A randomized controlled trial of presatovir for respiratory syncytial virus after lung transplant.

Background: Respiratory syncytial virus (RSV) infection in lung transplant recipients is associated with high morbidity. This study evaluated the RSV fusion inhibitor presatovir in RSV-infected lung transplant recipients.

Methods: In this international Phase 2b, randomized, double-blind, placebo-controlled trial (NCT02534350), adult lung transplant recipients with symptomatic confirmed RSV infection for ≤7 days received oral presatovir 200 mg on day 1 and 100 mg daily on days 2 to 14, or placebo (2:1), with follow-up through day 28.

Lung and liver transplantation in patients with alpha-1 antitrypsin deficiency.

Alpha-1 antitrypsin (AAT) augmentation is effective in slowing the progression of emphysema due to AAT deficiency (AATD) but cannot prevent eventual progression to end-stage lung disease and complete respiratory failure, which is the leading cause of death for individuals with severe AATD. When patients develop end-stage lung disease, lung transplantation is the only treatment option available, and this can improve lung physiology and patient health status. The available data suggest that survival rates for lung transplantation are significantly higher for patients with AATD-related chronic obstructive pulmonary disease (COPD) compared with non-AATD-related COPD, but, conversely, there is a higher risk of common post-lung transplant complications in patients with AATD non-AATD COPD.

Ribavirin and cellular ribavirin-triphosphate concentrations in blood and bronchoalveolar lavage fluid in two lung transplant patients with respiratory syncytial virus.

Respiratory syncytial virus (RSV) is responsible for significant morbidity and mortality in the lung transplant population. Oral and aerosolized ribavirin may improve outcomes in lung transplant patients with RSV; however, data relating ribavirin concentrations in plasma and intracellular ribavirin triphosphate (iRTP) concentrations in blood and bronchoalveolar lavage (BAL) fluid cells with efficacy and safety are lacking. We describe ribavirin and iRTP concentrations within various compartments in two adult lung transplant recipients with RSV who were sampled throughout successful treatment courses with oral and inhaled ribavirin.

Anti-LFA-1 induces CD8 T-cell dependent allograft tolerance and augments suppressor phenotype CD8 cells.

The induction of tolerance to transplanted organs is a major objective in transplantation immunology research. Lymphocyte function-associated antigen-1 (LFA-1) interactions have been identified as a key component of the T-cell activation process that may be interrupted to lead to allograft tolerance. In mice, αLFA-1 mAb is a potent monotherapy that leads to the induction of donor-specific transferable tolerance.

Pharmacologic Protection of Mitochondrial DNA Integrity May Afford a New Strategy for Suppressing Lung Ischemia-Reperfusion Injury.

Lung ischemia-reperfusion (IR) injury contributes to post-transplant complications, including primary graft dysfunction. Decades of reports show that reactive oxygen species generated during lung IR contribute to pulmonary vascular endothelial barrier disruption and edema formation, but the specific target molecule(s) that "sense" injury-inducing oxidant stress to activate signaling pathways culminating in pathophysiologic changes have not been established. This review discusses evidence that mitochondrial DNA (mtDNA) may serve as a molecular sentinel wherein oxidative mtDNA damage functions as an upstream trigger for lung IR injury.

ALN-RSV01 for prevention of bronchiolitis obliterans syndrome after respiratory syncytial virus infection in lung transplant recipients.

Background: Respiratory syncytial virus (RSV) infection in lung transplant (LTx) patients is associated with an increased incidence of bronchiolitis obliterans syndrome (BOS). ALN-RSV01 is a small interfering RNA targeting RSV replication that was shown in an earlier Phase 2a trial to be safe and to reduce the incidence of BOS when compared with placebo.

Methods: We performed a Phase 2b randomized, double-blind, placebo-controlled trial in RSV-infected LTx patients to examine the impact of ALN-RSV01 on the incidence of new or progressive BOS.

Invasive Microascus trigonosporus Species Complex Pulmonary Infection in a Lung Transplant Recipient.

