Twenty-eight patients had died at the time of publication. The median survival in these patients was 3 years from the first clinical manifestation. The immediate cause reported was right heart failure in 11, progressive deterioration of general status in 4 patients, respiratory insufficiency in 4, hemoptysis in 2 cases (32), and “sudden death” in 2 patients (22,23). The ultimate cause of death is not reported in 5 patients.
Chest X-ray findings were nonspecific; they usually showed a pattern of bilateral interstitial infiltrates (21 cases), in 1 case (6) showed bilateral pulmonary nodules, and were normal in 2 patients (18,23). Cardiomegaly was present in 8 cases and pulmonary artery enlargement in 13. Electrocardiograms were available for 15 patients. They disclosed signs of right ventricular hypertrophy in 13 cases and were normal in 2. Ultrasound heart examination was performed in 20 patients. The most commonly reported alteration was right ventricular dilatation (13 patients), and indirect signs of pulmonary hypertension were present in 6 patients. Finally, 1 patient had a pericardial effusion (39).
CT scan of the thorax was performed in 9 patients: 4 patients showed interstitial infiltrates (10), 2 patients had pulmonary artery enlargement, 2 were found to have mediastinal widening, and 1 case showed bilateral pulmonary nodules (6). Two patients had pleural involvement (2,18), and 1 patient with normal chest X-ray had a normal CT scan.
Pulmonary function tests were reported in 12 patients. They showed obstruction in 2 patients, restriction in 7 patients, and a mixed pattern in 3 patients. The DLCO was diminished in 6 patients (Table 3). Blood gas analysis usually showed hypoxemia. Bronchoscopic examination, even when transbronchial biopsy was performed, was not diagnostic in the 8 patients who had the procedure.
Pulmonary angiography was performed in 10 patients. Signs of pulmonary hypertension were present in 1 patient, and pulmonary embolism was suspected in another. Nonspecific vascular abnormalities were present in another patient and the angiography was strictly normal in the remaining patients. Pulmonary scintigraphy was done in 22 patients: 10 had nonspecific perfusion defects; 2 others had moderate to high probability of pulmonary embolism, while the other 10 patients had normal results.
Different modalities of treatment were used for PCH. The majority of patients were treated with anticoagulants, diuretics, ACE inhibitors, and oxygen. Calcium channel blockers and prostaglandins were used in 6 patients to treat pulmonary hypertension. In all cases prostaglandins had to be withdrawn because of hemodynamic intolerance (7,13,24) and were directly incriminated as the cause of death in 3 patients (14,18). Glucocorticoids were given to 4 patients with no improvement. Pneumonectomy was successfully performed in 1 patient because of massive hemoptysis (40). Interferon α-2a was used in 4 patients with clinical improvement in 3, and in 1 was also followed by improved exercise tolerance and hemodynamic parameters (45–47). Pulmonary transplantation was done in 5 patients (5,9,10) without reproduction of the disease.
Pulmonary capillary hemangiomatosis is a rare disease and an uncommon cause of primary pulmonary hypertension (30,33,41). To our knowledge, only 37 cases with primary pulmonary hypertension have been reported in the world literature. The diagnosis is difficult and requires a high degree of clinical suspicion and accurate pathologic study. Multiple sampling in pulmonary biopsy is essential given the patchy nature of the disease (19). Diagnosis was made with pulmonary biopsy in only 3 cases (2,35,45). The rest were wrongly classified as pulmonary fibrosis, pulmonary veno-occlusive disease, hemosiderosis, and other entities, and definitive diagnosis was reached only after pulmonary transplantation or necropsy.
Similar pathologic findings have been described in necropsies of patients without evidence of primary pulmonary hypertension. The significance of these findings is uncertain. We agree with Havlik et al (15) that PCH occurring in the absence of primary pulmonary hypertension should be considered as a nondiagnostic and incidental finding (1,15). However, patients with these findings should be followed closely since the natural history of the disease is not known. While long survival (up to 12 years) has been reported occasionally (11,37,39), most patients rapidly progress to death over several months of clinical disease (6,35).
