Association between pre-biologic T2-biomarker combinations and response to biologics in patients with severe asthma.

Background: To date, studies investigating the association between pre-biologic biomarker levels and post-biologic outcomes have been limited to single biomarkers and assessment of biologic efficacy from structured clinical trials. Aim: To elucidate the associations of pre-biologic individual biomarker levels or their combinations with pre-to-post biologic changes in asthma outcomes in real-life. Methods: This was a registry-based, cohort study using data from 23 countries, which shared data with the International Severe Asthma Registry (May 2017-February 2023). The investigated biomarkers (highest pre-biologic levels) were immunoglobulin E (IgE), blood eosinophil count (BEC) and fractional exhaled nitric oxide (FeNO). Pre- to approximately 12-month post-biologic change for each of three asthma outcome domains (i.e. exacerbation rate, symptom control and lung function), and the association of this change with pre-biologic biomarkers was investigated for individual and combined biomarkers. Results: Overall, 3751 patients initiated biologics and were included in the analysis. No association was found between pre-biologic BEC and pre-to-post biologic change in exacerbation rate for any biologic class. However, higher pre-biologic BEC and FeNO were both associated with greater post-biologic improvement in FEV1 for both anti-IgE and anti-IL5/5R, with a trend for anti-IL4Rα. Mean FEV1 improved by 27-178 mL post-anti-IgE as pre-biologic BEC increased (250 to 1000 cells/µL), and by 43-216 mL and 129-250 mL post-anti-IL5/5R and -anti-IL4Rα, respectively along the same BEC gradient. Corresponding improvements along a FeNO gradient (25-100 ppb) were 41-274 mL, 69-207 mL and 148-224 mL for anti-IgE, anti-IL5/5R, and anti-IL4Rα, respectively. Higher baseline BEC was also associated with lower probability of uncontrolled asthma (OR 0.392; p=0.001) post-biologic for anti-IL5/5R. Pre-biologic IgE was a poor predictor of subsequent pre-to-post-biologic change for all outcomes assessed for all biologics. The combination of BEC + FeNO marginally improved the prediction of post-biologic FEV1 increase (adjusted R2: 0.751), compared to BEC (adjusted R2: 0.747) or FeNO alone (adjusted R2: 0.743) (p=0.005 and <0.001, respectively); however, this prediction was not improved by the addition of IgE. Conclusions: The ability of higher baseline BEC, FeNO and their combination to predict biologic-associated lung function improvement may encourage earlier intervention in patients with impaired lung function or at risk of accelerated lung function decline.

Association study of human leukocyte antigen variants and idiopathic pulmonary fibrosis.

Introduction: Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial pneumonia marked by progressive lung fibrosis and a poor prognosis. Recent studies have highlighted the potential role of infection in the pathogenesis of IPF, and a prior association of the HLA-DQB1 gene with idiopathic fibrotic interstitial pneumonia (including IPF) has been reported. Owing to the important role that the human leukocyte antigen (HLA) region plays in the immune response, here we evaluated if HLA genetic variation was associated specifically with IPF risk. Methods: We performed a meta-analysis of associations of the HLA region with IPF risk in individuals of European ancestry from seven independent case-control studies of IPF (comprising 5159 cases and 27 459 controls, including a prior study of fibrotic interstitial pneumonia). Single nucleotide polymorphisms, classical HLA alleles and amino acids were analysed and signals meeting a region-wide association threshold of p<4.5×10-4 and a posterior probability of replication >90% were considered significant. We sought to replicate the previously reported HLA-DQB1 association in the subset of studies independent of the original report. Results: The meta-analysis of all seven studies identified four significant independent single nucleotide polymorphisms associated with IPF risk. However, none met the posterior probability for replication criterion. The HLA-DQB1 association was not replicated in the independent IPF studies. Conclusion: Variation in the HLA region was not consistently associated with risk in studies of IPF. However, this does not preclude the possibility that other genomic regions linked to the immune response may be involved in the aetiology of IPF.

