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Pulmonary Arterial Hypertension: Thin-Section CT Predictors of Epoprostenol Therapy Failure¹

¹ From the Departments of Radiology (A.R., S.M., D.M.), Pneumology and Respiratory Intensive Care (M.H., O.S., G.S.) and Pathologic Anatomy (F.C.), Hôpital Antoine Béclère, 157 rue de la Porte de Trivaux, 92140 Clamart, France. From the 2000 RSNA scientific assembly. Received March 26, 2001; revision requested April 30; revision received July 19; accepted October 22. Address correspondence to A.R. (e-mail: arnaud.resten@abc.ap-hop-paris.fr).

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To correlate pretherapeutic thin-section computed tomographic (CT) findings in patients with pulmonary hypertension with the risk of fatality with treatment with epoprostenol.

MATERIALS AND METHODS: Seventy-three consecutive patients with severe pulmonary hypertension treated with epoprostenol were retrospectively separated into two groups. The first group included 12 patients who had a fatal outcome with epoprostenol therapy. The second group (n = 61) was a reference group of patients with epoprostenol-induced clinical improvement. Pretherapeutic thin-section CT scans of each patient were reviewed.

RESULTS: Poorly defined nodular opacities (P = .003), septal lines (P = .04), pleural effusion (P = .01), and adenopathy (P = .009) strongly correlated with a risk of clinical worsening with treatment. In six patients in group 1, postmortem examination of the lung revealed either pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis.

CONCLUSION: On pretherapeutic thin-section CT scans, poorly defined nodular opacities, septal lines, pleural effusion, and adenopathy should raise suspicion for pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis and provoke possible further evaluation before epoprostenol therapy.

© RSNA, 2002

Index terms: Hypertension, pulmonary, 56.78 • Lung, CT, 68.12118 • Lung, vascular disease, 56.788

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Severe pulmonary arterial hypertension is a rare condition with a poor natural outcome (1,2). Lung or combined heart-lung transplantation may be performed according to the patient’s clinical status. Epoprostenol (also known as prostacyclin) now offers an alternative method of treatment. Indeed, continuous intravenous epoprostenol therapy produces substantial and sustained hemodynamic and symptomatic responses and improves survival in patients with primary pulmonary hypertension or other causes of pulmonary arterial hypertension (2,3). Unfortunately, the intravenous administration of epoprostenol may induce severe pulmonary edema in patients with pulmonary postcapillary vasculopathies, such as pulmonary veno-occlusive disease (1) or pulmonary capillary hemangiomatosis (4), that mimic pulmonary hypertension caused by arterial disease. Because of the weakness of these patients, it is clear that a noninvasive, pretherapeutic screening method would be beneficial in helping identify patients at risk for clinical worsening due to medical treatment. Consequently, the purpose of this study was to correlate pretherapeutic thin-section CT findings and the risk of fatality with medical treatment with epoprostenol.

	MATERIALS AND METHODS

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Patients
Pulmonary hypertension was classified according to the new World Health Organization guidelines (5). From January 1996 to January 1999, 101 consecutive patients were admitted to our hospital for severe pulmonary hypertension requiring epoprostenol therapy. All patients received continuous infusion of epoprostenol at doses based on their clinical signs and symptoms of pulmonary hypertension (dose range, 6–16 ng · kg^-1 · min^-1). Pulmonary hypertension was defined in all patients as a mean pulmonary artery pressure greater than 25 mm Hg at rest with a normal pulmonary artery wedge pressure (<12 mm Hg) measured with catheterization of the right side of the heart. Patients with secondary causes of pulmonary hypertension, such as chronic thromboembolic diseases (n = 11) or intracardiac shunts (n = 3), that were revealed at perfusion lung scanning and/or pulmonary angiography and echocardiography were excluded from the study. Patients with incomplete or lost radiologic records (n = 11) and patients with a follow-up of less than 4 months (n = 3) were also excluded from the study. Therefore, the study included 73 patients who had either primary pulmonary hypertension (sporadic [n = 46] or familial [n = 4]) or pulmonary hypertension related to anorexigenic drugs (n = 10), collagen vascular diseases (n = 11), or human immunodeficiency virus infection (n = 2). These 73 patients were separated into two study groups for data analysis (Table 1). Group 1 (n = 12) included patients in whom epoprostenol therapy had failed, leading to death in less than 4 months after initiation of drug therapy (mean, 1.9 months ± 1.2 [SD]). Group 2 (n = 61) included the reference group of patients with epoprostenol-induced improvement (ie, improvement in symptoms, exercise tolerance, and hemodynamics through a reduction in pulmonary artery pressure and an increase in cardiac output). Postmortem pathologic specimens were obtained from six patients in group 1 and were reviewed to evaluate the reasons for the failure of epoprostenol therapy. The remaining six patients in group 1 could not be evaluated at autopsy because of absence of consent from their relatives.