Because of the high incidence of morbidity and mortality associated with invasive fungal infections, antifungal prophylaxis is often used in solid organ transplant recipients. However, this prophylaxis is not universally effective and may contribute to the selection of emerging, resistant pathogens. Here we present a rare case of invasive infection caused by Microascus trigonosporus species complex in a human, which developed during voriconazole prophylaxis in a lung transplant recipient.

Increased resource use in lung transplant admissions in the lung allocation score era.

Rationale: In 2005, the lung allocation score (LAS) was implemented to prioritize organ allocation to minimize waiting-list mortality and maximize 1-year survival. It resulted in transplantation of older and sicker patients without changing 1-year survival. Its effect on resource use is unknown.

Ectopic expression of Fas Ligand on cardiomyocytes renders cardiac allografts resistant to CD4(+) T-cell mediated rejection.

Fas Ligand limits inflammatory injury and permits allograft survival by inducing apoptosis of Fas-bearing lymphocytes. Previous studies have shown that the CD4(+) T-cell is both sufficient and required for murine cardiac allograft rejection. Here, utilizing a transgenic mouse that over-expresses Fas Ligand specifically on cardiomyocytes as heart donors, we sought to determine if Fas Ligand on graft parenchymal cells could resist CD4(+) T-cell mediated rejection.

A consensus document for the selection of lung transplant candidates: 2014--an update from the Pulmonary Transplantation Council of the International Society for Heart and Lung Transplantation.

The appropriate selection of lung transplant recipients is an important determinant of outcomes. This consensus document is an update of the recipient selection guidelines published in 2006. The Pulmonary Council of the International Society for Heart and Lung Transplantation (ISHLT) organized a Writing Committee of international experts to provide consensus opinion regarding the appropriate timing of referral and listing of candidates for lung transplantation.

Ex vivo lung perfusion allows successful transplantation of donor lungs from hanging victims.

Background: Donor lungs acquired from victims of asphyxiation by hanging are not routinely used for lung transplantation because of the associated lung injury. Ex vivo lung perfusion (EVLP) is a technique to evaluate marginal donor lungs before transplantation. We report here our experience with the use of EVLP in donor lungs procured from victims of asphyxia by hanging.

Mechanical ventilation after lung transplantation. An international survey of practices and preferences.

Rationale: Between 10% and 57% of lung transplant (LTx) recipients develop primary graft dysfunction (PGD) within 72 hours of LTx. PGD is clinically and histologically analogous to the acute respiratory distress syndrome. In patients at risk for or with acute respiratory distress syndrome, lung-protective ventilation strategies (low tidal volume and positive end-expiratory pressure) improve outcomes.

The impact of genetic polymorphisms, diltiazem, and demographic variables on everolimus trough concentrations in lung transplant recipients.

Everolimus (EVR) has inter-individual pharmacokinetic (PK) variability and a narrow therapeutic index. The study objective was to determine whether genetic polymorphisms, co-medications, and/or demographic variables accounted for inter-individual variability in EVR PK in lung transplant recipients (LTxR). LTxR were genotyped for ABCB1 c.

Update on Bronchiolitis Obliterans Syndrome in Lung Transplantation.

Lung transplantation has become an important therapeutic option for patients with end-stage organ dysfunction; however, its clinical usefulness has been limited by the relatively early onset of chronic allograft dysfunction and progressive clinical decline. Obliterative bronchiolitis is characterized histologically by luminal fibrosis of the respiratory bronchioles and clinically by bronchiolitis obliterans syndrome (BOS) which is defined by a measured decline in lung function based on forced expiratory volume (FEV). Since its earliest description, a number of risk factors have been associated with the development of BOS, including acute rejection, lymphocytic bronchiolitis, primary graft dysfunction, infection, donor specific antibodies, and gastroesophageal reflux disease.

Recipient risk factors and lung transplant outcomes.

