Background. In lung transplantation, diverse clinical events may impact patient outcome. In clinical trials comparing intervention strategies, single primary endpoints require large populations, or long study durations, whereas composite endpoints (CEPs) do not take into account the respective impact of their components on patient survival. The objective of this study was to propose consensus recommendations on endpoints for clinical trials on immunosuppressants in lung transplantation.Methods. The consensus process was managed through the Internet using the Delphi method. Forty experts were invited by the pilot group with the help of the International Society for Heart and Lung Transplantation and The Transplantation Society. In the first round, a questionnaire was made available to the experts to complete, and the responses were analyzed. In each next round, a new questionnaire was developed from the previous responses and sent to the panel members.Results. Consensus between 17 experts was achieved after five rounds. Two score-type CEPs were defined for immunosuppressive drug efficacy (7 items) and for toxicity (15 items). Death related to graft loss or immunosuppressive drug toxicity was attributed a maximum weight of 100. The weights of the items included in the efficacy and toxicity CEPs ranged between 10 and 80 and between 25 and 70, respectively. The CEP scores are calculated by adding the weights of all the items composing them, without exceeding 90 as long as the patient is alive.Conclusion. This consensus conference proposed two score-type CEPs including relevant endpoints. After validation, they should allow clinical trials with higher statistical power, improving the evaluation of the interventions tested.

Primary graft dysfunction (PGD) and bronchiolitis obliterans (BO) are the leading causes of morbidity and mortality after lung transplantation. Reports from clinical and rodent models suggest the implication of IL-17A in either PGD or BO. We took advantage of the heterotopic trachea transplantation model in mice to study the direct role of IL-17A in post-transplant airway lesions. Across full MHC barrier, early lesions were controlled in IL-17A(-/-) or anti-IL17 treated recipients. In contrast, IL-17A deficiency did not prevent subsequent obliterative airway disease (OAD). Interestingly, this early protection occurred also in syngeneic grafts and was accompanied by a decrease in cellular stress, as attested by lower HSP70 mRNA levels, suggesting the involvement of IL-17A in ischemia-reperfusion injury (IRI). Furthermore, persistence of multipotent CK14(+) epithelial stem cells underlined allograft protection afforded by IL-17A deficiency or neutralisation. Recipient-derived γδ(+) and CD4(+) T cells were the major source of IL-17A. However, lesions still occurred in the absence of each subset, suggesting a high redundancy between the innate and adaptive IL-17A producing cells. Notably, a double depletion significantly diminished lesions. In conclusion, this work implicated IL-17A as mediator of early post-transplant airway lesions and could be considered as a potential therapeutic target in clinical transplantation.

Therapeutic drug monitoring of tacrolimus is a major support to patient management and could help improve the outcome of lung transplant recipients, by minimizing the risk of rejections and infections. However, despite the wide use of tacrolimus as part of maintenance immunosuppressive regimens after lung transplantation, little is known about its pharmacokinetics in this population. Better knowledge of the pharmacokinetics of tacrolimus in lung transplant recipients, and the development of tools dedicated to its therapeutic drug monitoring, could thus help improve their outcome.

The aim of the present study was to describe success rates, complications, and outcome in patients who underwent percutaneous endoscopic jejunostomy (PEJ) because of gastroparesis due to previous lung transplantation. Between October 2008 and May 2011, 14 attempts at PEJ placement were made in 12 patients in our center. Of the 14 attempts, 11 were successful, giving a technical success rate of 78.6 %. Median duration of followup was8.5 months (2–15 months). No immediate complications were reported. Two severe complications occurred during follow up (one volvulus and one jejunocolic fistula). Jejunal nutrition was well tolerated in most of patients (9 /10). PEJ insertion is a feasible technique, which could help to provide nutritional support for patients with gastroparesis and previous lung transplantation.

Several reports indicate that the immunogenicity of influenza vaccines is suboptimal in lung transplant (LTx) recipients while others suspect a link between vaccination and accelerated graft loss. On the eve of the H1N1 pandemic, vaccination was proposed to LTx recipients. The purpose of this study was to prospectively assess seroconversion and development of anti-human leukocyte antigen (HLA) and/or MHC class 1 chain-related A (MICA) antibodies (Abs) as a surrogate marker for immunological safety in LTx patients.

The immunosuppressive drug mycophenolate mofetil is used to prevent rejection after organ transplantation. In kidney transplant recipients, it has been demonstrated that adjustment of the mycophenolate mofetil dose on the basis of the area under the concentration-time curve (AUC) of mycophenolic acid (MPA), the active moiety of mycophenolate mofetil, improves the clinical outcome. Because of the high risks of rejections and infections in lung transplant recipients, therapeutic drug monitoring of the MPA AUC might be even more useful in these patients. The aims of this study were to characterize the pharmacokinetics of MPA in lung and kidney transplant recipients, describe the differences between the two populations and develop a Bayesian estimator of the MPA AUC in lung transplant recipients.