The pretherapeutic thin-section CT images were reviewed by two chest radiologists (A.R., S.M.) who knew only that the patients had been referred for severe pulmonary hypertension. They were blinded to the final pathologic analyses. Final decisions on the radiologic findings were reached by consensus.

Our institutional review board did not require its approval or informed consent for this study.

System for Grading CT Scans
CT scans were assessed for the presence of different pathologic features. When ground-glass opacities and septal lines were seen, their intensity and zonal predominance were also noted.

Intensity was analyzed with a three-point scale. Pathologic features involving less than one-third of the lungs were coded as intensity level 1, features involving between one-third and two-thirds of the lungs were coded as 2, and features involving more than two-thirds of the lungs were coded as 3.

Zonal predominance was assessed as upper or lower, subpleural or central, or random. The upper lung zone was defined as the area above the level of the carina; the lower lung zone was defined as the area below this level. The subpleural lung zone was defined as the area located in the outer third of the lung, and the central lung zone was defined as the area located in the inner two-thirds of the lung. The term random predominance was used to describe pathologic features that had a mixed upper and lower distribution or a mixed central and subpleural distribution.

CT scans were retrospectively assessed for the presence, intensity, zonal predominance, and patterns of ground-glass opacities. Ground-glass opacity was defined as increased opacity of the lung parenchyma that was not sufficient to obscure pulmonary vessels, in contradistinction to true consolidation. Patterns of ground-glass opacities were divided into two categories according to the classification of Engeler et al (6): Class I corresponded to poorly defined nodular opacities ranging in diameter from a few millimeters to 1 cm that were distinct or coalescent and had a centrilobular distribution, and class II corresponded to a panlobular distribution of geographic regions of lung attenuation that had relatively well-defined borders. When ground-glass opacities with a panlobular distribution were found to involve a large area, they were described as either homogeneous (ie, involving all the parenchyma to an equal degree) or heterogeneous (ie, having various degrees of increased attenuation throughout the parenchyma) (7–9).

CT scans were also assessed for the presence, intensity, and zonal distribution of septal lines. Septal lines were identified as thickened interlobular septa (ie, fine linear areas of high attenuation or a pattern of multiple polygonal lines).

CT scans were then assessed for the presence of pleural effusions, well-defined nodules (different from the poorly defined nodular opacities mentioned above), nonseptal lines, honeycombing, bronchiectasis, emphysema, and mediastinal abnormalities. Mediastinal abnormalities included pericardial effusion, cardiomegaly, adenopathy (defined as when the smallest diameter of the mediastinal node was greater than 10 mm), and enlargement of pulmonary arteries and pulmonary veins. The intrapericardial portions of the right and left pulmonary arteries, each measured 1 cm beyond origin, were considered dilated if they had a diameter of 18 mm or greater (10,11). Cardiomegaly was noted if the transverse diameter of the right atrium was greater than 35 mm or if the transverse diameter of the right ventricle was greater than 45 mm (10,12). The diameter of the central pulmonary veins was evaluated at the level of the left atrium, and assessment of enlargement was subjective.

Statistical Analysis
Statistical analysis was performed with StatView software (SAS Institute, Cary, NC).

