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Rationale: Prone positioning as a complement to oxygen therapy to treat hypoxemia in coronavirus disease (COVID-19) pneumonia in spontaneously breathing patients has been widely adopted, despite a lack of evidence for its benefit. Objectives: To test the hypothesis that a simple incentive to self-prone for a maximum of 12 h per day would decrease oxygen needs in patients admitted to the ward for COVID-19 pneumonia on low-flow oxygen therapy. Methods: Twenty-seven patients with confirmed COVID-19 pneumonia admitted to Geneva University Hospitals were included in the study. Ten patients were randomised to self-prone positioning and 17 to usual care. Measurements and Main Results: Oxygen needs assessed by oxygen flow on nasal cannula at inclusion were similar between groups. Twenty-four hours after starting the intervention, the median oxygen flow was 1·0 L/min (interquartile range, 0·1-2·9) in the prone position group and 2·0 L/min (interquartile range, 0·5-3·0) in the control group (P = 0·507). Median oxygen saturation/fraction of inspired oxygen ratio was 390 (interquartile range, 300-432) in the prone position group and 336 (interquartile range, 294-422) in the control group (P = 0·633). One patient from the intervention group who did not self-prone was transferred to the high-dependency unit. Self-prone positioning was easy to implement. The intervention was well tolerated and only mild side-effects were reported. Conclusions: Self-prone positioning in patients with COVID-19 pneumonia requiring low-flow oxygen therapy resulted in a clinically meaningful reduction of oxygen flow, but without reaching statistical significance. Trial Registration: The study was registered on the Swiss National Clinical Trial portal (SNCTP000003718). Funding Statement: None. Declaration of Interests: None. Ethics Approval Statement: The institutional ethics review committee approved the trial (CCER 2020-00705). All participants provided written informed consent before screening.

Background Noninvasive ventilation (NIV) is standard of care for chronic hypercapnic respiratory failure, but indications, devices, and ventilatory modes are in constant evolution. Research Question To describe changes in prevalence and indications for NIV over a 15-year period; to provide a comprehensive report of characteristics of the population treated (age, comorbidities, and anthropometric data), mode of implementation and follow-up, devices, modes and settings used, physiological data, compliance, and data from ventilator software. Study Design and Methods Cross-sectional observational study designed to include all subjects under NIV followed by all structures involved in NIV in the Cantons of Geneva and Vaud (1,288,378 inhabitants). Results A total of 489 patients under NIV were included. Prevalence increased 2.5-fold since 2000 reaching 38 per 100,000 inhabitants. Median age was 71 years, with 31% being > 75 years of age. Patients had been under NIV for a median of 39 months and had an average of 3 ± 1.8 comorbidities; 55% were obese. COPD (including overlap syndrome) was the most important patient group, followed by obesity hypoventilation syndrome (OHS) (26%). Daytime Pa co 2 was most often normalized. Adherence to treatment was satisfactory, with 8% only using their device Interpretation Use of NIV is increasing rapidly in this area, and the population treated is aging, comorbid, and frequently obese. COPD is presently the leading indication followed by OHS. Trial Registry ClinicalTrials.gov; No.: NCT04054570; URL: www.clinicaltrials.gov

Background: Lung ultrasound (LUS) has a good performance with a high sensitivity and specificity for the diagnosis of pneumonia compared with chest X-ray, and it has been extensively used to assess patients during the COVID-19 pandemic. This study aims to evaluate the potential advantages of the regular use of LUS for the assessment of the severity and prognosis of COVID-19 pneumonia and to propose an adapted protocol with its inclusion in current local validated and published guidelines.Methods: This is a single-center prospective study conducted during the first (April–May 2020) and second (October 2020–January 2021) waves of the SARS-CoV2 pandemic in Switzerland. All adult patients presenting to dedicated test centers with a suspicion of mild-to-moderate COVID-19 pneumonia and not requiring hospitalization at the time of diagnosis were included. Patients with confirmed COVID-19 pneumonia were referred to an ambulatory follow-up unit at our institution for reassessment, with the inclusion of the use of LUS in a random selection. Descriptive statistics were calculated for demographics using percentages, means, and standard deviations according to the distribution of variables.Results: Eighty-eight ambulatory patients with a confirmed COVID-19 pneumonia were included (men = 57 [59%]; mean age, 52.1 ± 13.5 years). Among these, 19 (21%) were hospitalized and none died. Twenty-five lung assessments by ultrasound were performed during the follow-up consultation. All were consistent with the clinical examination and confirmed the clinician's opinion.Conclusion: The use of a standardized pleuro-pulmonary ultrasound protocol for ambulatory patients with COVID-19 could help to reduce the use of chest X-rays and improve overall management at the time of referral and eventual follow-up. However, a specific study including LUS in a systematic approach should be performed to evaluate the outcome of patients according to findings.

The pathophysiology and management of primary spontaneous pneumothorax (PSP) are a subject of debate. Despite advances in the understanding of its etiopathogenesis and improvements in its management, implementation in clinical practice is suboptimal. In this manuscript, we review the recent literature with a focus on PSP pathophysiology and management. Blebs and emphysema-like changes (ELC) are thought to contribute to the pathophysiology of PSP but cannot explain all cases. Recent studies emphasize the role of a diffuse porosity of the visceral pleura. Others found a relationship between smoking, occurrence of a PSP and bronchiolitis, which could be the initial pathological process leading to ELC development. Recent or ongoing studies challenge the need to systematically remove air from the pleural cavity of stable patients, introducing conservative management as a valuable therapeutic option. Evidence is growing in favour of needle aspiration instead of chest tube insertion, when air evacuation is needed. In addition, ambulatory management is considered as a successful approach in meta-analyses and is under exploration in a large randomized study. Because of a high recurrence rate of PSP, the benefit of performing a pleurodesis at first occurrence is under evaluation with interesting but not generalizable results. Better identification of 'at risk patients' is needed to improve the investigation strategy. Finally, recent publications confirm the efficacy, security and cost-effectiveness of graded talc poudrage pleurodesis to prevent PSP recurrence. In conclusion, PSP pathophysiology and management are still under investigation. The results of recently published and ongoing studies should be more widely implemented in clinical practice.

Obesity has complex links to respiratory health. Mendelian randomization (MR) enables assessment of causality of body mass index (BMI) effects on airflow obstruction and mid-expiratory flow. In the adult SAPALDIA cohort, recruiting 9,651 population-representative samples aged 18–60 years at baseline (female 51%), BMI and the ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC) as well as forced mid-expiratory flow (FEF25–75%) were measured three times over 20 follow-up years. The causal effects of BMI in childhood and adulthood on FEV1/FVC and FEF25–75% were assessed in predictive (BMI averaged over 1st and 2nd, lung function (LF) averaged over 2nd and 3rd follow-up; N = 2,850) and long-term cross-sectional models (BMI and LF averaged over all follow-ups; N = 2,728) by Mendelian Randomization analyses with the use of weighted BMI allele score as an instrument variable and two-stage least squares (2SLS) method. Three different BMI allele scores were applied to specifically capture the part of BMI in adulthood that likely reflects tracking of genetically determined BMI in childhood. The main causal effects were derived from models containing BMI (instrumented by BMI genetic score), age, sex, height, and packyears smoked as covariates. BMI interactions were instrumented by the product of the instrument (BMI genetic score) and the relevant concomitant variable. Causal effects of BMI on FEV1/FVC and FEF25–75% were observed in both the predictive and long-term cross-sectional models. The causal BMI- LF effects were negative and attenuated with increasing age, and stronger if instrumented by gene scores associated with childhood BMI. This non-standard MR approach interrogating causal effects of multiplicative interaction suggests that the genetically rooted part of BMI patterns in childhood may be of particular relevance for the level of small airway function and airflow obstruction later in life. The methodological relevance of the results is first to point to the importance of a life course perspective in studies on the etiological role of BMI in respiratory health, and second to point out novel methodological aspects to be considered in future MR studies on the causal effects of obesity related phenotypes.

