Lung function decline is mitigated following liver transplantation in people with cystic fibrosis: A retrospective cohort study.

There is paucity of literature on the health outcomes following liver transplantation (LT) in people with cystic fibrosis (pwCF). We aim to evaluate changes in lung function following LT in pwCF. We performed a retrospective cohort study of pwCF who underwent LT between 1987 and 2019 in the United States and Canada. Simultaneous lung-liver transplants and individuals who had lung transplant prior to LT were excluded. We analyzed pre-LT and post-LT percent predicted forced expiratory volume in 1 second, body mass index, rates of pulmonary exacerbation, and post-LT overall survival. A total of 402 LT recipients were included. The median age of transplant was 14.9 years and 69.7% of the transplants were performed in children less than 18 years old. The rate of decline in percent predicted forced expiratory volume in 1 second was attenuated after LT from -2.2% to -0.7% predicted per year with a difference of 1.5% predicted per year (95% CI, 0.8, 2.2; p < 0.001). Following LT, the rate of decline in body mass index was reduced, and there were fewer pulmonary exacerbations (0.6 pre vs. 0.4 post; rate ratio 0.7, p < 0.01). The median survival time post-transplant was 13.9 years and the overall probability of survival at 5 years was 77.6%. Those with higher lung function pre-LT had a lower risk of death post-LT, and those with genotypes other than F508 deletion had worse survival. LT in pwCF occurs most often in children and adolescents and is associated with a slower rate of decline in lung function and nutritional status, and a reduction in pulmonary exacerbations.

Beyond borders: cystic fibrosis survival between Australia, Canada, France and New Zealand.

BACKGROUND: Life expectancy for people with cystic fibrosis (CF) varies considerably both within and between countries. The objective of this study was to compare survival among countries with single-payer healthcare systems while accounting for markers of disease severity. METHODS: This cohort study used data from established national CF registries in Australia, Canada, France and New Zealand from 2015 to 2019. Median age of survival for each of the four countries was estimated using the Kaplan-Meier method. A Cox proportional hazards model was used to compare risk of death between Canada, France and Australia after adjusting for prognostic factors. Due to low number of deaths, New Zealand was not included in final adjusted models. RESULTS: Between 2015 and 2019, a total of 14 842 people (3537 Australia, 4434 Canada, 6411 France and 460 New Zealand) were included. The median age of survival was highest in France 65.9 years (95% CI: 59.8 to 76.0) versus 53.3 years (95% CI: 48.9 to 59.8) for Australia, 55.4 years (95% CI: 51.3 to 59.2) for Canada and 54.8 years (95% CI: 40.7 to not available) for New Zealand. After adjusting for individual-level factors, the risk of death was significantly higher in Canada (HR 1.85, 95% CI: 1.48 to 2.32; p<0.001) and Australia (HR 2.08, 95% CI: 1.64 to 2.64; p<0.001) versus France. INTERPRETATION: We observed significantly higher survival in France compared with countries with single-payer healthcare systems. The median age of survival in France exceeded 60 years of age despite having the highest proportion of underweight patients which may be due to differences in availability of transplant.

Cystic fibrosis survival outcomes following second lung transplant: The north American experience.

INTRODUCTION: Re-transplant is an option for those who develop end-stage lung disease due to rejection; however, little data exist following re-transplantation in cystic fibrosis (CF). METHODS: Data from the Canadian CF Registry and US CF Foundation Patient Registry supplemented with data from United Network for Organ Sharing were used. Individuals who underwent a 2nd lung transplant between 2005 and 2019 were included. The Kaplan-Meier method was used to estimate the probability of survival post-second transplant at 1, 3, and 5-years. RESULTS: Of those people who were waitlisted for a second transplant (N = 818), a total of 254 (31%) died waiting, 395 (48%) were transplanted and 169 (21%) people were alive on the waitlist. Median survival time after 2nd lung transplant was 3.3 years (95% CI: 2.8-4.1). The 1-, 3- and 5-year survival rates were 77.4% (95% CI: 73.1-82%), 52% (95% CI: 46.7-58%) and 39.4% (95% CI: 34.1-45.6%). CONCLUSIONS: Survival following second lung transplant in CF patients is lower than estimates following the first transplant. Over half of subjects who are potentially eligible for a second transplant die without receiving a second organ. This warrants further investigation.

