paper and electronic patient charts were reviewed, and data including
initial symptoms, age at presentation with symptoms, time of diagnosis, additional diagnoses, risk factors, New York Heart Association
(NYHA) functional class, and physical examination at presentation
were collected. Additionally, the results of the following investigations
were evaluated: ECG, echocardiogram, chest radiograph, 6-min walk

Results
Nine patients were identified; demographic data are
shown in Table 1. The average time interval from onset
of symptoms until the diagnosis of pulmonary hypertension (PH) and PVOD was 14 months and 21 months,
respectively (range, , 1 month to 7 years). The mean
survival time after diagnosis with PVOD was 14 months
(range, , 1-47 months).
Initial symptoms included fatigue, decreased exercise tolerance, and shortness of breath on exertion. Other symptoms were cough, dizziness, chest pain with exercise,
palpitations, syncope, and nonspecific symptoms such as
headache, poor appetite, pallor, perioral cyanosis, and
hemoptysis (Table 2). Four children were previously diagnosed with a different pulmonary disease: three with
bronchial asthma and one with allergic alveolitis.
Additional diagnoses affecting other organs were present in three children and included bilateral renal dysplasia, ichthyosis, velopharyngeal incompetence, severe
developmental delay, and congenital heart disease. One
patient was diagnosed with Myhre syndrome, confirmed by mutational analysis of SMAD4.14
168 Original Research

There are a number of reports about adult patients,3,6-8

but, to our knowledge, only a few case reports exist
about children.9-13 We undertook a single-center retrospective review to summarize symptoms, associated factors, treatment, and outcomes in children with PVOD.

The lung samples were fixed in buffered formalin and embedded in

paraffin. In addition to routine stains with hematoxylin and eosin, we
also used special stains, including elastic trichrome to visualize vascular
changes, stain for iron for assessment of hemosiderosis, or stains for
microorganisms where indicated.
Due to the small number of patients and the large variation in their
clinical course, statistical analysis was not performed. This study was
approved by the Research Ethics Board at the Hospital for Sick Children, Toronto, Ontario, Canada (No. 100010504).

Two patients received long-term immunosuppressive

treatment (tacrolimus and tacrolimus, azathioprine and
prednisone) after (nonlung) solid organ transplantation.
Other risk factors, such as tobacco consumption, were
not documented. One patient was taking an antidepressant drug, three patients were treated with bronchodilators (puffers), and three were not on any medications.
The physical examination was unremarkable in one
patient; the others presented with abnormal findings
(Table 2). NYHA class at presentation ranged from I to
TABLE 1

] Demographic Data of Patients With PVOD

Demographic

Variable

Age at diagnosis, alive or

postmortem, mean (range), y

14.3 (10-16)

Age at diagnosis of pulmonary

hypertension, mean (range), y

13.5 (8-16)

Age at onset of symptoms,

mean (range), y

12.4 (7-15)

Sex, female:male

5:4

Postmortem diagnosis, No.

PVOD 5 pulmonary venoocclusive disease.

1 4 6 # 1 C H E S T J U LY 2 0 1 4

journal.publications.chestnet.org

169

Decreased Exercise
Tolerance

Shortness of
Breath

Syncope

Palpitations

Chronic Cough

C/PM

BWT

NLO

MPA

PAHIL

Loud S2

DV

RV Heave

MM/E

Murmur

PE

Elevated JVP

CM

Marked

Mild

Mild

Mild

Moderate

Mild

Marked

Moderate

92

88

87

96

93

85

90

98

98

RVH

II

III

IV

II

III

II

III

III

III

NYHA Class

Moderate

Moderate

Moderate

Moderate

Moderate

Moderate

Severe

Moderate

Severe

Tc Saturation, %

Moderate

Crackles

BWT 5 bronchial wall/peribronchial thickening; CM 5 cardiomegaly; C/PM 5 Increased interstitial or streaky markings, central and/or abutting to the pleural surfaces; DV 5 diminished vascularity in the periphery;
GGO 5 ground-glass opacity; MM/E 5 mediastinal and hilar edema or mass; MPA 5 dilated mean pulmonary artery segment; NLO 5 nodular or mottled lung opacity; PAHIL 5 dilated central pulmonary arteries at
hilum; PE 5 pleural eusion; RVH 5 right ventricular hypertrophy. See Table 1 legend for expansion of other abbreviation.

