INTRODUCTION

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Pulmonary hypertension is a well-known complication of severe lung diseases such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis (1). Pulmonary hypertension secondary to chronic lung diseases is usually moderate, rarely exceeding 35 to 40 mm Hg, and is related to alterations in blood gases, abnormal pulmonary mechanics, and relatively subtle vascular remodeling (5).

Pulmonary histiocytosis X is a smoking-related interstitial lung disease commonly associated with hyperinflation and/or obstructive lung disease (7). The clinical course of pulmonary histiocytosis X is unpredictable. It may regress either spontaneously or after steroid therapy and/or cessation of smoking. In a minority of patients, however, pulmonary histiocytosis X may progress to pulmonary fibrosis and honeycomb lung (7, 8), with obstructive, restrictive, or mixed patterns of lung mechanics. In contrast with chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis, diminished exercise capacity in advanced pulmonary histiocytosis X does not appear to be related to ventilatory limitation (9), but to a pulmonary vascular dysfunction (10). Histopathological observations have also suggested that pulmonary vascular involvement may be a central process in advanced pulmonary histiocytosis X (11). In addition to the characteristic bronchiolocentric inflammation with aggregates of Langerhans' cells and other inflammatory cells, and fibrosis (11, 12), widespread vascular abnormalities are found in the majority of cases (13, 14). Langerhans' cell granuloma can infiltrate the walls of small and medium-sized pulmonary arteries primarily in regions of prominent pulmonary histiocytosis X nodules, whereas medial and subintimal wall thickening may occur in areas uninvolved with pulmonary histiocytosis X nodules (13). However, pulmonary hemodynamics were not properly investigated in these physiological and histopathological studies.

In a preliminary study we reported elevated pulmonary pressure in patients with pulmonary histiocytosis X listed for lung transplantation (15). The present study was therefore designed to extend this observation. Accordingly, the objectives of this study were as follows: (1) to evaluate the pulmonary hemodynamics in consecutive patients with pulmonary histiocytosis X and other chronic lung diseases referred to our center for lung transplantation, and (2) to correlate pulmonary hemodynamics with respiratory function tests and pulmonary vessel histopathology.

	METHODS

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Three groups of patients with end-stage chronic lung diseases were studied: patients with pulmonary histiocytosis X (n = 21), and patients with other chronic lung diseases consisting of chronic obstructive pulmonary disease (n = 29) and idiopathic pulmonary fibrosis (n = 14). All patients referred to our center for lung transplantation from June 1989 to October 1996 were consecutively included in this study.

Diagnosis of pulmonary histiocytosis X was established either by pathological examination of pulmonary biopsy material (n = 16) or according to the characteristic association of clinical, functional ventilatory, and high-resolution computed tomography (HRCT) of the chest (n = 5). Diagnosis of chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis was made according to established criteria (16, 17). Complete clinical information was obtained from all patients with follow-up until October 1996.

Hemodynamic Study

Right-heart catheterization was performed with patients at rest, breathing room air, and lying supine in the proximity of an intensive care unit. No vasodilator or inotropic drugs were given to the patients for least 48 h before catheterization. A 7F triple-lumen flotation thermodilution catheter was introduced percutaneously through the internal jugular vein, and positioned in a branch of a lower pulmonary artery under fluoroscopic control. Heart rate and systemic arterial pressure were monitored continuously. Mean pulmonary arterial pressure (), right atrial pressure (Pra), pulmonary wedge pressure (Ppulm,we), and cardiac output () were measured. was measured by thermodilution and calculated as the mean of at least three consecutive injections of 10 ml of cold serum glucose (5%). Cardiac index (CI) was calculated as the cardiac output over the body surface area. The total pulmonary vascular resistance index (TPVRi) was calculated as divided by CI. Pulmonary hypertension was defined as the mean resting pulmonary artery pressure > 25 mm Hg and normal pulmonary wedge pressure. A short-term vasodilator trial was performed in 16 patients with pulmonary histiocytosis X by administering intravenous epoprostenol (Flolan; Glaxo-Wellcome, Research Triangle Park, NC) or inhaled nitric oxide as previously reported (18, 19). A positive pulmonary vasodilator response was defined by a decrease in TPVRi of at least 30% relative to mean TPVRi baseline values (18, 19).

