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.

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.

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.

Population pharmacokinetics of ribavirin in lung transplant recipients and examination of current and alternative dosing regimens.

BACKGROUND: Ribavirin is used in the treatment of respiratory paramyxovirus infection in lung transplant recipients; however, its pharmacokinetic profile in the transplant population is unknown despite the potential for alterations due to underlying pathology. Furthermore, the ability of current regimens to meet exposure targets has not been established. OBJECTIVES: This study examined the pharmacokinetics of ribavirin in a lung transplant population for which current and alternative dosing regimens were assessed. METHODS: Population pharmacokinetic modelling was conducted in NONMEM using concentration-time data from 24 lung transplant recipients and 6 healthy volunteers. Monte Carlo simulation was used to assess the ability of dosing regimens to achieve pre-specified target concentrations. RESULTS AND CONCLUSIONS: A three-compartment model with first-order elimination most adequately described ribavirin concentration-time data, with CLCR and patient type (i.e. lung transplant) identified as significant covariates in the model. Simulations indicate that current regimens achieve efficacious concentrations within 24 h of treatment initiation that increase to supra-therapeutic levels over the treatment period. A regimen of 8 mg/kg q6h orally for 48 h followed by 8 mg/kg q24h orally for the remainder of the treatment period was predicted to result in >90% of patients exhibiting concentrations within the defined target range throughout the entire treatment course. Additional work to formally establish target therapeutic concentrations is required; however, this study provides a valuable first step in determining optimal ribavirin treatment regimens for paramyxovirus infections in the lung transplant population.

Tacrolimus exposure early after lung transplantation and exploratory associations with acute cellular rejection.

AIMS: To (i) describe tacrolimus (TAC) pre-dose concentrations (C0), (ii) calculate apparent oral TAC clearance (CL/FHCT) adjusted for measured haematocrit (HCTi) and standardised to a HCT of 45%, across three observation time points and (iii) explore if low TAC C0 or high mean CL/FHCT are associated with an increased risk of rejection episodes early after lung transplantation. METHODS: TAC whole blood concentration-time profiles and transbronchial biopsies were performed prospectively at weeks 3, 6 and 12 after lung transplantation. The TAC pre-dose concentration (C0) was measured, and CL/FHCT was determined using non-compartmental analysis. The associations between TAC C0 and CL/FHCT and rejection status were explored using repeated measures logistic regression. RESULTS: Eighteen patients provided 377 TAC whole blood concentrations. Considerable variability around the median (IQR) CL/FHCT 6.8 (4.2-15.9) L h-1, and the median C0 12.7 (9.9-16.6) µg L-1 was noted. Despite adjustment for haematocrit, a significant decrease was observed in CL/FHCT in all patients over time: CL/FHCT 14 (5.4-23) at week 3, CL/FHCT 7.7 (4.5-12) at week 6 and CL/FHCT 3.9 (2.4-11) L h-1 at week 12 (p < 0.01). Seven (38.9%) patients experienced a single grade 2 rejection, whilst 11 (61.1%) patients experienced no rejection. Higher TAC C0 were associated with a reduced risk of rejection OR 0.68 (95% CI 0.51-0.91, p = 0.02), and greater mean CL/FHCT was associated with an increased risk of rejection OR 1.34 (95% CI 1.01-1.81 p = 0.04). CONCLUSION: Monitoring TAC C0, HCT and CL/FHCT in patients after lung transplantation may assist clinicians in detecting patients at risk of acute rejection and may guide future research into TAC and HCT monitoring after lung transplantation.

Clinical predictors for oropharyngeal dysphagia and laryngeal dysfunction after lung and heart transplantation.

