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INTRODUCTION
PATHOLOGY
EPIDEMIOLOGY
ETIOLOGY
CLINICAL FEATURES
PROGNOSIS AND TREATMENT
CONCLUSIONS
REFERENCES
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Introduction
Pathology
Epidemiology
Etiology
Infection
Genetic Factors
Toxic Exposures
Thrombotic Diathesis
Autoimmune Disorders
Clinical Features
Radiographic Findings
Cardiac Catheterization
Other Studies
Diagnosis
Prognosis and Treatment
Vasodilators
Immunosuppressive Medications
Anticoagulants
Oxygen
Lung Transplantation
Experimental Therapies
Conclusions
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A variety of processes can cause pulmonary hypertension (Table 1), defined by the current World Health Organization (WHO) criterion of a systolic pulmonary artery pressure > 40 mm Hg, which generally corresponds to a tricuspid regurgitant velocity on Doppler ultrasound of > 3.0 m/s (1). Of note, this criterion differs from the National Institutes of Health primary pulmonary hypertension registry criteria, which required catheterization to document a mean pulmonary artery pressure > 25 mm Hg at rest or > 30 mm Hg with exercise (2).
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Pulmonary veno-occlusive disease (PVOD) is a clinicopathologic syndrome that accounts for a small number of cases of pulmonary hypertension. The term was coined in 1966 (3, 4); prior to this, the terms "isolated pulmonary venous sclerosis," "obstructive disease of the pulmonary veins," or the "venous form of primary pulmonary hypertension" had been used to describe the syndrome (5, 6). The first well-documented case of PVOD was described in 1934 by Dr. Julius Höra of the University of Munich and involved a 48-yr-old, previously healthy baker who died after a year long course notable for the development of progressive edema, dyspnea, and cyanosis (7). Despite the passage of nearly seven decades since this report, PVOD remains a poorly understood entity, and fundamental questions remain about its epidemiology, causes, natural history, and optimal treatment. This review will summarize the current state of knowledge regarding PVOD.
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The pathologic hallmark of PVOD is the extensive and diffuse occlusion of pulmonary veins by fibrous tissue, which may be loose and edematous or dense and sclerotic, the former probably reflecting an earlier stage in the development of the lesion than the latter (1, 2, 8, 9) (Figure 1). The intimal thickening involves venules and small veins in lobular septa and, rarely, larger veins. The thickening tends to be eccentric, similar to arterial changes observed after thrombotic occlusion. The media of the veins may become arterialized with an increase in elastic fibers. Recanalization of completely occluded vessels occurs over time, and calcium may encrust elastic fibers in the walls of the veins or alveoli.
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Pulmonary arterioles exhibit moderate to severe medial hypertrophy in approximately one-half of cases, but arteritis and plexiform lesions are usually absent (10). Alveolar capillaries may become so engorged and tortuous as to resemble pulmonary capillary hemangiomatosis. Pulmonary and pleural lymphatics are dilated (11).
The most consistent parenchymal change is interstitial edema, best observed in lobular septa (Figure 2). In long-standing cases, by analogy to the changes in mitral lung disease (12), this progresses to deposition of collagen fibers in the lobular septa most prominently but also in alveolar walls (Figure 3). Fibrosis may be sufficiently extensive that the differential diagnosis of usual interstitial pneumonitis arises.
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A slightly less common but more obvious finding is hemosiderosis, which may be marked. Hemosiderin may be found in alveolar macrophages or the interstitium (Figure 4). Hemorrhage may also be present, but it is often difficult to distinguish blood in the lungs due to disease rather than secondary to the operative procedures employed in obtaining biopsy specimens. Occasionally, hemosiderin or blood is sufficiently prominent that the diagnosis of idiopathic pulmonary hemosiderosis or a healed vasculitis such as Wegener's granulomatosis is entertained. Concomitant type II pneumocyte hyperplasia, focal lymphocytic infiltrates, and interstitial fibrosis occur in many patients and can be extensive (9, 13).
