Ethical considerations in xenotransplantation of thoracic organs - a call for a debate on value based decisions.

Xenotransplant covers a broad ethical territory and there are several ethical questions that have arisen in parallel with the technological advances that have allowed the first porcine transplants to occur. This brief communication highlights ethical considerations regarding heart and lung xenotransplantation, with an emphasis on unresolved value-based concerns in the field. The aim of this text is therefore to encourage the readers to consider the vast potential of this emerging technique to do good, but also the risk of doing harm, and to participate in a discussion. The list of questions presented here is not exhaustive but hopefully represents some of the questions that appear to be most pressing as the field advances. The focus is on the value-based, or ethical questions, not the questions related to the practical medical procedures.

Candidate selection for lung transplantation - considerations beyond the medical evidence.

PURPOSE OF REVIEW: The scarcity of organs available for lung transplantation makes it necessary to develop consistent practices for candidate selection and organ allocation. Such policies are mainly built on prognostic estimations, which are again built on medical evidence. In addition, however, other factors also guide these practices. These factors are not always explicit. The purpose of this review is to discuss some of these factors. RECENT FINDINGS: While one candidate may be considered to be in need of a transplant, the extent to which this need is weighed up against other patients at need varies, depending on how societal responsibility is conceived at the transplant center. Individual survival benefit may be in conflict with the concept of a just distribution of life years ('fair innings'). Furthermore, the need to expand medical knowledge, and the perceived patient autonomy and right to choose may affect the selection and allocation practices. Finally, financial considerations and nationality may have great influence. SUMMARY: Although well trained in medical judgment, the clinicians' candidate selection for lung transplantation is often influenced by factors beyond the medical evidence. These factors should be discussed just as transparently and accountably as the medical judgments.

Lung transplantation in Norway 1999-2020. / Lungetransplantasjon i Norge 1999­2020.

BACKGROUND: Since 2009, patients with a rapidly progressing lung disease have been given a higher priority on the waiting list for a lung transplant. The purpose of our study was to examine diagnosis distribution, waiting list times, mortality and survival for patients on the waiting list in the period 1999-2020. MATERIAL AND METHOD: We conducted a descriptive, retrospective study of patients on the waiting list for a lung transplant in the periods 1999-2008 and 2009-2020. RESULTS: A total of 557 lung transplants were performed: 185 in 1999-2008 (median of 17.5 per year) and 372 in 2009-2020 (median of 32.5 per year). In the periods 1999-2008 and 2009-2020, the proportion of patients with chronic obstructive pulmonary disease (COPD)/emphysema was 67 % and 49 %, respectively. The corresponding figures for pulmonary fibrosis were 13 % and 23 %, and for cystic fibrosis 5 % and 11 %. Waiting list mortality was 27 % in 1999-2008 and 16 % in 2009-2020. Correspondingly for the two periods, waiting list mortality for patients with pulmonary fibrosis was 45 % and 22 %, and for cystic fibrosis 41 % and 2 %. Waiting times were shorter for all diagnoses in the period after the change in priority and longest for patients with COPD/emphysema (median of 381 days). Median survival after lung transplantation during the study period was ten years. INTERPRETATION: For patients with pulmonary fibrosis and cystic fibrosis, the change in transplant priority in 2009 may have played a role in reducing waiting list mortality.

Digital Outpatient Services for Adults: Development of an Intervention and Protocol for a Multicenter Non-Randomized Controlled Trial.

