Single-center, non-randomized, prospective phase II study evaluating the effectiveness of induction chemoimmunotherapy in the combined outcome of locally advanced non-small cell lung disease

Airway bacterial community composition in persons with advanced cystic fibrosis lung disease

Frailty increases morbidity and mortality in patients with advanced heart and lung disease. Emerging evidence shows that postoperative cardiac or pulmonary rehabilitation can improve the frailty status of these patients. The aim of this hypothesis-generating study was to test the relationship between prehabilitation and frailty in patients with advanced heart or lung disease referred for heart and lung transplantation. The study was a retrospective audit of consecutive patients with advanced heart or lung disease referred for transplant assessment between January 2021 and December 2022. Frailty scores were recorded using Fried's frailty phenotype (range, 0-5), and rehabilitation status of patients at the time of frailty assessment was recorded. Of 286 patients, 124 patients had advanced heart disease (mean age 53 ± 12 y; 82% men) and 162 patients had advanced lung disease (mean age 55 ± 12 y; 43% men). Sixty-nine (24%) patients were robust (score 0), 156 (55%) were prefrail (score, 1-2), and 61 (21%) were frail (score, 3-5). Eighty-two (29%) patients participated in hospital-based rehabilitation, 72 (25%) in home-based rehabilitation, and 132 (46%) in no rehabilitation. Frailty scores were significantly lower in patients participating in hospital-based or home-based rehabilitation compared with patients not participating in rehabilitation (0.8 ± 1.0 versus 0.8 ± 0.9 versus 2.3±1.2, P < 0.0001). This study shows that patients participating in cardiac or pulmonary rehabilitation are less frail compared with patients not participating in rehabilitation. These findings suggest that prehabilitation could be beneficial for patients awaiting heart or lung transplantation.

Mycobacterium avium Complex Lung Disease in Women

Low body mass index as a barrier to lung transplant in cystic fibrosis

Advanced cystic fibrosis lung disease remains the main cause of death in people with cystic fibrosis (pwCF). Cystic fibrosis transmembrane regulator (CFTR) modulators have changed the disease burden for eligible pwCF with access to this therapy. Real-world data show that there are no safety concerns for patients with advanced cystic fibrosis lung disease treated with highly effective triple CFTR modulator therapy. The improvements are comparable to those in other people with cystic fibrosis and in part even better. Mortality and rates of lung transplantation have decreased since the approval of CFTR modulator therapy and, especially, highly effective triple CFTR modulator therapy. Nevertheless, at least 10% of people with cystic fibrosis are not eligible for highly effective CFTR modulator therapy, and the development of alternative treatments remains important. The approval of highly effective CFTR modulator therapies has been a breakthrough in treatment for most people with cystic fibrosis, especially those with advanced lung disease, improving survival and reducing the burden of the disease.

Over the past decade, the development of highly effective cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators has dramatically ameliorated the manifestations of CF for most patients. Perhaps most importantly, CFTR modulators impact the development and progression of advanced lung disease (ALD) and are changing the CF population accessing lung transplant. A recent phase 3 trial of elexacaftor/tezacaftor/ivacaftor (ETI) demonstrated efficacy for individuals with at least one copy of the most common CF mutation, F508del. Studies of CFTR modulator therapy in patients with ALD have demonstrated similar improvements in lung function, nutrition, and pulmonary exacerbation frequency as seen in individuals with higher lung function. Due to improvements with ETI, rates of lung transplant for CF have declined and individuals are achieving stability in lung function. Nevertheless, the Cystic Fibrosis Foundation guidelines for lung transplant referral should be used to guide referral decisions for all individuals with CF, including those on CFTR modulator therapy, to allow remediation of modifiable barriers to transplant. ETI may be used in the posttransplant setting but for selected individuals and with close monitoring. Increasing access to highly effective CFTR modulators has changed the trajectory of lung disease in CF for many, but not all, individuals and there remain individuals who cannot access therapy or whose mutations do not respond to modulators. Lung transplant remains an important treatment option for individuals with advanced CF lung disease. Increasing attention will be required to optimize decisions of when to list for transplant.

A 12 year old boy with cystic fibrosis has advanced lung disease (FEV1 30%-40% predicted) and needs monthly intravenous antibiotics given through an implanted venous access device (visible in the...

