A case of pulmonary veno-occlusive disease: diagnostic dilemmas and therapeutic challenges

Abstract

Pulmonary veno-occlusive disease (PVOD) is a rare cause of pulmonary hypertension (PH). Misdiagnosis of the disease is common since PVOD presents with clinical and radiographic features mimicking idiopathic pulmonary arterial hypertension or even PH due to interstitial lung disease. Vasodilators may not be efficacious in PVOD and may in fact worsen hemodynamic status with the development of pulmonary edema. Lung transplantation represents the best treatment option. In the present report we describe the challenging diagnosis of PVOD in a patient with PH referred to our department. Final diagnosis was established by surgical lung biopsy. The patient was offered sequential combination therapy under close monitoring and maintained remarkable clinical stabilization while being on the waiting list for lung transplantation.

Introduction

Pulmonary veno-occlusive disease (PVOD) is a rare disease with a dismal prognosis. The syndrome is currently classified as a particular subgroup of pulmonary hypertensive disease [Galiè et al. 2009]. Unlike pulmonary arterial hypertension (PAH), which only affects the distal pulmonary arteries, PVOD is characterized by a widespread fibrous intimal proliferation that preferentially involves the pulmonary venules and small veins. Despite the different pathology, PVOD shares broadly similar clinical presentation and hemodynamic characteristics with PAH. Thus, the distinction between the two entities often represents a challenge for the clinicians, and it has previously been estimated that PVOD accounts for 5–10% of cases initially considered to be idiopathic PAH [Montani et al. 2009b]. In contrast, with idiopathic PAH the benefits of specific PAH treatments in patients with PVOD remain unclear [Boutet et al. 2008; Mandel et al. 2000]. In this report we describe a patient diagnosed with PVOD by surgical lung biopsy 6 years ago who maintained remarkable clinical stabilization under sequential combination therapy.

Case report

In February 2006, a 35-year-old man was referred to the Respiratory Failure Unit with the diagnosis of pulmonary hypertension (PH) and diffuse lung infiltrates on chest X-ray. He first presented to the emergency department of a regional hospital with rapidly progressive dyspnea [New York Heart Association (NYHA) class III] and episodes of chest pain on exertion, hemoptysis and chronic cough. Six months ago, the patient was diagnosed with bronchial asthma and placed on bronchodilators. He was an ex-smoker with a history of smoking 40–50 cigarettes/day for 10 years. On admission to our department, he was tachypneic with central cyanosis. Physical examination revealed crackles on both lungs and a prominent pulmonic component of the second heart sound. Blood gas analysis on room air was indicative of hypoxemia with oxygen saturation (SaO₂) 88%, partial pressure of oxygen (pO₂) 52 mmHg and partial pressure of carbon dioxide (pCO₂) 35 mmHg. Electrocardiogram showed right axis deviation and incomplete right bundle branch block. Chest X-ray demonstrated enlargement of proximal pulmonary arteries and interstitial infiltrates in both lower lobes [Figure 1(a)]. Hematological and biochemical tests were in the normal range. Transthoracic echocardiordiogram showed marked right atrial and ventricular enlargement with normal left ventricular systolic and diastolic function. Doppler systolic pulmonary artery pressure was estimated at 87 mmHg. No cardiac shunt was detected. Pulmonary function tests revealed a mild restrictive ventilator defect whereas diffusing capacity of the lung for carbon monoxide was markedly reduced at 49% of predicted. On the 6 minute walk test (6MWT), the patient only managed to walk 225 m and presented with severe arterial oxygen desaturation of 85%.

Figure 1.

(a) Chest X-ray with dilation of proximal pulmonary arteries and interstitial infiltrates in both lower lobes. (b) Chest computed tomography scan showing patchy ground-glass opacities, thickened septal lines and fissural thickening.