Impact of a high emergency lung transplantation programme for cystic fibrosis in France: insight from a comparison with Canada.

BACKGROUND: France implemented a high emergency lung transplantation (HELT) programme nationally in 2007. A similar programme does not exist in Canada. The objectives of our study were to compare health outcomes within France as well as between Canada and France before and after the HELT programme in a population with cystic fibrosis (CF). METHODS: This population-based cohort study utilised data from the French and Canadian CF registries. A cumulative incidence curve assessed time to transplant with death without transplant as competing risks. The Kaplan-Meier method was used to estimate post-transplant survival. RESULTS: Between 2002 and 2016, there were 1075 (13.0%) people with CF in France and 555 (10.2%) people with CF in Canada who underwent lung transplantation. The proportion of lung transplants increased in France after the HELT programme was initiated (4.5% versus 10.1%), whereas deaths pre-transplant decreased from 85.3% in the pre-HELT period to 57.1% in the post-HELT period. Between 2008 and 2016, people in France were significantly more likely to receive a transplant (hazard ratio (HR) 1.56, 95% CI 1.37-1.77; p<0.001) than die (HR 0.55, 95% CI 0.46-0.66; p<0.001) compared with Canada. Post-transplant survival was similar between the countries, and there was no difference in survival when comparing pre- and post-HELT periods in France. CONCLUSIONS: Following the implementation of the HELT programme, people living with CF in France were more likely to receive a transplant than die. Post-transplant survival in the post-HELT period in France did not change compared with the pre-HELT period, despite potentially sicker patients being transplanted, and was comparable to Canada.

Asthma Severity and Control and Their Association With Perinatal Mental Illness.

OBJECTIVE: Growing evidence suggests asthma increases perinatal mental illness risk, but few studies have explored the impact of asthma severity and control. Our objective was to explore the association between asthma severity and control and perinatal mental illness risk and the impact of asthma exacerbations during pregnancy on postpartum mental illness risk. METHODS: This was a population-based retrospective cohort study of all women in Ontario, Canada, from 2005 to 2015 with a singleton live birth who used public drug insurance, excluding women with recent history of mental illness. We constructed modified Poisson regression models to assess the risk of perinatal mental illness, defined as a mood or anxiety, psychotic or substance use disorder, self-harm or other mental illness diagnosed from conception to 365 days postnatally. Models controlled for socio-demographic factors and medical history. RESULTS: There were 62,583 women in the cohort (46.7% between 15 - 24 years), of whom 22.7% had asthma (94.3% mild, 5.7% moderate/severe; 86.5% controlled and 13.5% uncontrolled). After adjustment, there was increased risk of perinatal mental illness with mild asthma (adjusted relative risk [RR]: 1.12; 95% confidence interval [CI], 1.09 to 1.16) and moderate/severe asthma (aRR: 1.16; 95% CI, 1.04 to 1.30) compared to no asthma. Controlled asthma (aRR: 1.11; 95% CI, 1.08 to 1.15) and uncontrolled asthma (aRR: 1.19; 95% CI, 1.11 to 1.27) were also associated with increased perinatal mental illness risk compared to no asthma. Women with worsened asthma during pregnancy had the highest risk of postpartum mental illness compared to no change in asthma status (by severity: aRR: 1.57; 95% CI, 1.36 to 1.80; by control: aRR: 1.37; 95% CI, 1.22 to 1.54). CONCLUSION: Asthma is associated with increased risk of perinatal mental illness, particularly in the presence of asthma exacerbations in pregnancy. The results support multidisciplinary collaborative care programmes throughout the perinatal period, especially among women with asthma exacerbations during pregnancy.

Comparison of quadriceps muscle size and quality in adults with cystic fibrosis with different severities of cystic fibrosis transmembrane conductance regulator protein dysfunction.