BackgroundAdvanced lung diseases are prevalent in women, yet are underrecognized and under-treated due to differing epidemiology and pathophysiology.AimTo investigate any gender differences in access to palliative care and end-of-life management for patients with advanced lung diseases.MethodsA post-hoc analysis was conducted using three datasets that included information regarding the provision of palliative care to patients with advanced lung diseases - chronic obstructive pulmonary disease (COPD), fibrotic interstitial lung diseases (f-ILD) or non-small cell lung cancer (NSCLC) in tertiary and regional hospitals in Victoria, Australia, from 2004 to 2019.Results343 patients with advanced COPD, 67 with f-ILD and 1022 with NSCLC were included. Compared to men, women with COPD (n = 126, 36.7%) were less likely to have smoked (P = 0.024), had significantly worse lung function (P < 0.001), and were more likely to receive non-invasive ventilation at end of life (P = 0.021). Women with fibrotic ILDs (n = 30, 44.8%) had significantly worse lung function (P < 0.001) and were more likely to experience exacerbations during their last two years of life (P < 0.001). Women with NSCLC (n = 457, 44.7%) were significantly younger (P< 0.001), less likely to have smoked (P < 0.001) or had asbestos exposure (P < 0.001). There were no significant differences between men and women with advanced lung diseases regarding referral to palliative care services (P = 0.369), hospital place of death (P = 0.915), or end-of-life management.ConclusionsDespite differences in lung function, exacerbations and targeted therapies, men and women with advanced lung diseases received equal access to symptom palliation and palliative care services towards the end of life.

The pathogenesis of cystic fibrosis (CF) lung disease is the downstream result of multiple factors including chronic airways infection and unabated pulmonary and systemic inflammation resulting in progressive loss of lung function. Therapeutic advancements including airway clearance therapies, antibiotics, and highly effective CFTR modulators have resulted in improved health outcomes and improved survival; however, the predicted life expectancy for CF patients remains well below that of the rest of the population, and respiratory failure is the most common cause of death. As such, the patients, their families, and CF care providers must be prepared to manage the challenges of advanced stage lung disease. The focus of this chapter is the care of CF patients with advanced stage lung disease and includes defining advanced CF lung disease, risk factors associated with the development of advanced lung disease, the pulmonary complications associated with advanced CF lung disease and their corresponding management, and, finally, referral for transplantation and palliative care.KeywordsCystic fibrosisPneumothoraxHemoptysisRespiratory failureComplicationsPalliative

The frail phenotype has gained popularity as a clinically relevant measure in adults with advanced lung disease and in critical illness survivors. Because respiratory disease and chronic illness can greatly limit physical activity, the measurement of participation in traditional leisure time activities as a frailty component may lead to substantial misclassification of frailty in pulmonary and critical care patients. To test and validate substituting the Duke Activity Status Index (DASI), a simple 12-item questionnaire, for the Minnesota Leisure Time Physical Activity (MLTA) questionnaire, a detailed questionnaire covering 18 leisure time activities, as the measure of low activity in the Fried frailty phenotype (FFP) instrument. In separate multicenter prospective cohort studies of adults with advanced lung disease who were candidates for lung transplant and older survivors of acute respiratory failure, we assessed the FFP using either the MLTA or the DASI. For both the DASI and MLTA, we evaluated content validity by testing floor effects and construct validity through comparisons with conceptually related factors. We tested the predictive validity of substituting the DASI for the MLTA in the FFP assessment using Cox models to estimate associations between the FFP and delisting/death before transplant in those with advanced lung disease and 6-month mortality in older intensive care unit (ICU) survivors. Among 618 adults with advanced lung disease and 130 older ICU survivors, the MLTA had a substantially greater floor effect than the DASI (42% vs. 1%, and 49% vs. 12%, respectively). The DASI correlated more strongly with strength and function measures than did the MLTA in both cohorts. In models adjusting for age, sex, comorbidities, and illness severity, substitution of the DASI for the MLTA led to stronger associations of the FFP with delisting/death in lung transplant candidates (FFP-MLTA hazard ratio [HR], 1.42; 95% confidence interval [CI], 0.55-3.65; FFP-DASI HR, 2.99; 95% CI, 1.03-8.65) and with mortality in older ICU survivors (FFP-MLTA HR, 2.68; 95% CI, 0.62-11.6; FFP-DASI HR, 5.71; 95% CI, 1.34-24.3). The DASI improves the construct and predictive validity of frailty assessment in adults with advanced lung disease or recent critical illness. This simple questionnaire should replace the more complex MLTA in assessing the frailty phenotype in these populations.

