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. A comprehensive search of the medical literature was conducted with the assistance of a medical librarian. Writing Committee members were assigned specific topics to research and discuss. The Chairs of the Writing Committee were responsible for evaluating the completeness of the literature search, providing editorial support for the manuscript, and organizing group discussions regarding its content. The consensus document makes specific recommendations regarding the timing of referral and of listing for lung transplantation. These recommendations include discussions not present in previous ISHLT guidelines, including lung allocation scores, bridging to transplant with mechanical circulatory and ventilator support, and expanded indications for lung transplantation. In the absence of high-grade evidence to support decision making, these consensus guidelines remain part of a continuum of expert opinion based on available studies and personal experience. Some positions are immutable. Although transplant is rightly a treatment of last resort for end-stage lung disease, early referral allows proper evaluation and thorough patient education. Subsequent waiting list activation implies a tacit agreement that transplant offers a significant individual survival advantage. It is both the challenge and the responsibility of the transplant community globally to ensure organ allocation maximizes the potential benefits of a scarce resource, thereby achieving that advantage.
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.
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. Subjects were randomized (1:1) to receive aerosolized ALN-RSV01 or placebo daily for 5 days.
Of 3,985 symptomatic patients screened, 218 were RSV-positive locally, of whom 87 were randomized to receive ALN-RSV01 or placebo (modified intention-to-treat mITT cohort). RSV infection was confirmed by central laboratory in 77 patients (ALN-RSV01, n = 44; placebo, n = 33), which comprised the primary analysis cohort (central mITT mITTc). ALN-RSV01 was found to be safe and well-tolerated. At Day 180, in ALN-RSV01-treated patients, compared with placebo, in the mITTc cohort there was a trend toward a decrease in new or progressive BOS (13.6% vs 30.3%, p = 0.058), which was significant in the per-protocol cohort (p = 0.025). Treatment effect was enhanced when ALN-RSV01 was started <5 days from symptom onset, and was observed even without ribavirin treatment. There was no significant impact on viral parameters or symptom scores.
These results confirm findings of the earlier Phase 2a trial and provide further support that ALN-RSV01 reduces the risk of BOS after RSV in LTx recipients.
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 versus non-AATD COPD. Nevertheless, lung transplantation (single and bilateral) is favorable for patients with AATD. After respiratory failure, the second leading cause of death in patients with AATD is liver disease, for example, cirrhosis and hepatocellular carcinoma, caused by the accumulation of mutant forms of AAT retained within the liver. As with lung disease, the only treatment option for end-stage liver disease is liver transplantation. Survival rates for patients with AATD undergoing liver transplantation are also favorable, and patients, particularly pediatric patients, have benefitted from advancements in peri-/post-surgical care. As the majority of AAT is produced by the liver, the AAT phenotype of the recipient becomes that of the donor, meaning that AAT serum levels should be normalized (if the donor is AAT-replete), halting further lung and liver disease progression. However, post-liver transplant respiratory function may continue to decline in line with normal age-related lung function decline. In the most severe cases, where patients have simultaneous end-stage lung and liver disease, combined lung and liver transplantation is a treatment option with favorable outcomes. However, there is very little information available on this procedure in patients with AATD.
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.
To determine the safety and explore the efficacy of ALN-RSV01 in RSV infection.
We performed a randomized, double-blind, placebo-controlled trial in LTX recipients with RSV respiratory tract infection. Patients were permitted to receive standard of care for RSV. Aerosolized ALN-RSV01 (0.6 mg/kg) or placebo was administered daily for 3 days. Viral load was determined by quantitative reverse transcriptase-polymerase chain reaction on serial nasal swabs. Patients completed symptom score cards twice daily. Lung function, including the incidence of new-onset or progressive bronchiolitis obliterans syndrome, was recorded at Day 90.
We enrolled 24 patients (ALN-RSV01, n = 16; placebo, n = 8); randomization was stratified by ribavirin use. ALN-RSV01 was well tolerated, with no drug-related serious adverse events or post-inhalation perturbations in lung function. Interpretation of viral measures was confounded by baseline differences between the two groups in viral load and time from symptom onset to first dose. Mean daily symptom scores were lower in subjects receiving ALN-RSV01, and the mean cumulative daily total symptom score was significantly lower with ALN-RSV01 (114.7 ± 63.13 vs. 189.3 ± 99.59, P = 0.035). At Day 90, incidence of new or progressive bronchiolitis obliterans syndrome was significantly reduced in ALN-RSV01 recipients compared with placebo (6.3% vs. 50%, P = 0.027).
ALN-RSV01 was safe and may have beneficial effects on long-term allograft function in LTX patients infected with RSV. Clinical trial registered with www.clinicaltrials.gov (NCT 00658086).
