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. 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. RESULTS: 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. CONCLUSIONS: Presatovir treatment did not significantly improve change in nasal RSV load, symptoms, or lung function in lung transplant recipients.

Acute Rejection and Chronic Lung Allograft Dysfunction: Obstructive and Restrictive Allograft Dysfunction.

Lung transplantation is an established treatment of well-selected patients with end-stage respiratory diseases. However, lung transplant recipients have the highest rates of acute and chronic rejection among transplanted solid organs. Owing to ongoing alloimmune recognition and associated immune-driven airway/vascular remodeling, precipitated by multifactorial, endogenous or exogenous, post-transplant injuries to the bronchovascular axis of the secondary pulmonary lobule, most lung transplant recipients will suffer from a pathophysiological decline of their allograft, either functionally and/or structurally. This review discusses current knowledge, barriers, and gaps in acute cellular rejection and chronic lung allograft dysfunction-the greatest impediment to long-term post-transplant survival.

Bronchiolitis obliterans syndrome after lung or haematopoietic stem cell transplantation: current management and future directions.

Bronchiolitis obliterans syndrome (BOS) may develop after either lung or haematopoietic stem cell transplantation (HSCT), with similarities in histopathological features and clinical manifestations. However, there are differences in the contributory factors and clinical trajectories between the two conditions. BOS after HSCT occurs due to systemic graft-versus-host disease (GVHD), whereas BOS after lung transplantation is limited to the lung allograft. BOS diagnosis after HSCT is more challenging, as the lung function decline may occur due to extrapulmonary GVHD, causing sclerosis or inflammation in the fascia or muscles of the respiratory girdle. Treatment is generally empirical with no established effective therapies. This review provides rare insights and commonalities of both conditions, which are not well elaborated elsewhere in contemporary literature, and highlights the importance of cross disciplinary learning from experts in other transplant modalities. Treatment algorithms for each condition are presented, based on the published literature and consensus clinical opinion. Immunosuppression should be optimised, and other conditions or contributory factors treated where possible. When initial treatment fails, the ultimate therapeutic option is lung transplantation (or re-transplantation in the case of BOS after lung transplantation) in carefully selected candidates. Novel therapies under investigation include aerosolised liposomal cyclosporine, Janus kinase inhibitors, antifibrotic therapies and (in patients with BOS after lung transplantation) B-cell-directed therapies. Effective novel treatments that have a tangible impact on survival and thereby avoid the need for lung transplantation or re-transplantation are urgently required.

The pulmonary microbiome: recent advances in understanding its role in chronic lung allograft dysfunction.

PURPOSE OF REVIEW: Lung transplantation presents a rescue therapy for those with end-stage lung disease. Survival in lung transplant patients remains limited due to chronic lung allograft dysfunction (CLAD), a range of pathologic manifestations leading to graft loss. The mechanisms underlying CLAD remain poorly understood, and the lung microbiome has been suggested as a potential contributor to this condition. This review aims to explore how the pulmonary microbiome is impacted by lung transplantation, and how alterations in this microbiome may contribute to the pathogenesis of CLAD. RECENT FINDINGS: The pulmonary microbiome is made up of a range of microorganisms, and it varies considerably in lung transplant patients when compared with healthy controls. The lung microbiome changes over the early transplant period, and the composition of species appears to have an impact on inflammatory responses within the lungs. A number of studies have shown that an increase in bacterial biomass in the allograft, and enrichment with the genera Proteobacteria, or more specifically, Pseudomonas species, is associated with CLAD. SUMMARY: This area of research is still in its infancy; however, the suggestion that changes in the composition of the microbiome and enrichment with certain species may predispose to the pathologic changes that underlie CLAD indicate that modulation of the microbiome may be of use in potential future therapeutics.

Respiratory Syncytial Virus, Human Metapneumovirus, and Parainfluenza Virus Infections in Lung Transplant Recipients: A Systematic Review of Outcomes and Treatment Strategies.

