Jørn Carlsen

Prevalence, predictors, and survival in pulmonary hypertension related to end-stage chronic obstructive pulmonary disease

BACKGROUND The prevalence, prognostic importance, and factors that predict the presence and degree of pulmonary hypertension (PH) diagnosed with right heart catheterization (RHC) in patients with end-stage chronic obstructive pulmonary disease (COPD) remain unclear. METHODS This retrospective study included 409 patients (61% women) with COPD/emphysema or α-1-antitrypsin deficiency who underwent lung transplant evaluation during 1991 to 2010. We analyzed the occurrence and degree of PH and compared demographics, oxygenation, lung function, hemodynamics, functional capacity, and survival in patients with and without PH. Prediction of PH was assessed using univariate and multivariate regression analysis. RESULTS The mean age at evaluation was 54 ± 7 years. All patients were in New York Heart Association functional class III-IV, with forced expiratory volume in 1 second of 23% ± 7% and total lung capacity of 126% ± 21% of predicted. PH was present in 146 (36%). The analysis excluded 53 (13%) with pulmonary venous hypertension (PVH). The distribution of the mean pulmonary artery pressure (mPAP) in patients with or without PH showed a unimodal normally distributed population, with a mean of 23.8 ± 6.0 mm Hg. Predictors of PH were partial pressures of oxygen and carbon dioxide. The 5-year survival rate was 37% in COPD patients with PH vs 63% in patients without PH (p = 0.016). Survival after lung transplantation did not differ (p = 0.37). CONCLUSIONS RHC verified PH in 36% of COPD patients. Hypoxemia and hypercapnia were associated with mPAP. PH is associated with worse survival in COPD, but PH does not influence the prognosis after lung transplantation.

Apelin : A new plasma marker of cardiopulmonary disease

OBJECTIVES Dyspnea is a major symptom of both parenchymal lung disease and chronic heart failure. Underlying cardiac dysfunction can be assessed by measurement of cardiac-derived B-type natriuretic peptide or its precursor in plasma. However, no specific endocrine marker of the lung parenchyma has so far been identified. We therefore examined whether plasma concentrations of apelin, a novel inotropic hormone, is affected in patients with chronic parenchymal lung disease without cardiac dysfunction. METHODS AND RESULTS Patients with severe chronic parenchymal lung disease and normal cardiac function (n=53), idiopathic pulmonary hypertension with increased right ventricular pressure (n=10), and patients with severe left ventricular systolic dysfunction (n=22) were enrolled. Plasma apelin-36 and proBNP concentrations were measured with radioimmunoassays. While proBNP plasma concentrations were unaffected in chronic parenchymal lung disease patients compared to normal subjects, the apelin-36 concentration was reduced 3.3-fold (median 35 pmol/l (0-162 pmol/l) vs. 117 pmol/l (55-232 pmol/l), P<0.001). Moreover, the apelin-36 concentration was decreased in chronic heart failure patients (2.1-fold, P<0.01) and in patients with idiopathic pulmonary hypertension (4.0-fold, P<0.001). In contrast, the proBNP concentration was highly increased in both chronic heart failure and idiopathic pulmonary hypertension patients. CONCLUSION Plasma concentrations of apelin-36, a novel inotropic peptide, are decreased in patients with chronic parenchymal lung disease and preserved cardiac function. Combined measurement of apelin-36 and proBNP may be a new diagnostic approach in distinguishing pulmonary from cardiovascular causes of dyspnea.

Pulmonary Hypertension in End-stage Pulmonary Sarcoidosis: Therapeutic Effect of Sildenafil?