GGO

] CT Scan Findings of Patients With PVOD

Patient

TABLE 3

JVP 5 jugular venous pressure; NYHA 5 New York Heart Association; RV 5 right ventricular; Tc 5 transcutaneous.

Chest Pain

] Symptoms and Clinical Findings of Patients at Initial Presentation

Patient

TABLE 2

IV (Table 2). Transcutaneous oxygen saturation ranged

from 85% to 98% on room air (mean, 92%). Hypocapnia was present in 66% (n 5 6); the pH was within normal limits.

haziness of both lungs, or blurring of vessel margins

suggestive of pulmonary venous hypertension in eight
of nine cases. CT scan findings are summarized in
Table 3 and illustrated in Figure 1.

PFTs were performed in seven patients at our institution and revealed a restrictive pattern in all cases (in one
patient, the PFT was done at another hospital, and the
results were not available). In all patients, the FVC and
FEV1 were decreased, with a mean of 50% (range,
20%-81%) and 51% (range, 18%-81%), respectively. The
diffusing capacity of the lung for carbon monoxide
was reduced in the four patients tested (67%, 62%,
26%, and 83%), ranging from 5.9 mL/min/mm Hg to
14.2 mL/min/mm Hg. Five children completed a 6-min
walk test with a mean distance of 263 m (range, 19-382 m).

A diagnostic cardiac catheterization with acute vasodilator testing was performed in four patients and showed
elevated PAP (Table 4). During testing with pulmonary
vasodilators, one patient developed acute pulmonary
edema.

Eight patients had abnormal ECG findings, with frequent right-axis deviation, signs of right atrial enlargement, and right ventricular hypertrophy. Transthoracic
echocardiography showed a dilated right ventricle with
flattening or bowing of the interventricular septum, suggesting elevated right ventricular pressure in all patients.
The estimated right ventricular systolic pressure ranged
from more than one-half systemic to systemic (n 5 5) to
suprasystemic (n 5 3). In one patient, only mean PAP
could be estimated and exceeded 25 mm Hg.
The initial chest radiograph showed a prominent pulmonary arterial segment of the left heart border in all
cases and increased interstitial markings, ground-glass

Bronchoscopy with BAL was performed in only two

patients and did not reveal significant findings. Four children underwent elective lung biopsy; two had samples
taken from the explanted lungs at the time of transplantation, and three patients had the diagnosis of PVOD established at autopsy (Table 5). The main histologic findings
included extensive changes of PVOD similar to those previously described.1,2,13,15-17 These changes were characterized by extensive and diffuse occlusion of pulmonary
veins by fibrous tissue, which, in some areas, was loose
and edematous, while in others it was dense and sclerotic
(Fig 2A). The intimal thickening involving venules and
small veins exhibited an eccentric pattern resembling
organizing arterial thrombi. In most cases, the pulmonary
arterioles showed moderate to severe medial thickening
without plexiform lesions. In addition, several cases
showed variable interstitial thickening with focal fibrosis
and moderate to marked pulmonary hemosiderosis
(Table 5). In the two patients who underwent solid organ
transplantation, the lung biopsy specimens, in addition to

Figure 1 Classic image findings of pulmonary venoocclusive disease in a 16-year-old patient. A, Frontal chest radiograph shows mild cardiomegaly
with markedly dilated main pulmonary arterial segment of the left upper heart border due to pulmonary hypertension. Both lungs are diffusely hazy
and show increased interstitial markings with blurred vessel margins. B, CT images reconstructed in axial and coronal planes show diffuse ground-glass
opacity with a mosaic pattern, thickened septal lines extending to the pleura (black arrows), and peribronchial thickening (white arrows). Note that
there are low density areas in the mediastinum and hila (asterisks), which represent soft tissue edema or lymphatic dilatation. Extensive edematous
tissue in the posterior mediastinum is well appreciated in the coronal plane. The pulmonary arteries in the mediastinum and hila are dilated.