BACKGROUND: Oropharyngeal dysphagia and laryngeal dysfunction are two lesser known complications after lung and heart transplantation. The presence of these features places this immunocompromised population at high risk of pulmonary complications and subsequent medical deterioration. Early identification of swallowing and voice dysfunction would be beneficial to optimize management. AIMS: To examine the association between patient risk factors and postoperative outcomes with referral to speech pathology (SP) following signs of swallowing and voice dysfunction. METHODS & PROCEDURES: A retrospective review was conducted on demographic data, patient risk factors and postoperative course in 284 patients following lung and/or heart transplantation between 2010 and 2013. Variables were analysed for any association between pre- and postoperative factors and SP referral. OUTCOMES & RESULTS: A total of 24% were referred to SP with a mean age of 47 years. Binary logistic regression identified a statistically significant association between the number of intubations (odds ratio (OR) = 2.066, p = 0.028), intubation duration (OR = 1.004, p < 0.01), length of stay in the intensive care unit (ICU) (OR = 1.068, p < 0.01), and number of ICU admissions (OR = 1.384, p = 0.046) and SP referral. Intubation time and the total days in ICU were greater for patients referred to SP. Mortality also increased for these variables and for the numbers of reintubations and readmissions. Analysis of pre-operative risk factors revealed cerebrovascular disease to be a significant predictor of SP referral (OR = 6.747, p = 0.032). CONCLUSIONS & IMPLICATIONS: This study demonstrates significant clinical indicators for referral to SP for the management of oropharyngeal dysphagia and laryngeal dysfunction in patients after lung or heart transplantation. Further studies are needed to investigate the most efficacious intervention approaches to manage swallowing and voice dysfunction in these patients.

Older Patients' Perspectives of Online Health Approaches in Chronic Obstructive Pulmonary Disease.

Background: Chronic obstructive pulmonary disease (COPD) is a complex, chronic condition. Patients commonly have limited access to face-to-face support due to decreased mobility, symptom burden, and availability of services. Online health care approaches provide the potential for increased access to self-management education and support. This study sought to understand older patients with COPD's perspectives of online approaches to health care. Materials and Methods: Participants older than 65 years were recruited from a respiratory service at an academic medical center. Qualitative, focus groups were used and recorded, transcribed verbatim, and analyzed using thematic analysis to identify key and repeated emergent themes. Results: Focus groups were undertaken between January and May 2014. Thematic analysis resulted in five overall themes: (1) concern over risks in the online environment; (2) multimedia and technology use as part of everyday life; (3) online resources as an opportunity for revision of forgotten knowledge; (5) potential for facilitation of decision-making support across geographical and physical barriers; and (4) perceived benefits of online peer support for people with COPD. Conclusions: Overall, these older participants with COPD had positive views of online health information, but did raise the need for guidance to ensure valid and reliable online sources. The capacity for online sources to increase access to decision support and up-to-date information was viewed positively, as was the ability to interact with peers who had similar experiences. Telecommunication tools and approaches are already being utilized in health care interactions. Further research is required into the most appropriate, feasible, and sustainable online health approaches to support patients with chronic illnesses such as COPD.

Lung transplantation for non-small cell lung cancer and multifocal bronchioalveolar cell carcinoma.

Lung transplantation for primary bronchogenic cancer could lead to increased survival and improved quality of life for patients who have malignant disease, for which other therapies might be inappropriate. This Review examines the development of experience and outcomes for this indication and explores the limitations that are inherent in lung transplantation for malignant disease. Bronchogenic malignancy is a rare indication for lung transplantation constituting only 0·13% of all lung transplants in the USA from 1987 to 2010 and is only indicated for early-stage disease when conventional surgical techniques are contraindicated by poor lung function in which an unacceptably high risk of short-term mortality is expected. Outcomes can be extrapolated from the experience of finding an unexpected malignancy in an explanted lung for which approximately 30% of recipients, dependent on stage, succumb from distant metastatic disease in the first few years after transplant, after which long-term survival is similar to transplantation for other conditions. Care must be taken for lung transplantation for multifocal bronchoalveolar cell carcinoma to ensure that the donor lung is not contaminated with residual bronchoalveolar cell carcinoma cells in the upper airways during surgical implantation. The rarity of lung transplantation for cancer, and the absence of head-to-head trials comparing lung transplantation with conventional cancer care, limit the conclusions that can be drawn about lung transplantation for this indication. Furthermore, the ethical balance of how to allocate a scarce resource, such as a donor lung, remains an unresolved dilemma given the uncertainties regarding long-term survival. Conversely, individual patients might have substantial increases in survival and quality of life equivalent or superior to conventional cancer treatment methods.

