(all Exercise Physiology Research Laboratory, University of California,
Los Angeles, CA, USA).
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DOI: 10.1183/09031936.00037409
Sarcoidosis-related pulmonary veno-occlusive disease
presenting with recurrent haemoptysis
To the Editors:
A 52-yr-old female nonsmoker presented with haemoptysis
consisting of streaks of bright red blood daily for 3 weeks. She
gave a 3-yr history of dry cough, episodic wheeze and mild
exertional dyspnoea. The symptoms had not improved with
inhaled corticosteroids (fluticasone 250 mg b.i.d). The patient
denied fever, sweats or weight loss and had no significant past
medical history. Physical examination was unremarkable.
Chest radiograph showed no focal pulmonary abnormality or
obvious lymphadenopathy, and electrocardiogram was normal.
Pulmonary function tests recorded a forced expiratory volume in
1 s (FEV1) of 2.22 L (86% predicted), a forced vital capacity (FVC)
of 2.93 L (96% pred) and a diffusing capacity of the lung for
carbon monoxide (DL,CO) of 7.23 mmol?m-1?kPa-1 (88% pred).
Laboratory investigations showed a haemoglobin level of
12.9 g?dL-1, and a normal coagulation screen, metabolic screen
and erythrocyte sedimentation rate (21 mm?h-1). Serum autoantibodies were negative and the angiotensin converting
enzyme (ACE) level was 53 IU?L-1 (normal range 0–52 IU?L-1).
High-resolution computed tomography (HRCT) of the chest
showed thickening of central bronchovascular bundles and
scattered, nodular, ground-glass and airspace opacities (fig. 1a).
Fibreoptic bronchoscopy was requested. At 1 h prior to the
procedure, the patient had a large haemoptysis of 200 mL bright
red blood. Bronchoscopy showed diffuse fresh blood and
grossly hyperaemic bronchial mucosa with generalised oozing
from major and lobar bronchi (fig. 1b).
a)
b)
c)
d)
c)
FIGURE 1.
a) Axial high-resolution computed tomography (HRCT) image
showing nodular thickening extending along central bronchovascular bundles in the
apical segment of the left lower lobe. Elsewhere, there were scattered nodular,
ground-glass and airspace opacities consistent with pulmonary sarcoidosis. b)
Bronchoscopic view of the right main and right upper lobe bronchus (arrow)
showing diffuse mucosal erythema. c) HRCT thorax image taken 15 months after
initial presentation showing thickened interlobular septa and patchy ground-glass
attenuation. The subsegmental pulmonary arteries were enlarged relative to
accompanying bronchi, reflecting raised pulmonary artery pressure. There was a
small left pleural effusion. d) Contrast-enhanced computed tomography pulmonary
angiogram during the patient’s final illness, displaying a persistent left pleural
The patient subsequently underwent rigid bronchoscopy,
bronchial biopsies and surgical lung biopsies from the left
lower lobe. Histological examination of the bronchial biopsies
was unremarkable. Lung biopsies demonstrated a cluster of
noncaseating granulomata on the pleural surface but normal
lung parenchyma and pulmonary vessels. Based on clinical,
radiological and histological appearances, the patient was
diagnosed with sarcoidosis. No specific therapy was initiated
partly due to patient choice, because her symptoms had
resolved and lung function tests were within normal limits.
EUROPEAN RESPIRATORY JOURNAL
VOLUME 34 NUMBER 2
effusion with superadded bilateral, patchy airspace consolidation. In addition, a
filling defect, presumed thrombus, was seen in the right pulmonary venous
confluence (circled in red).
517
c
The patient remained well for 15 months. She subsequently
reported a deterioration in exercise capacity (New York Heart
Association (NYHA) class II). Pulmonary function tests
worsened, with an FEV1 of 1.89 L (74% pred), an FVC of
2.67 L (89% pred) and a DL,CO of 5.42 mmol?m-1?kPa-1 (68%
pred). Repeat HRCT revealed a generalised increase in lung
parenchymal attenuation, new thickened interlobular septa,
mediastinal and peri-hilar lymphadenopathy and left pleural
effusion (fig. 1c). In view of the clinio-radiological findings,
prednisolone (0.5 mg?kg-1?day-1) was commenced. Over
6 weeks, the patient’s condition deteriorated. She reported
increasing breathlessness (NYHA III) and formed a clear
opinion that steroids had made her worse.