Pulmonary Function Tests

Functional ventilatory data and blood gases were recorded at the time of inclusion. The main variables included forced expiratory volume in 1 s (FEV₁), FEV₁ divided by forced vital capacity (FEV₁/FVC), residual volume (RV) and transfer coefficient of carbon monoxide (DL_CO), and arterial partial pressures of oxygen (Pa_O2) and carbon dioxide (Pa_CO2) at room air. Predicted values of the measured variables were calculated according to European reference equations (European Coal and Steel Community) (20).

Radiological Findings

Chest X-ray and HRCT were performed at the time of referral to our center. As previously demonstrated, HRCT is of considerable value in the diagnosis of pulmonary histiocytosis X, including patients with advanced lung disease (21). In the five patients without histological confirmation of pulmonary histiocytosis X, the conjunction of anamnestic, clinical, and HRCT data was accepted to establish the diagnosis of pulmonary histiocytosis X (Figure 1).

View larger version (107K): [in this window] [in a new window]   View larger version (90K): [in this window] [in a new window]   Figure 1.   Chest X-ray (A) and high-resolution computed tomography (HRCT) of the chest (B) of a patient with advanced pulmonary histiocytosis X associated with severe pulmonary hypertension.

Histopathology

Histological diagnosis of pulmonary histiocytosis X included the characteristic presence of activated Langerhans' cells within the granuloma, centered by terminal and/or respiratory bronchioles (8). Pulmonary histiocytosis X lesions were defined as florid or intermediate when, respectively, composed of > 50% or between 10 and 50% of Langerhans' cells, and fibrotic when consisting of fibrous tissue. Pulmonary vessels (arteries and veins) were analyzed within the whole parenchymal areas, and classified as follows: medial hypertrophy, intimal and subintimal fibrosis and/or proliferation, obliteration with or without recanalization, and inflammatory vasculopathy. Diagnosis of pulmonary histiocytosis X was confirmed histologically in 16 patients. Open lung biopsies (n = 12) were performed to confirm the diagnosis of pulmonary histiocytosis X (n = 10), or at the time of surgical treatment of pneumothorax (n = 2). Lung samples were obtained at the time of lung transplantation or at autopsy from seven and five patients, respectively. Among the seven transplanted patients, four had a lung biopsy performed before transplantation. Among the five decreased patients, two had a history of open lung biopsy. Therefore, two consecutive lung samples taken before and after the diagnosis of pulmonary hypertension were obtained from six patients. We also analyzed the histopathology of the blood vessels of eight control explanted lungs (patients displaying pulmonary hypertension secondary to end-stage chronic obstructive pulmonary disease [n = 4] or interstitial pulmonary fibrosis [n = 4]).

Statistical Analysis

Values are expressed as means ± SEM unless stated otherwise. The Mann-Whitney U test was used for between-group comparisons. Statistical correlations were analyzed by simple regression analysis. A p value < 0.05 was considered significant.

	RESULTS

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Patients with Advanced Pulmonary Histiocytosis X

Clinical findings. From June 1989 to October 1996, 21 patients with pulmonary histiocytosis X (19 males, 39 ± 3 yr) were referred to our center for lung transplantation because of severe pulmonary histiocytosis X. All were former smokers. The time between the referral to our center and the first symptoms related to pulmonary histiocytosis X was 11 ± 2.6 yr (range, 1.3 to 25 yr). The first symptoms related to pulmonary histiocytosis X consisted of mild to moderate dyspnea (New York Heart Association [NYHA] functional class I or II) (n = 10), cough (n = 7), chest pain (n = 2), and pneumothorax (n = 2). Weight loss and fatigue revealed the disease in three patients. There was no evidence of right-heart failure at the onset of the illness.

At the time of referral to our center, patients displayed severe dyspnea (NYHA functional class III or IV) and had evidence of right-heart failure. No condition commonly associated with primary pulmonary hypertension was found except isolated Raynaud's phenomenon in two patients.