BACKGROUND: Health care services are being challenged by an increasing number of patients and limited resources. Hence, research investigating options to reduce costs and increase effectiveness is warranted. Digital outpatient services can provide flexible and tailored follow-up, improve patients' health literacy, and facilitate the identification of adverse courses of disease. However, previous research largely focused on disease-specific contexts and outcomes. Therefore, research on digital services investigating generic outcomes such as health literacy is warranted. OBJECTIVE: This article aims to describe the "digital outpatient service" intervention and present the protocol for an ongoing multicenter, nonrandomized trial evaluating this intervention. METHODS: Based on previous experiences and evidence-based knowledge, we developed this intervention through patient-journey maps in collaboration with each clinical specialty. The patients gain access to a mobile app for self-monitoring and patient-reported outcomes and a chat for contact between the patients and health care workers. The health care workers' dashboard includes a traffic light system to draw attention to the most urgent patient reports. In this multicenter, non-randomized controlled trial, patients are allocated to the control group receiving standard care or the 6-month intervention. Eligible patients are aged 18 years or older who receive outpatient care at the neurology, lung, pain, or cancer departments at 2 university hospitals in Norway. Our evaluation will include patient-reported outcomes, qualitative interviews, and clinical measures. The primary outcome will be health literacy using the Health Literacy Questionnaire. A sample size of 165 participants is split into a 1:2 ratio in favor of the intervention. We will analyze quantitative data in SPSS (IBM Corp) using descriptive statistics and logistic regression, and qualitative data using thematic analysis. RESULTS: This trial started in September 2021, and the intervention started in January 2022. Recruitment has ended, with 55 patients in the control group and 107 patients in the intervention group. Follow-up is expected to end in July 2023, with results expected to be obtained in December 2023. CONCLUSIONS: This study will evaluate an intervention facilitated by an already certified digital multicomponent solution, with intervention content based on patient-reported outcomes, health literacy, and self-monitoring. The intervention is specifically tailored to each participating center and the needs of their patients using patient journey maps. The comprehensive and generic evaluation of this digital outpatient service intervention is a strength as it targets a heterogeneous sample of patients. Thus, this study will provide important knowledge about the applicability and effects of digital health care services. As a result, patients and health care workers will gain a new, evidence-based understanding of whether and how digital tools may be used in clinical care. TRIAL REGISTRATION: ClinicalTrials.gov NCT05068869; https://clinicaltrials.gov/ct2/show/NCT05068869. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/46649.

Nausea Predicts Bacteremia in Immunocompetent Patients with Pneumococcal Community-Acquired Pneumonia: Secondary Data Analysis from a Prospective Cohort.

BACKGROUND: In pneumococcal community-acquired pneumonia (CAP), bacteremia is associated with increased mortality, but initial clinical severity scores frequently fail to identify bacteremic patients at risk. We have previously shown that gastrointestinal symptoms are common among patients admitted to the hospital with pneumococcal bacteremia. The aim of this study was to examine gastrointestinal symptoms and inflammatory responses in bacteremic and non-bacteremic pneumococcal CAP in a prospective cohort of immunocompromised and immunocompetent patients hospitalized with CAP. METHODS: Logistic regression analysis was used to estimate the predictive value of gastrointestinal symptoms for pneumococcal bacteremia in patients with CAP. The Mann-Whitney test was used to compare inflammatory responses in patients with bacteremic vs. non-bacteremic pneumococcal CAP. RESULTS: Eighty-one patients with pneumococcal CAP were included, of whom 21 (26%) had bacteremia. Immunocompetent patients with pneumococcal CAP had an odds ratio of 16.5 (95% CI 3.0-90.9, p = 0.001) for bacteremia if nausea was present, whereas no such association was found in the immunocompromised patients (OR 0.22, 95% CI 0.02-2.05, p = 0.18). The serum levels of C-reactive protein, procalcitonin and interleukin 6 were significantly higher in the patients with bacteremic pneumococcal CAP compared to non-bacteremic pneumococcal CAP patients (p < 0.001, p = 0.005, and p = 0.019, respectively). CONCLUSIONS: In immunocompetent patients hospitalized with pneumococcal CAP, nausea may be a predictor of bacteremia. Bacteremic pneumococcal CAP patients display an increased inflammatory response compared to non-bacteremic pneumococcal CAP patients.

