Validation of Clinical COPD Phenotypes for Prognosis of Long-Term Mortality in Swedish and Dutch Cohorts.

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease with variable mortality risk. The aim of our investigation was to validate a simple clinical algorithm for long-term mortality previously proposed by Burgel et al. in 2017. Subjects with COPD from two cohorts, the Swedish PRAXIS study (n = 784, mean age (standard deviation (SD)) 64.0 years (7.5), 42% males) and the Rotterdam Study (n = 735, mean age (SD) 72 years (9.2), 57% males), were included. Five clinical clusters were derived from baseline data on age, body mass index, dyspnoea grade, pulmonary function and comorbidity (cardiovascular disease/diabetes). Cox models were used to study associations with 9-year mortality. The distribution of clinical clusters (1-5) was 29%/45%/8%/6%/12% in the PRAXIS study and 23%/26%/36%/0%/15% in the Rotterdam Study. The cumulative proportion of deaths at the 9-year follow-up was highest in clusters 1 (65%) and 4 (72%), and lowest in cluster 5 (10%) in the PRAXIS study. In the Rotterdam Study, cluster 1 (44%) had the highest cumulative mortality and cluster 5 (5%) the lowest. Compared with cluster 5, the meta-analysed age- and sex-adjusted hazard ratio (95% confidence interval) for cluster 1 was 6.37 (3.94-10.32) and those for clusters 2 and 3 were 2.61 (1.58-4.32) and 3.06 (1.82-5.13), respectively. Burgel's clinical clusters can be used to predict long-term mortality risk. Clusters 1 and 4 are associated with the poorest prognosis, cluster 5 with the best prognosis and clusters 2 and 3 with intermediate prognosis in two independent cohorts from Sweden and the Netherlands.

The ALPACA study: (In)Appropriate LAMA prescribing in asthma: A cohort analysis.

INTRODUCTION: Since long-acting muscarinic antagonists (LAMA) are only indicated as add-on therapy in subjects with moderate-to-severe asthma, there are concerns whether LAMA monotherapy is associated with worse asthma control. AIM: To study the prevalence of LAMA monotherapy and its potential association with severe asthma exacerbations (SAE) in patients with asthma. METHODS: A cohort study (2007-2017) in the IPCI primary care database, in asthma patients aged 6-50, using LAMA during follow-up. Respiratory prescriptions were retrieved from the electronic medical records based on ATC code. Asthma treatment periods were created and categorized as LAMA mono, dual (LAMA + ICS), or triple therapy (LAMA + ICS + LABA). Relative rates (RR) of SAE, adjusting for patient characteristics, were estimated to compare treatments. RESULTS: From a total of 66,508 asthma patients, 1236 (1.9%) LAMA users were identified. Median age was 41 years, 65.9% were females. LAMA users were responsible for 3596 LAMA treatment periods of which 1390 (38.7%) were LAMA monotherapy, 553 (15.4%) dual therapy and 1653 (46.0%) triple therapy. The RR of SAE during LAMA monotherapy compared to dual therapy was 1.5 (95% CI 0.6-3.8). In patients alternating between mono and dual therapy (but never triple therapy), the RR for LAMA monotherapy increased to 5.7 (95% CI 1.4-23.6). CONCLUSIONS: This observational study shows that when LAMA is prescribed, it is often prescribed without concurrent ICS (LAMA monotherapy). LAMA monotherapy was associated with an increased risk of exacerbations when not used concurrently with ICS. This emphasizes the importance that LAMA should never be prescribed without concomitant ICS use in patients with asthma.

The Obesity Paradox in Lung Cancer: Associations With Body Size Versus Body Shape.