Background:Although not an approved therapy, nebulised hypertonic saline (HS) is widely used in CF.Based largely on a single study, various consensus guidelines provide qualified support for HS using 7% b.i.d., but not at a lower concentration or frequency [1].We sought to gain an understanding of patterns of HS use in a large cross-section of CF physicians.Methods: Specialist physicians in the USA, UK and the EU, currently treating respiratory disease in 20 patients (ages 6+) suffering from CF were asked to participate.Consenting physicians were asked to complete a questionnaire regarding use of HS in their patients with CF.Results: 200 physicians in the USA, UK, and EU were recruited.Collectively, these clinicians had a case-load of 10,600 patients with CF ( 18 years = 77%).Most physicians used HS although the proportion of patients treated varied by region from 30% to 53% and HS concentrations ranged from <3% to >10%.The highest use of 3% HS was in the USA (50%).In the EU overall, 40% patients were administered 6-7% HS concentrations irrespective of treatment frequency, 46% patients had therapy prescribed b.i.d.irrespective of HS concentrations and 16% pts were prescribed at least 6% HS b.i.d.

In lung transplantation, diverse clinical events may impact patients' outcome. In clinical trials comparing intervention strategies, large populations are required if the primary endpoint includes only mortality or morbidity. The objective of this study was to propose consensus recommendations on a CEP for clinical trials on IS in lung transplantation.

In 2010, lung transplantation is a valuable therapeutic option for a number of patients suffering from of end-stage non-neoplastic pulmonary diseases. The patients frequently regain a very good quality of life, however, long-term survival is often hampered by the development of complications such as the bronchiolitis obliterans syndrome, metabolic and infectious complications. As the bronchiolitis obliterans syndrome is the first cause of death in the medium and long term, an intense immunosuppressive treatment is maintained for life in order to prevent or stabilize this complication. The immunosuppression on the other hand induces a number of potentially severe complications including metabolic complications, infections and malignancies. The most frequent metabolic complications are arterial hypertension, chronic renal insufficiency, diabetes, hyperlipidemia and osteoporosis. Bacterial, viral and fungal infections are the second cause of mortality. They are to be considered as medical emergencies and require urgent assessment and targeted therapy after microbiologic specimens have been obtained. They should not, under any circumstances, be treated empirically and it has also to be kept in mind that the lung transplant recipient may present several concomitant infections. The most frequent malignancies are skin cancers, the post-transplant lymphoproliferative disorders, Kaposi's sarcoma and some types of bronchogenic carcinomas, head/neck and digestive cancers. Lung transplantation is no longer an exceptional procedure; thus, the pulmonologist will be confronted with such patients and should be able to recognize the symptoms and signs of the principal non-surgical complications. The goal of this review is to give a general overview of the most frequently encountered complications. Their assessment and treatment, though, will most often require the input of other specialists and a multidisciplinary and transversal approach.

Therapeutic drug monitoring of mycophenolic acid (MPA), the active moiety of MMF, could help decrease the rate of rejections and infections in lung transplant recipients. Most research is done in renal transplantation, in which promising results are shown. To extrapolate these results to lung transplantation, a better knowledge of the pharmacokinetics (PK) of MPA in lung transplantation is needed. The objective of this study was to characterize the PK of MPA in lung transplant recipients and describe the differences with renal transplant recipients.

Since the publication of the last edition of the Handbook of Physiology, lung transplantation has become widely available, via specialized centers, for a variety of end-stage lung diseases. Lung volume reduction surgery, a procedure for emphysema first conceptualized in the 1950s, electrified the pulmonary medicine community when it was rediscovered in the 1990s. In parallel with their technical and clinical refinement, extensive investigation has explored the unique physiology of these procedures. In the case of lung transplantation, relevant issues include the discrepant mechanical function of the donor lungs and recipient thorax, the effects of surgical denervation, acute and chronic rejection, respiratory, chest wall, and limb muscle function, and response to exercise. For lung volume reduction surgery, there have been new insights into the counterintuitive observation that lung function in severe emphysema can be improved by resecting the most diseased portions of the lungs. For both procedures, insights from physiology have fed back to clinicians to refine patient selection and to scientists to design clinical trials. This section will first provide an overview of the clinical aspects of these procedures, including patient selection, surgical techniques, complications, and outcomes. It then reviews the extensive data on lung and muscle function following transplantation and its complications. Finally, it reviews the insights from the last 15 years on the mechanisms whereby removal of lung from an emphysema patient can improve the function of the lung left behind.

The purposes of this study were to describe mycophenolic acid (MPA) exposure indices and create new tools for MMF dose adjustment in cystic fibrosis (CF) and non-CF lung transplant recipients on MMF and tacrolimus.

Chronic, progressive, and irreversible loss of lung function is the major medium-term and long-term complication after lung transplantation and the leading cause of death. Over the past decade, progress has been made in understanding the pathogenesis of bronchiolitis obliterans. Alloimmune factors and nonalloimmune factors may contribute to its development. Understanding the precise mechanism of each type of chronic allograft dysfunction may open up the field for new preventive and therapeutic interventions. This article reviews major new insights into the clinical aspects, pathophysiology, risk factors, diagnosis, and management of chronic allograft dysfunction after lung transplantation.