Raised Serum Markers of T Cell Activation and Exhaustion in Granulomatous-Lymphocytic Interstitial Lung Disease in Common Variable Immunodeficiency.

PURPOSE: About 20-30% of patients with common variable immunodeficiency (CVID) develop granulomatous-lymphocytic interstitial lung disease (GLILD) as one of several non-infectious complications to their immunodeficiency. The purpose of this study was to identify biomarkers that could distinguish GLILD from other non-infectious complications in CVID. METHODS: We analyzed serum biomarkers related to inflammation, pulmonary epithelium injury, fibrogenesis, and extracellular matrix (ECM) remodeling, and compared three subgroups of CVID: GLILD patients (n = 16), patients with other non-infectious complications (n = 37), and patients with infections only (n = 20). RESULTS: We found that GLILD patients had higher levels of sCD25, sTIM-3, IFN-γ, and TNF, reflecting T cell activation and exhaustion, compared to both CVID patients with other inflammatory complications and CVID with infections only. GLILD patients also had higher levels of SP-D and CC16, proteins related to pulmonary epithelium injury, as well as the ECM remodeling marker MMP-7, than patients with other non-infectious complications. CONCLUSION: GLILD patients have elevated serum markers of T cell activation and exhaustion, pulmonary epithelium injury, and ECM remodeling, pointing to potentially important pathways in GLILD pathogenesis, novel targets for therapy, and promising biomarkers for clinical evaluation of these patients.

ISHLT position paper on thoracic organ transplantation in controlled donation after circulatory determination of death (cDCD).

Controlled organ donation after circulatory determination of death is increasingly being used for the donation of organs also in thoracic transplantation. This document outlines the position of the International Society for Heart and Lung Transplantation on thoracic organ transplantation in circulatory determination of death. The document also includes a position regarding some of the methods applied to ensure the viability of Donation after Circulatory Death organs retrieved after certification of death.

Relation of sputum neutrophilia to the development of chronic lung allograft dysfunction after lung transplantation.

Chronic lung allograft dysfunction (CLAD) is a serious complication after lung transplantation (LuTx) and is associated with elevated proportions of neutrophils in bronchoalveolar lavage (BAL). Induced sputum is a less-invasive sampling method than BAL and assesses markers of inflammation on the surfaces of large central airways. We wanted to examine whether % neutrophil levels in induced sputum were elevated prior to CLAD diagnosis among LuTx recipients, and whether sputum markers of inflammation can be used as a tool for predicting the development of CLAD. Induced sputum samples were collected at 1, 3, 6, 12, and 24 months post-LuTx in 36 patients with a history of COPD or pulmonary fibrosis, and of these, 16 developed CLAD either during or after the sputum surveillance period. At 2 years, median (IQR) % neutrophils in induced sputum were significantly higher among patients with CLAD compared with those without CLAD [73 (52-80) % vs 59 (41-76) %, p = .01]. Interestingly, we found a significant increase in the rate of change in % neutrophils beginning at 90 days preceding the diagnosis of CLAD. This suggests using sputum neutrophil percentage as a surveillance modality for monitoring lung allograft function after LuTx.

Gastrointestinal symptoms in invasive pneumococcal disease: a cohort study.

BACKGROUND: The study aimed to assess whether gastrointestinal (GI) symptoms at admission are associated with increased short-term mortality in patients with invasive pneumococcal disease (IPD). METHODS: We included all patients with IPD at Aker University Hospital in Oslo, Norway, from 1993 to 2008. Clinical data were registered. Survival data were retrieved from official registries. We used Cox regression and Kaplan-Meier curve to compare mortality within 28 days of admission in patients with and without GI symptoms. RESULTS: Four hundred sixteen patients were included. Of these, 108 patients (26%) presented with GI symptoms, and 47 patients (11%) with GI symptoms only. Patients with GI symptoms were younger (p < 0.001) and had less cardiovascular disease (p < 0.001), pulmonary disease (p = 0.048), and cancer (p = 0.035) and received appropriate antibiotic treatment later. After adjusting for risk factors, we found an increased hazard ratio of 2.28 (95% CI 1.31-3.97) in patients presenting with GI symptoms. In patients with GI symptoms only there was an increased hazard ratio of 2.24 (95% CI 1.20-4.19) in univariate analysis, which increased to 4.20 (95% CI 2.11-8.39) after multivariate adjustment. Fewer patients with GI symptoms only received antibiotics upon admission. CONCLUSIONS: A large proportion of IPD patients present with GI symptoms only or in combination with other symptoms. GI symptoms in IPD are associated with increased short-term mortality.