Genome-wide SNP-sex interaction analysis of susceptibility to idiopathic pulmonary fibrosis.

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic lung condition that is more prevalent in males than females. The reasons for this are not fully understood, with differing environmental exposures due to historically sex-biased occupations, or diagnostic bias, being possible explanations. To date, over 20 independent genetic variants have been identified to be associated with IPF susceptibility, but these have been discovered when combining males and females. Our aim was to test for the presence of sex-specific associations with IPF susceptibility and assess whether there is a need to consider sex-specific effects when evaluating genetic risk in clinical prediction models for IPF. Methods: We performed genome-wide single nucleotide polymorphism (SNP)-by-sex interaction studies of IPF risk in six independent IPF case-control studies and combined them using inverse-variance weighted fixed effect meta-analysis. In total, 4,561 cases (1,280 females and 2,281 males) and 23,500 controls (8,360 females and 14,528 males) of European genetic ancestry were analysed. We used polygenic risk scores (PRS) to assess differences in genetic risk prediction between males and females. Findings: Three independent genetic association signals were identified. All showed a consistent direction of effect across all individual IPF studies and an opposite direction of effect in IPF susceptibility between females and males. None had been previously identified in IPF susceptibility genome-wide association studies (GWAS). The predictive accuracy of the PRSs were similar between males and females, regardless of whether using combined or sex-specific GWAS results. Interpretation: We prioritised three genetic variants whose effect on IPF risk may be modified by sex, however these require further study. We found no evidence that the predictive accuracy of common SNP-based PRSs varies significantly between males and females.

Association study of human leukocyte antigen (HLA) variants and idiopathic pulmonary fibrosis.

Introduction: Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial pneumonia marked by progressive lung fibrosis and a poor prognosis. Recent studies have highlighted the potential role of infection in the pathogenesis of IPF and a prior association of the HLA-DQB1 gene with idiopathic fibrotic interstitial pneumonia (including IPF) has been reported. Due to the important role that the Human Leukocyte Antigen (HLA) region plays in the immune response, here we evaluated if HLA genetic variation was associated specifically with IPF risk. Methods: We performed a meta-analysis of associations of the HLA region with IPF risk in individuals of European ancestry from seven independent case-control studies of IPF (comprising a total of 5,159 cases and 27,459 controls, including the prior study of fibrotic interstitial pneumonia). Single nucleotide polymorphisms, classical HLA alleles and amino acids were analysed and signals meeting a region-wide association threshold p<4.5×10-4 and a posterior probability of replication >90% were considered significant. We sought to replicate the previously reported HLA-DQB1 association in the subset of studies independent of the original report. Results: The meta-analysis of all seven studies identified four significant independent single nucleotide polymorphisms associated with IPF risk. However, none met the posterior probability for replication criterion. The HLA-DQB1 association was not replicated in the independent IPF studies. Conclusion: Variation in the HLA region was not consistently associated with risk in studies of IPF. However, this does not preclude the possibility that other genomic regions linked to the immune response may be involved in the aetiology of IPF.

Longitudinal lung function and gas transfer in individuals with idiopathic pulmonary fibrosis: a genome-wide association study.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is an incurable lung disease characterised by progressive scarring leading to alveolar stiffness, reduced lung capacity, and impeded gas transfer. We aimed to identify genetic variants associated with declining lung capacity or declining gas transfer after diagnosis of IPF. METHODS: We did a genome-wide meta-analysis of longitudinal measures of forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (DLCO) in individuals diagnosed with IPF. Individuals were recruited to three studies between June, 1996, and August, 2017, from across centres in the US, UK, and Spain. Suggestively significant variants were investigated further in an additional independent study (CleanUP-IPF). All four studies diagnosed cases following American Thoracic Society/European Respiratory Society guidelines. Variants were defined as significantly associated if they had a meta-analysis p<5 × 10-8 when meta-analysing across all discovery and follow-up studies, had consistent direction of effects across all four studies, and were nominally significant (p<0·05) in each study. FINDINGS: 1329 individuals with a total of 5216 measures were included in the FVC analysis. 975 individuals with a total of 3361 measures were included in the DLCO analysis. For the discovery genome-wide analyses, 7 611 174 genetic variants were included in the FVC analysis and 7 536 843 in the DLCO analysis. One variant (rs115982800) located in an antisense RNA gene for protein kinase N2 (PKN2) showed a genome-wide significant association with FVC decline (-140 mL/year per risk allele [95% CI -180 to -100]; p=9·14 × 10-12). INTERPRETATION: Our analysis identifies a genetic variant associated with disease progression, which might highlight a new biological mechanism for IPF. We found that PKN2, a Rho and Rac effector protein, is the most likely gene of interest from this analysis. PKN2 inhibitors are currently in development and signify a potential novel therapeutic approach for IPF. FUNDING: Action for Pulmonary Fibrosis, Medical Research Council, Wellcome Trust, and National Institutes of Health National Heart, Lung, and Blood Institute.