Subsequently, the patient experienced further haemoptyses of
f100 mL, necessitating hospital admission. She was treated
with intravenous methyl prednisolone, 1 g?day-1 for 3 days,
and 20 mg oral prednisolone daily. Right heart catheterisation
confirmed pulmonary hypertension (PH) (mean pulmonary
artery pressure 40 mmHg) with a normal mean pulmonary
capillary wedge pressure (9 mmHg). Cardiac index was
5.2 L?min-1?m-2.
Her condition continued to deteriorate rapidly with pleuritic
pain, worsening dyspnoea and further haemoptysis, with
resultant hypoxaemia requiring mechanical ventilation.
Transthoracic echocardiography showed a dilated, poorly
contractile right ventricle and an estimated pulmonary artery
systolic pressure of 80 mmHg. Contrast-enhanced computed
tomography (CT) pulmonary angiography revealed a filling
defect within the right pulmonary vein with bilateral patchy
consolidation and pleural effusions (fig. 1d). Despite increasing
doses of vasopressor support, the patient died of multi-organ
failure. At autopsy, lung parenchyma and bronchi were taken
for histological examination.
Lung parenchyma showed diffuse alveolar damage superimposed upon numerous non-necrotising epithelioid and
giant-cell granulomas within dense hyaline fibrosis with a
perilymphatic distribution, characteristic of sarcoidosis (fig. 2).
There was notable angiocentricity of the granulomatous
disease, particularly involving the pulmonary venous system
with sclerotic changes causing vessel occlusion resembling
pulmonary veno-occlusive disease (PVOD). There were also a
few foci of patchy but marked localised capillary congestion,
indirect evidence of post-capillary obstruction without capillary proliferation.
DISCUSSION
PH is an uncommon but increasingly recognised complication
of sarcoidosis, with an incidence of f5.7% [1, 2]. Postulated
aetiologies include extensive parenchymal fibrosis [2], extrinsic
compression of pulmonary vessels from lymphadenopathy [3]
and granulomatous involvement of the pulmonary vessels [3–7].
To our knowledge, there are only seven documented cases of
PVOD related to sarcoidosis, none of which were complicated by
haemoptysis [3–5].
The principal symptoms of PVOD, dyspnoea and lethargy, are
indistinguishable from other forms of PH. In one small series,
inspiratory crackles and clubbing were reported in around half
the patients with PVOD and the overall prognosis was worse
than for other causes of PH [8].
518
VOLUME 34 NUMBER 2
Characteristic pathological abnormalities in PVOD include
diffuse non-angiogenic narrowing and occlusion of postcapillary pulmonary veins by intimal fibrous tissue [9, 10].
Changes principally involve veins in lobular septa, although
25% may involve intra-acinar venules alone [10], with
compensatory arteriolar muscularisation and medial hypertrophy of pulmonary arteries, which may be so striking as to
misdiagnose PVOD as idiopathic pulmonary arterial hypertension. Localised capillary congestion and pulmonary capillary haemangiomatosis (PCH) are also frequently found in
cases of PVOD, suggesting a degree of overlap between these
two conditions [10]. Modest granulomatous involvement of
pulmonary vessels is common in sarcoidosis. In a post mortem
study of 40 patients, 65% had granulomatous invasion of
venules [11]. Despite this, the frequency of clinically significant
PH (particularly PVOD) is low.
Two remarkable features of the present case were the recurrent
episodes of profuse haemoptysis and associated bronchoscopic
abnormalities. Haemoptysis occurs in only 6% of patients with
sarcoidosis [12], usually from granulomatous airway inflammation. Other causes include complications of bronchiectasis,
aspergilloma or granulomatous vascular infiltration.
Haemoptysis is also rare in PVOD [13–15], although a recent
study demonstrated elevated numbers of haemosiderin-laden
macrophages in bronchoalveolar lavage, implying that occult
haemorrhage does occur [14]. In our patient, granulomatous
involvement of pulmonary veins resulting in alveolar and
bronchial capillary congestion was the likely cause of the
haemoptyses. Certainly, multiple bronchoscopic biopsies did
not reveal any endobronchial granulomas, nor were any
evident at autopsy. One previously published report of a
patient with idiopathic PVOD documented intense hyperaemia of lobar and segmental bronchi with bright red
longitudinal streaks at bronchoscopy, postulated to be due to
submucosal vasodilatation in bronchial walls [16]. Our patient
displayed similar but more extensive bronchoscopic abnormalities, which can be explained by the reverse flow and
drainage into visibly dilated bronchial veins from occluded
and congested pulmonary veins, comparable to other causes of
pulmonary venous hypertension [17].