Introduction and Objectives Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-associated pneumonia is associated with severe hypoxemic respiratory failure requiring treatment in intensive care units (ICUs) in approximately 5-10% of hospitalized patients Lung protective mechanical ventilation and intermittent prone positioning are standard care and evidence-based strategies in the management of severe acute respiratory distress syndrome These strategies are presented in Surviving Sepsis Campaign guidelines for the management of critically-ill adults with coronavirus disease (COVID-19) Prone positioning as a complement to oxygen therapy to treat hypoxemia in COVID-19 pneumonia in spontaneously breathing patients has been widely adopted, despite a lack of evidence for its benefit The objective of this single-center, cluster-randomised controlled trial is to test the hypothesis that a simple incentive to self-prone would decrease oxygen needs in patients admitted to the ward for COVID-19 pneumonia on low-flow oxygen therapy Methods Twenty-seven patients with confirmed COVID-19 pneumonia admitted to our University Hospital medical ward were included in the study Ten patients were randomised to self-prone positioning and 17 to usual care Main Results Oxygen needs assessed by oxygen flow on nasal cannula at inclusion were similar between groups Twenty-four hours after starting the intervention, the median oxygen flow was 1 0 L/min (interquartile range, 0 1-2 9) in the prone position group and 2 0 L/min (interquartile range, 0 5-3 0) in the control group (P = 0 507) (figure 1) Median oxygen saturation/fraction of inspired oxygen ratio was 390 (interquartile range, 300-432) in the prone position group and 336 (interquartile range, 294-422) in the control group (P = 0 633) No serious adverse events were observed Conclusions Self-prone positioning in patients with COVID-19 pneumonia requiring low-flow oxygen therapy resulted in a clinically meaningful reduction of oxygen flow, without reaching statistical significance Early interruption of the trial after the first wave most probably resulted in underpower of our study Self-prone positioning was easy to implement and well tolerated Given the rapid increase of cases during the COVID-19 pandemic, any simple intervention to limit the progression of hypoxemia and avoid transfers of patients to ICUs may be of benefit for the management of hospital resources

Background The symptomatic response to continuous positive airway pressure (CPAP) therapy in COPD-obstructive sleep apnea overlap syndrome (OVS) compared to OSA syndrome (OSA) alone has not been well studied so far. The aim of this study is to explore main differences in the clinical response to CPAP treatment in OVS compared to OSA alone. Study design and methods Using prospective data from the French National Sleep Apnea Registry, we conducted an observational study among 6320 patients with moderate-to-severe OSA, available spirometry, and at least one follow-up visit under CPAP therapy. Results CPAP efficacy measured on the residual apnea-hypopnea index and median adherence were similar between OVS and OSA patients. In both groups, the overall burden of symptoms related to sleep apnea improved with CPAP treatment. In a multivariable model adjusted for age, gender, body mass index, adherence to treatment and residual apnea-hypopnea index, OVS was associated with higher odds for persistent morning headaches (OR: 1.37 [95% CI; 1.04; 1.79]; P = 0.02), morning tiredness (OR: 1.33 [95% CI: 1.12; 1.59]; P Interpretation CPAP therapy was effective in normalizing the apnea-hypopnea index and significantly improved OSA-related symptoms, regardless of COPD status. CPAP should be offered to patients with OVS on a trial basis as a significant improvement in OSA-related symptoms can be expected, although the range of response may be less dramatic than in OSA alone.

BackgroundMore advanced knowledge is needed on how COPD alters the clinical presentation of obstructive sleep apnea (OSA) and how the association of both diseases, known as 'overlap syndrome' (OVS), impacts on cardiovascular health.ObjectiveTo investigate differences between patients with OVS and those with moderate-to-severe OSA alone.MethodsA cross-sectional study conducted in the French National Sleep Apnea Registry between January 1997 and January 2017. Univariable and multivariable logistic regression models were used to compare OVS versus OSA alone on symptoms and cardiovascular health.Results46,786 patients had moderate-to-severe OSA. Valid spirometry was available for 16,466 patients: 14,368 (87%) had moderate-to-severe OSA alone and 2098 (13%) had OVS. A lower proportion of OVS patients complained of snoring, morning headaches and excessive daytime sleepiness compared to OSA alone (median Epworth Sleepiness Scale score: 9 [interquartile range (IQR) 6-13] versus 10 (IQR 6-13), respectively; P ConclusionsIn adults with moderate-to-severe OSA, OVS was minimally symptomatic, but exhibited higher odds for prevalent coronary heart disease, heart failure and peripheral arteriopathy.

BACKGROUND Barriers and motives towards physical activity (PA) in lung transplant (LTx) recipients with cystic fibrosis (CF) are largely unknown. We aimed to explore perceptions towards PA in LTx recipients with CF to better understand individuals' needs and preferences. METHODS Participants completed an online survey at two Swiss LTx and one follow-up shared care centre between June and December 2018. RESULTS One hundred and eleven individuals completed the survey (87.4% response rate). Overall, survey participants perceive PA as important for their daily life and health. Perceived motives of PA were improving muscle strength, endurance and quality of life (QoL), to feel better, fun, to achieve personal goals and having more energy for everyday life. Fatigue was the most common perceived barrier to PA and associated with poorer QoL (r = -0.43, p

Background. Pulmonary alveolar proteinosis (PAP) is a pulmonary disease characterized by disruption of surfactant homeostasis resulting in its accumulation in the alveoli. PAP is classically classified into three categories (Table 1): 1/primary (or autoimmune) with antibodies targeting the GM-CSF pathway, 2/secondary to another disease, typically a hematologic malignancy, and 3/genetic. Case-report. A 30 year-old woman received an allogenic hematopoietic stem cell transplantation (HSCT) after treatment for acute myeloid leukemia (AML). Within the first 6 months post HSCT, she developed an ocular, oral, digestive and hepatic graft-versus-host disease associated with a mixed ventilatory defect with a very severe obstructive syndrome and a severe CO diffusion impairment. High resolution computed tomography showed a classical “crazy paving” pattern. Aspect and differential cell count of BAL were normal. All microbiological samples remained culture negative. Histo-pathological analysis of transbronchial biopsies was unremarkable. Because of the severity of the respiratory insufficiency, open-lung biopsy (OBL) could not be performed. Despite multiple immunosuppressive therapies, lung function deteriorated rapidly; the patient also developed an excavated fungal lesion unresponsive to treatment. She underwent a bilateral lung transplant 48 months after HSCT. Histo-pathological analysis of explanted lungs showed obliterative bronchiolitis (OB), diffuse PAP and invasive cavitary pulmonary aspergillosis. Conclusions. This case illustrates the simultaneous occurrence of OB, PAP and a fungal infection in a 30-year old female patient who underwent HSCT for acute myeloid leukemia (AML). To our knowledge this is the only documented case of PAP associated with OB treated by lung transplantation., Highlights • PAP is characterized by disruption of surfactant homeostasis resulting in its accumulation in the alveoli. • Secondary PAP represent less than 10 % of all cases, hematologic disorders account for the majority of them. • Bronchoalveolar-lavage can establish diagnosis in 75% of cases however lung biopsy remains thegold standard. • There is no specific treatment, whole-lung lavage remains the standard of care. • This case illustrates the simultaneous occurrence of OB, PAP and invasive pulmonary aspergillosis treated by BLT.