BACKGROUND: Cystic fibrosis (CF) is characterized by CF transmembrane conductance regulator (CFTR) dysfunction. CFTR protein is expressed in human skeletal muscle; however, its impact on skeletal muscle is unknown. The objectives of this study were to compare quadriceps muscle size and quality between adults with various severities of CFTR protein dysfunction. METHODS: We conducted a prospective, cross-sectional study comparing 34 adults with severe versus 18 with mild CFTR protein dysfunction, recruited from a specialized CF centre. Ultrasound images of rectus femoris cross-sectional area (RF-CSA) and quadriceps layer thickness for muscle size, and rectus femoris echogenicity (RF-ECHO) (muscle quality) were obtained. Multivariable linear regression models were developed using purposeful selection technique. RESULTS: People with severe CFTR protein dysfunction had larger RF-CSA by 3.22 cm2, 95% CI (1.03, 5.41) cm2, p=.0049], after adjusting for oral corticosteroid use and Pseudomonas aeruginosa colonization. However, a sensitivity analysis indicated that the result was influenced by the specific confounders being adjusted for in the model. We did not find any significant differences in quadriceps layer thickness or RF-ECHO between the two groups. CONCLUSION: We found no differential impact of the extent of diminished CFTR protein activity on quadriceps muscle size or quality in our study cohort. Based on these findings, CFTR mutation status cannot be used differentiate leg muscle size or quality in people with CF.

Morbidity and mortality associated with prescription cannabinoid drug use in COPD.

INTRODUCTION: Respiratory-related morbidity and mortality were evaluated in relation to incident prescription oral synthetic cannabinoid (nabilone, dronabinol) use among older adults with chronic obstructive pulmonary disease (COPD). METHODS: This was a retrospective, population-based, data-linkage cohort study, analysing health administrative data from Ontario, Canada, from 2006 to 2016. We identified individuals aged 66 years and older with COPD, using a highly specific, validated algorithm, excluding individuals with malignancy and those receiving palliative care (n=185 876 after exclusions). An equivalent number (2106 in each group) of new cannabinoid users (defined as individuals dispensed either nabilone or dronabinol, with no dispensing for either drug in the year previous) and controls (defined as new users of a non-cannabinoid drug) were matched on 36 relevant covariates, using propensity scoring methods. Cox proportional hazard regression was used. RESULTS: Rate of hospitalisation for COPD or pneumonia was not significantly different between new cannabinoid users and controls (HR 0.87; 95% CI 0.61-1.24). However, significantly higher rates of all-cause mortality occurred among new cannabinoid users compared with controls (HR 1.64; 95% CI 1.14-2.39). Individuals receiving higher-dose cannabinoids relative to controls were observed to experience both increased rates of hospitalisation for COPD and pneumonia (HR 2.78; 95% CI 1.17-7.09) and all-cause mortality (HR 3.31; 95% CI 1.30-9.51). CONCLUSIONS: New cannabinoid use was associated with elevated rates of adverse outcomes among older adults with COPD. Although further research is needed to confirm these observations, our findings should be considered in decisions to use cannabinoids among older adults with COPD.

Recent advances in developing therapeutics for cystic fibrosis.

Despite hope that a cure was imminent when the causative gene was cloned nearly 30 years ago, cystic fibrosis (CF [MIM: 219700]) remains a life-shortening disease affecting more than 70 000 individuals worldwide. However, within the last 6 years the Food and Drug Administration's approval of Ivacaftor, the first drug that corrects the defective cystic fibrosis transmembrane conductance regulator protein [CFTR (MIM: 602421)] in patients with the G551D mutation, marks a watershed in the development of novel therapeutics for this devastating disease. Here we review recent progress in diverse research areas, which all focus on curing CF at the genetic, biochemical or physiological level. In the near future it seems probable that development of mutation-specific therapies will be the focus, since it is unlikely that any one approach will be efficient in correcting the more than 2000 disease-associated variants. We discuss the new drugs and combinations of drugs that either enhance delivery of misfolded CFTR protein to the cell membrane, where it functions as an ion channel, or that activate channel opening. Next we consider approaches to correct the causative genetic lesion at the DNA or RNA level, through repressing stop mutations and nonsense-mediated decay, modulating splice mutations, fixing errors by gene editing or using novel routes to gene replacement. Finally, we explore how modifier genes, loci elsewhere in the genome that modify CF disease severity, may be used to restore a normal phenotype. Progress in all of these areas has been dramatic, generating enthusiasm that CF may soon become a broadly treatable disease.

Correlating Cystic Fibrosis Transmembrane Conductance Regulator Function with Clinical Features to Inform Precision Treatment of Cystic Fibrosis.