Systematic review and meta-analysis of post-transplant lymphoproliferative disorder in lung transplant recipients.

A systematic review of papers in English on post-transplant lymphoproliferative disorder (PTLD) in lung transplant recipients (LTR) using MEDLINE, EMBASE, SCOPUS, and Cochrane databases was performed. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations were strictly adhered to. Pooled odds ratios (pOR) were calculated from a random-effects model, and heterogeneity among studies was quantitated using I2 values. Fourteen studies published from 2005 to 2015 were included in the meta-analysis. One hundred and sixty-four lung transplant recipients were included. LTRs who received single vs bilateral were associated with a 7.67-fold risk of death after PTLD (6 studies with 64 LTRs; pOR 7.67 95% CI 1.98-29.70; P = .003). pOR of death for early onset PTLD (<1 year post-LT) vs late onset (>1 year post-LT) was not different (3 studies with 72 LTRS; pOR 0.62, 95% CI 0.20-1.86, P = .39). Standardized mean difference (SMD) in time from transplant to PTLD onset between LTRs who died vs alive was not different (9 studies with 109 LTRs; SMD 0.03, 95% CI -0.48-0.53, P = .92). Survival in polymorphic vs monomorphic PTLD and extranodal vs nodal disease was similar (4 studies with 31 LTRs; pOR 0.44, 95% CI 0.08-2.51; P = .36. 6 studies with 81 LTRs; pOR 1.05 95% CI 0.31-3.52, P = .94). This meta-analysis demonstrates that single LTRs are at a higher risk of death vs bilateral LTRs after the development of PTLD.

The Human Respiratory Microbiome: Implications and Impact.

Once considered a sterile site below the larynx, the tracheobronchial tree and parenchyma of the lungs are now known to harbor a rich diversity of microbial species including bacteria, viruses, fungi, and archaea. Many of these organisms, particularly the viruses which comprise the human respiratory virome, have not been identified, so their true role is unknown. It seems logical to conclude that a "healthy" respiratory microbiome exists which may be modified in disease states and perhaps by therapies such as antibiotics, antifungals, and antiviral treatments. It is likely that there is a critical relationship or equilibrium between components of the microbiome until such time as perturbations occur which lead to a state of dysbiosis or an "unhealthy" microbiome. The act of lung transplantation provides an extreme change to an individual's respiratory microbiome as, in effect, the donor respiratory microbiome is transplanted into the recipient. The mandatory ex-vivo period of the donor lungs appears to be associated with blooms of resident viral species in particular. Subsequently, allograft injury, rejection, and immune suppressive therapy all combine to create periods of dysbiosis which when combined with transient infections such as community acquired respiratory viruses may facilitate the development of chronic allograft dysfunction in predisposed individuals. As our understanding of the respiratory microbiome is rapidly expanding, based on the use of new-generation sequencing tools in particular, it is to be hoped that insights gained into the subtle relationship between the microbiome and the lung allograft will facilitate improved outcomes by directing novel therapeutic endeavors.

High prevalence of diabetes before and after lung transplantation: target for improving outcome?