High-resolution computed tomography (CT) of the thorax showed diffuse ground-glass opacities, thickened interlobular septa, bilateral pleural effusion and mediastinal lymph nodes enlargement [Figure 1(b)]. A ventilation–perfusion scan was performed to rule out thromboembolic disease and revealed normal ventilation with diffuse subsegmental areas of hypoperfusion consistent with a low probability for pulmonary embolism. Screening for connective tissue disorders was negative. A human immunodeficiency virus test was also negative. A bronchoscopic evaluation with bronchoalveolar lavage was carried out and showed hyperemia of mucosa and several newly formed vessels along the bronchial tree. Right heart catheterization confirmed severe precapillary PH, with high mean pulmonary arterial pressure at 53 mmHg, while pulmonary capillary wedge pressure was in the normal range (10 mmHg), cardiac output was 4 liters/min, and pulmonary vascular resistance were elevated at 860 dyn/s/cm⁵ (10.7 Wood units).

Idiopathic PAH but also PVOD and PH due to interstitial lung disease because of diffuse parenchymal abnormalities were considered in differential diagnosis. Treatment with anticoagulants, high-dose diuretics (oral furosemide 250 mg daily) and oxygen therapy was initiated. After 3 months of treatment, the patient reported marked improvement in his dyspnea with concomitant improvement of arterial blood gases at rest (pO₂ 62 mmHg). At that time, a lung biopsy was proposed to the patient for the purpose of a definite diagnosis and for guiding the appropriate treatment. The patient consented and in May 2006 a surgical biopsy was performed for histological study. After surgery the patient remained in the intensive care unit (ICU) and was successfully weaned from mechanical ventilation after 48 h. Histological analysis of lung tissue revealed diffuse occlusion of pulmonary small veins and venules by fibrous tissue. Hemosiderosis was present within the interstitial space and in alveolar spaces with iron-laden macrophages. On the basis of these pathological findings together with the clinical and radiographic features, the patient was diagnosed with PVOD. Cautious use of the endothelin-receptor antagonist bosentan (initial dose 62.5 mg twice daily uptitrated to 125 mg twice daily) was initiated. The patient was referred to the national lung transplant center for evaluation.

After 7 months of treatment, sildenafil (20 mg three times a day, uptitrated to 40 mg three times a day) was added to treatment due to progressive, slow deterioration in the patient’s functional capacity. Over a 1.5-year treatment period, the patient presented with remarkable clinical stabilization under double combination therapy (NYHA II, SpO₂ on room air 92%, and 6MWD 560 m). However, in the period between September 2009 and February 2010 there was a progressive deterioration in functional class (NYHA III–IV) and in radiographics [figure 2(a, b)] together with a rapid decline in exercise capacity (6MWD 315 m with severe oxygen desaturation at 77%). A trial with low doses of continuous intravenous epoprostenol (1–2 ng/kg/min) was performed under monitoring in the ICU but it was rapidly interrupted due to deterioration of SaO₂ at 83%. Inhaled iloprost (2.5 μg aerolized six times daily) was added to treatment and furosemide dose was increased to 375 mg daily.

Figure 2.

Marked deterioration in radiographics 4 years after diagnosis. (a) Chest X-ray and (b) chest computed tomography scan showing diffuse opacities of both lungs.

The patient was finally listed for double lung transplantation.

Discussion

PVOD is a rare cause of PH which preferentially affects the postcapillary venous pulmonary vessels [Mandel et al. 2000]. Even though its histopathology is distinctly different, the clinical presentation of PVOD is largely similar to other PAH types. Hemodynamics are also similar; right heart catheterization reveals evidence of severe precapillary PAH. The value of the pulmonary capillary wedge pressure obtained is generally normal despite the fact that pulmonary capillary pressures are elevated. This occurs because wedge pressure reflects the pressure in a pulmonary vein of similar diameter to the occluded pulmonary arterial branch, which is larger than the small veins affected by PVOD [Mandel et al. 2000]. Chronic pulmonary capillary hypertension with transudation of fluid into the interstitium and consequent alveolar septal thickening results in signs of pulmonary edema frequently seen in chest imaging in PVOD [Mandel et al. 2000]. Extensive obliteration of the pulmonary vascular bed, alveolar hemorrhage and pulmonary edema in the most severe cases leading to severe ventilation–perfusion mismatching and diffusion limitation are the likely pathophysiological mechanisms of exaggerated hypoxemia in PVOD compared with idiopathic PAH [Montani et al. 2009b].