Pulmonary function testing in PVOD often shows a severe
reduction in DL,CO (,50%) and normal or mild restrictive
spirometric defects [8, 15]. These are also features of
sarcoidosis with lung parenchymal involvement. In our
patient, the relative preservation of DL,CO may have reflected
alveolar congestion and haemorrhage caused by PVOD.
Chest radiographs in established PVOD may show evidence of
pulmonary venous hypertension with thickened interlobular
septa, dilated central pulmonary arteries and patchy groundglass opacities [8]. Such findings may be misinterpreted as
chronic interstitial changes of sarcoidosis. In this context,
HRCT is useful for identifying features of PVOD, which
typically consist of centrilobular ground-glass attenuation and
subpleural septal lines [18]. Ground-glass attenuation has been
reported in f45% of patients with sarcoidosis [19] and is
thought to be due to interstitial granulomata or fine fibrosis.
NUNES et al. [3] reported ground-glass attenuation in 85.7% of
patients with non-fibrotic sarcoidosis and associated PH,
EUROPEAN RESPIRATORY JOURNAL
a)
b)
V
V
V
c)
FIGURE 2.
d)
Histological haematoxylin–eosin (a and d) and Elastic van Gieson (b and c) stainings of post mortem lung tissue. a) High-power view showing granulomatous
vasculitis. b) Low-power view showing septal thickening, particularly marked around vessels, with veins (indicated by a V) showing patchy but marked stenosis with focal
arteriolisation (indicated by arrows). c) Higher power view of the obliterated vein. d) High-power view of the lung parenchyma showing focal grossly distended alveolar
capillaries adjacent to a vessel (probably septal vein) with patchy occlusive fibrosis, indicating post-capillary obstruction. Scale bars5250 mm.
compared to 14.3% of similar patients without PH; although
histopathological confirmation is lacking, it is likely that
ground-glass opacification in patients with PVOD reflects
pulmonary oedema and/or extravasated blood. This raises the
possibility that PVOD is underdiagnosed. Another important
radiological finding in PVOD is mediastinal lymphadenopathy
[18], which is unusual in most causes of PH, though common
in sarcoidosis and pulmonary oedema [20, 21]. At the time of
our patient’s final illness, CT pulmonary angiography demonstrated thrombi within the pulmonary veins. Similar CT
appearances have been reported in another case of sarcoidosis
with granulomatous occlusion of the pulmonary veins [22].
in systolic pulmonary arterial pressure in patients with nonfibrotic sarcoidosis-related PH following corticosteroid therapy,
with no response in patients with fibrotic disease [3]. As PVOD
affects the post-capillary veins, treatment with specific vasodilator therapy, such as prostacyclin, may result in lifethreatening pulmonary oedema. However, vasodilators such
as epoprostenol have demonstrated efficacy in sarcoidosisrelated PH [24] and have been used cautiously in patients with
idiopathic PVOD [25]. Thus, identifying PVOD is particularly
important to ensure close monitoring following initiation of
specific vasoreactive therapies in these patients.
Treatment of PVOD in sarcoidosis is problematic. The effect of
corticosteroids appears variable, with some studies demonstrating a benefit [6, 23] and others reporting no or even detrimental
effects [2]. A recent small study reported a favourable reduction
To our knowledge, there are no reported cases of PVOD related
to sarcoidosis with the combination of recurrent profuse
haemoptysis and abnormal bronchoscopic findings in the
absence of granulomatous bronchial inflammation. This case
highlights the possibility of PVOD complicating sarcoidosis,
EUROPEAN RESPIRATORY JOURNAL
VOLUME 34 NUMBER 2
519
c
particularly when haemoptysis is a feature, and emphasises the
importance of scrutinising radiographic changes for this overlapping condition. The prognosis for PVOD from any aetiology
is poor and most patients die within a few months of diagnosis
[25]. Lung transplantation is the only current treatment that may
significantly prolong survival and should be considered early.
R.M. Jones*, A. Dawson#, G.H. Jenkins", A.G. Nicholson+,
D.M. Hansell1 and N.K. Harrison*
*Respiratory Unit, #Dept of Histopathology and "Regional
Cardiac Centre, Morriston Hospital, Morriston, Swansea, and
Depts of +Respiratory Pathology and 1Thoracic Imaging, Royal
Brompton Hospital, London, UK.
Correspondence: R.M. Jones, Respiratory Unit, Morriston
Hospital, Morriston, Swansea, SA6 6NL, UK. E-mail: drmatjones
@hotmail.com
Statement of Interest: None declared.
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DOI: 10.1183/09031936.00044609
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