Hilario Nunes

Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: Prognostic factors and survival

OBJECTIVES We sought to determine the factors associated with long-term survival in patients with primary pulmonary hypertension (PPH) treated with continuous epoprostenol infusion. BACKGROUND Epoprostenol improves survival in patients with PPH in New York Heart Association (NYHA) functional class III or IV. However, some patients do not benefit from epoprostenol and must be considered for lung transplantation. The best timing for listing these patients on a lung transplantation program is currently unknown. METHODS Between December 1992 and January 2001, 178 patients with PPH in NYHA functional class III or IV were treated with epoprostenol. The 6-min walk test (WT) and right-sided heart catheterization were performed at baseline, after three months on epoprostenol and thereafter once a year. RESULTS Overall survival rates at one, two, three, and five years were 85%, 70%, 63%, and 55%, respectively. On univariate analysis, the baseline variables associated with a poor outcome were a history of right-sided heart failure, NYHA functional class IV, 6-min WT <or=250 m (median value), right atrial pressure >or=12 mm Hg, and mean pulmonary artery pressure <65 mm Hg. On multivariate analysis, including both baseline variables and those measured after three months on epoprostenol, a history of right-sided heart failure, persistence of NYHA functional class III or IV at three months, and the absence of a fall in total pulmonary resistance of >30%, relative to baseline, were associated with poor survival. CONCLUSIONS Survival of patients with PPH treated with epoprostenol depends on the severity at baseline, as well as the three-month response to therapy. These findings suggest that lung transplantation should be considered in a subset of patients who remain in NYHA functional class III or IV or in those who cannot achieve a significant hemodynamic improvement after three months of epoprostenol therapy, or both.

Combined pulmonary fibrosis and emphysema: A distinct underrecognised entity

The syndrome resulting from combined pulmonary fibrosis and emphysema has not been comprehensively described. The current authors conducted a retrospective study of 61 patients with both emphysema of the upper zones and diffuse parenchymal lung disease with fibrosis of the lower zones of the lungs on chest computed tomography. Patients (all smokers) included 60 males and one female, with a mean age of 65 yrs. Dyspnoea on exertion was present in all patients. Basal crackles were found in 87% and finger clubbing in 43%. Pulmonary function tests were as follows (mean±sd): total lung capacity 88%±17, forced vital capacity (FVC) 88%±18, forced expiratory volume in one second (FEV1) 80%±21 (% predicted), FEV1/FVC 69%±13, carbon monoxide diffusion capacity of the lung 37%±16 (% predicted), carbon monoxide transfer coefficient 46%±19. Pulmonary hypertension was present in 47% of patients at diagnosis, and 55% during follow-up. Patients were followed for a mean of 2.1±2.8 yrs from diagnosis. Survival was 87.5% at 2 yrs and 54.6% at 5 yrs, with a median of 6.1 yrs. The presence of pulmonary hypertension at diagnosis was a critical determinant of prognosis. The authors hereby individualise the computer tomography-defined syndrome of combined pulmonary fibrosis and emphysema characterised by subnormal spirometry, severe impairment of gas exchange, high prevalence of pulmonary hypertension, and poor survival.

Pulmonary hypertension associated with sarcoidosis: mechanisms, haemodynamics and prognosis

Background: Pulmonary hypertension (PH) is a rare complication of sarcoidosis, although it is not uncommon in advanced disease. Methods: A retrospective series of 22 sarcoidosis patients (16 men) of mean (SD) age 46 (13) years with PH was divided into two groups depending on the absence (stage 0: n = 2, stage II: n = 4, stage III: n = 1) or presence (n = 15) of radiographic pulmonary fibrosis at the time of PH diagnosis. Results: In both groups PH was moderate to severe and there was no response to acute vasodilator challenge. In non-fibrotic cases no other cause of PH was found, suggesting a specific sarcoidosis vasculopathy, although no histological specimens were available. In cases with fibrosis there was no correlation between haemodynamics and lung volumes or arterial oxygen tensions, suggesting other mechanisms for PH in addition to pulmonary destruction and hypoxaemia. These included extrinsic arterial compression by lymphadenopathies in three cases and histologically proven pulmonary veno-occlusive disease in the five patients who underwent lung transplantation. Ten patients received high doses of oral prednisone for PH (stage 0: n  =  1, stage II: n  =  4 and stage IV: n  =  5); three patients without pulmonary fibrosis experienced a sustained haemodynamic response. Survival of the overall population was poor (59% at 5 years). Mortality was associated with NYHA functional class IV but not with haemodynamic parameters or with lung function. Conclusion: Two very different phenotypes of sarcoidosis combined with PH are observed depending on the presence or absence of pulmonary fibrosis. PH is a severe complication of sarcoidosis.

Pathobiology of pulmonary hypertension. The role of platelets and thrombosis.

