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Background: Arterial and thromboembolic pulmonary hypertension (PH) lead to arterial hypoxaemia. Objective: To investigate whether cerebral tissue oxygenation (CTO) in patients with PH is reduced and whether this is associated with reduced exercise tolerance. Methods: 16 patients with PH (mean pulmonary arterial pressure ≥25mmHg, 14 arterial, 2 chronic thromboembolic) and 15 controls underwent right heart catheterisation with monitoring of CTO at rest, during maximal bicycle exercise and during inhalation of oxygen and NO. The 6min walk distance (6MWD) was measured. Results: Median CTO in PH-patients at rest was 62% (quartiles 53; 71), during exercise 60% (53; 65); corresponding values in controls were 65% (73; 73) (P=NS) and 68% (66; 70) (p=.013 vs. PH). Inhalation of NO and oxygen improved CTO in PH. In multivariate regression analysis CTO at maximal exercise predicted the work load achieved when controlled for age, pulmonary vascular resistance and mixed venous oxygen saturation (R 2=.419, p<.000); in addition, the 6MWD was predicted by CTO (adjusted R 2=.511, p<.000). Conclusion: In PH-patients but not in controls CTO decreased during exercise. Since CTO was an independent predictor of the work load achieved and the 6MWD cerebral hypoxia may contribute to exercise limitation in PH. Clinicaltrials.gov: NCT01463514.

Purpose: Pulmonary hypertension (PH) due to COPD has dismal prognosis. We reviewed the long-term effect of PH-target therapy in severe PH-COPD. Method: Patients attending our PH-clinic were reviewed for PH-COPD receiving PH-target therapy. Baseline characteristics, death/transplantation until 2014, therapy, NYHA functional class, 6min walk distance (6MWD) and oxygen saturation (SpO2) at baseline, 3, 6, 12 and 24months were analysed. Results: Of 48 PH-COPD identified 21 were excluded (insufficient data, comorbidity). 27 patients (7 females, 21 smokers, 23 emphysema) with median (quartiles) baseline age 70 (60; 76)years, FEV1 60 (46; 78)%, FEV1/FVC 57 (51; 64)%, DLCO 42 (36; 59)%, mean pulmonary artery pressure 39 (32;44) mmHg under inhaled iloprost (10), subcutaneous prostanoids (2), intravenous prostanoids (3), endothelin receptor antagonists (15) and phosphodiesterase-5-inhibitors (25) were included. Under therapy, NYHA functional class improved from 3.5 (3; 4) to 3 (2; 4) after 3months and 3 (2; 3.5) after 6months (p=.02 and .008). The 6MWD improved from 373 (236; 452) to 395 (339; 472), 414 (285; 492) and 396 (308; 497)m at 3, 6 and 12months (p=.005, .006 and .011) with unchanged resting-SpO2 but decreased peak-exercise SpO2. During median follow-up of 5.9 (2.3; 8.4) years, 10 died, 2 were transplanted and 2 were lost to follow-up. Transplant-free survival at 1,2,3years was 92,69,54% and was similar for GOLD stages 1-4, but worse for patients with mPAP ≥40mmHg (p=.026), 6MWD <370m (p=0.008), resting SpO2 <92% (p=0.02) and peak-walk SpO2 <87% (p=0.012). Conclusion: PH-target vasodilator therapy improved NYHA functional class and 6MWD up to one year in highly selected patients with severe PH-COPD. Poor exercise capacity, low SpO2 and high mean pulmonary artery pressure at baseline but not airflow obstruction were associated with unfavourable outcome.