Rationale: The advent of precision treatment for cystic fibrosis using small-molecule therapeutics has created a need to estimate potential clinical improvements attributable to increases in cystic fibrosis transmembrane conductance regulator (CFTR) function. Objectives: To derive CFTR function of a variety of CFTR genotypes and correlate with key clinical features (sweat chloride concentration, pancreatic exocrine status, and lung function) to develop benchmarks for assessing response to CFTR modulators. Methods: CFTR function assigned to 226 unique CFTR genotypes was correlated with the clinical data of 54,671 individuals enrolled in the Clinical and Functional Translation of CFTR (CFTR2) project. Cross-sectional FEV1% predicted measurements were plotted by age at which measurement was obtained. Shifts in sweat chloride concentration and lung function reported in CFTR modulator trials were compared with function-phenotype correlations to assess potential efficacy of therapies. Measurements and Main Results: CFTR genotype function exhibited a logarithmic relationship with each clinical feature. Modest increases in CFTR function related to differing genotypes were associated with clinically relevant improvements in cross-sectional FEV1% predicted over a range of ages (6-82 yr). Therapeutic responses to modulators corresponded closely to predictions from the CFTR2-derived relationship between CFTR genotype function and phenotype. Conclusions: Increasing CFTR function in individuals with severe disease will have a proportionally greater effect on outcomes than similar increases in CFTR function in individuals with mild disease and should reverse a substantial fraction of the disease process. This study provides reference standards for clinical outcomes that may be achieved by increasing CFTR function.

Development and external validation of 1- and 2-year mortality prediction models in cystic fibrosis.

INTRODUCTION: We aimed to develop a clinical tool for predicting 1- and 2-year risk of death for patients with cystic fibrosis (CF). The model considers patients' overall health status as well as risk of intermittent shock events in calculating the risk of death. METHODS: Canadian CF Registry data from 1982 to 2015 were used to develop a predictive risk model using threshold regression. A 2-year risk of death estimated conditional probability of surviving the second year given survival for the first year. UK CF Registry data from 2007 to 2013 were used to externally validate the model. RESULTS: The combined effect of CF chronic health status and CF intermittent shock risk provided a simple clinical scoring tool for assessing 1-year and 2-year risk of death for an individual CF patient. At a threshold risk of death of ≥20%, the 1-year model had a sensitivity of 74% and specificity of 96%. The area under the receiver operating curve (AUC) for the 2-year mortality model was significantly greater than the AUC for a model that predicted survival based on forced expiratory volume in 1 s <30% predicted (AUC 0.95 versus 0.68 respectively, p<0.001). The Canadian-derived model validated well with the UK data and correctly identified 79% of deaths and 95% of survivors in a single year in the UK. CONCLUSIONS: The prediction models provide an accurate risk of death over a 1- and 2-year time horizon. The models performed equally well when validated in an independent UK CF population.

Cluster and CART analyses identify large subgroups of adults with cystic fibrosis at low risk of 10-year death.

Our goal was to identify subgroups of adults with cystic fibrosis (CF) at low risk of death within 10 years.Factor analysis for mixed data followed by Ward's cluster analysis was conducted using 25 variables from 1572 French CF adults in 2005. Rates of death by subgroups were analysed over 10 years. An algorithm was developed using CART (classification and regression tree) analysis to provide rules for the identification of subgroups of CF adults with low rates of death within 10 years. This algorithm was validated in 1376 Canadian CF adults.Seven subgroups were identified by cluster analysis in French CF adults, including two subgroups with low (∼5%) rates of death at 10 years: one subgroup (22% of patients) was composed of patients with nonclassic CF, the other subgroup (17% of patients) was composed of patients with classic CF but low rates of Pseudomonas aeruginosa infection and diabetes. An algorithm based on CART analysis of data in 2005 allowed us to identify most French adults with low rates of death. When tested using data from Canadian CF adults in 2005, the algorithm identified 287 out of 1376 (21%) patients at low risk (10-year death: 7.7%).Large subgroups of CF adults share low risk of 10-year mortality.

Comparison of Nutrition and Lung Function Outcomes in Patients with Cystic Fibrosis Living in Canada and the United States.

