By Soumya Chatterjee, MD, MS, FRCP, and Joseph Parambil, MD
Cleveland Clinic is a non-profit academic medical center. Advertising on our site helps support our mission. We do not endorse non-Cleveland Clinic products or services Policy
A 69-year-old female ex-smoker with limited scleroderma (anti-centromere antibody-positive) and stable interstitial lung disease (on azathioprine) presented to Cleveland Clinic’s combined rheumatology-pulmonary clinic with increasing shortness of breath and clinical deterioration of pulmonary arterial hypertension (PAH). At the time of her PAH diagnosis 13 months earlier, right heart catheterization had shown mean pulmonary artery pressure (mPAP) of 41 mm Hg and mean pulmonary capillary wedge pressure (mPCWP) of 17 mm Hg. Her PAH had since been well-controlled on bosentan 125 mg twice daily, sildenafil 40 mg three times daily, inhaled treprostinil 54 μg four times daily and oxygen 2 L/min.
At her current presentation, in addition to increasing shortness of breath, she had substantial decline in her six-minute walking distance and increased diuretic needs.
Transthoracic echocardiogram revealed normal left ventricular systolic function. Ejection fraction was 69 (± 5) percent. Baseline left ventricular diastolic function was consistent with abnormal relaxation (stage I). The right ventricle was dilated, and right ventricular systolic function was moderately decreased. There was severe (3+to 4+) tricuspid valve regurgitation. Estimated right ventricular systolic pressure was 100 mm Hg, consistent with severe PAH.
One month after the patient’s presentation, a repeat right heart catheterization showed mPAP of 43 mm Hg and mPCWP of 14 mm Hg. Left ventricular filling pressure was normal. Cardiac output was 3.5L/min, and cardiac index was 2.0 L/min/m2.
Despite triple drug therapy, the patient’s hemodynamics remained suboptimal. To optimize control of her PAH, she was transitioned from inhaled to IV treprostinil, and its dose gradually was titrated upward with each cassette change, as tolerated. When the dose was increased to 21 ng/kg/min, she complained of worsening exertional shortness of breath. It was advised that she reduce the dose to 20 ng/kg/min, increase the dose of her diuretic (torsemide) to 40 mg daily and add spironolactone 25 mg daily.
Chest radiographs at the time of right heart catheterization showed an enlarged cardiac silhouette. There were bibasilar opacifications suggestive of pleural effusions, left greater than right. There was prominence of interstitial markings, and pulmonary edema was considered. A week later, the patient called to report that she was still very short of breath despite the medication adjustments. She was advised to further reduce the treprostinil dose, to 19 ng/kg/min.
As her shortness of breath continued to worsen, she was admitted for further evaluation and management. Chest radiography (Figure 1, left) revealed a significant left-sided pleural effusion. Approximately 950 mL of fluid was drained on thoracentesis, and it was determined to be a transudate. After thoracentesis, a thoracic CT scan (Figure 2) revealed bilateral septal thickening (Kerley B lines).
Figure 1. (Left) Chest radiograph taken at admission showing a significant left-sided pleural effusion. (Right) Chest radiograph at post-discharge follow-up showing resolution of the pleural effusion
Figure 2. Thoracic CT taken at admission revealing bilateral septal thickening.
The findings in this patient ‒ presence of a large transudative pleural effusion on radiography as well as septal thickening and Kerley B lines on CT, in the absence of significant left heart dysfunction ‒ were consistent with concomitant pulmonary venous outflow obstruction (pulmonary veno-occlusive disease [PVOD]) coexisting with scleroderma-associated PAH. The patient’s PVOD likely became unmasked on rapid upward titration of her IV treprostinil.
Her treprostinil dose was titrated down, and she was discharged on a higher torsemide dose (60 mg daily). At her follow-up visit in the combined rheumatology-pulmonary clinic, her dyspnea was significantly better. Chest radiography revealed resolution of the left pleural effusion (Figure 1, right). The plan was to continue her aggressive diuretic regimen and temporarily hold off on upward titration of the IV treprostinil, which might be attempted later as tolerated, but with extreme caution. She was advised to continue her oxygen therapy and her usual doses of bosentan and sildenafil
Comment: The case for collaborative care
PVOD is a clinicopathologic syndrome that accounts for a small number of PAH cases and is a known complication of scleroderma.1,2 It is more common than initially realized and may partly explain the poorer response to vasoactive therapy seen in scleroderma-associated PAH relative to idiopathic PAH.1,2 The pathologic feature of PVOD is widespread occlusion of the pulmonary veins by fibrous tissue (Figure 3). The signs of PVOD are the same as those seen in other types of PAH, so clinical features alone are often insufficient to distinguish the conditions. PVOD is suggested by the following triad:
- Severe PAH
- Pleural effusions and radiographic signs of pulmonary edema
- Normal PCWP on right heart catheterization
Figure 3. Illustration showing the site of pathology in pulmonary veno-occlusive disease (PVOD). PVOD characteristically leads to fibrotic occlusion of the venous end of the pulmonary capillaries, pulmonary venules and small pulmonary veins, with consequent elevation of the true pulmonary capillary pressure and pre-capillary pulmonary arterial pressure. Larger pulmonary veins (where the pulmonary artery catheter balloon wedges) are usually not affected by PVOD, which explains why the pulmonary capillary wedge pressure is not affected.
However, this triad of findings is insensitive. Therefore, definitive diagnosis of PVOD requires a surgical lung biopsy, which makes delays in the diagnosis common. Many patients are initially presumed to have heart failure (due to the abnormalities on chest radiography and CT) or advanced interstitial lung disease.
This case exemplifies the advantages of collaborating with an expert pulmonologist to provide optimal evidence-based care to our very complex patients with multisystem diseases. In the absence of a lung biopsy, it is nearly impossible to establish the diagnosis of PVOD with certainty. However, the knowledge that concomitant PVOD physiology is not uncommon in scleroderma-associated PAH helped us make the right management decision in this case, where circumstantial evidence of PVOD was strong and the favorable response to down-titrating the treprostinil dosage virtually established the diagnosis.
Important and sometimes life-saving management decisions about rare and complex conditions in rheumatology often must be based on expert opinions alone because well-designed randomized trials are not available. This is frequently the case when pulmonary diseases complicate autoimmune rheumatic conditions. It is imperative that such complex cases be managed conjointly by a rheumatologist and a pulmonologist. Our combined rheumatology-pulmonary clinic makes such close collaboration possible.
Dr. Chatterjee is a staff physician in the Department of Rheumatic and Immunologic Diseases, directs Cleveland Clinic’s combined rheumatology-pulmonary clinic with staff pulmonologists Joseph Parambil, MD, and Kristin Highland, MD. The clinic integrates evidence-based care with clinical and translational research on the complex pathogenesis and management of rheumatic diseases affecting the lungs.
Dr. Parambil is a member of the Department of Pulmonary, Allergy and Critical Care Medicine with a special interest in autoimmune rheumatic disease-associated interstitial lung disease and pulmonary hypertension.
- Overbeek MJ, Vonk MC, Boonstra A, et al. Pulmonary arterial hypertension in limited cutaneous systemic sclerosis: a distinctive vasculopathy. Eur Respir J. 2009;34:371-379.
- Dorfmuller P, Humbert M, Perros F, et al. Fibrous remodeling of the pulmonary venous system in pulmonary arterial hypertension associated with connective tissue diseases. Hum Pathol 2007;38:893-902.