Using patient experiences to evaluate care and expectations in lung cancer: analysis of the English Cancer Patient Experience Survey linked with the national cancer registry.

PURPOSE: Identification of unmet needs in person centred and supportive care could be limited by differences in experience across specific cancer populations. Using the experiences of people with lung cancer, we assess distinctions according to demographic and clinical characteristics. METHODS: The English Cancer Patient Experience Survey was linked to the national cancer registry. The primary outcome was experience of the lung cancer pathway when assessed in multi-question models developed with item response theory. Secondary outcomes were experience by treatment received and in separate dimensions of the care pathway: up to diagnosis, treatment information, and staff support. RESULTS: Responses from 15,967 adults with a lung cancer diagnosis between 2009 and 2015 were included. Positive experiences were more likely to be reported by people aged between 65 and 80 (adjusted coefficient 0.08, 95%CI 0.05;0.11), those living in the most deprived areas (adjusted coefficient 0.10, 95%CI 0.05;0.14), diagnosed at lung cancer stage IIA-B (adjusted coefficient 0.09, 95%CI 0.04;0.14), and those diagnosed through inpatient elective admissions (adjusted coefficient 0.17, 95%CI 0.07;0.28). Specific experiences differed across dimensions of care and within lung cancer treatment groups. CONCLUSIONS: Experiences differed according to gender and ethnicity, supporting previous observations in cancer. In contrast to previous studies, people with lung cancer were more likely to report positive pathway experiences at older ages, living in more deprived areas, or diagnosed after stage I, all frequently associated with worse clinical outcomes. The distinct observations in lung cancer specific analyses suggest potential unmet needs, such as in early stage disease and younger age groups.

Selection of eligible participants for screening for lung cancer using primary care data.

Lung cancer screening is effective if offered to people at increased risk of the disease. Currently, direct contact with potential participants is required for evaluating risk. A way to reduce the number of ineligible people contacted might be to apply risk-prediction models directly to digital primary care data, but model performance in this setting is unknown. METHOD: The Clinical Practice Research Datalink, a computerised, longitudinal primary care database, was used to evaluate the Liverpool Lung Project V.2 (LLPv2) and Prostate Lung Colorectal and Ovarian (modified 2012) (PLCOm2012) models. Lung cancer occurrence over 5-6 years was measured in ever-smokers aged 50-80 years and compared with 5-year (LLPv2) and 6-year (PLCOm2012) predicted risk. RESULTS: Over 5 and 6 years, 7123 and 7876 lung cancers occurred, respectively, from a cohort of 842 109 ever-smokers. After recalibration, LLPV2 produced a c-statistic of 0.700 (0.694-0.710), but mean predicted risk was over-estimated (predicted: 4.61%, actual: 0.9%). PLCOm2012 showed similar performance (c-statistic: 0.679 (0.673-0.685), predicted risk: 3.76%. Applying risk-thresholds of 1% (LLPv2) and 0.15% (PLCOm2012), would avoid contacting 42.7% and 27.4% of ever-smokers who did not develop lung cancer for screening eligibility assessment, at the cost of missing 15.6% and 11.4% of lung cancers. CONCLUSION: Risk-prediction models showed only moderate discrimination when applied to routinely collected primary care data, which may be explained by quality and completeness of data. However, they may substantially reduce the number of people for initial evaluation of screening eligibility, at the cost of missing some lung cancers. Further work is needed to establish whether newer models have improved performance in primary care data.