BACKGROUND: Respiratory syncytial virus (RSV), parainfluenza virus (PIV), and human metapneumovirus (hMPV) are increasingly associated with chronic lung allograft dysfunction (CLAD) in lung transplant recipients (LTR). This systematic review primarily aimed to assess outcomes of RSV/PIV/hMPV infections in LTR and secondarily to assess evidence regarding the efficacy of ribavirin. METHODS: Relevant databases were queried and study outcomes extracted using a standardized method and summarized. RESULTS: Nineteen retrospective and 12 prospective studies were included (total 1060 cases). Pooled 30-day mortality was low (0-3%), but CLAD progression 180-360 days postinfection was substantial (pooled incidences 19-24%) and probably associated with severe infection. Ribavirin trended toward effectiveness for CLAD prevention in exploratory meta-analysis (odds ratio [OR] 0.61, [0.27-1.18]), although results were highly variable between studies. CONCLUSIONS: RSV/PIV/hMPV infection was followed by a high CLAD incidence. Treatment options, including ribavirin, are limited. There is an urgent need for high-quality studies to provide better treatment options for these infections.

High-resolution Metatranscriptomic Characterization of the Pulmonary RNA Virome After Lung Transplantation.

BACKGROUND: Lung transplantation provides a unique opportunity to investigate the constituents and temporal dynamics of the human pulmonary microbiome after lung transplantation. For methodological reasons, prior studies using metagenomics have detected DNA viruses but not demonstrated the presence of RNA viruses, including those that are common community acquired. In this proof-of-concept study, we aimed to further characterize the pulmonary microbiome after lung transplantation by using metagenomic next-generation sequencing (mNGS), with a particular focus on the RNA virome. METHODS: We performed a single-center longitudinal study of lower respiratory tract RNA viruses and bacteria using bronchoalveolar lavage at postoperative day 1 and week 6 analyzed with total RNA sequencing (metatranscriptomics). Five primary and 5 repeat transplant recipients were recruited. RESULTS: mNGS identified 5 RNA viruses (nil in the normal saline control), including 4 species of human rhinovirus not previously reported in Australia: A7 (HRV-A7), C22 (HRV-C22), B52 (HRV-B52), and B72 (HRV-B72). Overall, 12/20 specimens were virus positive in 7/10 cases. Human parainfluenza virus 3 was the most frequent virus in 7/20 specimens in 5/10 cases. In this small study, we did not detect a significant difference in abundance and diversity of RNA viruses and bacteria at postoperative day 1 and 6 wk, nor differences between retransplant recipients and primary lung transplant recipients. CONCLUSIONS: Our study demonstrates how mNGS can also identify RNA viruses within the human pulmonary virome, including novel RNA viruses, and paves the way for a greater understanding of the complex relationships among the constituents of the pulmonary infectome.

ISHLT consensus document on lung transplantation in patients with connective tissue disease: Part III: Pharmacology, medical and surgical management of post-transplant extrapulmonary conditions statements.

Patients with connective tissues disease (CTD) are often on immunomodulatory agents before lung transplantation (LTx). Till now, there's no consensus on the safety of using these agents perioperative and post-transplant. The International Society for Heart and Lung Transplantation-supported consensus document on LTx in patients with CTD addresses the risk and contraindications of perioperative and post-transplant management of the biologic disease-modifying antirheumatic drugs (bDMARD), kinase inhibitor DMARD, and biologic agents used for LTx candidates with underlying CTD, and the recommendations and management of non-gastrointestinal extrapulmonary manifestations, and esophageal disorders by medical and surgical approaches for CTD transplant recipients.

Consensus document for the selection of lung transplant candidates: An update from the International Society for Heart and Lung Transplantation.

Tens of thousands of patients with advanced lung diseases may be eligible to be considered as potential candidates for lung transplant around the world each year. The timing of referral, evaluation, determination of candidacy, and listing of candidates continues to pose challenges and even ethical dilemmas. To address these challenges, the International Society for Heart and Lung Transplantation appointed an international group of members to review the literature, to consider recent advances in the management of advanced lung diseases, and to update prior consensus documents on the selection of lung transplant candidates. The purpose of this updated consensus document is to assist providers throughout the world who are caring for patients with pulmonary disease to identify potential candidates for lung transplant, to optimize the timing of the referral of these patients to lung transplant centers, and to provide transplant centers with a framework for evaluating and selecting candidates. In addition to addressing general considerations and providing disease specific recommendations for referral and listing, this updated consensus document includes an ethical framework, a recognition of the variability in acceptance of risk between transplant centers, and establishes a system to account for how a combination of risk factors may be taken into consideration in candidate selection for lung transplantation.