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The histopathologic diagnosis of PVOD usually is made at open biopsy, although much of the literature is based upon tissue examined at autopsy. The diagnosis cannot generally be made upon examination of transbronchial biopsy specimens but may be suggested by the finding of hemosiderosis and one or more sclerosed venules. However, intimal sclerosis occurs as a normal consequence of aging, so that the presence of an occasional sclerosed pulmonary vein is not sufficient for diagnosis and must be interpreted in conjunction with clinical and radiographic features.
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The true incidence of PVOD is not known precisely because many cases are probably misclassified as primary pulmonary hypertension. The proportion of primary pulmonary hypertension cases that in reality fulfill criteria for PVOD has ranged from less than 5% to 25% in different reports. Pooling of seven series of primary pulmonary hypertension between 1970 and 1991, which involved a total of 465 patients, found that PVOD accounted for approximately 10% of cases (2, 14- 20). Application of this figure to the incidence rate of primary pulmonary hypertension yields an estimate of the annual incidence of PVOD of 0.1 to 0.2 case per million persons in the general population (21). The age at diagnosis has ranged from 8 wk to the seventh decade of life. Unlike primary pulmonary hypertension, which has a higher incidence in women, the ratio of men to women with PVOD approaches 1:1 (22, 23).
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It is likely that PVOD represents a common acquired pattern of injury resulting from a multiplicity of possible insults. A variety of risk factors for PVOD have been described; however, most are based upon case reports and small case series. No case-control or cohort studies have been performed, which specifically address the potential causes of this condition.
Infection
Since Höra's initial description, infection has been considered as a possible cause of PVOD (7, 24). No convincing data have linked PVOD to a specific infectious insult, although an "influenzalike illness" has preceded the development of PVOD in many cases, and serologic evidence suggestive of recent infection with one of several agents (including Toxoplasma gondii and measles) has been documented around the time when PVOD was diagnosed (3, 4, 25). Other patients have displayed features suggestive of Epstein-Barr or cytomegalovirus infection, such as lymphadenopathy, fever, and erythrophagocytosis, around the time the diagnosis of PVOD was established (26). Two cases have been reported in association with human immunodeficiency virus (HIV) infection (27, 28).
Genetic Factors
A genetic risk factor in the development of PVOD is suggested by several cases which have occurred in siblings (6, 19, 29, 30). The ages at disease presentation have ranged from 8 wk to the mid-teens, but in each report, both members of the sibling pair became symptomatic from PVOD at ages within 1 yr of each other. Nonaffected siblings have been present in some of these families (30).
While the occurrence of a rare disease in two members of the same family may reflect the importance of a genetic component in PVOD, the significance of common exposures to food, drugs, environmental agents, or infectious diseases cannot be discounted. In each of the previously mentioned reports, no unusual common source exposures could be readily identified, but neither could they be definitively excluded.
Toxic Exposures
Chemical exposures have been invoked to explain a number of cases of PVOD. An early case of PVOD occurred in a 14-yr-old boy who had a 2-yr history of ingesting and sniffing a powdered cleaning product containing silica, soda ash, dodecyl benzyl sulfonate, and trichloro-s-triazinetriome (31).
Later, as hepatic veno-occlusive disease (HVOD) became a well-recognized complication of antineoplastic chemotherapy, associations between some cases of PVOD and the treatment of a variety of different tumors with various chemotherapy regimens were also appreciated (32). Many patients were exposed to numerous regimens over several years, making identification of culprit agents difficult, but bleomycin, mitomycin, and carmustine (BCNU) are thought by some investigators to confer the greatest risk (32). Anecdotally, PVOD appears to be a more common complication after bone marrow transplantation (both allogeneic and autologous) than routine cytoreductive chemotherapy (37); however, data are insufficient to definitively confirm this clinical impression.
HVOD may result from alterations in drug metabolism that allow toxic metabolites to reach and damage the hepatic venules. Lung tissue is also metabolically active, and it is possible that a similar mechanism may produce PVOD in patients who develop the syndrome after antineoplastic chemotherapy. Nonetheless, most patients with PVOD develop the disease over a much longer time course than occurs with HVOD, and the relative contributions of genetics, inflammation, thrombosis, and fibrosis may be different in the pathogenesis of the two conditions.