With the rare exceptions of PAH associated with antiphospholipid antibodies, genetic platelet dysfunction, or inherited deficiencies of antithrombotic pathways, the thrombotic lesions are secondary, but frequently occurring, in most cases of primary or secondary PAH. Pulmonary arterial hypertension is associated with thrombotic lesions and persistent vasoconstriction and structural remodeling of PA. Activated platelets interact with the PA wall and may contribute to the functional and structural alterations of pulmonary vessels by releasing vasoactive factors and mitogenic mediators.

Risk factors for pulmonary arterial hypertension.

The present limitations in knowledge of the potential risk factors for PPH undoubtedly are attributable to the facts that PPH is a rare disease with an unknown pathogenesis and lacking large case series. Moreover, definite epidemiologic data are rare and ideally should be obtained from epidemiologic surveys such as large case-control studies. The increased incidence of the disease in young women, the familial cases, the association with autoimmune disorders, and the recent discovery that mutation of the PPH1 gene may not be restricted to familial PPH support the hypothesis that the development of pulmonary hypertension likely implies an individual susceptibility or predisposition, which is probably genetically determined. It is also now commonly believed that the development of pulmonary hypertension in some of these predisposed individuals could be hastened or precipitated by various expression factors (some of them yet unrecognized), such as ingestion of certain drugs or diets, portal hypertension, or HIV infection.

Hierarchical cluster and survival analyses of antisynthetase syndrome: phenotype and outcome are correlated with anti-tRNA synthetase antibody specificity.

The clinical phenotype and evolution of antisynthetase syndrome (ASS) are heterogeneous. This study was therefore undertaken to identify subgroups of ASS patients with similar clinico-biological features and outcomes. This retrospective multicentric study included 233 consecutive patients with three different anti-aminoacyl-tRNA-synthetase antibodies (anti-ARS): anti-Jo1 (n=160), anti-PL7 (n=25) and anti-PL12 (n=48). To characterise ASS patients, bivariate, multiple correspondence (MCA), cluster and survival analyses were performed. Interstitial lung disease (ILD) and myositis were the most common ASS manifestations. However, their respective frequencies were correlated to anti-ARS specificity: ILD was more frequent (80% and 88% vs 67%, p=0.014) whereas myositis was less common (44% and 47% vs 74%, p<0.001) in patients with anti-PL7 and anti-PL12 compared to anti-Jo1. The MCA suggested that anti-PL7 and anti-PL12 phenotypes were close to one another and distinct from anti-Jo1. The clustering analysis confirmed these data, identifying subgroups strongly defined by the anti-ARS specificity and other clinical features. Cluster 1 (n=175, 86% of anti-Jo1) defined patients with the most diffuse phenotype, whereas patients from cluster 2 (n=48, 96% of anti-PL12 and anti-PL7) exhibited a disease more restricted to the lung. Patient survival was also conditioned by the anti-ARS specificity, and was significantly lower in patients with anti-PL7/12 rather than anti-Jo1 (p=0.012). Other factors associated with poor survival were mostly related to pulmonary involvement, including severe dyspnea (p=0.003) and isolated ILD (p=0.009) at diagnosis. In patients with ASS, the phenotype and the survival were correlated with the anti-ARS specificity.

Combined Pulmonary Fibrosis and Emphysema Syndrome in Connective Tissue Disease

OBJECTIVE Connective tissue diseases (CTDs) are associated with several interstitial lung diseases. The aim of this study was to describe the recently individualized syndrome of combined pulmonary fibrosis and emphysema (CPFE) in a population of patients with CTD. METHODS In this multicenter study, we retrospectively investigated data from patients with CTD who also have CPFE. The demographic characteristics of the patients, the results of pulmonary function testing, high-resolution computed tomography, lung biopsy, and treatment, and the outcomes of the patients were analyzed. RESULTS Data from 34 patients with CTD who were followed up for a mean±SD duration of 8.3±7.0 years were analyzed. Eighteen of the patients had rheumatoid arthritis (RA), 10 had systemic sclerosis (SSc), 4 had mixed or overlap CTD, and 2 had other CTDs. The mean±SD age of the patients was 57±11 years, 23 were men, and 30 were current or former smokers. High-resolution computed tomography revealed emphysema of the upper lung zones and pulmonary fibrosis of the lower zones in all patients, and all patients exhibited dyspnea during exercise. Moderately impaired pulmonary function test results and markedly reduced carbon monoxide transfer capacity were observed. Five patients with SSc exhibited pulmonary hypertension. Four patients died during followup. Patients with CTD and CPFE were significantly younger than an historical control group of patients with idiopathic CPFE and more frequently were female. In addition, patients with CTD and CPFE had higher lung volumes, lower diffusion capacity, higher pulmonary pressures, and more frequently were male than those with CTD and lung fibrosis without emphysema. CONCLUSION CPFE warrants inclusion as a novel, distinct pulmonary manifestation within the spectrum of CTD-associated lung diseases in smokers or former smokers, especially in patients with RA or SSc.