Pulmonary hypertension (PH) is a haemodynamic syndrome defined by a mean pulmonary arterial pressure (mPAP) >25 mmHg determined by right heart catheterisation (RHC) [1, 2]. A lot of ­diseases fulfil this definition, but they differ widely between each other in respect to their pathophysiology, their haemodynamic characteristics, their clinical presentation, their natural prognosis and their potential therapeutic strategies. The current guidelines on PH diagnosis and management make the distinction between five groups of more than 200 causes of PH [2], but these diseases are very different from one another. In the current classification, the first group (group 1) represents a progressive vasculopathy leading to pre-capillary PH called pulmonary arterial hypertension (PAH), characterised by a characteristic small-calibre pulmonary artery remodelling, as a result of proliferation of endothelial and smooth muscle cells as well as medial hypertrophy. So, if we compare PAH (for example idiopathic PAH) from PH due to valvular disease like mitral insufficiency (group 2.3) it is easy to understand that apart from the fact that mean pulmonary arterial pressure (mPAP) exceeds 25 mmHg in both cases, these two entities have very different pathophysiological pathways. In the first case, there is a true pulmonary vasculopathy. In the second, PH is mainly related to the consequences of an increased hydrostatic pressure in the left atrium ­transmitted to the venous compartment of the pulmonary circulation and then back through the capillary bed. If the pathophysiology of these entities is different, the targets of their treatments are too. The main goal of PAH treatment consists in reducing pulmonary vascular resistance (PVR) with specific medication and, when appropriate, with specific treatment of the underlying disease as it is the case for associated-PAH (group 1.4). Alternatively, the management of PH related to a mitral regurgitation would be to improve the ventricular preload, diminish the ventricular afterload and, if necessary, to correct the anatomical anomaly., The distinction between PH in the elderly and normal ageing might make diagnosis difficult http://ow.ly/YYF1Q

New Onset Diabetes after Transplantation (NODAT) is a frequent complication after solid organ transplantation, with higher incidence during the first year. Several clinical and genetic factors have been described as risk factors of Type 2 Diabetes (T2DM). Additionally, T2DM shares some genetic factors with NODAT. We investigated if three genetic risk scores (w-GRS) and clinical factors were associated with NODAT and how they predicted NODAT development 1 year after transplantation. In both main (n = 725) and replication (n = 156) samples the clinical risk score was significantly associated with NODAT (ORmain: 1.60 [1.36-1.90], p = 3.72*10-8 and ORreplication: 2.14 [1.39-3.41], p = 0.0008, respectively). Two w-GRS were significantly associated with NODAT in the main sample (ORw-GRS 2:1.09 [1.04-1.15], p = 0.001 and ORw-GRS 3:1.14 [1.01-1.29], p = 0.03) and a similar ORw-GRS 2 was found in the replication sample, although it did not reach significance probably due to a power issue. Despite the low OR of w-GRS on NODAT compared to clinical covariates, when integrating w-GRS 2 and w-GRS 3 in the clinical model, the Area under the Receiver Operating Characteristics curve (AUROC), specificity, sensitivity and accuracy were 0.69, 0.71, 0.58 and 0.68, respectively, with significant Likelihood Ratio test discrimination index (p-value 0.0004), performing better in NODAT discrimination than the clinical model alone. Twenty-five patients needed to be genotyped in order to detect one misclassified case that would have developed NODAT 1 year after transplantation if using only clinical covariates. To our knowledge, this is the first study extensively examining genetic risk scores contributing to NODAT development.

The Swiss National Guidelines 2013 for chronic obstructive pulmonary disease have been revised in order to acknowledge recent progress in diagnosis and management of this disease. The resulting new Swiss recommendations are based on best evidence from the literature, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2018 report and other published national guidelines. Misdiagnosis of chronic obstructive pulmonary disease is common and means that patients do not always receive optimal treatment. To improve the management of patients with chronic obstructive pulmonary disease in Switzerland, these recommendations encourage a more comprehensive assessment of patients, based on the combined assessment of symptoms, degree of airflow limitation, risk of exacerbation and the presence of comorbidities. Recommendations for evidence-based preventive measures, as well as pharmacological and non-pharmacological strategies for the management of both stable and acute exacerbations of chronic obstructive pulmonary disease are provided in this update.

Background: Predicting outcome after index admission in the ICU for COPD-related acute hypercapnic respiratory failure (AHRF) is difficult. Simple tools to stratify this risk and to promote interventions to mitigate it are needed. Aim: To prospectively evaluate the ability of severe dyspnea (NYHAIII-IV) to predict hospital readmission or death in COPD patients surviving AHRF in the ICU. Methods: 50 consecutive COPD patients were recruited from a larger cohort of patients (n = 78) surviving AHRF in the ICU. All predictive variables were collected within 15 days after resolution of respiratory failure before hospital discharge. COPD was diagnosed by spirometry. Heart failure was diagnosed with clinical rules and echocardiography. NYHA was measured upon hospital discharge. Hospital readmission and death were recorded at regular intervals for 3 months. Results: 21/50 (42%) COPD patients died or were readmitted to the hospital during the observation period: 12 out of the 20 NYHA III-IV patients (60%) and 8 out of the 28 NYHA I-II patients (29%). NYHA III-IV was associated with risk of readmission or death (univariate HR: 2.73, IC95: 1.11-6.69, p = 0.028). After controlling for age, FEV1, heart failure and BMI, NYHA III-IV remained associated with readmission or death (multivariate HR: 2.71, IC95: 1.06-6.93, p = 0.038). Conclusions: Our findings suggest that severe dyspnea measured upon hospital discharge in COPD patients surviving AHRF can stratify patient's risk of 3-month readmission or death.

Rationale Acute hypercapnic respiratory failure (AHRF) treated with non-invasive ventilation in the ICU is frequently caused by chronic obstructive pulmonary disease (COPD) exacerbations and obesity-hypoventilation syndrome, the latter being most often associated with obstructive sleep apnea. Overlap syndrome (a combination of COPD and obstructive sleep apnea) may represent a major burden in this population, and specific diagnostic pathways are needed to improve its detection early after ICU discharge. Objectives To evaluate whether pulmonary function tests can identify a high probability of obstructive sleep apnea in AHRF survivors and outperform common screening questionnaires to identify the disorder. Methods Fifty-three patients surviving AHRF (31 males; median age 67 years (interquartile range: 62–74) participated in the study. Anthropometric data were recorded and body plethysmography was performed 15 days after ICU discharge. A sleep study was performed 3 months after ICU discharge. Results The apnea-hypopnea index was negatively associated with static hyperinflation as measured by the residual volume to total lung capacity ratio in the % of predicted (coefficient = -0.64; standard error 0.17; 95% CI -0.97 to -0.31; p

Complications following lung transplantation may impede allograft function and threaten patient survival. The five main complications after lung transplantation are primary graft dysfunction, post-surgical complications, alloimmune responses, infections, and malignancy. Primary graft dysfunction, a transient ischemic/reperfusion injury, appears as a pulmonary edema in almost every patient during the first three days post-surgery. Post-surgical dysfunction could be depicted on computed tomography (CT), such as bronchial anastomosis dehiscence, bronchial stenosis and bronchomalacia, pulmonary artery stenosis, and size mismatch. Alloimmune responses represent acute rejection or chronic lung allograft dysfunction (CLAD). CLAD has three different forms (bronchiolitis obliterans syndrome, restrictive allograft syndrome, acute fibrinoid organizing pneumonia) that could be differentiated on CT. Infections are different depending on their time of occurrence. The first post-operative month is mostly associated with bacterial and fungal pathogens. From the second to sixth months, viral pneumonias and fungal and parasitic opportunistic infections are more frequent. Different patterns according to the type of infection exist on CT. Malignancy should be depicted and corresponded principally to post-transplantation lymphoproliferative disease (PTLD). In this review, we describe specific CT signs of these five main lung transplantation complications and their time of occurrence to improve diagnosis, follow-up, medical management, and to correlate these findings with pathology results. Key Points • The five main complications are primary graft dysfunction, surgical, alloimmune, infectious, and malignancy complications. • CT identifies anomalies in the setting of unspecific symptoms of lung transplantation complications. • Knowledge of the specific CT signs can allow a prompt diagnosis. • CT signs maximize the yield of bronchoscopy, transbronchial biopsy, and bronchoalveolar lavage. • Radiopathological correlation helps to understand CT signs after lung transplantation complications.