Functional ventilatory findings. (See Table 1.) In terms of lung function, patients displayed moderate to severe airflow obstruction and gas trapping (FEV₁ = 46 ± 4%, FEV₁/FVC = 52 ± 4%, TLC = 95 ± 4%, RV = 166 ± 8%) and significant hypoxemia (Pa_O2 = 53 ± 3 mm Hg). DL_CO (n = 17) was markedly decreased (27 ± 3%).

Hemodynamic findings. (See Table 2.) In all patients with pulmonary histiocytosis X, severe precapillary pulmonary hypertension was demonstrated by right-heart catheterization: = 59 ± 4 mm Hg, CI = 2.6 ± 0.8 L/min/m², and TPVRi = 25 ± 3 IU/m². An acute pulmonary vasodilator trial was positive in 31% of the patients, with a 36% mean fall in TPVRi (range, 30.5-47%). This rate in acute vasodilator response is similar to that reported by our group in an investigation of patients with severe primary pulmonary hypertension (18).

Pathological findings. Lung samples were obtained at the time of pulmonary hypertension from 12 patients. The major findings included morphologic changes involving both small to medium-sized pulmonary arteries and septal veins (Table 3).

Involvement of the intralobular pulmonary arteries consisted of proliferative arteriopathy with intimal fibrosis (Figure 2) and medial hypertrophy, leading to arterial obliteration in 60% of the cases. Involvement of the septal pulmonary veins consisted of intimal fibrosis, medial hypertrophy, and obliteration in 75% of the patients (Figure 3). Veno-occlusive-like disease with venular obliteration, hemosiderosis, and capillary dilatation was seen in one-third of the patients (Figure 3). Involvement of both arteries and veins was observed in most patients. Langerhans' histiocytic infiltration of a vessel was observed in only one patient. Pulmonary vascular involvement occurred in regions unaffected by parenchymal lesions of pulmonary histiocytosis X in about 50% of the patients. Comparisons of subsequent samples obtained before and during established pulmonary hypertension (n = 6) showed a clear progression of the pulmonary vessel involvement at the time of pulmonary hypertension. In contrast, parenchymal and bronchiolar pulmonary histiocytosis X lesions remained relatively stable in three patients (Table 4).

View larger version (136K): [in this window] [in a new window]   Figure 2.   Intimal fibrosis of muscular pulmonary artery within Langerhans' granuloma. (Weigert's elastic stain; original magnification, ×20.)

View larger version (132K): [in this window] [in a new window]   Figure 3.   Venular intimal fibrosis; partial occlusion in a lobular septum. (Weigert's elastic stain; original magnification, ×20.)

Patients with Other Chronic Lung Diseases

Chronic obstructive pulmonary disease. We reviewed data from 29 patients with chronic obstructive pulmonary disease (23 males, 45 ± 3 yr) referred to our center for lung transplantation during the same period. Patients with chronic obstructive pulmonary disease displayed severe functional ventilatory impairment (FEV₁ = 22 ± 2%, FEV₁/FVC = 40 ± 2%) and mild to moderate hypoxemia (Pa_O2 = 59 ± 4 mm Hg). Right-heart catheterization revealed mild to moderate pulmonary hypertension, with = 36 ± 3 mm Hg, CI = 3.7 ± 0.7 L/min/m², and TPVRi = 9.3 ± 2 IU/m² (Figure 4).

View larger version (15K): [in this window] [in a new window]   Figure 4.   Hemodynamic profiles of patients with interstitial pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), and pulmonary histiocytosis X (PHX).

Interstitial pulmonary fibrosis. During the same period, 14 patients with interstitial pulmonary fibrosis (six males, 45 ± 4 yr) were referred for lung transplantation. Functional ventilatory impairment (FEV₁ = 32 ± 3%, FEV₁/FVC = 82 ± 3%, TLC = 41 ± 2%) and hypoxemia (Pa_O2 = 47 ± 3 mm Hg) were severe. Right-heart catheterization revealed mild to moderate pulmonary hypertension, with = 33 ± 3 mm Hg, CI = 3.8 ± 0.5 L/min/m², and TPVRi = 9.5 ± 2 IU/m² (Figure 4).