Incidence of early diaphragmatic dysfunction after lung transplantation: results of a prospective observational study.

BACKGROUND: Diaphragmatic dysfunction is common after cardiothoracic surgery, but few studies report its incidence and consequences after lung transplantation. We aimed to estimate the incidence of diaphragmatic dysfunction using ultrasound in lung transplant patients up to 3 months postoperatively and evaluated the impact on clinical outcomes. METHODS: This was a single-center prospective observational cohort study of 27 lung transplant recipients using diaphragmatic ultrasound preoperatively, at 1 day, 1 week, 1 month, and 3 months postoperatively. Diaphragmatic dysfunction was defined as excursion < 10 mm in men and < 9 mm in women during quiet breathing. Clinical outcomes measured included duration of mechanical ventilation, length of stay (LOS) in Intensive Care (ICU), and hospital LOS. RESULTS: Sixty-two percentage of recipients experienced new, postoperative diaphragmatic dysfunction, but the prevalence fell to 22% at 3 months. No differences in clinical outcomes were found between those with diaphragmatic dysfunction compared to those without. Patients who experienced diaphragmatic dysfunction at 1 day postoperatively were younger and had a lower BMI than those who did not. CONCLUSIONS: Diaphragmatic dysfunction is common after lung transplant, improves significantly within 3 months, and did not impact negatively on duration of mechanical ventilation, LOS in ICU or hospital, or discharge destination.

The Impact of Resistant Bacterial Pathogens including Pseudomonas aeruginosa and Burkholderia on Lung Transplant Outcomes.

Pseudomonas and Burkholderia are gram-negative organisms that achieve colonization within the lungs of patients with cystic fibrosis, and are associated with accelerated pulmonary function decline. Multidrug resistance is a hallmark of these organisms, which makes eradication efforts difficult. Furthermore, the literature has outlined increased morbidity and mortality for lung transplant (LTx) recipients infected with these bacterial genera. Indeed, many treatment centers have considered Burkholderia cepacia infection an absolute contraindication to LTx. Ongoing research has delineated different species within the B. cepacia complex (BCC), with significantly varied morbidity and survival profiles. This review considers the current evidence for LTx outcomes between the different subspecies encompassed within these genera as well as prophylactic and management options. The availability of meta-genomic tools will make differentiation between species within these groups easier in the future, and will allow more evidence-based decisions to be made regarding suitability of candidates colonized with these resistant bacteria for LTx. This review suggests that based on the current evidence, not all species of BCC should be considered contraindications to LTx, going forward.

RNAi therapeutics: an antiviral strategy for human infections.

Gene silencing induced by RNAi represents a promising antiviral development strategy. This review will summarise the current state of RNAi therapeutics for treating acute and chronic human virus infections. The gene silencing pathways exploited by RNAi therapeutics will be described and include both classic RNAi, inducing cytoplasmic mRNA degradation post-transcription and novel RNAi, mediating epigenetic modifications at the transcription level in the nucleus. Finally, the challenge of delivering gene modifications via RNAi will be discussed, along with the unique characteristics of respiratory versus systemic administration routes to highlight recent advances and future potential of RNAi antiviral treatment strategies.

Endothelial to mesenchymal transition (EndMT) and vascular remodeling in pulmonary hypertension and idiopathic pulmonary fibrosis.

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and irreversible fibrotic disease associated with respiratory failure. The disease remains idiopathic, but repeated alveolar epithelium injury, disruption of alveolar-capillary integrity, abnormal vascular repair, and pulmonary vascular remodeling are considered possible pathogenic mechanisms. Also, the development of comorbidities such as pulmonary hypertension (PH) could further impact disease outcome, quality of life and survival rates in IPF. AREAS COVERED: The current review provides a comprehensive literature survey of the mechanisms involved in the development and manifestations of IPF and their links to PH pathology. This review also provides the current understanding of molecular mechanisms that link the two pathologies and will specifically decipher the role of endothelial to mesenchymal transition (EndMT) along with the possible triggers of EndMT. The possibility of targeting EndMT as a therapeutic option in IPF is discussed. EXPERT OPINION: With a steady increase in prevalence and mortality, IPF is no longer considered a rare disease. Thus, it is of utmost importance and urgency that the underlying profibrotic pathways and mechanisms are fully understood, to enable the development of novel therapeutic strategies.