Metabolic syndrome after transplantation is a major concern following solid organ transplantation (SOT). The CREB-regulated transcription co-activator 2 (CRTC2) regulates glucose metabolism. The effect of CRTC2 polymorphisms on new-onset diabetes after transplantation (NODAT) was investigated in a discovery sample of SOT recipients (n1=197). Positive results were tested for replication in two samples from the Swiss Transplant Cohort Study (STCS, n2=1294 and n3=759). Obesity and other metabolic traits were also tested. Associations with metabolic traits in population-based samples (n4=46'186, n5=123'865, n6>100,000) were finally analyzed. In the discovery sample, CRTC2 rs8450-AA genotype was associated with NODAT, fasting blood glucose and body mass index (PcorrectedA was significantly associated with several metabolic abnormalities. CRTC2 rs8450G>A appears to have an important role in the high prevalence of metabolic traits observed in patients with SOT. A weak association with metabolic traits was also observed in the population-based samples.The Pharmacogenomics Journal advance online publication, 8 December 2015; doi:10.1038/tpj.2015.82.

Background: Cystic fibrosis-related diabetes (CFRD) is the most frequent extrapulmonary complication of cystic fibrosis (CF). Methods: We report the first combined pancreatic islet-lung-liver transplantation in a 14-year-old adolescent. CFTR was analyzed by Sanger sequencing. Further genes were analyzed by high-throughput sequencing. Results: The patient was diagnosed with CF at the age of 14 months. Nine years later, after diagnosis of CFRD, the patient’s BMI and lung function began to decline. Bilateral lung transplantation with simultaneous liver transplantation was performed at the age of 14.5 years. The first islet transplantation (IT) was carried out 10 days later. Six months later, C-peptide secretion after arginine stimulation showed peak values of 371 pmol/L (vs. 569 pmol/L before IT) and insulin doses had slightly increased (1.40 vs. 1.11 units/kg/day before IT). A second IT was performed at the age of 15 years, a third at 16 years. Two years after the first IT, arginine-stimulated C-peptide secretion increased to 2,956 pmol/L and insulin doses could be reduced to 0.82 units/kg/day. HbA1c decreased from 7.3% (57.4 mmol/mol) to 5.9% (41.0 mmol/mol). Conclusion: IT following lung and liver transplantation, with injection of islets into a transplanted organ, is feasible. It improves C-peptide secretion, decreases insulin needs, and lowers HbA1c.

We sought to assess the use of an electro pulmonary nodule (EPN) scanner (FreshMedx, Salt Lake City, UT) in the noninvasive characterization of pulmonary nodules using transcutaneous bioconductance.Monocentric prospective study including patients with a pulmonary nodule identified on a chest computed tomography scan. Study protocol approved by the institutional review board and written consent was obtained for every patient. 32 patients (12 females and 20 males), average age 65 years, and average lesion size 33.1 mm (range: 9-123 mm). Data collection by a trained physician, 62 skin surface measurements on the chest, arms, and hands bilaterally. Results were anonymized and mailed to a central data center for analysis and compared to histopathology.Pathology results obtained by percutaneous biopsy (n = 14), surgical biopsy (n = 1), or surgical resection (n = 17) showed 29 malignant lesions (adenocarcinoma n = 21, squamous cell carcinoma n = 5, typical carcinoid n = 1, metastasis n = 2), and 3 benign lesions (necrotic granuloma n = 1, no malignant cells on biopsy n = 2). EPN scanner results had a specificity of 66.67% (95% confidence interval [CI] 0.09-0.99), sensitivity 72.41% (95% CI 0.53-0.87), positive predictive value 95.45% (95% CI 0.81-0.99), and a negative predictive value 20.00% (95% CI 0.08-0.40).This pilot study showed a high positive predictive value of the EPN scanner, allowing aggressive management of lung nodules characterized as malignant. The low negative predictive value warrants further investigation of nodules that are characterized as benign.

New-onset diabetes mellitus after transplantation (NODAT) is a complication following solid organ transplantation (SOT) and may be related to immune or inflammatory responses. We investigated whether single nucleotide polymorphisms (SNPs) within 158 immune- or inflammation-related genes contribute to NODAT in SOT recipients. The association between 263 SNPs and NODAT was investigated in a discovery sample of SOT recipients from the Swiss Transplant Cohort Study (STCS, n 1 = 696). Positive results were tested in a first STCS replication sample (n 2 = 489) and SNPs remaining significant after multiple test corrections were tested in a second SOT replication sample (n 3 = 156). Associations with diabetic traits were further tested in several large general population-based samples (n > 480 000). Only SP110 rs2114592C>T remained associated with NODAT in the STCS replication sample. Carriers of rs2114592-TT had 9.9 times (95% confidence interval [CI]: 3.22-30.5, P = .00006) higher risk for NODAT in the combined STCS samples (n = 1184). rs2114592C>T was further associated with NODAT in the second SOT sample (odds ratio: 4.8, 95% CI: 1.55-14.6, P = .006). On the other hand, SP110 rs2114592C>T was not associated with diabetic traits in population-based samples, suggesting a specific gene-environment interaction, possibly due to the use of specific medications (ie, immunosuppressants) in transplant patients and/or to the illness that may unmask the gene effect.

Introduction: Feature tracking is a new technique allowing measurement of right ventricular strains and strain rates from magnetic resonance imaging (MRI), based on the detection of image pattern motion during the cardiac cycle. This present work uses feature tracking MRI to investigate the modification of the right ventricle diastolic function in Chronic Thromboembolic Pulmonary Hypertension (CTEPH). Methods: Thirteen patients with CTEPH were assessed by right heart catheterization (RHC) and cardiac MRI, including standard cine acquisitions. Global right ventricular longitudinal, circumferential and radial strain and strain rates were correlated with the mean pulmonary artery pressure (mPAP). Systolic, E and A decelerations (corresponding to the early diastolic filling and to the atrial contraction) were measured from the descending slopes of the global longitudinal strain rates (in %.ms-2) (Figure). Results: The mPAP was 30.3±15.2mmHg. Feature tracking was successful in all the patients, but in 2 patients, it was not possible to separate the E and A waves. Peak diastolic circumferential strain rate (R2=0.58, p=0.01) and the E deceleration (R2=0.48, p=0.03) but not systolic strain indices were significantly correlated with mPAP. Conclusion: The correlation between the RV diastolic function and the mPAP in CTEPH patients could reflect subclinical compensatory hypertrophy of the RV wall following chronic pressure overload. This suggests a strong potential of feature tracking MRI to diagnose and monitor patients with pulmonary hypertension.

Purpose.Cardiac output (CO) is a cornerstone parameter in precapillary pulmonary hypertension (PH). The Modelflow (MF) method offers a reliable noninvasive determination of its beat-by-beat changes. So MF allows exploration of CO adjustment with the best temporal resolution.Methods.Fifteen subjects (5 PH patients, 10 healthy controls) performed a submaximal supine exercise on a cycle ergometer after 5 min of rest. CO was continuously determined by MF (COMF). Kinetics of heart rate (HR), stroke volume (SV), and CO were determined with 3 monoexponential models.Results.In PH patients, we observed a sudden and transitory drop of SV upon exercise onset. This implied a transitory drop of CO whose adjustment to a new steady state depended on HR increase. The kinetics of HR and CO for PH patients was slower than that of controls for all models and for SV in model 1. SV kinetics was faster for PH patients in models 2 and 3.Conclusion.This is the first description of beat-by-beat cardiovascular adjustments upon exercise onset in PH. The kinetics of HR and CO appeared slower than those of healthy controls and there was a transitory drop of CO upon exercise onset in PH due to a sudden drop of SV.