The presence or absence of each pretherapeutic CT finding described in the section above was compared with the patient’s outcome with medical treatment with epoprostenol (ie, death or improvement). Two nominal variables were compared by means of the ² test. Both nominal variables studied had exactly two groups. The Fisher exact test was used when the expected frequencies were small (ie, <5). The null hypothesis was rejected when the P value was less than .05.

Additionally, when they were taken into account, the intensity and zonal predominance of the CT findings were compared with patient fatality with treatment. These variables had more than two groups. Therefore, the ² test was performed first. If the null hypothesis was rejected (P < .05), post hoc cell contributions indicated what each cell in the table contributed to the ² statistic.

	RESULTS

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CT Findings
The CT findings are summarized in Table 2.

View larger version (113K): [in this window] [in a new window] [Download PPT slide]   Figure 1. Pretherapeutic transverse thin-section CT scan in a patient with severe pulmonary hypertension. After continuous intravenous epoprostenol therapy was initiated, the patient died. Postmortem examination of the lungs revealed pulmonary veno-occlusive disease. Scan shows centrilobular ground-glass opacities, with poorly defined nodular opacities ranging in diameter from a few millimeters to 1 cm (arrows). Nodules have a random distribution.

View larger version (128K): [in this window] [in a new window] [Download PPT slide]   Figure 2. Pretherapeutic transverse thin-section CT scan in a patient with severe pulmonary hypertension. After continuous intravenous epoprostenol therapy was initiated, the patient’s clinical outcome was favorable. Scan shows panlobular ground-glass opacities with a predominantly central distribution (arrows).

View larger version (120K): [in this window] [in a new window] [Download PPT slide]   Figure 3. Pretherapeutic transverse thin-section CT scan in a patient with severe pulmonary hypertension. After continuous intravenous epoprostenol therapy was initiated, the patient died. Postmortem examination of the lungs revealed pulmonary veno-occlusive disease. Scan shows centrilobular ground-glass opacities, with poorly defined nodular opacities (arrowheads) and septal thickening (arrows).

The presence of ground-glass opacities was significantly more frequent among the patients in group 1 than among those in group 2 (P = .004, ² test). The pattern of ground-glass opacities was an important factor, because only the centrilobular pattern correlated with a higher risk of fatality with treatment (P = .003, Fisher exact test); the panlobular pattern did not correlate (P = .76).

There was no correlation between the risk of fatality and the intensity (P = .29) or zonal predominance (craniocaudal predominance, P = .42; peripheral zonal predominance, P = .26) of ground-glass opacities.

Septal Lines
CT scans revealed thickened interlobular septa (Fig 3) in 23 of the 73 patients (32%) (Table 4). The intensity of these septal lines was coded as 1 in 16 patients, as 2 in four patients, and as 3 in three patients.

The presence of thickened interlobular septa was more frequent in group 1 than in group 2 (P = .04, Fisher exact test), and their intensity correlated with a higher risk of fatality (P = .007, ² test).

There was no correlation between the risk of fatality and the zonal predominance (craniocaudal predominance, P = .51; peripheral zonal predominance, P = .11) of septal lines.

Other Pathologic Parenchymal Findings
CT scans revealed well-defined nodules (poorly defined nodular opacities are not discussed in this section) in five patients (group 1, n = 1; group 2, n = 4), nonseptal lines in nine patients (group 1, n = 3; group 2, n = 6), honeycombing in two patients (group 1, n = 2; group 2, n = 0), bronchiectasis in 12 patients (group 1, n = 3; group 2, n = 9), and emphysema in 14 patients (group 1, n = 2; group 2, n = 12). None of these parenchymal findings correlated with a higher risk of fatality (P > .05).

Pleural Effusion
CT scans revealed a pleural effusion (Fig 4) in 36 (49%) of 73 patients, including 10 (83%) of the 12 patients who had a fatal outcome (group 1) and 26 of the 61 patients (43%) who had a favorable outcome (group 2). Pleural effusion was more frequent in the patients in group 1 (P = .01, ² test).