170 Original Research

1 4 6 # 1 C H E S T J U LY 2 0 1 4

TABLE 4

] Hemodynamic Findings in Cardiac

Catheterization in Patients With PVODa

Patient

mPAP, mm Hg

PVRi, WU3m2

PCWP

50 (80/40)

18.1

42 (62/30)

11.3

67 (85/55)

74 (96/55)

37

3
13
8

mPAP 5 mean pulmonary artery pressure; PCWP 5 pulmonary capillary

wedge pressure; PVRi 5 pulmonary vascular resistance indexed for body
surface area; WU 5 Wood Units. See Table 1 legend for expansion of
other abbreviation.
aBaseline with 100% oxygen and inhaled nitric oxide (40 parts per million).

prominent involvement of pulmonary veins by PVOD,

also showed granulomatous inflammatory changes with
aggregates of multinucleated giant cells in the alveoli,
alveolar septae, or both (Figs 2B, 2C). In contrast to
other patients with PVOD, the pulmonary arteries in
these two patients appeared relatively unaffected (Fig 2B).
Special stains for acid-fast bacilli and fungal organisms
were negative. These changes were interpreted as most
likely representing extrinsic allergic alveolitis or a drug
reaction.
The therapeutic approach was heterogeneous because
patients were diagnosed over a relatively long time span
and had a variable clinical disease course and severity.
In some, the definite diagnosis was not established prior
to biopsy or autopsy. Five children received oxygen,
four were started on diuretics as initial treatment, and
four were treated with warfarin. The patient diagnosed
with allergic alveolitis received pulse steroid therapy. In
four patients, pulmonary vasodilators were added
TABLE 5

(inhaled nitric oxide, sildenafil, epoprostenol) in the

absence of a definitive diagnosis of PVOD, leading to
acute deterioration in one, and no improvement or
subacute worsening in the others.
Five patients were assessed for lung transplantation and
four were listed. One patient died while awaiting heartlung transplantation, and three underwent lung transplantation with waiting times of 27 to 240 days. One
patient and family declined assessment for lung transplantation, and three patients were not eligible.
Two of the listed patients required mechanical support.
One patient was supported with extracorporeal membrane oxygenation and converted to an interventional
lung assist (Novalung GmBH), and the other was semiurgently cannulated to the interventional lung assist;
both underwent lung transplantation. Following lung
transplantation, one patient is alive; the two deaths were
related to rejection and multiorgan failure.

Discussion
While there are several reports regarding adults with
PVOD, to our knowledge, this is the first reported series
of children with this disease. In 1934, Hra15 published
findings of an adult patient followed by a detailed pathologic description emphasizing differences between
classical pulmonary arterial hypertension and
PVOD.16 Further cases were reported,17,18 including the
first pediatric patient in 1967,9 and several adult case
series.1,3,19
The underlying cause and the pathophysiology of
PVOD remain unclear. Associations of PVOD with

] Pathology Findingsa in Patients With PVOD

Patient

PVOD

PH

Hemosiderosis

Parenchymal Disease or Other Findings

31

2-31

None

None

31

21

1-21

None

31

2-31

1-21

Interstitial fibrosis/DAD

31

21

2-31

Interstitial fibrosis, focal

31

31

21

Interstitial fibrosis, BOOP

31

11

11

Granulomatous/giant cell

31

21

2-31

Focal fibrosis, thrombosis

31

1-21

2-31

None

Biopsy performed

31

11

11

Granulomatous/giant cells

Explanted lung

31

11

31

Interstitial fibrosis/no giant cells

BOOP 5 bronchiolitis obliterans organizing pneumonia; DAD 5 diuse alveolar damage; PH 5 pulmonary hypertension. See Table 1 legend for
expansion of other abbreviation.
aSemiquantitative histologic evaluation: 11 5 minimal to mild, 21 5 moderate, 31 5 severe.