Factors associated with survival in small cell lung cancer: an analysis of real-world national audit, chemotherapy and radiotherapy data.

BACKGROUND: The mainstay of treatment for small cell lung cancer (SCLC) involves platinum doublet chemotherapy but the optimal duration, 4 vs. 6 cycles, is not known. Concurrent thoracic radiotherapy followed by prophylactic cranial irradiation (PCI) is recommended for fit individuals with limited stage. However, outside of clinical trials, the efficacy of sequential thoracic radiotherapy and PCI for extensive stage is uncertain. METHODS: This retrospective, observational, cohort study used English national lung cancer data to determine the factors associated with survival for all people diagnosed with SCLC. More precisely, for individuals who received chemotherapy, we examined survival by the chemotherapy duration, thoracic radiotherapy dose and the use of PCI. RESULTS: In total 6,438 people were diagnosed with SCLC. We identified that male sex (OR 0.7; 95% CI: 0.62-0.80), increasing age (P=0.01) greater comorbidity (P≤0.01), extensive stage (OR 0.21; 95% CI: 0.19-0.25) and worse performance status (PS2 vs. PS0 adjusted OR 0.38 95% CI: 0.31-0.48) were associated with reduced 1-year survival. Receipt of chemotherapy augmented survival. We analysed data for 1,761 people who had received chemotherapy. Thoracic radiotherapy (≥30 Gy for extensive stage and ≥40 Gy for limited stage) and PCI were independently associated with better survival (P≤0.01 for each), but 6 cycles of chemotherapy instead of 4 was not (limited stage adjusted OR 0.97; 95% CI: 0.48-1.97) extensive stage adjusted OR 1.34; 95% CI: 0.81-2.21). CONCLUSIONS: Extending chemotherapy beyond 4 cycles to 6 does not augment survival. Appropriately prescribed thoracic radiotherapy and PCI can prolong survival in both limited and extensive stage SCLC.

Worldwide relative smoking prevalence among people living with and without HIV.

OBJECTIVE AND DESIGN: People living with HIV (PLH) suffer disproportionately from the chronic diseases exacerbated by smoking tobacco. We performed a systematic review and meta-analysis to establish the relative prevalence of smoking among PLH. METHODS: We included observational studies reporting current smoking rates among PLH and comparators without HIV. We searched Medline, EMBASE, LILACS and SciELO from inception to 31 August 2019. We excluded studies that recruited participants with smoking related illness. We used a random effects model to estimate the odds ratio for current smoking in PLH and people without HIV. We used the Newcastle--Ottawa scale to assess methodological bias. We performed subgroup analysis based on sex and WHO region. We quantified heterogeneity with meta-regression and predictive distributions. PROSPERO registration:CRD42016052608. RESULTS: We identified 6116 studies and included 37. Of 111 258 PLH compared with 10 961 217 HIV-negative participants pooled odds of smoking were 1.64 [(95% confidence interval, 95% CI: 1.45-1.85) (95% prediction interval: 0.66-4.10, I2 = 98.1%)]. Odds for men and women living with HIV were 1.68 [(95% CI: 1.44-1.95) (95% prediction interval: 0.71-3.98, I2 = 91.1%)] and 2.16 [(95% CI: 1.77-2.63) (95% prediction interval: 0.92-5.07, I2 = 81.7%)] respectively. CONCLUSION: PLH are more likely to be smokers than people without HIV. This finding was true in subgroup analyses of men, women and in four of five WHO regions from which data were available. Meta-regression did not explain heterogeneity, which we attribute to the diversity of PLH populations worldwide. Smoking is a barrier to PLH achieving parity in life expectancy and an important covariate in studies of HIV-associated multimorbidity.