View larger version (128K): [in this window] [in a new window] [Download PPT slide]   Figure 4. Pretherapeutic transverse thin-section CT scan in a patient with severe pulmonary hypertension. After continuous intravenous epoprostenol therapy was initiated, the patient died. Postmortem examination of the lungs revealed pulmonary veno-occlusive disease. Scan shows mediastinal lymph node enlargement (*) and a right pleural effusion (E). Note the enlargement of the left pulmonary artery (arrowhead).

In group 1, nine patients (75%) had a pericardial effusion, eight (67%) had adenopathy (size range, 12.8 mm ± 1.8), 11 (92%) had cardiomegaly, and 12 (100%) had enlarged pulmonary arteries (23 mm ± 4.1 and 23.9 mm ± 3.7 for right and left pulmonary arteries, respectively). Among the 61 patients with a favorable outcome (group 2), 26 (43%) had a pericardial effusion, 10 (16%) had adenopathy (size range, 11.6 mm ± 2), 58 (95%) had cardiomegaly, and 60 (98%) had enlarged pulmonary arteries (21.9 mm ± 3.4 and 24.3 mm ± 4.2 for right and left pulmonary arteries, respectively). Adenopathy strongly correlated with a higher risk of failure of epoprostenol therapy (P = .009, Fisher exact test). Pericardial effusion also correlated with failure of epoprostenol therapy (P = .040, ² test).

Anatomic Findings
Six patients in group 1 underwent postmortem examination of the lungs that revealed pulmonary vasculopathy affecting capillaries and veins corresponding to either pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis. Because of their many pathologic similarities, we did not separate these two entities in evaluating our results. The remaining six patients in group 1 did not undergo postmortem examination.

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Pulmonary hypertension is a severe condition with a dismal natural outcome (1). Epoprostenol therapy offers an alternative to lung transplantation in patients with severe pulmonary artery hypertension. Epoprostenol (prostaglandin I₂) is a potent vasodilator and inhibitor of platelet aggregation. It is produced by vascular endothelium and reduces pulmonary vascular resistance and increases cardiac output and oxygen delivery when administered immediately to patients with pulmonary arterial hypertension (1,3). Continuous infusion of epoprostenol improves hemodynamics, exercise tolerance, quality of life, and survival in patients with pulmonary arterial hypertension in New York Heart Association functional classes III and IV (1,3). Drug-induced side effects are usually minor and include jaw pain, cutaneous erythema, diarrhea, and arthralgia (3,13).

However, continuous intravenous epoprostenol therapy can sometimes promote the occurrence of life-threatening pulmonary edema, particularly in patients with pulmonary postcapillary vasculopathies, such as pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis, that mimic pulmonary hypertension caused by arterial disease (1,4,13). The diagnosis of these diseases in living patients is difficult; most cases are not recognized until signs of marked pulmonary hypertension have developed (4,14,15). Indeed, the clinical presentation of patients with pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis is often indistinguishable from that of patients with classic pulmonary arterial hypertension. Furthermore, surgical biopsy, which is generally required for the diagnosis of these diseases, is hazardous due to the weakness of these patients. Consequently, a safe, alternative noninvasive method should be promoted to enable the identification of these patients. Thin-section CT of the chest may help detect pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis (4,13–19).

To assess the value of pretherapeutic thin-section CT, we have thus reviewed the pretherapeutic thin-section CT scans of 73 consecutive patients with severe pulmonary hypertension before the start of treatment with epoprostenol. Pretherapeutic thin-section CT scans revealed some substantial differences between patients whose disease worsened with treatment, resulting in death (group 1), and patients who had a favorable outcome with treatment (group 2). A centrilobular pattern of ground-glass opacities (including poorly defined nodular opacities), septal lines, pleural effusion, pericardial effusion, and adenopathy were substantially more frequent among patients in group 1 than among those in group 2. Indeed, septal lines were not only more frequently present but were also more abundant in patients in group 1.