Dual-energy computed tomography (DECT) angiography of the chest provides a combined morphological and functional analysis of the lung, usually obtained in a single acquisition without extra radiation or injection of extra intravenous iodine contrast. The parenchymal iodine maps generated by DECT are well correlated with scintigraphy, and are becoming an essential tool for evaluating patients with pulmonary vascular diseases. With a single DECT acquisition, complete imaging of pulmonary hypertension is now available, displaying vascular anatomy, parenchymal morphology and functional assessment. Triangular pulmonary perfusion defects in chronic thromboembolic pulmonary hypertension may be clearly analysed even in the presence of distal arterial occlusion. Perfusion heterogeneities seen in patients with pulmonary arterial hypertension reflect mosaic perfusion and may be helpful for the diagnosis, severity assessment and prognosis of the disease. Vascular or parenchymal abnormalities can also be analysed with perfusion defects to determine their aetiology. Pulmonary arterial hypertension due to congenital heart disease can be assessed with a single DECT, even in the neonatal population. Furthermore, new applications are emerging with ventilation imaging or myocardial perfusion imaging obtained by DECT and should be considered. In conclusion, DECT of the thorax enables the simultaneous and noninvasive assessment of vascular anatomy, parenchymal morphology and functional pulmonary imaging in various groups of PH.

Lung transplant recipients present an increased risk for severe complications associated with respiratory infections. We conducted a review of the literature examining the clinical relationship between viral respiratory infection and graft complications. Thirty‐four studies describing the clinical impact of influenza, respiratory syncytial virus, parainfluenza, human metapneumovirus, rhinovirus, enterovirus, coronavirus, bocavirus or adenovirus were identified. The detection rate of respiratory viral infection ranged from 1.4% to 60%. Viruses were detected five times more frequently when respiratory symptoms were present [odds ratio (OR) = 4.97; 95% CI = 2.11–11.68]. Based on available observations, we could not observe an association between respiratory viral infection and acute rejection (OR = 1.35; 95% CI = 0.41–4.43). We found a pooled incidence of 18% (9/50) of bronchiolitis obliterans syndrome (BOS) in virus‐positive cases compared to 11.6% (37/319) in virus‐negative cases; however, limited number of BOS events did not allow to confirm the association. Our review confirms a causal relationship between respiratory viruses and respiratory symptoms, but cannot confirm a link between respiratory viruses and acute lung rejection. This is related in part to the heterogeneity and limitations of available studies. The link with BOS needs also to be reassessed in appropriate prospective studies., The authors find, through a review of the literature, a causal relationship between respiratory viral infections and respiratory symptoms among lung transplant recipients.

Background. Lung transplant recipients are frequently exposed to respiratory viruses and are particularly at risk for severe complications. The aim of this study was to assess the association among the presence of a respiratory virus detected by molecular assays in bronchoalveolar lavage (BAL) fluid, respiratory symptoms, and acute rejection in adult lung transplant recipients. Methods. Upper (nasopharyngeal swab) and lower (BAL) respiratory tract specimens from 77 lung transplant recipients enrolled in a cohort study and undergoing bronchoscopy with BAL and transbronchial biopsies were screened using 17 different polymerase chain reaction—based assays. Results. BAL fluid and biopsy specimens from 343 bronchoscopic procedures performed in 77 patients were analyzed. We also compared paired nasopharyngeal and BAL fluid specimens collected in a subgroup of 283 cases. The overall viral positivity rate was 29.3% in the upper respiratory tract specimens and 17.2% in the BAL samples (P < .001). We observed a significant association between the presence of respiratory symptoms and positive viral detection in the lower respiratory tract (P = .012). Conversely, acute rejection was not associated with the presence of viral infection (odds ratio, 0.41; 95% confidence interval, 0.20–0.88). The recovery of lung function was significantly slower when acute rejection and viral infection were both present. Conclusions. A temporal relationship exists between acute respiratory symptoms and positive viral nucleic acid detection in BAL fluid from lung transplant recipients. We provide evidence suggesting that respiratory viruses are not associated with acute graft rejection during the acute phase of infection.

Introduction: The use of extracorporeal membrane oxygenation (ECMO) is considered a risk factor for, or even a potential con- traindication to, lung transplantation. However, only a few pediatric cases have been described thus far. Case Presentation: A 9-year-old boy with idiopathic pulmonary arterial hypertension developed cardiac arrest after the insertion of a central catheter. ECMO was used as a bridge to lung transplantation. However, after prolonged resuscitation, he developed medullary ischemia and medullary syndrome. After 6 weeks of ECMO and triple combination therapy for pulmonary hypertension, including continuous intravenous prostacyclin, he was weaned off support, and after 2 weeks, bilateral lung transplantation was performed. At 4 years post-transplant, he has minimal problems. The medullary syndrome has also alleviated. He is now back to school and can walk with aids. Conclusions: Increasing evidence supports the use of ECMO as a bridge to LT, reporting good outcomes. In the modern era of PAH therapy, it is feasible to use prolonged ECMO support as a bridge to lung transplant, with the aim of weaning off this support; however, its use requires more experience and knowledge of long-term outcomes.

When right ventricular failure develops secondary to primary pulmonary hypertension, right-left ventricular interaction may lead to severe impairment of left ventricular function. In such cases, many experts favor combined heart-lung transplantation by fear that the left ventricle may not recover after transplantation of the lungs alone. We report a case of primary pulmonary hypertension with severely diminished right and left ventricular function. The patient was rendered amenable to isolated pulmonary transplantation with the endothelin-receptor antagonist bosentan. The medication improved right and left ventricular function to the point that heart transplantation no longer appeared necessary. After double-lung transplantation the patient's cardiac function made a full recovery. This approach might be particularly welcome considering both the current donor organ shortage and the limited number of surgical teams with expertise in heart-lung transplantation.

Background Cardiac output (CO) is a major diagnostic and prognostic factor in pre-capillary pulmonary hypertension (PH). Reference methods for CO determination, like thermodilution (TD), require invasive procedures and allow only steady-state measurements. The Modelflow (MF) method is an appealing technique for this purpose as it allows non-invasive and beat-by-beat determination of CO. Methods We aimed to compare CO values obtained simultaneously from non-invasive pulse wave analysis by MF (COMF) and by TD (COTD) to determine its precision and accuracy in pre-capillary PH. The study was performed on 50 patients with pulmonary arterial hypertension (PAH) or chronic thrombo-embolic PH (CTEPH). CO was determined at rest in all patients (n = 50) and during nitric oxide vasoreactivity test, fluid challenge or exercise (n = 48). Results Baseline COMF and COTD were 6.18 ± 1.95 and 5.46 ± 1.95 L·min-1, respectively. Accuracy and precision were 0.72 and 1.04 L·min-1, respectively. Limits of agreement (LoA) ranged from -1.32 to 2.76 L·min-1. Percentage error (PE) was ±35.7%. Overall sensitivity and specificity of COMF for directional change were 95.2% and 82.4%, (n = 48) and 93.3% and 100% for directional changes during exercise (n = 16), respectively. After application of a correction factor (1.17 ± 0.25), neither proportional nor fixed bias was found for subsequent CO determination (n = 48). Accuracy was -0.03 L·min−1 and precision 0.61 L·min−1. LoA ranged from -1.23 to 1.17 L·min−1 and PE was ±19.8%. Conclusions After correction against a reference method, MF is precise and accurate enough to determine absolute values and beat-by-beat relative changes of CO in pre-capillary PH.