BACKGROUND The objectives of this study were to assess the frequency and severity of pulmonary hypertension (PH) and the effect of sildenafil treatment in patients with recalcitrant pulmonary sarcoidosis. METHODS This investigation was a single-center, retrospective study of all patients (n = 25) with end-stage pulmonary sarcoidosis referred for lung transplantation. Hemodynamic measurements were evaluated by right-side cardiac catheterization in 24 of 25 patients. Sildenafil treatment for patients with sarcoidosis-associated PH was introduced in April 2004. RESULTS The study group of 24 patients (16 men, 8 women) had a median age of 45 (range 35 to 58) years, and duration of sarcoidosis of 11 (range 2 to 38) years. Mean pulmonary arterial pressure (MPAP) was median 36 (range 18 to 73) mm Hg. PH (MPAP >25 mm Hg) was present in 19 of 24 patients (79%). Sildenafil was administered to 12 of 13 patients at a dose of 150 (range 75 to 225) mg/day for 4 (range 1 to 12) months. Sildenafil treatment was associated with reductions in MPAP of -8 mm Hg (CI -1 to -15 mm Hg), and PVR -4.9 Wood units (CI -7.2 to -2.6 Wood units). Cardiac output and cardiac index also increased during treatment (p = 0.01, respectively). There were no consistent changes in 6-minute walk distance. CONCLUSIONS Patients with severe pulmonary sarcoidosis have a high prevalence of PH. Sildenafil treatment was associated with significant improvements in hemodynamic parameters.

Acute cellular rejection is a risk factor for bronchiolitis obliterans syndrome independent of post-transplant baseline FEV1.

BACKGROUND Post-transplant baseline forced expiratory volume in 1 second (FEV(1)) constitutes a systematic bias in analyses of bronchiolitis obliterans syndrome (BOS). This retrospective study evaluates risk factors for BOS adjusting for the confounding of post-transplant baseline FEV(1). METHODS A multivariate survival and competing risk analysis of a large consecutive series of patients (n = 389) from a national center 1992 to 2004. Exclusion criteria were patients not surviving at least 3 months after transplantation (n = 39) and no available lung function measurements (n = 4). RESULTS The first maximum FEV(1) occurred at a median 183 days post-transplant. Freedom from BOS was 81%, 53%, 38% and 15%, and cumulative incidence of BOS was 18%, 43%, 57% and 77% at 1, 3, 5 and 10 years post-transplantation, respectively. Acute cellular rejection was independently associated with an increased cause-specific hazard of BOS (hazard ratio 1.4, confidence interval 1.1 to 1.8, p = 0.009). The absolute value of baseline FEV(1) was a significant confounder in all survival and competing risk analyses of BOS (p < 0.05). CONCLUSION Despite early diagnosis and prompt treatment, acute cellular rejection remains an independent risk factor for the development of BOS after adjusting for the confounding of post-transplant baseline FEV(1).

Myocardial perfusion scintigraphy as a screening method for significant coronary artery stenosis in cardiac transplant recipients

BACKGROUND Several studies have explored the feasibility of using myocardial perfusion imaging to detect allograft vasculopathy after heart transplantation. We undertook the present prospective consecutive study to comparatively evaluate the role of serial myocardial perfusion single-photon emission computed tomography (SPECT) scanning and coronary arteriography (CAG) in detecting coronary artery stenosis suitable for coronary angioplasty in heart transplant recipients. METHODS Within a 2-week interval during a follow-up period of 5.6 (95% confidence limits 2.1 to 12) years, 255 serial CAGs and myocardial perfusion scintigraphies were performed in 67 patients. Arteriography and scintigraphy were performed once yearly after heart transplantation. We retrospectively analyzed the data. RESULTS Myocardial scintigraphy showed pathologic reversible defects in 9 out of 67 patients. Four of these patients had significant (>50% and also >70%) focal segmental stenosis in the middle and proximal parts of the coronary arteries (Type A lesions), 1 had diffuse and circumferential narrowing in the distal parts (Type B lesions), whereas CAG showed no lesions in the remaining 4 patients. The patients with significant Type A lesions were revascularized with percutaneous coronary angioplasty. Coronary arteriography showed that 1 patient had extensive Type A and Type B lesions, whereas myocardial perfusion scans detected no. The predictive value of a negative (normal) SPECT was 98% (95% confidence limits 94% to 100%) for the detection of lesions suited for revascularization. CONCLUSIONS Annual myocardial SPECT seems well suited to screen for significant coronary artery stenosis. A SPECT study without reversible defects virtually excludes lesions suitable for coronary artery revascularization.