A vasculopathy affecting capillaries and veins (pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis) was found in the six patients in group 1 who underwent postmortem examination of the lung. These vasculopathies are rare entities that have many pathologic similarities and may in fact overlap (4); hence, we did not separate these two entities in evaluating our results. The characteristic anatomic abnormality in pulmonary veno-occlusive disease is obstruction of the pulmonary veins and venules by intimal fibrosis, cellular proliferation, and muscularization (14,20). Pulmonary capillary hemangiomatosis is characterized by a proliferation of small blood vessels within the peribronchovascular, septal, or pleural connective tissue. The infiltration and compression of pulmonary veins by these neocapillaries can result in a secondary pulmonary veno-occlusive disease (4,21,22). To our knowledge, few reports have been published about CT and thin-section CT findings in pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis. The most common CT findings that have been reported are very similar to the CT findings in our study (interlobular septal thickening, poorly defined nodular opacities, pleural effusions, and lymph nodes) (4,14–19).

To our knowledge, no other disease process would be expected to consistently produce this constellation of thin-section CT findings. These findings are unusual in primary pulmonary hypertension. Some reports have described similar findings in cases of pulmonary hypertension, but these findings are usually secondary to a well-established cause such as chronic thromboembolic disease. Several studies have revealed the presence of ground-glass opacities in patients with pulmonary hypertension of different causes (23,24). Ground-glass opacities were identified substantially more often in patients with chronic thromboembolic pulmonary hypertension than in patients with primary pulmonary hypertension (12). Furthermore, these reports generally described a mosaic pattern of lung attenuation, not the poorly defined nodular opacities of class I ground-glass opacity found in our study. Another report described the presence of centrilobular nodules in patients with pulmonary hypertension, but these findings were isolated (ie, no septal lines, adenopathy, or pleural or pericardial effusions were present) (25). Histopathologic examination of the lungs of these patients revealed cholesterol granulomas. Primary pulmonary hypertension is usually not cited as a cause of pericardial effusion, although the results of a recent study indicated that moderate pericardial thickening is not rare with severe pulmonary hypertension (26). However, most of the patients in that study had secondary pulmonary hypertension; the study did not evaluate the frequency of pericardial effusion in primary pulmonary hypertension. Similarly, primary pulmonary hypertension is not a common cause of mediastinal lymph node enlargement (27,28).

A limitation of our study is the small number of pathologic examinations of the lung. Indeed, only half of the patients in group 1 underwent postmortem lung examination. Therefore, the histopathologic diagnosis of the remaining six cases remains unknown. We cannot exclude, in these cases, a failure of epoprostenol therapy associated with arterial hypertension. Strikingly, histologic examination of the lungs of the patients who underwent postmortem examination revealed a predominant pulmonary veno-occlusive disease pattern more or less associated with pulmonary capillary hemangiomatosis. Hence, we suspect that this type of mainly postcapillary occlusive vasculopathy is among the most important factors associated with a risk of failure of epoprostenol therapy.

In conclusion, thin-section CT scans of the chest can reveal some specific findings that strongly correlate with a risk of failure of continuous intravenous epoprostenol therapy in patients with pulmonary hypertension, emphasizing the importance of this radiologic procedure before initiation of vasodilator therapy in these patients. The presence of a centrilobular pattern of ground-glass opacities (including poorly defined nodular opacities), septal lines, pleural effusion, pericardial effusion, and/or adenopathy should raise suspicion for pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis. Further examinations and the need for a diagnostic open lung biopsy should then be discussed.

	FOOTNOTES

 
Author contributions: Guarantors of integrity of entire study, D.M., G.S.; study concepts, A.R., S.M., M.H., O.S., F.C., D.M.; study design, A.R., S.M., D.M.; literature research, A.R., S.M.; clinical studies, A.R., S.M., O.S.; data acquisition, A.R., S.M., O.S.; data analysis/interpretation, A.R., S.M., F.C., O.S.; statistical analysis, A.R.; manuscript preparation, A.R.; manuscript definition of intellectual content, A.R., M.H., G.S., D.M.; manuscript editing, A.R.; manuscript revision/review, A.R., S.M., M.H., D.M., G.S.; manuscript final version approval, A.R., G.S., D.M.

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