2014, Volume 30, Number 3, Page(s) 206-209
Plexiform Pulmonary Arteriopathy in a 2 Year-Old Boy
Sabah BOUDJEMAA1, Valérie MEAU-PETIT2, Fazia HALLALEL2, Aurore COULOMB1, Jill LIPSETT3
1Department of Pathology, Hopital Armand Trousseau, PARIS, FRANCE
2Department of Reanimation, Hopital Armand Trousseau, PARIS, FRANCE
3Department of Pathology, Women’s and Children’s Hospital, ADELAIDE, AUSTRALIA
Keywords: Child, Pulmonary hypertension, Lung Diseases
Idiopathic pulmonary arterial hypertension is a rare disease in
children. We report a case of a 2-year old boy admitted to the intensive
care unit of our hospital for severe dyspnea and epistaxis. Laboratory
investigations showed hemolytic anemia with schizocytes and severe
thrombocytopenia. Cardiac investigations diagnosed supra-systemic
pulmonary arterial hypertension, which was refractory to maximal
medical treatment. On evolution, he had several cardiac arrests
and finally died 8 days after admission. Autopsy was performed
and showed typical lesions of idiopathic pulmonary hypertensive
arteriopathy characterized by plexiform lesions of the interlobular
arteries containing numerous disseminated intravascular
microthrombi. The rest of the family was screened, DNA was stored,
and genetic study of BMPR2 was planned.
Idiopathic pulmonary arterial hypertension (PAH) is a
rare disease in children. Classical clinical presentation
in children is nonspecific as in adults including dyspnea,
syncope and chest pain. Plexiform lesions constitute the
hallmark of irreversible lung vessel disease, seen in severe,
advanced pulmonary hypertension and are associated with
a poor prognosis. The pathogenesis of these lesions is not
well understood but they appear related to endothelial
cells growth deregulation and increased migration and
proliferation of smooth muscle cells and fibroblasts leading
to structural changes in the pulmonary arterial wall and
pulmonary vascular remodeling. We report a case of a
2-year-old boy admitted to the intensive care unit for
severe dyspnea and epistaxis. Despite intensive treatment,
he had several cardiac arrests and died 8 days after
admission. Autopsy was performed and showed typical
lesions of idiopathic pulmonary hypertensive arteriopathy
characterized by plexiform lesions of the interlobular
arteries with numerous disseminated intravascular
A 2-year old boy was admitted via the Emergency
Department to the Intensive Care Unit of our hospital for
severe asthma, and profuse epistaxis. His mother reported
that he had experienced recurrent episodes of epistaxis and
bronchitis treated with inhaled steroids over the last year.
His immunizations were up to date. The current history
started with dyspnea that had progressively worsened over
a few days.
On examination, he was conscious and tachypneic (70/
min). His central temperature was 39°C and his oxygen
saturation on air was 88%. He had bilateral profuse
epistaxis. Chest examination showed wheezing, ronchi and
a diastolic 3/6 heart murmur. The rest of the examination
was normal. Chest X-ray showed an enlarged pulmonary
artery trunk with right heart dilation, while the lungs
demonstrated consolidation of the right inferior lobe and
diffuse interstitial opacities. Laboratory investigations
results were as follow: Arterial gas on 3l/min oxygen: pH
7.45, PCO2 18.4 mmHg, PO2 70 mmHg. Full blood count:
hemoglobin (Hb) 9.4 g/dl with 4% schizocytes, platelets
(Pts) 18 000/mm3 and white blood cells (WBC) 34 000/
mm3 with 80% of neutrophils. Hemostasis: Factor I 4g/l, II
58%, V 51%, VII + X 52%. Haptoglobin was undetectable.