Background Differentiating between acute rejection and cytomegalovirus (CMV) infection is one of the major challenges of lung transplantation. The aims of this study were to: (1) quantify the transcription of the cytotoxic T lymphocyte (CTL) effector molecules in the bronchoalveolar lavage (BAL) of lung transplant recipients and (2) evaluate the clinical usefulness of this technique. Methods Sixty-six single-lung, double-lung, or heart-lung transplant patients were prospectively enrolled in the study. BAL was performed either for routine surveillance or for acute graft dysfunction. RNA was extracted from BAL cell pellets and underwent competitive reverse transcription-assisted polymerase chain reaction (RT-PCR) for perforin, granzyme B, granulysin, and Fas ligand. Gene transcript analysis was compared to clinical diagnosis established by conventional methods [BAL microbiological and transbronchial biopsy (TBB) analyses]. Results After exclusion of several BAL according to the study criteria, 62 BAL were submitted for data analysis. Significantly higher expression of all the analyzed transcripts was found during CMV infection, compared with each of the other defined diagnostic categories, namely nonsignificant pathology, acute rejection, and nonviral pulmonary infection. Conclusion Quantification by competitive RT-PCR of the CTL effector molecule transcripts (perforin, granzyme B, granulysin, and Fas ligand) could represent a valuable tool for the differential diagnosis of graft dysfunction in lung transplantation.

Rationale: In the absence of active tuberculosis, a positive tuberculin skin test (TST) or interferon-gamma release assay (IGRA) result defines latent infection with Mycobacterium tuberculosis, although test results may vary depending on immunodeficiency. Objectives: This study compared the performance of TST and IGRAs in five different groups of immunocompromised patients, and evaluated their ability to identify those at risk for development of tuberculosis. Methods: Immunocompromised patients with HIV infection, chronic renal failure, rheumatoid arthritis, solid-organ or stem-cell transplantation, and healthy control subjects were evaluated head-to-head by the TST, QuantiFERON-TB-Gold in-tube test (ELISA), and T-SPOT. TB test (enzyme-linked immunospot) at 17 centers in 11 European countries. Development of tuberculosis was assessed during follow-up. Measurements and Main Results: Frequencies of positive test results varied from 8.7 to 15.9% in HIV infection (n = 768), 25.3 to 30.6% in chronic renal failure (n = 270), 25.0% to 37.2% in rheumatoid arthritis (n = 199), 9.0 to 20.0% in solid-organ transplant recipients (n = 197), 0% to 5.8% in stem-cell transplant recipients (n = 103), and 11.2 to 15.2% in immunocompetent control subjects (n = 211). Eleven patients (10 with HIV infection and one solid-organ transplant recipient) developed tuberculosis during a median follow-up of 1.8 (interquartile range, 0.2-3.0) years. Six of the 11 patients had a negative or indeterminate test result in all three tests at the time of screening. Tuberculosis incidence was generally low, but higher in HIV-infected individuals with a positive TST (3.25 cases per 100 person-years) than with a positive ELISA (1.31 cases per 100 person-years) or enzyme-linked immunospot result (1.78 cases per 100 person-years). No cases of tuberculosis occurred in patients who received preventive chemotherapy. Conclusions: Among immunocompromised patients evaluated in this study, progression toward tuberculosis was highest in HIV-infected individuals and was poorly predicted by TST or IGRAs.

Background: Electromagnetic navigation bronchoscopy (ENB) is an emerging endoscopic technique for the diagnosis of peripheral lung lesions. A thorough analysis of ENB's yield and safety is required for comparison to other sampling modalities. Objectives: To describe ENB's yield and safety profile. Methods: The MEDLINE and EMBASE databases were systematically searched for studies reporting ENB's yield for peripheral lung lesions. Two independent investigators extracted data and rated each study on a scale of methodological quality. Clearly defined performance outcomes were reconstructed and meta-analyzed. Subgroup analysis and meta-regression were used to identify possible sources of study heterogeneity. Results: A total of 15 trials were included (1,033 lung nodules). A positive and definitive diagnosis was obtained after 64.9% of all ENB procedures (95% CI 59.2-70.3). Overall diagnostic accuracy was 73.9% (95% CI 68.0-79.2). Sensitivity to detect cancer was 71.1% (95% CI 64.6-76.8), with a negative predictive value of 52.1% (95% CI 43.5-60.6). Pneumothorax occurred in 3.1% of patients, requiring chest tube drainage in 1.6% of these cases. Original trials identified 6 variables associated with higher ENB yields: nodule location in the upper or middle lobes, nodule size, lower registration error, presence of a bronchus sign on CT imaging, combined use of an ultrasonic radial probe, and catheter suctioning as a sampling technique. Heterogeneity exploration revealed that studies using general anesthesia or rapid on-site cytological evaluation reported better yields. Conclusions: ENB is effective and particularly safe. Prospective studies are needed to clarify the role of several variables conditioning the yield of this technique.

Important advances in non small cell lung cancer (NSCLC) diagnosis, staging and treatment have been made over the last decade. Minimally-invasive endoscopic techniques including endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) and navigational bronchoscopy have emerged as valid alternatives to transthoracic and/or surgical approaches, providing aspiration cytology material instead of histological material for diagnosis and staging of mediastinal and lung lesions. Several drugs designed to target molecular pathways involved in cancer-cell growth and survival have been shown to be effective in a selected fraction of NSCLC patients, mostly with adenocarcinoma (targeted therapy). Somatic activating mutations in several genes involved in those pathways (EGFR/KRAS) can predict patients’ responses to targeted therapies (individualized therapy). Those mutations are commonly detected in histopathological samples (core-needle biopsy/surgical resection). However, when histological tissues are not available, molecular testing can be performed on cytological specimens. This scenario is increasing in frequency, due to the use of less invasive procedure for diagnosis and staging such EBUS-TBNA and/or patients in advanced stage of disease who are not candidates for surgery. Several strategies exist and may be combined to ensure that the less abundant material that results from minimally invasive techniques can be used efficiently for molecular analyses. These include Rapid On-Site Evaluation (ROSE) of EBUS-TBNA cytological material, to ensure optimal sampling and triage of the material (e.g. cell-block preparation), and microdissection techniques, to select an adequate population of tumor cells. Major issues raised by cytological diagnosis of NSCLC and molecular testing on cytological specimen are discussed in this article.

BACKGROUND: Memory responses require immune competence. We assessed the influence of priming with AS03-adjuvanted pandemic vaccine (Pandemrix®) on memory responses of HIV patients, kidney recipients (SOT) and healthy controls (HC). METHOD: Participants (HIV: 197, SOT: 53; HC: 156) were enrolled in a prospective study and 390/406 (96%) completed it. All had been primed in 2009/2010 with 1 (HC) or 2 (patients) doses of Pandemrix®, and were boosted with the 2010/2011 seasonal influenza vaccine. Geometric mean titres and seroprotection rates were measured 12 months after priming and 4 weeks after boosting. Primary and memory responses were directly compared in 191 participants (HCW: 69, HIV: 71, SOT: 51) followed during 2 consecutive seasons. RESULTS: Most participants (HC: 77.8%, HIV: 77.6%, SOT: 66%) remained seroprotected at 12 months post-priming. Persisting A/09/H1N1 titers were high in HIV (100.2) and HC (120.1), but lower in SOT (61.4) patients. Memory responses reached higher titers in HIV (507.8) than in HC (253.5) and SOT (136.9) patients. Increasing age and lack of HAART reduced persisting and memory responses, mainly influenced by residual antibody titers. Comparing 2009/2010 and 2010/2011 titers in 191 participants followed for 2 seasons indicated lower post-2010/2011 titers in HC (240.2 vs 313.9), but higher titers in HIV (435.7 vs 338.0) and SOT (136 vs 90.3) patients. CONCLUSIONS: Priming with 2 doses of Pandemrix® elicited persistent antibody responses and even stronger memory responses to non-adjuvanted seasonal vaccine in HIV patients than 1 dose in healthy subjects. Adjuvanted influenza vaccines may improve memory responses of immunocompromised patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT01022905.