Purpose Of Review: Scientific and technical developments in the field of lung transplantation have allowed it to become a successful treatment option for various end-stage lung diseases. As the demand for lung allografts increases and waitlists expand, it is vital that lung transplant centers optimize use of this limited resource by selecting recipients who have the best prospects of positive long-term outcomes. Recipient selection criteria vary across transplant selection committees.

Four decades of vascularized heterotopic cardiac transplantation in the mouse.

Since the first clinical heart transplant in 1967, there has been a heightened need to understand immune and inflammatory responses to "foreign" tissues. Research efforts in those early days were based on species that would now be considered "large" and were typically out-bred individuals. While this closely mirrors the clinical scenario, where genetic mismatches of donors and recipients can only be minimized in the selection process, these were not ideal models for studying the complexities and nuances of the immune system.

Evaluation of valganciclovir pharmacokinetics in lung transplant recipients.

Background: Valganciclovir is commonly used for cytomegalovirus prevention after lung transplantation. The pharmacokinetic profile of valganciclovir in lung transplant patients has not been well described or linked to efficacy and safety.

Methods: This prospective, randomized, crossover study determined the steady-state pharmacokinetic profile of 2 different doses of valganciclovir in lung transplant recipients and compared these profiles with intravenous ganciclovir.

Respiratory viral infections post-lung transplantation.

Community-acquired respiratory viruses (CARVs) are common pathogens in lung transplant recipients. Infection due to these viruses is associated with multiple complications including: rhinitis, pharyngitis, bronchitis, pneumonia, respiratory failure and even death. CARVs have also become increasingly recognized as a risk factor for acute rejection (AR) and bronchiolitis obliterans syndrome (BOS).

Pre-transplant presence of antibodies to MICA and HLA class I or II are associated with an earlier onset of bronchiolitis obliterans syndrome in lung transplant recipients.

Previous reports using cell-based methods (CDC-AHG) suggest that the presence of pre-transplant HLA Class I and II antibodies are associated with worse survival following lung transplantation. Similarly, antibodies to major histocompatibility complex Class I chain-related gene A (MICA) have been associated with increased graft failure following kidney transplantation. Using highly sensitive solid phase assays, we sought to determine whether the pre-transplant presence of antibodies to MICA or HLA Class I or II predicted short or long-term lung allograft function.

Updates in lung transplantation.

The past two years have seen major advances in the lung transplant (LTX) field. In 2010, for the first time, over 3500 lungs were reported to the International Society for Heart and Lung Transplantation Registry. Widening application of extracorporeal life support as a bridge to transplant, or as intra- or postoperative support, has allowed transplantation of critically ill candidates with end-stage pulmonary parenchymal or vascular disease.

DNA viruses (CMV, EBV, and the herpesviruses).

The human Herpesviridae family consists of eight members: cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus 1 and 2 (HSV-1, -2), varicella-zoster virus (VZV), and human herpesvirus 6, 7, and 8 (HHV-6, -7, -8). Lifelong latency may develop in the host with reactivation during periods of relative immunosuppression that occurs in transplant recipients. These are pleiotropic viruses: in addition to their direct effects of tissue injury and clinical illness, they exhibit several indirect effects, including immunomodulation and effects on angiogenesis and tumorigenesis, which may result in long-term adverse sequelae in the lung allograft.

Update and review: state-of-the-art management of cytomegalovirus infection and disease following thoracic organ transplantation.

Purpose: Cytomegalovirus (CMV) is among the most important viral pathogens affecting solid organ recipients. The direct effects of CMV (eg, infection and its sequela; tissue invasive disease) are responsible for significant morbidity and mortality. In addition, CMV is associated with numerous indirect effects, including immunomodulatory effects, acute and chronic rejection, and opportunistic infections.

RNA interference therapy in lung transplant patients infected with respiratory syncytial virus.

Rationale: Lower respiratory tract infections due to respiratory syncytial virus (RSV) are associated with development of bronchiolitis obliterans syndrome in lung transplant (LTX) recipients. ALN-RSV01 is a small interfering RNA targeting RSV replication.

Objectives: To determine the safety and explore the efficacy of ALN-RSV01 in RSV infection.