BACKGROUND: The association between obesity and lung cancer (LC) remains poorly understood. However, other indices of obesity on the basis of body shape instead of body size have not been examined yet. The aim of this study was to evaluate the association between different indices of body size and body shape and the risk of LC. In particular, this study examined the association between A Body Shape Index, a more precise indicator of abdominal fat than traditional anthropometric measures, and the risk of LC. METHODS: In the prospective cohort the Rotterdam Study, we analysed data of 9,689 participants. LC diagnoses were based on medical records and anthropometric measurements were assessed at baseline. Cox-regression analyses with corresponding Hazard Ratios were used to examine the association between the anthropometric measurements and the risk of LC with adjustment for potential confounders. Potential non-linear associations were explored with cubic splines using the Likelihood ratio (LR) test. RESULTS: During follow-up, 319 participants developed LC. Body mass Index (BMI) was inversely associated with the risk of lung cancer (HR 0.94, 95% CI: 0.91-0.97) and persisted after excluding lung cancer cases during the first 10 years of follow-up. There was evidence for a non-linear association between BMI and the risk of lung cancer (0,04, df = 1), which indicated that the inverse association between BMI and lung cancer was mainly present in non-obese participants. Waist circumference (WC) (HR 1.03 95% CI: 1.01-1.05), Waist-to-Hip Ratio (WHR) (HR 1.23 95% CI: 1.09-1.38) and ABSI (A Body Shape Index) (HR 1.17 95% CI: 1.05-1.30) were positively and linearly associated with the risk of lung cancer. CONCLUSIONS: Body shape rather than body size may be an important risk indicator of LC. Future research should focus on the role of visceral fat and the risk of LC as well as the underlying mechanisms.

Genes and pathways underlying susceptibility to impaired lung function in the context of environmental tobacco smoke exposure.

BACKGROUND: Studies aiming to assess genetic susceptibility for impaired lung function levels upon exposure to environmental tobacco smoke (ETS) have thus far focused on candidate-genes selected based on a-priori knowledge of potentially relevant biological pathways, such as glutathione S-transferases and ADAM33. By using a hypothesis-free approach, we aimed to identify novel susceptibility loci, and additionally explored biological pathways potentially underlying this susceptibility to impaired lung function in the context of ETS exposure. METHODS: Genome-wide interactions of single nucleotide polymorphism (SNP) by ETS exposure (0 versus ≥1 h/day) in relation to the level of forced expiratory volume in one second (FEV1) were investigated in 10,817 subjects from the Dutch LifeLines cohort study, and verified in subjects from the Swiss SAPALDIA study (n = 1276) and the Dutch Rotterdam Study (n = 1156). SNP-by-ETS exposure p-values obtained from the identification analysis were used to perform a pathway analysis. RESULTS: Fourty Five SNP-by-ETS exposure interactions with p-values <10-4 were identified in the LifeLines study, two being replicated with nominally significant p-values (<0.05) in at least one of the replication cohorts. Three pathways were enriched in the pathway-level analysis performed in the identification cohort LifeLines, i.E. the apoptosis, p38 MAPK and TNF pathways. CONCLUSION: This unique, first genome-wide gene-by-ETS interaction study on the level of FEV1 showed that pathways previously implicated in chronic obstructive pulmonary disease (COPD), a disease characterized by airflow obstruction, may also underlie susceptibility to impaired lung function in the context of ETS exposure.

Targeted Therapy for Older Patients with Uncontrolled Severe Asthma: Current and Future Prospects.

Severe asthma in the elderly places a high burden on affected individuals and society. Emerging therapies target specific phenotypes of the asthma disease spectrum, and can be beneficial for older asthmatics, albeit their response might be altered due to age-related characteristics. Paradoxically, these characteristics are often ground for exclusion from clinical trials. The question thus arises how the senior asthmatic population can successfully enter the era of targeted therapy. Therefore, we highlight characteristics of this population relevant to effective treatment, and review the evidence for targeted therapy in elderly patients. For targeted therapy it is important to account for aging, as this affects the distribution of phenotypes (e.g. late-onset asthma, non-eosinophilic asthma) and may alter biomarkers and drug metabolism. Elderly asthmatics suffer from age-related comorbidities and subsequent polypharmacy. A systematic search into targeted asthma therapy yielded no randomized clinical trials dedicated to older asthmatics. Post hoc analyses of the anti-immunoglobulin E agent omalizumab indicate similar efficacy in both younger and older adults. Conference abstracts on anti-interleukin-5 and anti-interleukin-13 therapy suggest even more pronounced effects of targeted treatments in late-onset disease and in asthmatic patients 65 years or older, but full reports are lacking. For non-eosinophilic asthma in the elderly, there is not yet high-level evidence for targeted therapy, but macrolides may offer a viable option. In conclusion, there is a gap in knowledge regarding the effect of older age on the safety and efficacy of targeted asthma therapy. Further investigations in the elderly are needed, with special emphasis on both late-onset asthma and therapeutics for non-eosinophilic asthma.