Chronic obstructive pulmonary disease (COPD) is the primary indication for lung transplantation (LTx), but survival benefit is still under debate. We analysed the survival impact of LTx in COPD with a new approach, using the BODE (body mass index, airway obstruction, dyspnoea, exercise capacity) index. We retrospectively reviewed 54 consecutive lung transplants performed for COPD. The pre-transplant BODE score was calculated for each patient and a predicted survival was derived from the survival functions of the original BODE index validation cohort. Predicted and observed post-transplant survival was then compared. In the subgroups with a BODE score ≥ 7 and

BACKGROUND: since 1999 data from pulmonary hypertension (PH) patients from all PH centres in Switzerland were prospectively collected. We analyse the epidemiological aspects of these data. METHODS: PH was defined as a mean pulmonary artery pressure of >25 mm Hg at rest or >30 mm Hg during exercise. Patients with pulmonary arterial hypertension (PAH), PH associated with lung diseases, PH due to chronic thrombotic and/or embolic disease (CTEPH), or PH due to miscellaneous disorders were registered. Data from adult patients included between January 1999 and December 2004 were analysed. RESULTS: 250 patients were registered (age 58 +/- 16 years, 104 (41%) males). 152 patients (61%) had PAH, 73 (29%) had CTEPH and 18 (7%) had PH associated with lung disease. Patients 50 years (76% vs. 53%, p

OBJECTIVE: To assess the incidence and epidemiological pattern of respiratory viruses in HIV-infected patients and to evaluate their potential clinical impact. DESIGN AND METHODS: A prospective population-based cohort study was conducted at three Swiss university hospitals. Study participants were HIV-infected patients who underwent a bronchoalveolar lavage to rule out an opportunistic event. All bronchoalveolar lavage specimens were screened using a set of real-time reverse transcriptase-polymerase chain reaction assays targeting 17 different respiratory viruses. RESULTS: Between November 2003 and November 2006, 59 bronchoalveolar episodes from 55 HIV-infected patients were analysed. Eleven of 59 episodes (18.6%) were positive for at least one respiratory virus. Coronavirus OC43 was identified in three cases (27.3%) followed by influenza A in two (18.2%). Parainfluenza virus (PIV) 2, PIV 3, PIV 4, bocavirus, human rhinovirus A and human metapneumovirus were each identified in one case (9%). In the majority of these cases (63.6%) no other concomitant microorganism was isolated. CONCLUSIONS: Clinical investigation of respiratory viral infections in HIV-infected patients should not be restricted to prototype viruses and also need to target all the different family of viruses as it seems likely that these viruses contribute to pulmonary complications and morbidity in this population.

BACKGROUND: Outcome after lung transplantation (LTx) is affected by the onset of bronchiolitis obliterans syndrome (BOS) and lung function decline. Reduced health-related quality of life (HRQL) and physical mobility have been shown in patients developing BOS, but the impact on the capacity to walk is unknown. We aimed to compare the long-term HRQL and 6-minute walk test (6MWT) between lung recipients affected or not by BOS Grade > or =2. METHODS: Fifty-eight patients were prospectively followed for 5.6 +/- 2.9 years after LTx. Assessments included the St George's Respiratory Questionnaire (SGRQ) and the 6MWT, which were performed yearly. Moreover, clinical complications were recorded to estimate the proportion of the follow-up time lived without clinical intercurrences after transplant. Analyses were performed using adjusted linear regression and repeated-measures analysis of variance. RESULTS: BOS was a significant predictor of lower SGRQ scores (p < 0.01) and reduced time free of clinical complications (p = 0.001), but not of 6MWT distance (p = 0.12). At 7 years post-transplant, results were: 69.0 +/- 21.8% vs 86.9 +/- 5.6%, p < 0.05 (SGRQ); 58.5 +/- 21.6% vs 88.7 +/- 11.4%, p < 0.01 (proportion of time lived without clinical complications); and 82.2 +/- 10.9% vs 91.9 +/- 14.2%, p = 0.27 (percent of predicted 6MWT), respectively, for patients with BOS and without BOS. CONCLUSIONS: Despite significantly less time lived without clinical complications and progressive decline of self-reported health status, the capacity to walk of patients affected by BOS remained relatively stable over time. These findings may indicate that the development of moderate to severe BOS does not prevent lung recipients from walking independently and pursuing an autonomous life.

Background. In addition to the human coronaviruses (HCoVs) OC43 and 229E, which have been known for decades to cause infection in humans, 2 new members of this genus have recently been identified: HCoVs NL63 and HKU1. Their impact as a cause of respiratory tract disease in adults at risk for complications needs to be established. Methods. We prospectively assessed the clinical impact of coronavirus infection (excluding cases of severe acute respiratory syndrome) among hospitalized adults. All patients with respiratory disease for whom bronchoalveolar lavage was performed were screened by reverse-transcriptase polymerase chain reaction for the presence of all 4 HCoVs. Results. HCoV was identified in 29 (5.4%) of 540 bronchoalveolar lavage fluid specimens from 279 subjects (mean age, 51 years; 63% male). HCoV OC43 was identified most frequently (12 isolates), followed by 229E (7 isolates), NL63 (6 isolates), and HKU1 (4 isolates). In all, 372 (69%) of 540 bronchoalveolar lavage fluid specimens were negative for bacteria, and 2 persons were coinfected with other respiratory viruses. Transplantation was the most common underlying condition. Of the 29 patients who had HCoV identified in their bronchoalveolar lavage fluid specimens, 9 (31%) were hospitalized in the intensive care unit, 22 (76%) presented to the hospital with acute respiratory symptoms, 16 (55%) presented with cough and/or sputum, 13 (45%) presented with dyspnea, 16 (55%) had experienced prior respiratory infection, and 18 (62%) had a new infiltrate that was visible on chest radiograph. The most frequent final diagnosis was a lower respiratory tract infection. Conclusions. The recently discovered HCoVs NL63 and HKU1 contribute significantly to the overall spectrum of coronavirus infection. Our study also suggests that coronaviruses contribute to respiratory symptoms in most cases.

Matrix metalloproteinases (MMPs) are involved in the pathogenesis of several diseases of the CNS, that share common pathophysiological processes, such as blood-brain barrier (BBB) disruption, oxidative stress, remodeling of the extracellular matrix (ECM) and inflammation. In ischemic brain injury, MMPs are implicated in various stages of the disease. Early after the onset of ischemia, MMPs contribute to the disruption of the BBB leading to vasogenic edema and to the influx of leucocytes into the CNS. The ability of MMPs to digest the basal lamina of capillaries increases the risk of hemorrhagic transformation of the ischemic tissue. During the acute ischemic phase, maintenance of the ECM is essential for neuronal survival. However, ECM degradation and its reconstitution are critical to tissue recovery. MMPs as a key modulator of ECM homeostasis play a role in the cascades leading to neuronal cell death and tissue regeneration. This pleiotropic implication of MMPs in brain injury has open new areas of investigation, which should lead to innovative therapeutic strategies. Yet MMPs may have a detrimental or beneficial role depending on the stage of brain injury. Simple therapeutic strategies based on MMP inhibition have thus little chance to favorably alter prognosis.

Increased microvascular permeability and extravasation of inflammatory cells are key events of lung ischemia-reperfusion (IR) injury. The purpose of this study was to investigate the role of matrix metalloproteinases (MMP) in IR-induced alveolar capillary membrane disruption after experimental lung transplantation. We used a rat model of lung orthotopic transplantation (n = 86) with a prolonged cold ischemic phase. MMP2 and MMP9 were elevated 4 h after the onset of ischemia and further increased during reperfusion. Compared to sham values, the alveolar-capillary membrane permeability increased by 105% and 82.6% after 4 h of ischemia and 2 h or 24 h of reperfusion, respectively. A 4- and 5-fold increase of the infiltration of ischemic tissue by neutrophils was also observed after 2 h and 24 h of reperfusion. The PO2/FIO2 ratio dropped significantly from 244 to 76.6 after 2 h of reperfusion and from 296.4 to 127.6 after 24 h of reperfusion. A nonselective inhibitor of MMP, administered to the rats and added to the preservation solution, reduced significantly the alveolar-capillary leakage, the transmigration of neutrophils and improved gas exchanges in animals submitted to 4 h of ischemia combined with 2 h or 24 h of reperfusion. We conclude that inhibition of MMP attenuates IR injury after experimental lung transplantation.