Lung allocation for transplant: The European perspective.

Since the first successful lung transplants in humans were done in the 1980s, lung transplantation has become an established treatment for end-stage pulmonary disease. Because the access to transplantable organs is limited and unpredictable, rules that guide the allocation of lungs for transplants have emerged. Such rules are governed not only by medical and bioethical necessities, but also by local traditions, legislation, and practical circumstances. Therefore, there may be significant differences between the organ allocation practices in various parts of the world. In this brief communication, the European perspective on lung allocation is presented, also adding a very brief description of other parts of the world.

Outcomes in cystic fibrosis lung transplant recipients infected with organisms labeled as pan-resistant: An ISHLT Registry‒based analysis.

BACKGROUND: The presence of pan-resistant organisms in patients with cystic fibrosis (CF) potentially impacts mortality after lung transplant (LT). In this study we aimed to study LT mortality in CF patients with and without pan-resistant infection. METHODS: The International Society for Heart and Lung Transplantation (ISHLT) Thoracic Transplant Registry was used to identify adults with CF, first-time, bilateral LT from 1991 to 2015. Extracted data included demographics, clinical characteristics, post-transplant outcomes, and mortality (infection-related, overall). Multivariate binary logistic regression models were created with 90-day and 1-year mortality as primary outcomes. RESULTS: Among 3,256 LT recipients with CF, 697 were labeled as having pan-resistant infection, the others were included as controls (n = 2,649). Pre-transplant, those labeled as pan-resistant were more likely to require ventilator support, have an infection requiring intravenous antibiotics, and have had ≥2 pneumonia episodes within 1 year. Ninety-day and 1-year mortality was similar between groups, but infection-related mortality at 90days (3.3% vs 1.88%, p = 0.01) and 1 year (6.6% vs 4.6%, p < 0.001) was higher in those labeled as pan-resistant. In multivariate analysis, presence of organisms labeled as pan-resistant was not associated with 90-day (odds ratio [OR] 1.5, 95% confidence interval [CI] 0.93 to 2.42, p = 0.09) or 1-year mortality (OR 1.32, 95% CI 0.95 to 1.83, p = 0.097). CONCLUSIONS: CF patients with pre-transplant infection from organisms labeled as pan-resistant had similar 90-day and 1-year mortality as those without. Despite increased infection-related mortality in these patients, it was not predictive of mortality in multivariate analysis. The higher occurrence of post-transplant infections in these patients warrants diligent follow-up. A multicenter cohort study will be required to validate the findings of our study.

Effect of Donor Age on Outcome of Lung Transplantation Stratified by Recipient Diagnosis: A Nordic Multicenter Study.