Whereas the risk of primary pulmonary hypertension is increased by the use of cocaine and certain anorectic agents such as fenfluramine, PVOD has not been reported after ingestion of these compounds (30, 41). Likewise, "bush teas" containing pyrrolizidine alkaloids have been responsible for outbreaks of HVOD but have not been identified as a risk factor for isolated PVOD (42, 43).
Thrombotic Diathesis
Because the thrombotic occlusion of pulmonary veins can be a prominent feature of PVOD, a number of researchers have theorized that a thrombotic diathesis may play some role in the pathogenesis of the condition. Although characterization of the rheology of patients with PVOD has not been assessed by state-of-the art techniques, several early reports described increased platelet adhesiveness in patients with the condition, in one case to a level 4 standard deviations above the mean for normals (3, 44). Support for the importance of a thrombotic diathesis is also drawn from cases in which PVOD has occurred in conjunction with known risk factors for hypercoagulability, such as oral contraceptive use or pregnancy (45, 46).
Nonetheless, several factors argue against a predisposition toward thrombosis or a defect in fibrinolysis as fundamental in the pathogenesis of the condition. First, a history of documented venous or arterial thrombi in the extrapulmonary circulation, which might be expected in patients with thrombotic diatheses, has been rare among patients with PVOD. Second, many patients with PVOD do not in fact have evidence of recent pulmonary venous thrombi on histopathologic examination (11).
Autoimmune Disorders
Autoimmune destruction of pulmonary venules, either as a primary event or secondary to viral infection, followed by thrombosis, fibrosis, or both, could help explain the anatomic specificity of PVOD but has not been commonly observed. Granulomatous venulitis is an uncommon finding but was described in one 21-yr-old man with PVOD and a history of occasional marijuana use, and has rarely occurred in conjunction with sarcoidosis (47, 48).
In general, patients with PVOD have lacked other features of autoimmune syndromes. Several patients have had associated myopathy, alopecia, positive antinuclear antibodies, rheumatoid arthritis, systemic lupus erythematosus, or features of the limited (CREST: calcinosis cutis, Raynaud's phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia) variant of progressive systemic sclerosis, but such cases are clearly in the minority (49). In one case, PVOD occurred as part of a systemic venulitis syndrome that had not been previously described (56).
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Most patients with PVOD present with nonspecific complaints such as dyspnea on exertion and lethargy, presumed secondary to an inability to adequately increase cardiac output with exercise (23). Many cases present after a respiratory infection and progress despite treatment with antibiotics (4). Chronic cough (either productive or nonproductive) is present in some individuals (57). As pulmonary hypertension becomes more severe, cyanosis, chest pain, right upper quadrant pain secondary to hepatic congestion, and exertional syncope may be noted. Hemoptysis may occur but is rarely massive and life-threatening (58). Orthopnea is reported by patients with PVOD, but is unusual among those with primary pulmonary hypertension (13). Rarer presentations of PVOD include diffuse alveolar hemorrhage and sudden death (58).
The physical examination is similarly quite nonspecific and generally shows findings consistent with pulmonary hypertension of any cause. Auscultatory crackles may occur in patients with PVOD in whom chronic pulmonary infiltrates are prominent (6, 13). Clubbing is an unusual feature (13).
Pleural effusions are frequently observed in patients with PVOD whereas they are rare among those with primary pulmonary hypertension. This difference is probably due to the fact that pulmonary capillary and visceral pleural capillary hydrostatic pressures are elevated in PVOD because of postcapillary obstruction, leading to transudation of fluid into the pleural space (61, 62). In contrast, the high resistance vessels are proximal to the pulmonary capillaries in primary pulmonary hypertension, and increased accumulation of pleural liquid generally does not occur until systemic venous hypertension increases the hydrostatic pressure within the parietal pleural capillaries.