Pulmonary arterial lesions in explanted lungs after transplantation correlate with severity of pulmonary hypertension in chronic obstructive pulmonary disease

BACKGROUND Pulmonary vascular findings are largely unreported in end-stage chronic obstructive pulmonary disease (COPD). METHODS Pulmonary vascular lesions in explanted lungs from 70 patients with COPD/emphysema or α-1-antitrypsin deficiency were analyzed retrospectively. Patients were stratified by the presence and severity of pulmonary hypertension (PH) assessed by right-heart catheterization in 3 hemodynamically distinct groups: (1) non-PH (mean pulmonary arterial pressure [mPAP]<25 mm Hg), (2) mild to moderate PH (mPAP, 25-34 mm Hg), and (3) severe PH (mPAP≥35 mm Hg). The control group comprised 18 patients with idiopathic pulmonary arterial hypertension (IPAH). Vascular lesions were graded 1-6 according to a modified Heath and Edwards (HE) scale. RESULTS All COPD patients were in New York Heart Association Functional Class III-IV (forced expiratory volume in 1 second, 23%±8%; total lung capacity, 128%±20% of predicted). Non-PH group: 30 patients (60% women) aged 54±6 years; mPAP, 17.2±3.8 mm Hg; median HE Grade 1 (range, 0-3), with medial hypertrophy of muscular pulmonary arteries and muscularization of pulmonary arterioles. Mild-moderate PH group: 30 patients (50% women) aged 53±6 years; mPAP, 28.6±2.8 mm Hg; median HE Grade 3 (range, 1-3), with additional cellular intimal proliferation. Severe PH group: 10 patients (50% women) aged 54±6 years; mPAP, 40.7±5.2 mm Hg; median HE Grade 3 (range, 2-5), with additional intimal fibrosis. IPAH controls: 18 patients (67% women) aged 36±4 years; mPAP,>50 mm Hg; median HE Grade 4 (range 3-6), with generalized arterial dilatation and plexiform lesions. CONCLUSIONS The extent of pulmonary vascular lesions in COPD correlate with the severity of PH. Morphologic lesions similar to those characteristic of IPAH can be observed as PH in COPD progresses to levels characteristic of IPAH.

Minimal acute cellular rejection remains prevalent up to 2 years after lung transplantation: a retrospective analysis of 2697 transbronchial biopsies.

Background. Acute cellular rejection (ACR) is the most consistently reported risk factor for the development of bronchiolitis obliterans syndrome, an important cause of late mortality after lung transplantation. This retrospective study comprised all transbronchial biopsies (TBB) obtained during the first 2 years after transplantation in a consecutive cohort of 299 patients transplanted 1996–2006 (n=2697). Methods. TBB were aligned to the closest TBB surveillance schedule. Results. Patients completed a mean of 6±2 (median 8) TBB schedules. The proportion of patients demonstrating ACR (≥A2) decreased with increasing time from transplantation from 43% at 2 weeks to 27% at 6 months, and 13% and 4% at 1 and 2 years, respectively (trend test, P<0.0001). There was a significant trend between increased previous occurrence of ACR and increasing subsequent risk of A≥2 from 1, 3, and 12 months after transplantation (P<0.0001, P=0.0005, and P=0.001, respectively). Multivariate analyses identified interleukin-2-receptor induction with daclizumab versus antithymocyte globulin was independently associated with more frequent/severe ACR (P<0.0001). Conclusions. Minimal ACR remains prevalent up to 2 years after lung transplantation. Previous occurrence of ACR was associated with an increased risk of subsequent ACR.

Pro-brain natriuretic peptide as marker of cardiovascular or pulmonary causes of dyspnea in patients with terminal parenchymal lung disease