Abstract 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. Due to the potentially devastating effects of CMV, transplant surgeons and physicians have been challenged to fully understand this infectious complication and find the best ways to prevent and treat it to ensure optimal patient outcomes. Summary Lung, heart, and heart-lung recipients are at considerably high risk of CMV infection. Both direct and indirect effects of CMV in these populations have potentially lethal consequences. The use of available treatment options depend on the level of risk of each patient population for CMV infection and disease. Those at the highest risk are CMV negative recipients of CMV positive organs (D+/R−), followed by D+/R+, and D−/R+. More than 1 guideline exists delineating prevention and treatment options for CMV, and new guidelines are being developed. It is hoped that new treatment algorithms will provide further guidance to the transplantation community. The first part describes the overall effects of CMV, both direct and indirect; risk factors for CMV infection and disease; methods of diagnosis; and currently available therapies for prevention and treatment. Part 2 similarly addresses antiviral-resistant CMV, summarizing incidence, risk factors, methods of diagnosis, and treatment options. Parts 3 and 4 present cases to illustrate issues surrounding CMV in heart and lung transplantation, respectively. Part 3 discusses the possible mechanisms by which CMV can cause damage to the coronary allograft and potential techniques of avoiding such damage, with emphasis on fostering strong CMV-specific immunity. Part 4 highlights the increased incidence of CMV infection and disease among lung transplant recipients and its detrimental effect on survival. The possible benefits of extended-duration anti-CMV prophylaxis are explored, as are those of combination prophylaxis with valganciclovir and CMVIG. Conclusion Through improved utilization of information regarding optimized antiviral therapy for heart and lung transplant recipients to prevent and treat CMV infection and disease and through increased understanding of clinical strategies to assess, treat, and monitor patients at high risk for CMV recurrence and resistance, the health care team will be able to provide the coordinated effort needed to improve patient outcomes.
Cytomegalovirus (CMV) infection remains a serious problem in lung transplant recipients. Development of potent oral antiviral agents, molecular techniques for the detection of infection and its ...response to therapy and the emergence of isolates with antiviral resistance have had significant impacts on the approach to CMV in these patients. This article discusses the following issues as part of a comprehensive CMV management strategy in lung transplant recipients: (1) Prevention strategies in the era of potent oral antiviral agents, (2) the role of new diagnostic techniques in the management of CMV, (3) treatment regimens for established CMV infection or disease, (4) the potential impact of treatment of CMV on the indirect effects on long‐term allograft function, and (5) the incidence, risk factors for and impact of ganciclovir resistance following lung transplantation.
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.
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. There were 2 coprimary endpoints: time-weighted average change in nasal RSV load from day 1 to 7, calculated from nasal swabs, in the full analysis set (FAS; all patients who received study drug and had quantifiable baseline nasal RSV load) and time-weighted average change in nasal RSV load from day 1 to 7 in the subset of patients with pretreatment symptom duration at the median or shorter of the FAS. Secondary endpoints were changes in respiratory infection symptoms assessed using the Influenza Patient-Reported Outcomes questionnaire and lung function measured by spirometry.
Sixty-one patients were randomized, 40 received presatovir, 20 placebo, and 54 were included in efficacy analyses. Presatovir did not significantly improve the primary endpoint in the FAS (treatment difference 95% CI, 0.10 −0.43, 0.63 log10 copies/ml; p = 0.72) or the shorter symptom-duration subgroup (−0.12 −0.94, 0.69 log10 copies/ml; p = 0.76). Secondary endpoints were not different between presatovir and placebo groups. Presatovir was generally well tolerated.
Presatovir treatment did not significantly improve change in nasal RSV load, symptoms, or lung function in lung transplant recipients.
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. CMV and HHV-6 and -7 are increasingly recognized as major causes of morbidity and mortality in lung transplant recipients. EBV and HHV-8 have proven oncogenic potential. HSV-1 and -2 and VZV are neurotropic, causing perioral fever blisters, genital ulcerations, and, rarely, encephalitis. This article discusses the individual pathogens, preventive strategies in the era of potent treatment regimens for established viral infection or disease and their potential impact on the indirect effects of these viruses on long-term allograft function, and the incidence, risk factors for, and impact of antiviral resistance.
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.
To determine changes in resource use over time in lung transplant admissions.
Solid organ transplant recipients were identified within the Nationwide Inpatient Sample (NIS) data from 2000 to 2011. Joinpoint regression methodology was performed to identify a time point of change in mean total hospital charges among lung transplant and other solid-organ transplant recipients. Two temporal lung transplant recipient cohorts identified by joinpoint regression were compared for baseline characteristics and resource use, including total charges for index hospitalization, charges per day, length of stay, discharge disposition, tracheostomy, and need for extracorporeal membrane oxygenation.
A significant point of increased total hospital charges occurred for lung transplant recipients in 2005, corresponding to LAS implementation, which was not seen in other solid-organ transplant recipients. Total transplant hospital charges increased by 40% in the post-LAS cohort ($569,942 $53,229 vs. $407,489 $28,360) along with an increased median length of stay, daily charges, and discharge disposition other than to home. Post-LAS recipients also had higher post-transplant use of extracorporeal membrane oxygenation (odds ratio, 2.35; 95% confidence interval, 1.56-3.55) and higher incidence of tracheostomy (odds ratio, 1.52; 95% confidence interval, 1.22-1.89).
LAS implementation is associated with a significant increase in resource use during index hospitalization for lung transplant.
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