Radiographic Findings
Chest radiographs may show Kerley B lines, which result from chronic pulmonary capillary hypertension with consequent transudation of fluid into the interstitium and enlargement of pulmonary lymphatic channels (Figure 5). Central pulmonary arteries may be engorged, and scattered patchy opacities may be present (3). However, the absence of Kerley B lines or other radiographic abnormalities does not exclude the condition (23, 55, 63, 64).
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Computed tomographic (CT) scans may reveal smooth septal thickening, diffuse or mosaic ground glass opacities, multiple small nodules, pleural effusions, or areas of alveolar consolidation, which may be gravitationally dependent (61, 65- 67) (Figure 6). The pathologic correlate of ground glass attenuation is uncertain but may result from alveolar septal thickening with associated hyperplasia of lining epithelium. The central pulmonary veins and the left atrium are not enlarged, in contrast to patients with mitral stenosis, cor triatriatum, or left atrial myxoma. Prominent mediastinal lymphadenopathy has been present in some cases (68, 69).
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Ventilation-perfusion images reveal normal ventilation and commonly display focal areas of hypoperfusion. This finding may lead to a misdiagnosis of chronic thromboembolic pulmonary hypertension (13, 23, 57, 58, 63, 65, 70).
Cardiac Catheterization
One hemodynamic finding described by many researchers is the failure to obtain a pulmonary artery wedge pressure tracing; when the distal port of the wedged catheter is flushed in this position, pressure rises disproportionately and falls extremely slowly to baseline because the infused saline becomes trapped between the catheter tip and narrowed pulmonary veins (3, 58, 74). Slow aspiration of blood from the distal port of the pulmonary artery catheter and demonstration of a partial pressure of oxygen similar to that of arterial blood may be required to document successful catheter wedging. Ideally, the pulmonary capillary wedge pressure should be measured in several different locations to ensure that a given measurement is not spurious or the result of a local phenomenon.
If the pulmonary artery catheter is successfully wedged, the value of the pulmonary artery wedge pressure obtained is generally normal or decreased despite the fact that pulmonary capillary pressures are elevated. This occurs because in the wedged position the catheter abuts a static column of blood that extends beyond the pulmonary venules to the central pulmonary veins and left atrium, the latter of which largely determines pulmonary artery wedge pressure and is hemodynamically normal in PVOD. Extensive pulmonary venule stenosis may dampen this pressure tracing somewhat but does not fundamentally alter the fact that the pulmonary artery wedge pressure is determined by structures distal to the small pulmonary veins, and these tend to be normal in PVOD (75, 76).
If a short-acting pulmonary arterial vasodilator such as inhaled nitric oxide or intravenous epoprostenol or adenosine is administered at the time of catheterization, acute pulmonary edema may ensue (69). Presumably, 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. While not pathognomonic of PVOD, the development of pulmonary edema in response to a pulmonary vasodilator is strongly suggestive of the diagnosis.
Other Studies
The single-breath diffusing capacity for carbon monoxide (DLCO) is usually reduced (63), and a restrictive ventilatory defect has also been reported in many cases (65). Laboratory parameters are generally unremarkable, although microangiopathic hemolytic anemia (36), heavy proteinuria (4), and elevations in serum IgG and IgM concentrations (51) have occurred in isolated cases.
The bronchoscopic appearance of intense hyperemia of the lobar and segmental bronchi with vascular engorgement in the form of bright red longitudinal streaks has been noted in this condition (71). These findings were not present in the trachea and main bronchi, likely because the venous drainage of central airways is into nonoccluded bronchial veins, whereas the lobar bronchi and more distal airways drain into the pulmonary veins, and thus become hyperemic by virtue of decreased venous runoff.
Diagnosis
Clinically, the triad of severe pulmonary arterial hypertension, radiographic evidence of pulmonary edema, and a normal pulmonary artery occlusion pressure has been thought to be diagnostic of PVOD (76). However, many patients with PVOD do not have this triad. Delays in diagnosis frequently are encountered by patients with PVOD, with many individuals assumed to have congestive heart failure (because of radiographic abnormalities) or chronic thromboembolic pulmonary hypertension (because of nonresolving perfusion defects on ventilation-perfusion imaging). In some cases of PVOD, advanced parenchymal lung diseases, such as sarcoidosis, cystic fibrosis, or pneumoconioses, may be considered as diagnostic possibilities because of prominent chronic interstitial changes on chest radiographs (77).
