Eur Respir J 2009; 33: 666–669 DOI: 10.1183/09031936.00001208 CopyrightßERS Journals Ltd 2009 CASE STUDY Granulomatous angiitis leading to a pulmonary veno-occlusive disease-like picture N. Dwyer*, R. Smith#, D. Challis#, D. Reid" and D. Kilpatrick* ABSTRACT: Pulmonary veno-occlusive disease (PVOD) is a rare cause of pulmonary AFFILIATIONS hypertension characterised by extensive fibrotic occlusion of pulmonary veins. PVOD has a *Depts of Cardiology, #Anatomical Pathology, and similar insidious presentation to idiopathic pulmonary arterial hypertension but responds poorly "Respiratory Medicine, Royal Hobart to conventional therapies and has a worse prognosis. Hospital The current study reports the case of a Caucasian female with a long history of progressive Tasmania, Australia. dyspnoea ultimately diagnosed as focal granulomatous venulitis leading to a pulmonary veno- CORRESPONDENCE occlusive disease-like pathology. The present study highlights the challenges in diagnosing and N. Dwyer treating this condition. Cardiology Dept Royal Hobart Hospital KEYWORDS: Acute pulmonary oedema, bosentan, granulomatous venulitis, infliximab, pulmonary 48 Liverpool St Hobart veno-occlusive disease, sildenafil Tasmania Australia 7000 Fax: 61 62342852 E-mail: [email protected] CASE REPORT and introduction of a corticosteroid/long-acting Received: A 43-yr-old female was extensively investigated b2-agonist combination inhaler device. This inter- January 03 2008 vention was ineffective and did not improve lung because of progressive exercise induced fatigue Accepted after revision: and breathlessness without wheeze or cough. The function tests. A cardiopulmonary exercise test September 04 2008 patient was otherwise well. She ceased smoking was aborted due to severe fatigue at 87% of at the time of symptom onset, having accumu- predicted workload. The maximal oxygen uptake lated a 25 pack-yr smoking history. There was no (V9O2,max) was 93% of predicted with no exercise STATEMENT OF INTEREST relevant family history or occupational and drug induced fall in SaO2. The patient was then lost to Statements of interest for D. Reid and exposures. There were no abnormal examination follow-up. D. Kilpatrick can be found at findings early in the natural history of the www.erj.ersjournals.com/misc/ The patient re-presented with worsening breath- statements.shtml disease. Arterial oxygen saturation (Sa,O ) at rest 2 lessness and tender, erythematous nodules on was 97% on room air. her legs consistent with a diagnosis of erythema A chest radiograph (CXR), electrocardiogram, nodosum 3 yrs later. The cutaneous lesions echocardiogram and myocardial thallium scan resolved spontaneously without any treatment. were all unremarkable. Lung function tests A ventilation/perfusion (V9/Q9) scan was nor- demonstrated a mild degree of airflow obstruc- mal. High-resolution computed tomography tion with no reversibility: forced expiratory (HRCT) of the lungs showed mild expiratory volume in one second (FEV1) 2.15 L (85% gas trapping with patchy peripheral broncho- predicted); forced vital capacity (FVC) 2.84 L centric opacities and minor septal thickening, but (94% pred); FEV1/FVC ratio 76%; mean forced no mediastinal lymphadenopathy. Her serum expiratory flow between 25 and 75% FVC 61% biochemistry and full blood count were normal, pred; diffusing capacity of the lung for carbon erythrocyte sedimentation rate (ESR) was ele- -1 -1 monoxide (DL,CO) 94% pred. A histamine chal- vated at 41 mm?h (normal rate ,15 mm?h ) lenge showed a provocation concentration caus- and angiotensin-converting enzyme level was -1 -1 -1 ing a fall in FEV1 of 20% of 0.825 mg?mL , which 21.5 IU?L (normal range 8.3–21.4 IU?L ). The is consistent with severe airway hyperrespon- patients’ serum antinuclear (ANA) and antineu- European Respiratory Journal siveness. A provisional diagnosis of asthma trophil cytoplasmic (ANCA) antibody titres were Print ISSN 0903-1936 prompted a 3-week trial of oral prednisolone negative. A diagnosis of pulmonary sarcoid was Online ISSN 1399-3003 666 VOLUME 33 NUMBER 3 EUROPEAN RESPIRATORY JOURNAL N. DWYER ET AL. GRANULOMATOUS ANGIITIS AND PVOD considered but endobronchial and transbronchial biopsies Histological examination of the lung biopsies showed intra- along with bronchoalveolar lavage were unremarkable. vascular granulomas, some of which contained central necrosis Without a satisfactory explanation of her symptoms, the (fig. 1), as well as sparse interstitial and peribronchial patient was lost to follow-up for 1 yr. granulomas. Routine culture of the lung biopsies was negative for Mycobacteria. Widespread fibro-intimal changes in the The patient continued to complain of severe exertional walls of small venules were present, causing luminal oblitera- breathlessness