Pathology. In patients displaying pulmonary hypertension secondary to end-stage chronic obstructive pulmonary disease, the histopathology of the pulmonary blood vessels consisted of medial thickening and mild intimal fibrosis of the intralobular pulmonary arteries, without significant septal pulmonary vein involvement. In patients displaying pulmonary hypertension secondary to end-stage interstitial pulmonary fibrosis, the modifications consisted of medial thickening and mild intimal fibrosis of the intralobular pulmonary arteries, and mild intimal fibrosis of the septal pulmonary vein. Veno-occlusive-like disease with venular obliteration, hemosiderosis, and capillary dilatation was not observed in these control lungs. Therefore the vasculopathy observed in pulmonary histiocytosis X seems to be a specific entity.

Comparisons of Patients with Pulmonary Histiocytosis X and Other Chronic Lung Diseases

Patients with pulmonary histiocytosis X, chronic obstructive pulmonary disease, or interstitial pulmonary fibrosis were similar in terms of NYHA functional class. As compared with patients with pulmonary histiocytosis X, FEV₁ and FEV₁/FVC were lower in patients with chronic obstructive pulmonary disease or interstitial pulmonary fibrosis (p < 0.01), but Pa_O2 values were similar (Table 5). TLC was lower in patients with interstitial pulmonary fibrosis (p < 0.05).

The incidence and the severity of pulmonary hypertension were markedly lower in chronic obstructive pulmonary disease and interstitial pulmonary fibrosis as compared with pulmonary histiocytosis X (, CI, and TPVRi, p < 0.001). Mild to moderate pulmonary hypertension (25 to 35 mm Hg) was found in 62 and 71% of patients with chronic obstructive pulmonary disease and interstitial pulmonary fibrosis, respectively. Severe pulmonary hypertension was found in only about 30% of patients with chronic obstructive pulmonary disease and interstitial pulmonary fibrosis.

Last, we attempted to correlate functional and hemodynamic variables in the patients with pulmonary histiocytosis X and other chronic lung diseases. In patients with pulmonary histiocytosis X, no correlation was found between FEV₁, FEV₁/ FVC, DL_CO, Pa_O2, or Pa_CO2 and , CI, or TPVRi (all p > 0.1). Conversely, correlated with FEV₁/FVC (r = 0.38, p = 0.03) and there was a trend for TPVRi to correlate with Pa_O2 (r = 0.35, p = 0.06) in patients with chronic obstructive pulmonary disease. In patients with interstitial pulmonary fibrosis, TPVRi correlated with TLC (r = 0.67, p = 0.01).

	DISCUSSION

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The major finding of this study was the demonstration of severe pulmonary hypertension in all patients with end-stage pulmonary histiocytosis X in relationship with specific vasculopathy (pulmonary arteriopathy and veno-occlusive disease).

None of our patients with pulmonary histiocytosis X had evidence of left-to-right cardiac shunt, pulmonary thromboembolism, or left ventricular failure that may account for the increase in pulmonary arterial pressure. Pulmonary hypertension in pulmonary histiocytosis X was unlikely to be related to chronic hypoxia and/or abnormal pulmonary mechanics. Contrary to our findings in patients with chronic obstructive pulmonary disease or interstitial pulmonary fibrosis, pulmonary hemodynamics were unrelated to lung function variables in pulmonary histiocytosis X. Despite similar hypoxemia and less severe ventilatory limitation, the incidence and severity of pulmonary hypertension in pulmonary histiocytosis X were higher than was observed in patients with chronic obstructive pulmonary disease and interstitial pulmonary fibrosis. Indeed, pulmonary hypertension secondary to chronic obstructive pulmonary disease and interstitial pulmonary fibrosis exceeded rarely 35 mm Hg in our series (Figure 4), as well as in the literature. In contrast, the level of pulmonary artery pressure in pulmonary histiocytosis X (59 ± 4 mm Hg [range, 36 to 80 mm Hg]) was similar to that observed in primary pulmonary hypertension reported in the NIH registry (26). All these observations suggest that pulmonary hypertension in pulmonary histiocytosis X might be related to an intrinsic pulmonary vascular disease in which the pulmonary circulation is involved independently of small airways and lung parenchymal injury.