PVOD can be diagnosed definitively only by surgical lung biopsy, and this procedure should be considered to confirm the clinical suspicion of PVOD. The utility of lung biopsy has been questioned because the current therapy of PVOD appears minimally efficacious. However, we feel that biopsy is generally warranted in patients with clinical and radiographic features suggestive of the disorder (e.g., the combination of pulmonary hypertension, radiographic features of pulmonary edema, and a normal pulmonary artery occlusion pressure) if surgical risk is acceptable because establishing the diagnosis of PVOD can provide important prognostic information for the patient and impact upon the timing of evaluation and listing for lung transplantation.
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The prognosis of PVOD is grim, with most reported patients dying within 2 yr of diagnosis (73). Because PVOD is a rare condition, randomized therapeutic trials have not been undertaken, and the degree to which current treatments favorably impact outcomes is unclear. With the possible exception of lung transplantation, the impression of most clinicians is that the impact of current treatments is not profound.
Vasodilators
Pulmonary vasodilators such as calcium-channel antagonists and epoprostenol (prostacyclin) have an established role in the treatment of primary pulmonary hypertension (78), but the generalizability of these data to patients with PVOD is unclear. There are theoretical reasons why vasodilators may not be efficacious in PVOD and may in fact worsen cardiopulmonary status; if the pulmonary arterioles dilate but the resistance of the pulmonary veins remains fixed, an increase in transcapillary hydrostatic pressure may ensue and produce florid pulmonary edema.
Clinical data in this regard are scant and conflicting. Modest improvements in hemodynamics and exercise tolerance have been reported in some, but not all, patients with PVOD treated with nifedipine, hydralazine, or prazosin (81, 82). Epoprostenol has been reported to have salutary effects on hemodynamics and to reverse the increased vasomotor tone in pulmonary venules (83), but also has been reported to produce massive pulmonary edema and death (69, 84). Because of the limited therapeutic possibilities in patients with PVOD, we continue to cautiously administer vasodilators, beginning with an initial trial of a short-acting agent such as nitric oxide, adenosine, or epoprostenol.
Immunosuppressive Medications
Immunosuppressive medications, such as glucocorticoids and antimetabolites, have been employed in PVOD, particularly among patients with extensive interstitial lung disease or concomitant features of autoimmune syndromes, despite the fact that serum indices such as complement levels and the erythrocyte sedimentation rate are frequently within normal limits (77). Immunosuppressive protocols have been neither standardized nor randomized, so firm conclusions regarding efficacy cannot be drawn. However, only in rare cases have these drugs appeared to significantly palliate the symptoms of PVOD or affect the terminal nature of the condition (38, 51, 85). The best reported response occurred in a 46-yr-old woman with biopsy-proven PVOD who was treated with 10 mg/d of prednisone plus 150 mg/d of azathioprine and demonstrated progressive improvement in subjective and objective exercise capacity during approximately 2 yr of follow-up (51). Of note, this patient had a variety of features suggesting concomitant autoimmune phenomena, which are unusual in PVOD, including Raynaud's phenomenon with digital ulceration, alopecia, arthritis, elevated serum IgG and IgM concentrations, and a positive antinuclear antibody.
The precise role of immunosuppressive medications in the treatment of PVOD remains undefined. It is possible that these medications are modestly effective in a subset of patients with the condition. Despite the paucity of data supporting efficacy, the fact that some apparent responses have occurred and few other treatment options are available leads us to favor a 4-wk trial of prednisone at doses of 0.75 to 1 mg/kg/d in patients with autoimmune features. We follow symptoms, radiographs, diffusing capacity, and alveolar-arterial oxygen gradient, and if a patient improves on this therapy, the dose is slowly tapered to 20 to 40 mg/d.