Aims Dysregulation of the bone morphogenetic protein receptor type 2 (BMPR2) is a hallmark feature that has been described in several forms of pulmonary hypertension. We recently identified the microRNA miR-20a within a highly conserved pathway as a regulator of the expression of BMPR2. To address the pathophysiological relevance of this pathway in vivo, we employed antagomiR-20a and investigated whether specific inhibition of miR-20a could restore functional levels of BMPR2 and, in turn, might prevent pulmonary arterial vascular remodelling. Methods and results For specific inhibition of miR-20a, cholesterol-modified RNA oligonucleotides (antagomiR-20a) were synthesized. The experiments in mice were performed by using the hypoxia-induced mouse model for pulmonary hypertension and animal tissues were analysed for right ventricular hypertrophy and pulmonary arterial vascular remodelling. Treatment with antagomiR-20a enhanced the expression levels of BMPR2 in lung tissues; moreover, antagomiR-20a significantly reduced wall thickness and luminal occlusion of small pulmonary arteries and reduced right ventricular hypertrophy. To assess BMPR2 signalling and proliferation, we performed in vitro experiments with human pulmonary arterial smooth muscle cells (HPASMCs). Transfection of HPASMCs with antagomiR-20a resulted in activation of downstream targets of BMPR2 showing increased activation of Id-1 and Id-2. Proliferation of HPASMCs was found to be reduced upon transfection with antagomiR-20a. Conclusion This is the first report showing that miR-20a can be specifically targeted in an in vivo model for pulmonary hypertension. Our data emphasize that treatment with antagomiR-20a restores functional levels of BMPR2 in pulmonary arteries and prevents the development of vascular remodelling

Background. Until recently, cytomegalovirus (CMV) infection represented a major threat to lung transplant recipients. Preliminary studies have shown that antiviral prophylaxis might improve the outcome for these patients. Methods. We extended our initial pilot trial of prolonged prophylaxis with either oral ganciclovir (1 g 3 times per day) or valganciclovir (450 mg twice per day). The trial included 96 patients who were at risk for CMV-related events. Results. CMV prophylaxis resulted in a significant decrease in CMV-related events (i.e., active infection and disease), from 75% in a control group and for 274 cases from the literature who did not receive prophylaxis to a cumulative incidence of 27% (P<.001). Only 11% of the prophylaxis recipients experienced CMV disease (P<.001). Moreover, at 5 years, there was a significant decrease in the rate of bronchiolitis obliterans syndrome, from 60% to 43% (P=.002), and an improved rate of survival, from 47% to 73% (P=.036), irrespective of the immunosuppressive regimen received. CMV strains with UL97 mutations were recovered from 7 of 12 analyzed cases, but the presence of this mutation had no impact on the severity of CMV disease. Conclusions. A regimen of prolonged ganciclovir or valganciclovir prophylaxis decreased the rate of active CMV infection and disease, reduced the incidence of bronchiolitis obliterans syndrome, and improved the survival rate. Drug-resistant CMV strains may occur, but such strains appeared to have no impact on the outcome of CMV-related events

Infectious complications are still a significant cause of morbidity and death in solid-organ transplant patients, with significant infection being found in up to two-thirds of these individuals. The risk of infection in the organ transplant patient, particularly of opportunistic infection, is largely determined by 3 factors: the net state of immunosuppression, the epidemiologic exposures the patient encounters, and the consequences of the invasive procedures to which the patient is subjected. The most important principles of patient treatment are prevention, early diagnosis, and specific therapy. This issue is designed as a position paper by a group of experts on epidemiology, prevention, diagnosis, and management of infections in solid-organ transplant patients. We feel that our efforts may serve as an important first step in the development of guidelines in this area

Cytomegalovirus (CMV) continues to be a cause of substantial morbidity and death after solid-organ transplantation. There are 3 major consequences of CMV infection: CMV disease, including a wide range of clinical illnesses; superinfection with opportunistic pathogens; and injury to the transplanted organ, possibly enhancing chronic rejection. This article discusses the considerable progress that has been made in elucidating risk factors for CMV disease, in the rapid detection of CMV in clinical specimens, and in the use of antiviral chemotherapy and immunoglobulin to prevent and treat CMV disease after solid-organ transplantation

This study aimed to assess the long-term course of pulmonary arterial hypertension related to infection with human immunodeficiency virus (PAHRH) and the influence of antiretroviral therapy (ART) on its characteristics. We retrospectively analyzed all 47 patients in the Swiss HIV Cohort Study in whom PAHRH was diagnosed. Among 35 patients who underwent follow-up Doppler echocardiography, the right ventricular systolic pressure over right atrial pressure gradient increased by a median of 25 mm Hg in 9 patients who had not received ART, decreased by a median of 3 mm Hg in 12 patients who had received nucleoside analogs, and decreased by a median of 21 mm Hg in 14 patients who had received highly active ART (HAART) (P < .005). Among all 47 patients, median duration of survival after PAHRH diagnosis was 2.7 years. HAART significantly decreased mortality due to PAHRH as well as other causes. This study suggests a beneficial effect of combination ART in patients with PAHRH