and fatigue and ceased full-time employment. tion with the development of dilated collateral vascular She developed acute onset of left-sided pleuritic chest pain and channels in the visceral pleura and interlobular septa. In some increased breathlessness 4 yrs after initial presentation. A CXR areas, obliterated and recanalised veins were located in areas revealed a 2-cm area of focal consolidation in the left lung-mid of collagenous scarring (fig. 2). Areas of haemorrhagic infarc- zone. Liver and renal function tests and full blood count were tion and subpleural scarring were present that were thought to ? -1 all normal but her ESR was elevated at 73 mm h . The patient be a further consequence of the vasculopathy. had a positive ANA titre at 1:40 with a nucleolar pattern. Anti- glomerular basement membrane antibody titres and National and international opinions on the pathological perinuclear-staining- and cytoplasmic-staining-ANCA were diagnosis and management were sought. Opinions differed, all normal. Her urine microscopy was normal and urinary with some favouring a diagnosis of necrotising sarcoid calcium excretion was 9.8 mmol?24 h-1 (normal range 2– granulomatosis, whilst others argued that the relative paucity 8 mmol?24 h-1). Arterial blood gases demonstrated hypoxae- of extravascular granulomata and the extensive fibro-intimal mia: pH 7.46; carbon dioxide arterial tension (Pa,CO2) thickening and occlusive venulopathy favoured a diagnosis of 31 mmHg; arterial oxygen tension (Pa,O2) 64 mmHg; and pulmonary veno-occlusive disease (PVOD), possibly second- HCO3 20.8 mmol. The uncertain diagnosis and progression ary to focal granulomatous venulitis. of symptoms prompted a thoracoscopic lung biopsy. A diagnosis of sarcoid was considered most likely and the patient was started on prednisolone 40 mg daily and weekly a) oral methotrexate. Given the prominent vasculitis and throm- bosis, she was anti-coagulated with warfarin. This regimen provided little symptomatic benefit after 6 months, but there was apparent stabilisation of disease progression with some improvement in gas exchange as measured by arterial blood gases: pH 7.45; Pa,CO2 34 mmHg; Pa,O2 72 mmHg; and HCO3 24 mmol. Reduction of prednisolone below 10 mg daily resulted in the development of recurrent episodes of migratory superficial thrombophlebitis. The patient also developed a small fibre peripheral neuropathy, which was confirmed on nerve con- duction studies. Azathioprine 100 mg daily was introduced to replace methotrexate. Prednisolone could then be ceased without recurrence of thrombophlebitis. b) FIGURE 1. a, b) Histological examination showing occlusive intravascular FIGURE 2. Elastic stain (orcein giemsa) demonstrating fibro-intimal oblitera- c granulomas with necrosis (haematoxylin and eosin stain). tion of small vessels. EUROPEAN RESPIRATORY JOURNAL VOLUME 33 NUMBER 3 667 GRANULOMATOUS ANGIITIS AND PVOD N. DWYER ET AL. Exercise testing 7 yrs after the onset of symptoms showed a fall DISCUSSION in Sa,O2 from 97% to 85% at a workload 60% of the predicted PVOD is a clinicopathological syndrome accounting for ,10% maximum. Right heart studies and pulmonary angiography of pulmonary hypertension cases [1]. The estimated annual did not identify significant pulmonary hypertension or arterial incidence is 0.2 per million in the general population [2]. Little obstruction. A trial of infliximab, an anti-tumour necrosis is understood of its epidemiology, aetiology, natural history factor-a monoclonal antibody, was undertaken and resulted in and optimal treatment. Diagnosis remains difficult with a an increase in exercise capacity with V9O2,max improving from mean duration of 49 months from symptom onset to diagnosis 51 to 61% after 3 months. Therefore, infliximab was continued [3]. Prognosis is poor with most patients dying within 2 years at 12-weekly intervals. After 2 yrs, there appeared to be of diagnosis [4]. PVOD should be suspected in patients with evidence of disease progression with Sa,O2 falling to 77% on pulmonary hypertension, radiographic evidence of pulmonary room air at only 50% of maximal workload. Increasing the oedema and a normal pulmonary capillary wedge pressure. dosing frequency of infliximab to every 6 weeks stabilised the A multitude of factors including infection, genetics, toxic patients’ exercise capacity and led to a minimal Sa,O2 of 87% at peak exercise over the next year. exposure, thrombotic diathesis and autoimmune disorders have been implicated in the aetiology of PVOD [5, 6]. Nearly 10 yrs from symptom onset there was rapid worsening Interestingly, granulomatous phlebitis, with or without gen- of breathlessness and fatigue. After 100 m of slow walking, eralised venulitis, has been reported in the setting of