Anticoagulants
Observational trials have suggested that patients with primary pulmonary hypertension may survive longer when anticoagulated (78, 86). Because of this, we treat all patients with PVOD with long-term warfarin titrated to achieve an international normalized ratio of 2.0 to 3.0 unless contraindications are present. Small-volume hemoptysis does not usually require discontinuation of therapy, but we usually terminate treatment if more than 50 ml of blood are expectorated over a 24-h period or if significant extrapulmonary hemorrhage results.
Oxygen
Long-term oxygen therapy is indicated for hypoxemic patients with PVOD. Criteria for implementing oxygen therapy are based upon trials of patients with chronic obstructive pulmonary disease rather than experiments directly involving patients with PVOD or other primary pulmonary vascular disorders (87, 88). Case reports of patients with primary pulmonary hypertension have failed to document improvement in pulmonary artery pressures after the initiation of oxygen therapy (89). Nonetheless, the adverse effects (other than cost) of oxygen therapy are few, and it seems prudent to initiate oxygen therapy in patients with PVOD who meet the standard Health Care Financing Administration (HCFA) requirements for reimbursement. Transtracheal oxygen therapy permits delivery of higher oxygen flow rates, but local bleeding complications may be problematic in patients receiving chronic anticoagulation.
Lung Transplantation
Lung transplantation is at present the only therapy that appears capable of significantly prolonging the lives of patients with PVOD. Single-lung and double-lung transplantation procedures have both been employed. Recurrence after transplantation has not been reported, although the cumulative experience with PVOD is too small to permit confident generalizations regarding outcome (66, 90, 91).
We refer all patients with PVOD for evaluation for lung transplantation at the time of diagnosis. However, the utility of lung transplantation is diminished by the fact that the average waiting times in many parts of the United States exceed the life expectancy of patients with PVOD. Infection and the development of obliterative bronchiolitis remain major causes of morbidity and mortality in patients who successfully undergo transplantation.
Experimental Therapies
A number of experimental therapies are undergoing evaluation in patients with HVOD, and some have also been used in patients with PVOD. There are almost no data regarding the effectiveness of these modalities in PVOD, and assessment of efficacy in HVOD is complicated by the fact that many patients with the condition recover spontaneously.
Most of these interventions involve antithrombotic treatment with agents such as heparin, thrombolytic agents such as recombinant tissue plasminogen activator (tPA), or antithrombin III concentrate in patients with a documented antithrombin III deficiency (92). Defibrotide, a polydeoxyribonucleotide derived from mammalian cells, is associated with little bleeding risk but has multiple activities that may hasten the resolution of thrombi, including its actions as an adenosine receptor agonist, in increasing concentrations of endogenous prostaglandins (PGI2 and E2), stimulating expression of thrombomodulin in endothelial cells, modulating platelet activity, and increasing the function of endogenous tPA while diminishing the activity of plasminogen activator inhibitor-1 (PAI-1) (93, 94).
The time course of the development of PVOD suggests that acute thrombosis probably plays less of a pathogenic role in PVOD than HVOD, and it is therefore unlikely that these novel antithrombotic drugs will effect a marked improvement in patients with PVOD. Pending further experience, we do not recommend treatment of patients with PVOD with these agents except in the context of well-defined clinical trials.
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PVOD remains a rare and poorly understood syndrome that likely represents a final common pathway of disease caused by a variety of insults. The importance of diagnosing the condition is due largely to its poorer prognosis than either primary pulmonary hypertension or chronic thromboembolic pulmonary hypertension; this necessitates more rapid evaluation and listing for lung transplantation. In addition, the frequent deterioration that has been reported in response to vasodilators necessitates that these agents be used more judiciously than when primary pulmonary hypertension is present. Future research is required to more precisely define the risk factors for this condition and to determine optimal therapy.
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Dr. Hales is partially supported by a grant from the National Institutes of Health.
Correspondence and requests for reprints should be addressed to Jess Mandel, M.D., Division of Pulmonary and Critical Care Medicine, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215. E-mail: jmandel{at}caregroup.harvard.edu
(Received in original form December 31, 1999 and in revised form June 13, 2000).
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