Drug compounds that augment the production and activity of the cystic fibrosis (CF) transmembrane regulator (CFTR) have revolutionised CF care. Many adults and some children with CF suffer advanced and severe lung disease or await lung transplantation. While the hope is that these drug compounds will prevent lung damage when started early in life, there is an ongoing need to care for people with advanced lung disease. The focus of this review is the accumulating data from clinical trials and case series regarding the benefits of CFTR modulator therapy in people with advanced pulmonary disease. We address the impact of treatment with ivacaftor, lumacaftor/ivacaftor, tezacaftor/ivacaftor and elexacaftor/tezacaftor/ivacaftor on lung function, pulmonary exacerbations, nutrition and quality of life. Adverse events of the different CFTR modulators, as well as the potential for drug-drug interactions, are discussed.

International Society for Heart and Lung Transplantation Consensus Statement on the Referral and Selection of Pediatric Lung Transplant Candidates.

Inhaled morphine has been used to treat dyspnea in a variety of clinical settings. There are, however, no reports of its use in treating patients with end-stage lung disease due to cystic fibrosis (CF). We report on the use of inhaled morphine sulfate in a 13-year-old boy with CF, advanced lung disease, and acute respiratory failure. Therapy was effective in reducing his subjective feeling of air hunger and improving his BORG score. His sole significant adverse effect was headache after 2 days of treatment at 4-hourly intervals.

Elexacaftor/tezacaftor/ivacaftor (ETI) is a cystic fibrosis (CF) transmembrane conductance regulator modulator, which has shown efficacy in people with CF (pwCF) carrying the F508del (F) variant, both in homozygosity and heterozygosity with a minimal function (MF) variant. Limited data exist on the effects of ETI in pwCF with advanced lung disease. Our aim was to investigate ETI safety and effectiveness in this patient group in a real-life setting over 2 years. A multicenter observational cohort study was designed to gather real-world information on the effect of ETI treatment on CF patients (aged >12 years, genotype: F/MF mutation) with advanced lung disease as defined by a FEV1 < 40% predicted. Retrospective demographic and clinical data were recorded for the two years preceding and the two years following ETI initiation. The following outcomes were investigated: treatment-associated adverse events (AEs), drug interruptions (temporary or permanent), variations in percent predicted FEV1 (ppFEV1), sweat chloride concentration (SwCl), antibiotic use, body mass index (BMI), and quality of life. A total of 124 (51.6% males) pwCF were treated with ETI over 2 years. The median (IQR) age and ppFEV1 were 34 (26, 43) years and 34 (29, 41) percentage points, respectively. ETI was discontinued in two pwCF due to lung transplantation, and temporarily interrupted in two because of skin rash, and in three following elevated levels of aminotransferase. Most AEs were mild and short-lasting. In 12.1% pwCF, we registered an increase greater than twice the upper limit of the normal range in alanine aminotransferase, and in 16% we registered an increase in conjugated bilirubin with no increase in aminotransferase. Both increases were recurrent in about half of the subjects. The mean differences (95% CI) for ppFEV1 and SwCl, assessed as mean values in the pre-ETI and ETI treatment periods, were +11.8 (11.1 to 12.6) and −43.7 (−47.6 to −39.9) mmol/L. A modest increase in ppFEV1 persisted during the second year of treatment. Number of oral and IV antibiotic cycles/year, as well as hospitalizations/year, decreased significantly from 3.6 to 1.2, from 2.4 to 0.6, and from 2.1 to 0.5 during ETI treatment. A total of 8 of 16 (50%) pwCF were taken off the waiting list for lung transplantation, and significant reductions in the percentages of pwCF using long-term oxygen therapy and non-invasive ventilation were observed. A poor concordance between ppFEV1 and SwCl was found. In only 3/82 (3.7%), subjects with chronic airway infection by Pseudomonas aeruginosa cultures were always negative during ETI treatment. In CF patients with advanced lung disease on ETI treatment, we observed an improvement in a number of clinically significant outcomes over a 2-year study period. However, several additional observations, such as liver dysfunction, variable degrees of lung function improvement, and limited impact on chronic airway infection, underscore the fact that the benefit–risk profile of ETI treatment in cystic fibrosis patients with advanced lung disease has not been fully elucidated and warrants prolonged-term monitoring.

Functional Status and Survival Following Pulmonary Rehabilitation