journal.publications.chestnet.org

171

connective tissue and autoimmune diseases, HIV

infection, bone marrow transplantation, sarcoidosis,
and pulmonary Langerhans cell granulomatosis have
been described,20-23 but were not found in the patients.
Occurrence of PVOD after solid organ transplantation
is most likely drug induced, not accounting for a different disease. There are case reports of affected siblings,
suggesting a genetic association.10 Furthermore, mutation in bone morphogenetic protein receptor II was
discovered in a patient with biopsy specimen-proven
PVOD.24 Interestingly, one of the patients was diagnosed with Myrhe syndrome, a developmental disorder characterized by short stature, short hands and
feet, facial dysmorphism, muscular hypertrophy, deafness, and cognitive delay.14 Studies have identified
mutations in SMAD4 as a cause of this syndrome.25 The
patient with Myhre syndrome appears to be the first
recognized case of this disorder associated with pulmonary vascular disease, specifically PVOD; a
manuscript is in preparation about this case. It is of
interest to note that SMAD4 plays a critical role in the
BMPR2/SMAD signaling implicated in the pathogenesis of familial PH.26
Other possible risk factors include tobacco use, chemotherapy, appetite-suppressing agents, and thoracic radiation.3,27-29 Histology in two of our cases revealed
prominent granulomatous inflammation suggestive of
hypersensitivity reaction or drug effect, and both of
these patients underwent preceding solid organ transplantation and were receiving immunosuppressive medication. We are not aware of previous reports of PVOD
associated with granulomatous interstitial inflammation
in this setting.
The onset of the disease varies between a few months of
age to the seventh decade of life; however, in the patient
group, clinical signs became apparent between 8 and
16 years of age. PVOD does not appear to be sex specific,3 which is also reflected in the almost equal sex
distribution in our series.

Figure 2 Histologic images from two patients are presented. A, Low

magnification view of lung biopsy specimen showing fibrous obliteration
of medium size PVs as well as small peripheral pulmonary venules (arrows).
A bronchovascular bundle contains normal BR and PA with thickened
media. Small peripheral branches of pulmonary artery appear relatively
normal (arrowheads) (Elastic trichrome). B, Low power view of lung
biopsy specimen with PVs showing striking fibrous and fibrointimal
proliferation causing total lumenal obliteration. In contrast, PAs are
widely open. A small BR contains an aggregate of macrophages. Adjacent
lung parenchyma shows interstitial thickening, congestion, and recent
hemorrhage (Elastic trichrome). C, A close up view from Figure 1B
showing lung parenchyma with focal aggregates of multinucleated giant

172 Original Research

Shortness of breath and decreased exercise tolerance

were the major clinical signs; however, other symptoms like chronic cough, pulmonary edema, hemoptysis, and exertional syncope are also possible. The
time between onset of symptoms and diagnosis varies.

cells (arrows) in interstitium and alveolar space. Note the complete obliteration of a small pulmonary venule outlined by elastic (black) and
collagen (green) in the wall (Elastic trichrome). BR 5 bronchiole;
GC 5 giant cell; PA 5 pulmonary artery; PV 5 pulmonary vein.