RATIONALE: A 10-year gap in the median age of survival for patients with cystic fibrosis (CF) was reported between patients living in Canada compared with patients living in the United States. OBJECTIVES: Because both malnutrition and poor lung function are associated with an increased risk of mortality in CF, we investigated the temporal and longitudinal trends in lung function and nutrition between Canada and the United States. METHODS: This cohort study used Canadian CF Registry and U.S. CF Foundation Patient Registry data from 1990 to 2013. A unified dataset was created to harmonize the variables collected within the two registries for the purpose of comparing outcomes between the two countries. MEASUREMENTS AND MAIN RESULTS: We conducted three analyses: survival differences by birth cohort; population trends for FEV1 and body mass index (BMI) over time; and individual patient FEV1 and BMI trajectories. The study included a total of 37,772 patients in the United States and 5,149 patients in Canada. Patients with CF experienced significant improvements in nutritional status and lung function in both Canada and the United States during the study. In addition, the survival gap between the two countries is narrowing within younger birth cohorts. The improvements for the patients within the United States were most prominent in the BMI trajectories, where patients born after 1990 in the United States have higher BMI that has persisted over time. CONCLUSIONS: The reasons for the observed improvements, and catch-up in the United States, are likely multifactorial and include the introduction of high-fat, high-calorie diets; introduction of newborn screening; and/or improved access to care for CF children in the United States.

Reference percentiles of FEV1 for the Canadian cystic fibrosis population: comparisons across time and countries.

BACKGROUND: Forced expiratory volume in 1 s (FEV1) indicates lung health in cystic fibrosis (CF). FEV1 is commonly communicated as a per cent predicted of a healthy individual sharing the same age, sex, race and height. CF-specific reference equations are complementary and calibrate a patient's FEV1 to that of their CF peers. OBJECTIVES: (1) To derive Canadian CF-specific FEV1 reference percentiles (FEV1%iles), (2) characterize how they have changed over time and (3) compare the Canadian FEV1%iles to those for USA and European CF populations. METHOD: CF FEV1%iles are calculated using the Canadian CF Registry and quantile regression. RESULTS: The Canadian FEV1%iles demonstrated better lung function in more recent time periods within Canada, especially below the 50% percentile and in males. When compared to USA and European FEV1%iles for the same time period, Canadian FEV1%iles were higher. CONCLUSION: CF-specific FEV1%iles can provide useful information about changes in lung health. An online calculator (available at cfpercentile. RESEARCH: sickkids.ca) makes these FEV1%iles accessible.

Serotonergic antidepressant use and morbidity and mortality among older adults with COPD.

We evaluated the relationship between new selective serotonin reuptake inhibitor (SSRI) or serotonin-noradrenaline reuptake inhibitor (SNRI) drug use and respiratory-related morbidity and mortality among older adults with chronic obstructive pulmonary disease (COPD).This was a retrospective population-based cohort study using heath administrative data from Ontario, Canada. Individuals aged ≥66 years, with validated, physician-diagnosed COPD (n=131 718) were included. New SSRI/SNRI users were propensity score matched 1:1 to controls on 40 relevant covariates to minimise potential confounding.Among propensity score matched community-dwelling individuals, new SSRI/SNRI users compared to non-users had significantly higher rates of hospitalisation for COPD or pneumonia (hazard ratio (HR) 1.15, 95% CI 1.05-1.25), emergency room visits for COPD or pneumonia (HR 1.13, 95% CI 1.03-1.24), COPD or pneumonia-related mortality (HR 1.26, 95% CI 1.03-1.55) and all-cause mortality (HR 1.20, 95% CI 1.11-1.29). In addition, respiratory-specific and all-cause mortality rates were higher among long-term care home residents newly starting SSRI/SNRI drugs versus controls.New use of serotonergic antidepressants was associated with small, but significant, increases in rates of respiratory-related morbidity and mortality among older adults with COPD. Further research is needed to clarify if the observed associations are causal or instead reflect unresolved confounding.

Cystic fibrosis survival: the changing epidemiology.