BACKGROUND: Organs from older donors are increasingly used in lung transplantation, and studies have demonstrated that this could be safe in selected recipients. However, which recipient groups that have the largest benefit of older organs are unclear. This multicenter study reviews all bilateral lung transplantations (BLTx) from donors 55 years or older stratified by recipient diagnosis and compares outcomes with transplantations from younger donors. METHODS: All BLTx recipients (excluding retransplantation) at 5 Scandiatransplant centers between 2000 and 2013 were included (n = 913). Recipients were stratified to diagnosis groups including cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), and "other." Intensive care unit (ICU) length of stay (LOS) and survival were assessed. RESULTS: Overall, there was no difference in survival among patients transplanted from donors 55 years or older compared with younger donors. However, in CF recipients, donor age 55 years or older was associated with inferior survival (P = 0.014), and this remained significant in a multivariate model (hazard ratio, 5.0; 95% confidence interval, 1.8-14.1; P = 0.002). There was no significant effect of donor age on survival in recipients with COPD, ILD, or in the "other" group in multivariate models. Utilization of older donors was associated with increased ICU LOS for recipients with CF and ILD, but not in the COPD or "other" group. CONCLUSIONS: The BLTx recipients with CF had inferior survival and longer ICU LOS when receiving organs from donors 55 years or older. Recipients with COPD, ILD, or in the "other" group did not have inferior survival in multivariate models.

Urgent lung allocation system in the Scandiatransplant countries.

BACKGROUND: Throughout the world, the scarcity of donor organs makes optimal allocation systems necessary. In the Scandiatransplant countries, organs for lung transplantation are allocated nationally. To ensure shorter wait time for critically ill patients, the Scandiatransplant urgent lung allocation system (ScULAS) was introduced in 2009, giving supranational priority to patients considered urgent. There were no pre-defined criteria for listing a patient as urgent, but each center was granted only 3 urgent calls per year. This study aims to explore the characteristics and outcome of patients listed as urgent, assess changes associated with the implementation of ScULAS, and describe how the system was utilized by the member centers. METHODS: All patients listed for lung transplantation at the 5 Scandiatransplant centers 5 years before and after implementation of ScULAS were included. RESULTS: After implementation, 8.3% of all listed patients received urgent status, of whom 81% were transplanted within 4 weeks. Patients listed as urgent were younger, more commonly had suppurative lung disease, and were more often on life support compared with patients without urgent status. For patients listed as urgent, post-transplant graft survival was inferior at 30 and 90 days. Although there were no pre-defined criteria for urgent listing, the system was not utilized at its maximum. CONCLUSIONS: ScULAS rapidly allocated organs to patients considered urgent. These patients were younger and more often had suppurative lung disease. Patients with urgent status had inferior short-term outcome, plausibly due to the higher proportion on life support before transplantation.

The Role of Airway Inflammation and Bronchial Hyperresponsiveness in Athlete's Asthma.

PURPOSE: Asthma is frequently reported in endurance athletes. The aim of the present study was to assess the long-term airway inflammatory response to endurance exercise in high-level athletes with and without asthma. METHODS: In a cross-sectional design, 20 asthmatic athletes (10 swimmers and 10 cross-country skiers), 19 athletes without asthma (10 swimmers and 9 cross-country skiers), and 24 healthy nonathletes completed methacholine bronchial challenge, lung function tests, and sputum induction on two separate days. All athletes competed on a national or international level and exercised ≥10 h·wk. The nonathletes exercised ≤5 h·wk and reported no previous lung disease. Bronchial hyperresponsiveness (BHR) was defined as a methacholine provocation dose causing 20% decrease in the forced expiratory volume in 1 s of ≤8 µmol. RESULTS: BHR was present in 13 asthmatic athletes (62%), 11 healthy athletes (58%), and 8 healthy nonathletes (32%), and the prevalence differed among groups (P = 0.005). Sputum inflammatory and epithelial cell counts did not differ between groups and were within the normal range. Median (25th to 75th percentiles) sputum interleukin-8 was elevated in both asthmatic (378.4 [167.0-1123.4]) and healthy (340.2 [175.5-892.4]) athletes as compared with healthy nonathletes (216.6 [129.5-314.0], P = 0.02). No correlations were found between provocation dose causing 20% decrease and sputum cell counts. CONCLUSION: Independent of asthma diagnosis, a high occurrence of BHR and an increased sputum interleukin-8 were found in athletes as compared with nonathletes. Airway inflammation or epithelial damage was not related to BHR.

An association of particulate air pollution and traffic exposure with mortality after lung transplantation in Europe.