Although most cases appear to be sporadic, 3 cases in a family have been described (23). Associations with other entities, including Takayasu arteritis (22), systemic lupus erythematosus (13), Kartagener syndrome (34), and hypertrophic myocardiopathy (20), have been described.
Signs of postcapillary pulmonary hypertension (Kerley B lines, transudative pleural effusion, or a high pulmonary artery wedge pressure) are absent in primary pulmonary hypertension. When hemoptysis or hemorrhagic pulmonary effusion, interstitial lung infiltrates, or signs of postcapillary pulmonary hypertension are present in the setting of primary pulmonary hypertension, both PCH and pulmonary veno-occlusive disease should be strongly considered. Exceptionally, all these signs can be absent (26,35). These findings are reminiscent of those described in pulmonary veno-occlusive disease (3,17,27), which is clinically indistinguishable from PCH. Occasionally, as in our first case, hemosiderin-laden macrophages may be seen in bronchoalveolar lavage and can be a helpful clue to diagnosis. The diagnosis of PCH is established by pulmonary biopsy. It has been stated that transbronchial biopsy should never be performed in this setting because of the high risk of bleeding. Nevertheless, in the 4 cases in whom it was done, included our first patient, no complications were reported (9,28,42).
As in pulmonary veno-occlusive disease, a normal pulmonary artery wedge pressure does not exclude PCH. This can occur because in the wedged position the catheter produces a static column of blood that extends beyond the pulmonary venules to the central pulmonary veins and left atrium. Because central pulmonary vein pressure is measured in this position, it may be normal in PCH (5,44,49).
Several hypotheses have been advanced to explain the presence of pulmonary hypertension in PCH. The most accepted is that proliferating vessels produce “in situ” thrombosis or vascular obliteration with pulmonary hypertension (12,16,38). Other hypotheses focus on local production of vasoconstrictor substances or changes due to pulmonary bleeding and scarring (11,19,26).
In our first patient PCH was associated with mechanical intravascular hemolysis. Rupture of erythrocytes is thought to be produced by their transit through the hemangiomatous vessels. This feature has been reported previously in other hemangiomatous diseases (45,47) but only exceptionally in primary pulmonary hypertension or pulmonary veno-occlusive disease (21,43). This is the first report in relation to PCH, to our knowledge.
There is no etiologic treatment for PCH. Supportive and symptomatic treatment with ACE inhibitors, diuretics, oxygen, and warfarin have been widely used without any measurable impact on the natural course of the disease, but may be considered in those patients with right heart failure. Corticosteroids have not been shown to be useful. Pneumonectomy was successfully performed in 1 patient with massive hemoptysis with no recurrence reported (40). Epoprostenol and other prostaglandins enhance hemodynamic parameters, quality of life, and survival in primary pulmonary hypertension (4), but in the setting of PCH, no benefit has been reported (7,13,24). In fact, worsening of hypoxemia, pulmonary edema, and 3 cases of death have been described in relation to epoprostenol administration (14,18). These data indicate that the use of prostaglandins should be avoided in PCH.
Interferon α-2a has been proposed as an attractive treatment. In 1 child treated with interferon α-2a, clinical improvement and histologic regression were documented after 30 months (45,46). These results were later confirmed by the same author in 2 other cases (47), while in a fourth case no apparent response was obtained (6). In another child with pulmonary cavernous hemangiomatosis, a tumoral variety of PCH, clinical and radiologic improvement was maintained after 2 years (50). The mechanism of action of interferon α-2a is not well understood. In vitro studies have shown both an inhibition of endothelial proliferation and migration, and an inhibition of endothelial growth factors (34,43,45). Although interferon inhibits fibrosis by acting in collagen synthesis of fibroblasts, regression of fibrotic areas surrounding hemangiomatous lesions should not be expected. Interferon is especially effective in inhibiting angiogenesis in those situations where rapid cellular turnover is present (hemangiomas, sarcomas, and others).
Interferon should be considered in the treatment of PCH along with supportive treatment. The potential benefit of α-interferon should encourage physicians to perform lung biopsies to confirm this diagnosis. Surgery should be kept in mind in cases of massive hemoptysis. Pulmonary transplantation was the only possible treatment before the implementation of interferon, and should be reserved for suitable nonresponders.
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