The current treatment of obliterative bronchiolitis in lung transplant recipients is sub-optimal. Triptolide is a novel immunosuppressant that has a mechanism of action distinct from currently available immunosuppressants, including induction of T-cell apoptosis, blockade of fibroblast proliferation/maturation and inhibition of transforming growth factor-beta (TGF-beta) mRNA production. We hypothesized that triptolide may be helpful in blocking obliterative airway disease in lung transplant recipients. We investigated the effect of PG490-88, a water-soluble derivative of triptolide, in a mouse heterotopic tracheal allograft model of obliterative airway disease. We show that PG490-88 attenuates airway obliteration in this model and inhibits accumulation of inflammatory cells, and therefore may have preventive or therapeutic benefits for patients with obliterative airway disease (OAD) following lung transplantation.

Purpose: Metalloproteinases (MMPs) regulate extracellular matrix turnover and degrade basal lamina. Aim of the study was to examine the regulation of MMPs and the effect of an MMP inhibitor in transplant related ischemia/reperfusion injury. Methods: Heterotopic cardiac transplantation was performed after 4 h of ischemia in three groups of six rats: allografts (black hooded inbred strain, PVG donor/August Copenhagen Irish inbred strain recipient); allografts treated with a competitive MMP-inhibitor (Batimastat) 15 mg/kg every 24 h; isografts (PVG donor and recipient). Normal PVG hearts served as a control. Hearts were explanted after 72 h of reperfusion. Expression of MMP-2 and -9 was measured using gelantin zymography. Proteolytic activity was measured using a gelatinase activity assay. Myeloperoxidase activity and tumor necrosis factor-alpha (TNF-alpha) were measured as markers of inflammatory response. Immunostaining for collagen IV and laminin was used to study degradation of basal lamina. Results: There was a significant increase of MMP-2 expression in allografts (2271 ^ 571 mg/ml) as compared to normal (683 ^ 139 mg/ml) and the Batimastat-treated (259 ^ 140 mg/ml, P , 0:05) groups. Although pro-MMP-2 expression was equally high in the untreated iso- and allograft group (75 ^ 23 versus 62 ^ 30 mg/ml) MMP-2 expression in the isograft hearts was significantly lower (359 ^ 267 mg/ml) suggesting activation of the pro-form by an immunologic mechanism. Pro-MMP-9 levels were significantly higher in the untreated iso- and allograft groups as opposed to normal hearts and MMP-inhibited hearts. MMP-9 was completely inhibited by Batimastat treatment. Collagenolytic activity was lower in the treated group as compared to untreated allografts (538 ^ 140 versus 384 ^ 97 mg/ml, P , 0:05), demonstrating effective inhibition of MMPs by Batimastat. In the treated group a lesser extent of basement membrane component alterations could be demonstrated by laminin and collagen IV staining. There was a significant reduction in myeloperoxidase activity (P ¼ 0:027) as well as lower TNF-alpha levels (ns) in the in the Batimastat treated group. Conclusion: Ischemia leads to an increase in MMP expression and degradation of basal lamina. This process is enhanced in allografts as compared to isografts suggesting additional activation of MMPs by immunologic mechanisms. MMP-inhibition is effective in preventing the proteolytic activity of MMPs and may alter the host rejection response by preserving extracellular matrix components and basement membranes. q 2002 Published by Elsevier Science B.V.

Background. Recent animal data suggest that inducible nitric oxide synthase (iNOS) mRNA expression in the bronchoalveolar lavage (BAL) may be useful for the diagnosis of lung rejection. The aim of this study was to evaluate iNOS mRNA transcription in the BAL fluid of human lung allografts. Methods, iNOS mRNA transcription was quantified by competitive reverse transcription-polymerase chain reaction in 51 BAL cell pellets of lung transplant patients. According to bacteriological and histological results, BAL samples were divided into three groups: normal (n=21), acute rejection (AR, n=15), and infection (INF, n=15). Results. Compared with the control group, iNOS transcription increased significantly with INF (P=0.0005) but only slightly with AR (P>0.05). INF values were significantly higher than AR values (P=0.0029). Conclusion. BAL iNOS mRNA transcript determination by competitive reverse transcription-polymerase chain reaction may be useful in differentiating infected from normal and/or acutely rejecting allografts.

Antigen presentation by lung macrophages/dendritic cells (DC) is thought to be important in obliterative bronchiolitis/bronchiolitis obliterans syndrome (OB/BOS), which severely limits survival post-lung transplantation. However, a recent study found minimal numbers of DC in lung allografts. We looked at numbers and phenotype of macrophages/DC in lung allografts using endobronchial biopsy (EBB) and transbronchial biopsy (TBB) from 22 lung transplant patients. Biopsies were stained with monoclonal markers of DC (CD1a, RFD1, and major histocompatibility complex [MHC] Class II), and "suppressor macrophages" (RFD1 and RFD7). Dendritic cells were also stained for the costimulatory molecules CD80 and CD86. Significantly greater numbers of DC/high-power field (HPF) were seen in biopsies when we defined DC using dendritic morphology and Class II MHC expression instead of CD1a expression. Dendritic cell numbers were significantly higher in eight patients with OB/BOS compared with 14 stable patients. Fifty percent of DC expressed CD86 and 20% expressed CD80. There was no difference in CD80 or CD86 expression between OB/BOS patients and stable patients. There was no correlation between DC numbers and presence or absence of acute rejection (AR), and/or cytomegalovirus (CMV) pneumonitis on current or prior biopsies. There were significantly more MHC Class II DC in EBB compared with TBB. We found minimal staining for lung macrophages capable of suppressing T-cell inflammation. We conclude that studies of lung allografts may underestimate DC numbers if relying on CD1a as the sole marker of DC. DC are increased in patients with OB/BOS compared with stable patients. EBB may be more important than TBB in looking for inflammatory changes of OB. DC expressing costimulatory molecules are present in lung allografts, and costimulatory pathway blockade may be useful in human lung allografts. Also, the absence of "suppressor" macrophages may increase susceptibility of human lung allografts to the rejection process.

Matrix metalloproteinases (MMPs) are able to degrade the endothelial basal lamina and increase vascular permeability.In a porcine model of isolated-reperfused lung, we studied the alveolar-capillary permeability and the zymographic expression of MMP-9 and MMP-2 in the bronchoalveolar lavage fluid of lungs submitted ex vivo to ischemia in three preservation solutions [modified Euro-Collins (EC), low-potassium-dextran, modified-blood]. Twenty-two pigs were randomly divided into three groups according to the preservation solution used. One lung of each pig was rapidly reperfused and analyzed (control lung) although the other lung was reperfused and analyzed after 8 hr of ischemia (ischemic lung).Alveolar-capillary permeability, evaluated by the transferrin leak index, was increased after 8 hr of ischemia compared with controls in the three groups, but was significantly higher in the modified EC group. In the EC group, after 8 hr of ischemia, both proMMP-9 and MMP-9 increased significantly (8.8- and 22-fold, respectively) compared with controls and this increase correlated with the transferrin leak index. Neither proMMP-9 nor MMP-9 increased with the other two preservation solutions. The MMP-2 increase after ischemia was smaller and was also restricted to the EC group.MMP expression is enhanced during lung ischemia-reperfusion, especially in the presence of EC and this phenomenon correlates with the alteration of alveolar-capillary permeability.