Air pollution from road traffic is a serious health risk, especially for susceptible individuals. Single-centre studies showed an association with chronic lung allograft dysfunction (CLAD) and survival after lung transplantation, but there are no large studies.13 lung transplant centres in 10 European countries created a cohort of 5707 patients. For each patient, we quantified residential particulate matter with aerodynamic diameter ≤10 µm (PM10) by land use regression models, and the traffic exposure by quantifying total road length within buffer zones around the home addresses of patients and distance to a major road or freeway.After correction for macrolide use, we found associations between air pollution variables and CLAD/mortality. Given the important interaction with macrolides, we stratified according to macrolide use. No associations were observed in 2151 patients taking macrolides. However, in 3556 patients not taking macrolides, mortality was associated with PM10 (hazard ratio 1.081, 95% CI 1.000-1.167); similarly, CLAD and mortality were associated with road lengths in buffers of 200-1000 and 100-500 m, respectively (hazard ratio 1.085- 1.130). Sensitivity analyses for various possible confounders confirmed the robustness of these associations.Long-term residential air pollution and traffic exposure were associated with CLAD and survival after lung transplantation, but only in patients not taking macrolides.

Occurrence, Characteristics, and Predictors of Pain in Patients with Chronic Obstructive Pulmonary Disease.

Few studies have provided a detailed characterization of pain in patients with chronic obstructive pulmonary disease (COPD). The aims of this cross-sectional study were to describe the occurrence, intensity, locations, and level of interference associated with pain, as well as pain relief; to identify differences in demographic, clinical, and symptom characteristics between COPD patients with and without pain; and to determine which demographic, clinical, and symptom characteristics were associated with average pain, worst pain, and pain interference. A total of 258 patients with COPD provided information on demographic characteristics; comorbidities; respiratory parameters including dyspnea; body mass index; and symptom characteristics (i.e., anxiety, depression, sleep disturbance, and fatigue). Pain was measured using the Brief Pain Inventory. Of these 258 COPD patients, 157 (61%) reported pain. Multiple linear regression analyses were performed to determine which demographic, clinical, and symptom characteristics were associated with average pain severity, worst pain severity, and mean pain interference. Lower stages of COPD were associated with higher worst pain and higher pain interference scores. Higher depression scores were associated with higher average pain and higher pain interference scores. In addition, higher number of pain locations was associated with higher average and higher worst pain severity scores. Findings from this study confirm that pain is a significant problem and highlights the need for specific pain management interventions for patients with COPD. More research is needed about specific pain characteristics and symptoms to gain an increased knowledge about the causes of pain in these patients.

Differences in Symptom Burden Among Patients With Moderate, Severe, or Very Severe Chronic Obstructive Pulmonary Disease.

CONTEXT: The symptom experience of patients with chronic obstructive pulmonary disease (COPD) is extremely complex. It is characterized by multiple co-occurring symptoms. However, very few studies have described this experience in COPD patients. OBJECTIVES: The aims of this study were to evaluate for differences in symptom occurrence rates, as well as ratings of symptom severity, frequency, and distress among patients (n = 267) with moderate, severe, and very severe COPD. METHODS: The Memorial Symptom Assessment Scale was used to evaluate the multiple dimensions of the patient's symptom experience. Binary and ordinal logistic regression analyses with stage of disease as an ordinal predictor variable were used to evaluate for differences in symptom occurrence rates and ratings of symptom severity, frequency, and distress. RESULTS: Regardless of the severity of their disease, patients reported an average of 12 co-occurring symptoms. Shortness of breath and lack of energy were the only two symptoms that differed significantly among the three disease severity groups in terms of occurrence, severity, frequency, and distress. Patients with very severe COPD reported the highest ratings for shortness of breath and lack of energy across all four symptom dimensions. CONCLUSION: Regardless of stage of disease, the high symptom burden identified in this study underscores the need for COPD patients to be screened for multiple co-occurring symptoms.