C-reactive protein (CRP), ferritin, renal and liver function
tests were normal. Myelogram was normal. HIV, HBV, HCV
and CMV serologies were negative. Treatment comprised
nasal oxygen 3l/min, 4 hourly antibiotics (tazocillin
and gentamycin), platelet infusions and intravenous
immunoglobulins. Two days after admission, a thoracic
and abdominal CT-scan showed intraparenchymal micronodules
throughout the lungs, with marked dilation of the
main pulmonary artery trunk (35 mm) and the right and
left main pulmonary branches (18 mm). There was marked
dilation of the right atrium and ventricle, and polysplenia.
The Ivemark syndrome was thus suspected. On Day 3, he
experienced his first cardiac arrest. He was intubated and
ventilated on 100% oxygen. Cardiac ultrasound diagnosed
systemic pulmonary hypertension with a right to left shunt
through the foramen ovale and confirmed the dilation of the
right heart chambers and of the main pulmonary trunk and
branches. Right and left ventricular function was impaired.
The heart was otherwise anatomically normal.
Nitric oxide and epoprostenol infusion were added to his
management but he was unresponsive, experiencing 3
further cardiac arrests and requiring inotropic support with
dobutamine and milrinone. He finally succumbed eight
days after his admission.
The autopsy confirmed polysplenia with 10 small
spleens identified (Figure 1). The liver was abnormal
macroscopically with 2 symmetrical lobes located either
side of the gallbladder. Basic cardiac anatomy was normal
with atrial situs solitus, atrio-ventricular and ventriculoatrial
concordance. The right heart chambers were dilated.
The lungs were very dense and dark red/blue (Figure 2).
Both lungs were bilobed, with the right lung weighing 211
g and the left lung 165 g. On microscopic examination, the
basic underlying pulmonary architecture was normal.
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|Figure 1: Polysplenia: Presence of about 10 spleens measuring 5 to 60 mm.
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|Figure 2: Both lungs were bilobed, with dense and dark red/blue appearance and firm consistency.
There were generalised severe changes observed involving
the muscular pulmonary arteries, most developed in
intralobular arterioles. These changes included medial
thickening with cellular intimal proliferation and
concentric laminar fibrosis in an “onion-skin” pattern
that was associated, in some vessels, with complete
luminal obstruction. Medial thickening was estimated
to be 65% of the external vascular diameter. Intimal
changes demonstrated a cellular proliferation between
the endothelium and the internal elastic lamina with
concentric fibrosis, encroaching on the lumen. Dilatation
and plexiform lesions were also observed (Figure 3). The
latter were characterized by an angiomatoid, glomeruloid
proliferation of small, slit-like vessels within a dilated
lumen of arteries that showed destruction of the wall, loss
of the elastic lamina and thinning of the media. Dilatation
lesions comprised arterioles with thinned walls, clustering
into angioma-like proliferations around thickened parent
arterioles. Numerous microthrombi were seen within the
lumina of these lesions (Figure 4). The presence of medial
hypertrophy and the extension of the lesion outside the
lumen of the parent artery ruled out recanalized thrombi
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|Figure 3: Plexiform lesions consisting in: stenotic muscular arteries (onion skin pattern), proliferation of endothelial cells in stenotic muscular arteries (angiomatoid proliferation) and distal network of dilated thin-wall vessels (dilatation lesions) (H&E; x400).
There was no veno-occlusion and no hemosiderin deposition
evident. Focally there were numerous capillaries with a
pseudo pulmonary capillary hemangiomatosis pattern.
These lesions were not associated with inflammatory cells.
Numerous megakaryocytes could be identified throughout
the lung parenchyma. There was alveolar edema and
congestion related to the multivisceral failure. Airways
appeared normal and hilar lymph nodes showed vascular
In conclusion, the appearances were typical of idiopathic
pulmonary arteriopathy characterized by plexiform lesions
involving interlobular arteries containing numerous
disseminated intravascular microthrombosis. DNA was
stored and genetic study of BMPR2 was planned.