Objectives: Single lung transplantation is a viable option for patients with end-stage pulmonary disease; despite encouraging results, we observed serious complications arising in the native lung. We retrospectively reviewed 36 single lung transplants to evaluate the incidence of complications arising in the native lung, their treatment and outcome. Methods: Between 1991 and 1997, 35 patients received 36 single lung transplants for emphysema (16), pulmonary fibrosis (14), lymphangioleiomyomatosis (4), primary pulmonary hypertension (1) and bronchiolitis obliterans (1). The clinical records were reviewed and the complications related to the native lung were divided into early (up to 6 weeks after the transplant) and late complications. Results: Nineteen complications occurred in 18 patients (50%), leading to death in nine (25%). Early complications (within 6 weeks from the transplant) were bacterial pneumonia (1), overinflation (3), retention of secretions with bronchial obstruction and atelectasis (1), hemothorax (1), pneumothorax (1) and invasive aspergillosis (3); one patient showed active tuberculosis at the time of transplantation. Two patients developed bacterial pneumonia and invasive aspergillosis leading to sepsis and death. The other complications were treated with separate lung ventilation (1), bronchoscopic clearance (1), chest tube drainage (1) and wedge resection and pleurodesis (mechanical) by VATS (1). One patient with hyperinflation of the native lung eventually required pneumonectomy and died of sepsis. The patient with active tuberculosis is alive and well after 9 months of medical treatment. Late complications were recurrent pneumothorax (4), progressive overinflation with functional deterioration (2), aspergillosis (1) and pulmonary nocardiosis (1). Recurrent pneumothorax was treated with chest tube drainage alone (1), thoracoscopic wedge resection and/or pleurodesis (2) and pneumonectomy (1); hyperinflation was treated with thoracoscopic lung vo

Aim Sleep-disturbed breathing (SDB) is common in pre-capillary pulmonary hypertension (PH) and impairs daytime performance. In lack of proven effective treatments, we tested whether nocturnal oxygen therapy (NOT) or acetazolamide improve exercise performance and quality of life in patients with pre-capillary PH and SDB. Methods This was a randomized, placebo-controlled, double-blind, three period cross-over trial. Participants received NOT (3 L/min), acetazolamide tablets (2 × 250 mg), and sham-NOT/placebo tablets each during 1 week with 1-week washout between treatment periods. Twenty-three patients, 16 with pulmonary arterial PH, 7 with chronic thromboembolic PH, and with SDB defined as mean nocturnal oxygen saturation <90% or oxygen saturation dips >10 h−1 with daytime PaO2 ≥7.3 kPa participated. Assessments at the end of the treatment periods included a 6 min walk distance (MWD), SF-36 quality of life, polysomnography, and echocardiography. Results Medians (quartiles) of the 6 MWD after NOT, acetazolamide, and placebo were 480 m (390;528), 440 m (368;468), and 454 m (367;510), respectively, mean differences: NOT vs. placebo +25 m (95% CI 3-46, P= 0.027), acetazolamide vs. placebo −9 m (−34-17, P = 0.223), and NOT vs. acetazolamide +33 (12-45, P < 0.001). SF-36 quality of life was similar with all treatments. Nocturnal oxygen saturation significantly improved with both NOT and acetazolamide. Right ventricular fractional area change was greater on NOT compared with placebo (P = 0.042) and acetazolamide (P = 0.027). Conclusions In patients with pre-capillary PH and SDB on optimized pharmacological therapy, NOT improved the 6 MWD compared with placebo already after 1 week along with improvements in SDB and haemodynamics. ClinicalTrials.gov NTC01427192