PVOD represents a difficult-to-diagnose entity, often leading to challenges in discriminating the disease from other forms of PAH [Palazzini and Manes, 2009; Ye et al. 2011]. Alternative diagnosis that should be considered and excluded through the diagnostic workup are parenchymal lung diseases, such as interstitial pneumonia, sarcoidosis, or even pneumoconiosis, congestive heart failure, and chronic thromboembolic PH (because of frequent perfusion defects on ventilation–perfusion scan). Features suggestive of the diagnosis of PVOD in our patient included the presence of PH with a normal pulmonary artery occlusion pressure together with radiographic features of pulmonary edema, a low pO₂ at rest with severe desaturation during 6MWT, a markedly reduced diffusing capacity, and finally chest high-resolution CT findings such as centrilobular ground-glass opacities, septal lines and lymph node enlargement.

We decided to perform a surgical lung biopsy in our patient to establish a definite diagnosis since surgical risk was evaluated as acceptable. At that time, when our experience in the diagnosis of the disease was quite limited, we felt that biopsy was warranted because it could provide important therapeutic and prognostic information. Even if histological analysis of a lung sample is still considered to be the ‘gold standard’ for the diagnosis of PVOD, it is generally not recommended by the current guidelines since it represents a high-risk procedure as this patient population often presents with more advanced disease [Galiè et al. 2009]. A noninvasive approach using clinical evaluation, radiographics, arterial blood gases, pulmonary function tests and bronchoalveolar lavage could be helpful to detect a subgroup of PAH with a high probability of PVOD and may avoid lung biopsy in most cases [Huertas et al. 2011; Montani et al. 2010].

There is no established medical therapy for PVOD. Lung transplantation is the only curative intervention. Patients with PVOD should be referred to a transplant centre for evaluation as soon as the diagnosis is established. Data regarding the use of newer medical therapies such as endothelin receptor antagonists or phosphodiesterase type 5 inhibitors in the treatment of PVOD are scant and conflicting and it has recently been reported that the lack of response to medical therapy in clinically diagnosed PAH can be explained by misdiagnosed PVOD [Harch et al. 2009]. The primary risk is the development of pulmonary edema with specific PAH therapies. The mechanism of edema development relates to pulmonary arterial vasodilation without concomitant pulmonary venodilation, producing increased transcapillary hydrostatic pressures and transudation of fluid into the pulmonary interstitium and alveoli [Mandel et al. 2000]. Pulmonary edema is not limited to a single therapeutic class and has been described with different specific PAH therapies. However, since transplantation waiting times are often lengthy, trials of these medical therapies may be cautiously performed under close medical monitoring from physicians specialized in the management of patients with PAH. Continuous intravenous epoprostenol should be considered in patients with the most severe disease with a slowly increasing dose and high-dose diuretics as a bridge therapy to lung transplantation [Montani et al. 2009a]. Unfortunately, the trial with low-dose epoprostenol in our patient was unsuccessful and resulted in worsening of hypoxemia, apparently due to the development of pulmonary edema.

Despite a lack of robust evidence, combination therapy with gradual addition of agents from different classes when predefined treatment goals are not met is common clinical practice for patients with PAH [Levinson and Klinger, 2011; Pitsiou et al. 2009; Fares and Trow, 2012]. In our case, we gradually escalated therapy under close monitoring because the patient maintained a poor functional status while on the waiting list for lung transplantation. Certainly, using a regimen involving more than one pulmonary vasodilator theoretically might further increase the risk of pulmonary edema and requires increased vigilance [Montani et al. 2009a].

Diagnosis and treatment of PVOD often represent a challenge. Since misdiagnosis is common, a comprehensive diagnostic approach is required for an accurate diagnosis. Although pulmonary vasodilators have an established role in the treatment of idiopathic PAH, their role in the management of PVOD remains unclear. Due to the limited therapeutic possibilities and the long transplantation waiting times, sequential combination therapy with vasodilators was considered in our patient and resulted in remarkable sustained clinical stabilization. The present report emphasizes the value of PAH-specific therapies as a bridge to lung transplantation and not the generalizability of these therapies to patients with underlying PVOD. The establishment of centers specialized in the management of PH having clinical protocols for quick referral to lung transplantation services is central to optimizing survival outcomes in this patient population.