BACKGROUND Increased plasma concentrations of pro-atrial natriuretic peptide (proANP) and pro-brain natriuretic peptide (proBNP) are features of left ventricular impairment. However, concentrations of proANP and proBNP in patients with isolated terminal parenchymal lung disease are not known. Therefore, we measured the plasma concentrations of natriuretic precursor peptides in patients with terminal parenchymal lung disease who had normal left ventricular function and who were referred for evaluation for lung transplantation. METHODS We measured plasma N-terminal proANP and proBNP in patients undergoing right heart catheterization (n = 50) and related results to hemodynamic variables obtained during catheterization. RESULTS Plasma proBNP concentrations were unaffected in patients with terminal parenchymal lung disease and normal left ventricular function (median, 2.5 pmol/liter; range, 0-22; upper reference limit, 15 pmol/liter). In contrast, patients with primary pulmonary hypertension displayed more than a 40-fold increase in plasma proBNP concentrations (median, 107 pmol/liter vs 2.5 pmol/liter, p < 0.0001). Plasma N-terminal proANP increased moderately (median, 664 pmol/liter; range, 36-1620; upper reference limit, 600 pmol/liter) but correlated to plasma proBNP concentrations (r = 0.47, p < 0.0001). Finally, regional vascular proBNP concentrations revealed the heart as the secretory site. CONCLUSIONS Our findings strongly support the contention that natriuretic peptide measurements are efficient markers for cardiovascular causes of dyspnea. Moreover, our results eliminate natriuretic peptides as markers of moderate pulmonary hypertension in patients with terminal parenchymal lung disease.

Chronic rejection of a lung transplant is characterized by a profile of specific autoantibodies

Obliterative bronchiolitis (OB) continues to be the major limitation to long‐term survival after lung transplantation. The specific aetiology and pathogenesis of OB are not well understood. To explore the role of autoreactivity in OB, we spotted 751 different self molecules onto glass slides, and used these antigen microarrays to profile 48 human serum samples for immunoglobulin G (IgG) and IgM autoantibodies; 27 patients showed no or mild bronchiolitis obliterans syndrome (BOS; a clinical correlate of OB) and 15 patients showed medium to severe BOS. We now report that these BOS grades could be differentiated by a profile of autoantibodies binding to 28 proteins or their peptides. The informative autoantibody profile included down‐regulation as well as up‐regulation of both IgM and IgG specific reactivities. This profile was evaluated for robustness using a panel of six independent test patients. Analysis of the functions of the 28 informative self antigens showed that eight of them are connected in an interaction network involved in apoptosis and protein metabolism. Thus, a profile of autoantibodies may reflect pathological processes in the lung allograft, suggesting a role for autoimmunity in chronic rejection leading to OB.

Interstitial inflammatory lesions of the pulmonary allograft: a retrospective analysis of 2697 transbronchial biopsies.

Background. Parenchymal and bronchial inflammatory and fibrotic lesions other than acute cellular rejection (ACR) and lymphocytic bronchiolitis are prevalent; however, the context in which they appear is unknown, and often no specific treatment is instigated. Objectives. To describe the prevalence, incidence and possible associations between commonly identified inflammatory and fibrotic lesions in the pulmonary allograft. Methods. Retrospective chart review of all transbronchial biopsies performed within the first 2 years of 299 lung-transplanted patients in the period 1996 to 2006. Results. A total of 2697 biopsies were evaluated corresponding to a mean of 6±2 (median 8) completed schedules per patient. Diffuse alveolar damage (DAD) was the second most common histological finding within the first 2 weeks after transplantation. The peak prevalence of bronchiolitis obliterans organizing pneumonia (BOOP) and interstitial pneumonitis occurred at 4 to 6 weeks, and 6 to 12 weeks, respectively. There was a steady increase in the cumulative proportion of patients with fibrosis and bronchiolitis obliterans, at each successive scheduled surveillance time point beyond 3 months posttransplantation. The strongest histological correlations were between ACR and lymphocytic bronchiolitis (OR 5.1, P<0.0001) or interstitial fibrosis (OR 3.2, P<0.0001). Patients with interstitial pneumonitis and pulmonary hemosiderosis were also more likely to demonstrate the finding of interstitial fibrosis (OR 3.0 and 3.7, P<0.0001, respectively). Acute cellular rejection was not associated with DAD, and patients with lymphocytic bronchiolitis were not more likely to demonstrate features of organizing pneumonia (DAD or BOOP). Conclusions. Histologic findings of ACR, lymphocytic bronchiolitis, BOOP, and interstitial pneumonitis were directly associated with the development of interstitial fibrosis and bronchiolitis obliterans.