Objective: The aim of this study was to delineate the profile of extended donor lungs in comparison to ideal donor lungs and to analyse their outcome. Particular attention was given to donor lungs with a low PaO2 (≪250mmHg) before harvesting or with multiple extended criteria. Methods: Between 1993 and 2003, 148 patients (79 women, 69 men, mean age 39.9 years) underwent lung transplantation. Indications were cystic fibrosis in 35.8%, emphysema in 26.4%, pulmonary fibrosis in 12.2%, pulmonary hypertension in 9.5%, and others in 16.1%. Donor data and recipients medical files were reviewed. Criteria for donor lungs were considered extended if one or more of the following criteria were met: age ≫55 years, smoking ≫20 pack-years, PaO2 before harvesting ≪300mmHg, pathologic chest X-ray, and purulent secretion at bronchoscopy. A comparison between recipients from ideal and from extended donor lungs was performed with respect to the median duration of mechanical ventilation, the median length of stay at the intensive care unit, postoperative complications, the 30-day and the 1-year survival, and the 6-month follow-up spirometry. Results: Sixty-three (42.6%) donor lungs were considered extended and 20 (31.7%) met more than one criteria. Outcome comparison between recipients from ideal (I) and extended (II) donor lungs did not statistically differ in postoperative complications (18.8% (I) vs. 26.9% (II), P=0.32), mean duration of mechanical ventilation (d) (4.4±2.7 (I) vs. 2.6±2.1 (II), P=0.2), mean length of stay at the ICU (d) (11.5±8.8 (I) vs. 9.2±6.9 (II), P=0.4), 6-month pulmonary function (FEV1=83±23% of the predicted value (I) vs. 82±18% (II), P=0.81), 30-day survival (90.6% (I) vs. 93.7% (II), P=0.56), 1-year survival (83.5% (I) vs. 81% (II), P=0.83). Thirty-day survival was also comparable even in recipients from donor lungs with PaO2≪250mmHg (n=8) (90.6% (I) vs. 87.5%, P=0.57). The number of extended criteria had no impact on the outcome. The combination of PaO2≪300

Lung transplantation has become an accepted treatment for end-stage pulmonary parenchymal and vascular diseases. Infections still are the most common cause of early and late morbidity and mortality in lung transplant recipients. Bacterial infections comprise approximately half of all infectious complications. Cytomegalovirus (CMV) infections and disease have become less frequent, because of prophylaxis with ganciclovir. Because CMV is also involved in the pathogenesis of obliterative bronchiolitis, the frequency of this infection may also reduce the occurrence of this main obstacle to successful lung transplantation. Invasive fungal infections remain a problem, but they have also decreased in frequency because of better control of risk factors such as CMV disease and preemptive antifungal therapy. Nonherpes respiratory viral infections have emerged as a serious problem. Their severity may be reduced by treatment with ribavirin. Meticulous postoperative surveillance, however, is still crucial for the management of lung transplant patients with respect to early detection and treatment of rejection and infection

BACKGROUND: Pulmonary hypertension (PH) leads to reduced health-related quality of life (HRQoL). OBJECTIVE: To investigate the prevalence and course of anxiety and depression and their association with HRQoL, disease severity and survival in PH. METHODS: 131 PH patients (91 pulmonary arterial, 30 chronic thromboembolic, 10 due to lung disease; 84 female, 47 male) had repeated assessments with the Hospital Anxiety and Depression Scale (HADS), HRQoL, six-minute walk distance and WHO functional class during a mean course of 16 ± 12 months. RESULTS: Among the 49 incident and 82 prevalent PH patients, the HADS score was positive in 53%/21% (depression), 51%/24% (anxiety) and 63%/26% (total score) (all p < 0.05). The HADS score was improved at the second assessment in incident patients. The HADS score correlated with HRQoL at all consecutive assessments and with functional class until the third assessment, but not with baseline hemodynamics, age or gender. CONCLUSION: Mood disorders remain underdiagnosed in PH. The higher prevalence of anxiety/depression in incident versus prevalent patients and the improvement over time may indicate an amelioration of mood disorders after PH diagnosis and treatment.

Pulmonary capillary hemangiomatosis (PCH) is a rare histological substrate within the spectrum of pulmonary arterial hypertension that possibly represents an unusual manifestation of pulmonary veno-occlusive disease (PVOD). One of the histological hallmarks of PCH is the proliferation of pulmonary capillaries in the alveolar septa that infiltrate adjacent structures such as bronchioles, vessels, and visceral pleura. The hyperplastic process involving the smallest vessels of the pulmonary vascular bed might reflect uncontrolled angiogenesis, but whether this vascular proliferation is idiopathic or, conversely, a reactive process remains to be elucidated. Here we discuss the pathogenesis of PCH exemplified by the first reported case of a young patient with repaired scimitar syndrome that developed unilateral PCH.