PURPOSE OF REVIEW: Tracking patient outcomes using cystic fibrosis (CF) national data registries, we have seen a dramatic improvement in patient survival. As there are multiple ways to measure survival, it is important for readers to understand these different metrics in order to clearly translate this information to patients and their families. The aims of this review were to describe measures of survival and to review the recent literature pertaining to survival in CF to capture the changing epidemiology. RECENT FINDINGS: Although survival has improved on a population level, several individual factors continue to impact survival such as sex, age of diagnosis, ethnic background and lung function. Survival estimates, conditional on surviving to a specified age, are more relevant to individuals living with CF today and are higher than the reported overall median age of survival. There is some evidence to suggest that newborn screening (NBS) has resulted in prolonged survival in CF. SUMMARY: Prognosis in CF is often described by reporting the median age of survival, the median age of death, the median survival conditional on living to a certain age and the survival by birth cohort. Each of these metrics provide useful information depending on an individual's personal disease trajectory. The median age of survival continues to increase in CF in many countries while mortality rates are decreasing. Several factors have been associated with worse survival such as female sex, ethnicity, worse nutritional status, lower lung function and microbiology. When comparing survival between countries, one needs to ensure that similar data collection and processing techniques are used to ensure valid and robust comparisons.

Clinical characteristics of cystic fibrosis patients prior to lung transplantation: An international comparison between Canada and the United States.

BACKGROUND: Cystic fibrosis (CF) patients from Canada have better-reported post-lung transplant survival compared to patients from the United States. We hypothesized the clinical characteristics of CF patients prior to lung transplant differ between the two countries. METHODS: Population-based cohort study utilizing combined Canadian CF Registry and US CF Foundation Patient Registry data from 1986 to 2013. Demographic and clinical variables were analyzed prior to lung transplant. RESULTS: Between 1986 and 2013, 607 (10.2%) CF patients underwent lung transplantation in Canada and 3428 (7.5%) in the United States. A lower proportion of recipients had growth of B. cepacia complex prior to transplant in the United States compared to Canada (0.8% vs 4.3%). Lung function was similar between recipients from the two countries. The proportion of patients classified as underweight was significantly higher in the United States compared to Canada (39.8% vs 28.0%; SD 26.1) despite higher rates of feeding tube use (42.5% vs 28.6%; SD 29.0). CONCLUSIONS: CF lung transplant recipients from the United States have similar lung function, lower rates of B. cepacia complex, and worse nutritional parameters prior to transplant compared to counterparts in Canada. Future studies are necessary to evaluate the impact of these differences on post-transplant survival.

Survival Comparison of Patients With Cystic Fibrosis in Canada and the United States: A Population-Based Cohort Study.

BACKGROUND: In 2011, the median age of survival of patients with cystic fibrosis reported in the United States was 36.8 years, compared with 48.5 years in Canada. Direct comparison of survival estimates between national registries is challenging because of inherent differences in methodologies used, data processing techniques, and ascertainment bias. OBJECTIVE: To use a standardized approach to calculate cystic fibrosis survival estimates and to explore differences between Canada and the United States. DESIGN: Population-based study. SETTING: 42 Canadian cystic fibrosis clinics and 110 U.S. cystic fibrosis care centers. PATIENTS: Patients followed in the Canadian Cystic Fibrosis Registry (CCFR) and U.S. Cystic Fibrosis Foundation Patient Registry (CFFPR) between 1990 and 2013. MEASUREMENTS: Cox proportional hazards models were used to compare survival between patients followed in the CCFR (n = 5941) and those in the CFFPR (n = 45 448). Multivariable models were used to adjust for factors known to be associated with survival. RESULTS: Median age of survival in patients with cystic fibrosis increased in both countries between 1990 and 2013; however, in 1995 and 2005, survival in Canada increased at a faster rate than in the United States (P < 0.001). On the basis of contemporary data from 2009 to 2013, the median age of survival in Canada was 10 years greater than in the United States (50.9 vs. 40.6 years, respectively). The adjusted risk for death was 34% lower in Canada than the United States (hazard ratio, 0.66 [95% CI, 0.54 to 0.81]). A greater proportion of patients in Canada received transplants (10.3% vs. 6.5%, respectively [standardized difference, 13.7]). Differences in survival between U.S. and Canadian patients varied according to U.S. patients' insurance status. LIMITATION: Ascertainment bias due to missing data or nonrandom loss to follow-up might affect the results. CONCLUSION: Differences in cystic fibrosis survival between Canada and the United States persisted after adjustment for risk factors associated with survival, except for private-insurance status among U.S. patients. Differential access to transplantation, increased posttransplant survival, and differences in health care systems may, in part, explain the Canadian survival advantage. PRIMARY FUNDING SOURCE: U.S. Cystic Fibrosis Foundation.