1 4 6 # 1 C H E S T J U LY 2 0 1 4

In the adult population, it is reported as an

average of 49 months30 and averaged 21 months in
our cohort.
Transthoracic echocardiography remains also in the
pediatric population a useful tool to assess the presence
of elevated right-sided pressures and exclude underlying cardiac causes. Right-sided heart catheterization
provides detailed hemodynamic information (PAP, pulmonary capillary wedge pressure, and indexed pulmonary vascular resistance), and also allows pulmonary
vasoreactivity testing.
The triad of severe PH and radiographic pulmonary
edema in the presence of a normal pulmonary artery
wedge pressure is highly suggestive of PVOD and was
present in the majority of the patients. Several diagnostic tools (arterial blood gas analysis, PFT, highresolution CT scan of the chest, and BAL) may help
explore the underlying cause, but are not always performed in children. The gold standard for a definitive
diagnosis of PVOD remains histology, but a lung biospy
is invasive and often associated with a high risk in
patients with PH.31,32 In our series, all patients with PFTs
had decreased FEV1 and FVC, in contrast to the reports
in adults.33
High-resolution CT scans often reveal three typical radiologic features: centrilobular ground-glass opacities,
septal lines (interlobular septal thickening), and mediastinal lymph node enlargement.34,35 Ground-glass opacities were seen in all of the present patients; however,
septal thickening and nodular/mottled lung opacities
were not consistently present, underlining the difficulties in making the diagnosis by imaging alone. Interestingly, CT imaging for the diagnostic workup of
pediatric patients with PH was only used in 41% of a
large patient cohort, with 74% being reported as
abnormal.36
Despite thorough noninvasive tests, the accurate
diagnosis of PVOD was not recognized in three of the
patients (30%) until postmortem examination. Especially if medical treatment of PH fails, PVOD should
be strongly considered,7 as it is often misdiagnosed as

journal.publications.chestnet.org

idiopathic arterial hypertension.8 As epidemiologic

data suggest, a proportion of 5% to 25% of primary
PH will fulfill criteria for PVOD if fully investigated;
the prevalence of only six pediatric patients (1.7%) in
a large current registry37 suggests underdiagnosis of
the disease.
The use of pulmonary vasodilators (inhaled nitric oxide,
epoprostenol, sildenafil) leads to improvement in some
patients. Given the risk of pulmonary edema as a result
of the relatively greater degree of vasodilatation in the
precapillary vessels compared with the postcapillary vessels with resultant increased transcapillary hydrostatic
pressure, this treatment avenue should be used with caution.38 Pulmonary edema may also present later despite a
favorable (or uncomplicated) response during cardiac
catheterization prior to initiation of therapy. Mechanical
lung-assist devices might be an additional option in
these situations.
At present, the only therapeutic option is lung transplantation; hence, early diagnosis and assessment are crucial.
Holcomb et al1 reported 72% mortality in the first year
and nearly 100% within 2 years of diagnosis. In our
cohort, the mean survival after diagnosis was 14 months.
In conclusion, PVOD is an important differential diagnosis in children with PH and may be underdiagnosed.
CT imaging is an important tool to narrow down the
etiology of PH, but definitive diagnosis in most cases
can only be made by histology. With small numbers of
patients, variable workup, and heterogeneous nature of
the disease, a multicenter registry approach may be
helpful to further define disease characteristics and to
evaluate treatment benefits. Currently, with limited
therapeutic options and the progressive nature of the
disease, the overall prognosis is very poor. However,
multicenter studies of carefully titrated vasodilator
therapy should be considered in the future. With the
short mean survival time following diagnosis, early
mechanical support and/or early listing for lung transplantation must be considered, as the average waiting
time frequently exceeds the individuals remaining lifespan. Given delay in diagnosis, clinical course, and overall outcome, early recognition of PVOD is essential.

173

Acknowledgments
Author contributions: T. H. had full access
to all the data in the study and takes responsibility for the integrity of the data and the
accuracy of the data analysis. C. W. served as
principal author. C. W. and T. H. contributed
to data acquisition; C. W., E. C., S.-J. Y., H. G.,
and T. H. contributed to data analysis and
interpretation; T. H. contributed to study
conception and design; C. W. contributed to
the drafting of the submitted article; E. C.,
S.-J. Y., H. G., and T. H. contributed to the
revision of the manuscript for important
intellectual content; and E. C., S.-J. Y., H. G.,
and T. H. approved the final version.
Financial/nonfinancial disclosures: The
authors have reported to CHEST that no
potential conflicts of interest exist with any
companies/organizations whose products or
services may be discussed in this article.

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