Pulmonary arterial hypertension (PAH) is rare in
childhood. A clinical classification of PAH for both adults
and children was proposed in 1998 at Evian, France and
was revised in 2003 in Venice1
. International diagnostic
and management guidelines were published in 20042
. The most common causes of PAH in children are
idiopathic or familial PAH, congenital heart disease with
left-to-right shunt, chronic hypoxia (chronic lung disease
of prematurity) and persistent pulmonary hypertension of
the newborn. Connective tissue disease, chronic thromboembolism,
HIV, portal hypertension, sarcoidosis, sickle cell
disease and anorexigen related PAH are mainly observed in
adults. A Swiss registry established in 1999 categorised 23
children over a 7-year period and showed a high prevalence
of congenital heart disease (52%), with idiopathic PAH
(34%) and PAH associated with pulmonary disease (13%)3
To achieve the best outcomes, PAH in children should
ideally be recognised early so as to institute life-saving
treatment, and minimize complications. In this case the
child presented with asthma and epistaxis. The clinical
presentation of PAH in children and adults is notoriously
non-specific and includes dyspnea, syncope and chest pain.
In children, the main differential diagnosis is asthma but
the respiratory signs do not resolve with bronchodilatators.
In addition this child presented with epistaxis related to
thrombopenia. Hemolytic anemia with schizocytes and
thrombopenia can be explained on the basis of numerous
microthrombi within the plexiform lesions and sequestration
of the numerous megakaryocytes in the lung parenchyma.
Epistaxis at presentation, related to intrapulmonary platelet
sequestration has not been described before in PAH.
Cardiac catheterization remains the “gold standard” for
diagnosis, assessing the severity of PAH, determining
prognosis and thus establishing the appropriate treatment
regime. PAH in children is characterized by increased acute
vasoreactivity when compared to adults, thus permitting
more responsive treatment with calcium channel blockers.
Recent therapeutic advances have dramatically improved
the prognosis of PAH. These advances include the use of
intravenous prostacyclin derivatives, including epoprostenol
and targeted therapy with endothelin-receptor antagonists
(bosentan) and phosphodiesterase type 5 inhibitor
(sildenafil). Some of these treatments have been used in
children. In children with syncope, atrial septostomy may
be performed. For this patient, clinical evolution was acute
and the child didn’t respond to vasodilatator treatment with
nitric oxide and epoprostenol.
In this observation, pathological examination ruled out
secondary causes of PAH. There was no evidence of venoocclusive
disease, pulmonary capillary hemangiomatosis,
interstitial or alveolar lung disease, chronic thrombotic
or embolic disease. Post-mortem examination showed no
heart anomalies except a distended right heart without
any shunts. Polysplenia was identified but without situs
Plexiform lesions represent the hallmark of this disease.
It is speculated they develop in areas of fibrinoid necrosis
in association with spastic vasoconstriction4. Research
into the molecular pathways triggering the remodeling
process is incomplete but studies have shown an important
role for the TGF family in modulating extracellular matrix
synthesis5. In a recent study6 performed to assess
whether matrix cross-linking enzymes played a role in
experimental pulmonary hypertension, all 5 lysyl oxidases
were detected in concentric and plexiform vascular lesions.
Lox, Lox1, Lox 2 and Lox 4 expression was elevated in lungs
of patients with idiopathic PAH. Lysyl oxydases seem then
to play a role in experimental pulmonary hypertension and
may represent an interesting therapeutic target.
Genetic abnormalities are thought to account for 10% to
20% of all patients with idiopathic PAH within half of whom
mutations in BMPRII gene have been identified encoding
one of the TGF superfamily receptors7. In this case,
there was no family history of pulmonary hypertension
and prospective screening of the whole family, the parents
and three older sisters, confirmed no other cases. The
presence of other abnormalities noted at autopsy, including
abnormalities of lung, liver lobation and polysplenia lend
support to an underlying genetic developmental basis. The
parents were counselled and consented to DNA extraction,
storage and investigations including BMPRII mutation
In conclusion, pediatric idiopathic pulmonary arterial
hypertension is a rare disease with usually nonspecific
symptoms. The pathognomonic histological pattern
(plexiform lesions) of this disease should be known by
pathologists to allow an early diagnosis and a precocious
management of these children.
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