A clinical tool to calculate post-transplant survival using pre-transplant clinical characteristics in adults with cystic fibrosis.

BACKGROUND: We previously identified factors associated with a greater risk of death post-transplant. The purpose of this study was to develop a clinical tool to estimate the risk of death after transplant based on pre-transplant variables. METHODS: We utilized the Canadian CF registry to develop a nomogram that incorporates pre-transplant clinical measures to assess post-lung transplant survival. The 1-, 3-, and 5-year survival estimates were calculated using Cox proportional hazards models. RESULTS: Between 1988 and 2012, 539 adult Canadians with CF received a lung transplant with 208 deaths in the study period. Four pre-transplant factors most predictive of poor post-transplant survival were older age at transplantation, infection with B. cepacia complex, low FEV1 percent predicted, and pancreatic sufficiency. A nonlinear relationship was found between risk of death and FEV1 percent predicted, age at transplant, and BMI. We constructed a risk calculator based on our model to estimate the 1-, 3-, and 5-year probability of survival after transplant which is available online. CONCLUSIONS: Our risk calculator quantifies the risk of death associated with lung transplant using pre-transplant factors. This tool could aid clinicians and patients in the decision-making process and provide information regarding the timing of lung transplantation.

Adverse cardiac events associated with incident opioid drug use among older adults with COPD.

PURPOSE: We evaluated whether incident opioid drug use was associated with adverse cardiac events among older adults with chronic obstructive pulmonary disease (COPD). METHODS: This was an exploratory, retrospective cohort study using health administrative data from Ontario, Canada, from 2008 to 2013. Using a validated algorithm, we identified adults aged 66 years and older with non-palliative COPD. Hazard ratios (HR) were estimated for adverse cardiac events within 30 days of incident opioid receipt compared to controls using inverse probability of treatment weighting using the propensity score. RESULTS: There were 134,408 community-dwelling individuals and 14,685 long-term care residents with COPD identified, 67.0 and 60.6% of whom received an incident opioid. Incident use of any opioid was associated with significantly decreased rates of emergency room (ER) visits and hospitalizations for congestive heart failure (CHF) among community-dwelling older adults (HR 0.84; 95% CI 0.73-0.97), but significantly increased rates of ischemic heart disease (IHD)-related mortality among long-term care residents (HR 2.15; 95% CI 1.50-3.09). In the community-dwelling group, users of more potent opioid-only agents without aspirin or acetaminophen combined had significantly increased rates of ER visits and hospitalizations for IHD (HR 1.38; 95% CI 1.08-1.77) and IHD-related mortality (HR 1.83; 95% CI 1.32-2.53). CONCLUSIONS: New opioid use was associated with elevated rates of IHD-related morbidity and mortality among older adults with COPD. Adverse cardiac events may need to be considered when administering new opioids to older adults with COPD, but further studies are required to establish if the observed associations are causal or related to residual confounding.

Inhaled Long-acting Anticholinergics and Urinary Tract Infection in Individuals with COPD.

Inhaled, long-acting anticholinergic medication (LAA), commonly used for moderate-to-severe chronic obstructive pulmonary disease (COPD), has been shown to decrease COPD hospitalizations, emergency department visits, and acute exacerbations but has also been associated with urinary tract infection (UTI) in a prior meta-analysis. The objective of this study was to verify if there was an association between LAA and UTI in older individuals with COPD. A population-based, real-world cohort study using health administrative data from Ontario, Canada was conducted. Incidence of UTI was compared between older people with physician-diagnosed COPD, who were new users of inhaled long-acting anticholinergics and new users of inhaled corticosteroids-a reference medication used in similar clinical settings that has no known association with UTI. Propensity score matching was used to minimize the effects of confounding. An overall association between LAA and various measures of UTI in older individuals was not found. However, in a priori defined stratified analyses, men newly initiated on LAA were 75% more likely to develop a UTI than men newly started on an inhaled corticosteroid (hazard ratio 1.75; 95% confidence interval 1.05-2.92). No significant association was seen in women. In conclusion, older men with COPD newly started on LAA are at increased risk of UTI. Men considering an inhaled LAA should be informed of this risk and, if they decide to take it, be provided with appropriate monitoring.