Prevention of hepatopulmonary syndrome and hyperdynamic state by pentoxifylline in cirrhotic rats

Inhibition of tumour necrosis factor‐α (TNF‐α), levels of which are increased in the blood of cirrhotic rats, prevents hyperdynamic circulatory state, mainly by decreasing the vascular overproduction of nitric oxide. Hepatopulmonary syndrome, which is characterised by intrapulmonary vascular dilatation and increased alveolar to arterial oxygen tension difference (PA-a,O2), is mainly related to pulmonary overproduction of NO by macrophages accumulated in lung vessels. Since TNF‐α is a potent activator of macrophagic inducible nitric oxide synthase (NOS), the aim of this study was to investigate whether TNF‐α inhibition prevented hepatopulmonary syndrome and hyperdynamic circulatory state in rats with cirrhosis. TNF‐α was inhibited by 5 weeks of pentoxifylline (10 mg·kg body weight−1·day−1) in rats with cirrhosis induced by common bile duct ligation. Cardiac output, pulmonary and systemic vascular resistance, PA-a,O2 and cerebral uptake of intravenous technetium‐99m‐labelled albumin macroaggregates (which reflects intrapulmonary vascular dilatation) were similar in sham- and pentoxifylline-treated cirrhotic rats. Blood TNF‐α concentrations and pulmonary intravascular macrophage sequestration, as assessed by morphometric analysis and radioactive colloid uptake, were decreased with pentoxifylline. Pentoxifylline also prevented increases in aorta and lung NOS activities and inducible NOS expression. Thus pentoxifylline prevents development of hyperdynamic circulatory state and hepatopulmonary syndrome, probably by inhibiting the effects of tumour necrosis factor‐α on vascular nitric oxide synthase and intravascular macrophages. These results support an important role for tumour necrosis factor‐α in the genesis of hepatopulmonary syndrome.

Progression of idiopathic pulmonary fibrosis: lessons from asymmetrical disease

Background In idiopathic pulmonary fibrosis (IPF) the distribution and spatial-temporal progression of fibrotic changes may be influenced by general or locoregional conditions. From this perspective, patients with asymmetrical disease (AIPF) may be unique. Methods This retrospective study included 32 patients (26 men, mean±SD age 69±7 years) with AIPF, as defined by an asymmetry ratio (most affected – least affected fibrosis score)/(most affected + least affected fibrosis score) >0.2. The global fibrosis score was the average of the right and left scores. Patients with AIPF were compared with 64 matched controls with symmetrical IPF. Results Patients with AIPF did not differ from controls in global fibrosis score and forced vital capacity, but carbon monoxide transfer factor was less decreased (52±19% vs 43±13%, p=0.009). The rate of gastro-oesophageal reflux and acute exacerbations was significantly higher in patients with AIPF (62.5% vs 31.3%, p=0.006 and 46.9% vs 17.2%, p=0.004, respectively). In patients with AIPF the right side was more likely to be involved (62.5%); the median asymmetry ratio was 0.5 (range 0.24–1). Although the global fibrosis score worsened significantly in all 23 patients with AIPF with serial high-resolution CT scans (p<0.0001), pulmonary fibrosis remained asymmetrical in all except three. During follow-up, 15 patients with AIPF experienced 18 acute exacerbations. The first episode was virtually unilateral, occurring in the most affected lung in 10 patients (66.7%). Survival was similar between patients with AIPF and controls. Conclusion AIPF may be related to locoregional factors including gastro-oesophageal reflux which may be responsible for both disease expansion and the occurrence of acute exacerbations.

Stage IV sarcoidosis: comparison of survival with the general population and causes of death

The objectives of this study were to compare the survival of sarcoid patients with pulmonary fibrosis with that of the general population and to determine the causes of death and the incidence of evolutive complications. This retrospective cohort included 142 sarcoid patients in radiographic stage IV (74 males; mean±sd age 48.1±12 yrs). Their survival was compared with that of the general French population, matched for the year and age at diagnosis of stage IV disease, sex and length of follow-up. Expected survival probabilities were calculated year-by-year on the basis of probabilities provided by official demographic data for France. Survival curves were based on the Kaplan–Meier method and compared using the log-rank test. During the follow-up period (7.1±4.8 yrs), pulmonary hypertension (PH) was observed in 29.7% of cases and aspergilloma in 11.3%. Long-term oxygen therapy was required in 12%. Survival was 84.1% at 10 yrs, which was worse than for the general population (p=0.013). 16 (11.3%) patients died from the following causes: refractory PH (n=5), chronic respiratory insufficiency (n=4), acute respiratory insufficiency (n=2), haemoptysis due to aspergilloma (n=1), heart sarcoidosis (n=1), nocardiosis (n=1) and unknown causes (n=2). Survival is significantly decreased in stage IV patients. 75% of fatalities are directly attributable to respiratory causes.