Histopathological data strongly support this hypothesis. Severe diffuse pulmonary vasculopathy was found in all patients with pulmonary histiocytosis X, involving the pulmonary muscular arteries and intralobular veins, with prominent involvement of the pulmonary veins. These vascular changes consisted of medial hypertrophy and intimal and subintimal fibrosis and/or proliferation leading to various degree of lumenal obstruction. Proliferative involvement of both arteries and veins, and aspects of pulmonary veno-occlusive disease, were commonly detected. Thrombotic pulmonary arteriopathy was not found. Langerhans' histiocytic infiltration of a vessel was observed in only one patient. Moreover, in half of the patients vascular lesions were found in areas uninvolved with pulmonary histiocytosis X nodules. Last, in the six patients with pulmonary histiocytosis X from whom two subsequent lung samples (before and after the occurrence of pulmonary hypertension) were available, the pulmonary vasculopathy worsened, whereas parenchymal and bronchiolar lesions remained relatively unchanged. Nevertheless our patient population was characterized by significant parenchymal lesions, and severe pulmonary hypertension has not been described to our knowledge in patients with minor parenchymal involvement or when the disease remits. Therefore one might hypothesize that parenchymal lesions are involved in the genesis of the vasculopathy. We speculate that the pulmonary Langerhans' cells may play a role in the genesis of pulmonary vascular remodeling through the production of cytokines and growth factors (27- 32). Pulmonary histiocytosis X vasculopathy was clearly distinct from that described in other chronic lung diseases, including medial thickening of the muscular arteries, intimal fibrosis, and deformation of small arteries in regions of emphysema (33). Moreover, these structural changes remain relatively subtle, with mild or no septal vein involvement.

The causes of the pulmonary vascular remodeling in pulmonary histiocytosis X as well as in primary pulmonary hypertension remain undetermined. As already discussed, various cytokines and growth factors have been proposed to act as regulators of cell growth in pulmonary vascular remodeling, including interleukins 1 and 6, transforming growth factor , and platelet-derived growth factor. Interestingly, the pulmonary histiocytosis X granuloma produces several of these mediators (27).

This study clearly demonstrates that pulmonary vasculopathy occurs in all patients with advanced pulmonary histiocytosis X, leading to severe pulmonary hypertension. Such a pulmonary vasculopathy presumably explains the severe reduction in DL_CO and exercise limitation in patients with pulmonary histiocytosis X, which were out of proportion with the alterations in lung mechanics, as previously suggested by Craussman and colleagues (10). Thus, pulmonary vascular involvement must be considered as a central process in advanced pulmonary histiocytosis X.

The present study may have important therapeutic implications. Long-term epoprostenol (prostacyclin) therapy given by continuous intravenous infusion improves exercise tolerance, quality of life, and survival in patients with primary pulmonary hypertension independent of the presence of a positive response to acute vasodilator challenge (36). The single exception may be patients with pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis, who have been reported to develop severe pulmonary edema with prostacyclin (37, 38). Acute pulmonary edema occurred in the two patients with pulmonary histiocytosis X treated with intravenous epoprostenol in our series (Muriel Fartoukh, Marc Humbert, and Gérald Simonneau, unpublished observation). This effect, which probably resulted from the increase in pulmonary blood flow in the setting of downstream venular obstruction, pleads in favor of the clinical relevance of a pulmonary venous involvement in severe pulmonary histiocytosis X (37, 38). Therefore, pulmonary hypertension in patients with pulmonary histiocytosis X may constitute a novel contraindication to long-term epoprostenol infusion. Given the high incidence of pulmonary venular obstruction in advanced pulmonary histiocytosis X, epoprostenol therapy is hazardous in this setting.

In conclusion, the incidence and severity of pulmonary hypertension in advanced pulmonary histiocytosis X is much higher than in other chronic lung diseases and appear to be at least in part independent of chronic hypoxemia and abnormal pulmonary mechanics. The severity of pulmonary hypertension and the vasodilator responsiveness in pulmonary histiocytosis X are indistinguishable from those observed in primary pulmonary hypertension, although the pathogenesis of pulmonary hypertension is presumably different in these two clinical conditions. Nevertheless, given the prominent venous involvement and the incidence of pulmonary veno-occlusive disease in pulmonary histiocytosis X, epoprostenol therapy may be hazardous in this patient population, which constitutes a clear indication for lung transplantation.