BACKGROUND: Diabetes increases morbidity and mortality of lung transplantation. However, the reported prevalence of diabetes varies post-transplantation partly due to lack of detection protocols. AIM: To determine the prevalence of diabetes in patients (i) waitlisted for lung transplant and (ii) early post-transplantation. METHODS: We analysed patients on the St Vincent's Heart Lung database from 1 April 2014 to 30 September 2015 on the waitlist (Study 1) and those transplanted (Study 2). Standard of care required all non-diabetic patients to have an oral glucose tolerance test (modified for patients with cystic fibrosis (CF) to screen for CF-related hyperglycaemia (CFRH) (plasma glucose ≥8.2 mmol/L at 60 or 90 min). RESULTS: Study 1 included 114 patients (32 with CF and 82 without CF). Of 30 CF patients with glycaemic data, 27 (90%) had abnormal glucose metabolism: 18 had diabetes and nine had CFRH. In 50 patients without CF, 20 (40%) had abnormal glucose metabolism: eight had diabetes and 12 had impaired fasting glucose and/or impaired glucose tolerance. Study 2 included 78 transplanted patients (25 with CF and 53 without CF). Fourteen CF patients had pre-existing diabetes and seven had pre-existing CFRH. All but one patient were diagnosed with diabetes post-transplantation. Hence, diabetes prevalence in CF patients post-transplantation was 96%. Among 53 transplanted patients without CF, seven (13%) had abnormal glucose metabolism but 30 (57%) were diagnosed with post-transplant diabetes. CONCLUSION: There is a high prevalence of diabetes in lung transplant patients. Earlier endocrine participation in lung transplant services is likely to lower diabetes-related morbidity and mortality further.

Herpes simplex virus-2 transmission following solid organ transplantation: Donor-derived infection and transplantation from prior organ recipients.

BACKGROUND: Owing to limited availability of donor organs, previous solid organ transplant (SOT) recipients are increasingly considered as potential organ donors. We report donor-derived transmission of herpes simplex virus type-2 (HSV-2) to two clusters of SOT recipients with transmission from the original donor and an HSV-2-infected recipient who subsequently became a donor. METHODS: We reviewed medical records of the donors and recipients in both clusters. Pre-transplant serology and virological features of HSV-2 were characterized. Genotyping of HSV-2 isolates to determine potential for donor transmission of HSV-2 through transplantation of organs from prior organ recipients was performed. RESULTS: A kidney-pancreas recipient died day 9 post transplant. Following confirmation of brain death, the lungs and recently transplanted kidney were donated to two further recipients. The liver was not retrieved, but biopsy confirmed HSV-2 infection. Testing on the original donor showed negative HSV-2 polymerase chain reaction and HSV immunoglobulin (Ig)M, but positive HSV-2 IgG. The liver recipient from the original donor developed HSV-2 hepatitis and cutaneous infection that responded to treatment with intravenous acyclovir. In the second cluster, lung and kidney recipients both developed HSV-2 viremia that was successfully treated with antiviral therapy. Genotyping of all HSV-2-positive samples showed 100% sequence homology for three recipients. CONCLUSIONS: Donor-derived HSV infection affected two clusters of recipients because of transplantation of organs from a prior organ recipient. HSV should be considered as a possible cause of illness in febrile SOT recipients in the immediate post-transplant period and may cause disseminated disease and re-infection in HSV-2-seropositive recipients. Testing of HSV serology and prophylaxis may be considered in SOT recipients not receiving cytomegalovirus prophylaxis.

Translational Aspects of the Human Respiratory Virome.

Despite the dominant role of community-acquired respiratory viruses as etiological agents of disease, there has been little focus to date on the translation of rapidly developing diagnostic modalities, such as next-generation sequencing techniques in the examination of lower respiratory tract samples. When applied, these techniques should inform strategies to both understand the nexus between health and disease states of the respiratory virome, and drive a paradigm shift in how the practicing pulmonologist views the conceptual framework of respiratory infections. The lower respiratory tract was once thought to be a sanctuary site from microbiological colonization owing to the efficacy of upper airway-protective mechanisms and the host mucosal barrier function of the lower airways, combined with both innate and adaptive immune responses. As a small number of recent studies confirm, this is a naive vision of the lung, the viral component of which parallels recent revelations from respiratory microbiome studies. Hence, it is now timely to revise our thinking regarding the constituents, diversity, and changing nature of the respiratory virome in health and disease. One area worthy of focus is the interface between community-acquired respiratory viruses and the respiratory virome to better understand the dynamics in acute infection, as well as the factors that may lead to viral persistence and chronic disease. Given recent advances in metagenomics, the tools are now at hand to accomplish these goals.