Nitrogen-Containing Bisphosphonates Are Associated With Reduced Risk of Pneumonia in Patients With Hip Fracture.

The objective of this work was to study the risk of pneumonia and pneumonia mortality among patients receiving nitrogen-containing bisphosphonates (N-BPs), non-N-BP anti-osteoporosis medications, and no anti-osteoporosis medications after hip fracture. We studied a historical cohort using a population-wide database. Patients with first hip fracture during 2005-2015 were identified and matched by time-dependent propensity score. The cohort was followed until December 31, 2016, to capture any pneumonia and pneumonia mortality. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox-proportional hazards regression. Absolute risk difference (ARD) and number needed to treat (NNT) were calculated. We identified 54,047 patients with hip fracture. Of these, 4041 patients who received N-BPs and 11,802 without anti-osteoporosis medication were propensity score-matched. N-BPs were associated with a significantly lower risk of pneumonia compared with no treatment (6.9 versus 9.0 per 100 person-years; HR 0.76; 95% CI, 0.70 to 0.83), resulting in an ARD of 0.02 and NNT of 46. A similar association was observed with pneumonia mortality (HR 0.65; 95% CI, 0.56 to 0.75). When N-BPs were compared with non-N-BP anti-osteoporosis medications, the association remained significant. N-BPs were associated with lower risks of pneumonia and pneumonia mortality. Randomized controlled trials are now required to determine whether N-BPs, non-vaccine-based medications, can reduce pneumonia incidence in high risk groups. © 2020 American Society for Bone and Mineral Research.

A systematic review of survival following anti-cancer treatment for small cell lung cancer.

OBJECTIVES: We conducted a systematic review and meta-analysis of survival following treatment recommended by the European Society of Medical Oncology for SCLC in order to determine a benchmark for novel therapies to be compared with. MATERIALS AND METHODS: Randomized controlled trials and observational studies reporting overall survival following chemotherapy for SCLC were included. We calculated survival at 30 and 90-days along with 1-year, 2-year and median. RESULTS: We identified 160 for inclusion. There were minimal 30-day deaths. Survival was 99 % (95 %CI 98.0-99.0 %, I233.9 %, n = 77) and 90 % (95 %CI 89.0-92.0 %, I279.5 %, n = 73) at 90 days for limited (LD-SCLC) and extensive stage (ED-SCLC) respectively. The median survival for LD-SCLC was 18.1 months (95 %CI 17.0-19.1 %, I277.3 %, n = 110) and early thoracic radiotherapy (thoracic radiotherapy 18.4 months (95 %CI 17.3-19.5, I278.4 %, n = 100)) vs no radiotherapy 11.7 months (95 %CI 9.1-14.3, n = 10), prophylactic cranial irradiation (PCI 19.7 months vs No PCI 13.0 months (95 %CI 18.5-21.0, I275.7 %, n = 78 and 95 %CI 10.5-16.6, I281.1 %, n = 15 respectively)) and better performance status (PS0-1 22.5 months vs PS0-4 15.3 months (95 %CI 18.7-26.1, I272.4 %, n = 11 and 95 %CI 11.5-19.1 I277.9 %, n = 13)) augmented this. For ED-SCLC the median survival was 9.6 months (95 %CI 8.9-10.3 %, I295.2 %, n = 103) and this improved when irinotecan + cisplatin was used, however studies that used this combination were mostly conducted in Asian populations where survival was better. Survival was not improved with the addition of thoracic radiotherapy or PCI. Survival for both stages of cancer was better in modern studies and Asian cohorts. It was poorer for studies administering carboplatin + etoposide but this regimen was used in studies that had fewer patient selection criteria. CONCLUSION: Early thoracic radiotherapy and PCI should be offered to people with LD-SCLC in accordance with guideline recommendations. The benefit of the aforementioned therapies to treat ED-SCLC and the use of chemotherapy in people with poor PS is less clear.

Is the English Cancer Patient Experience Survey representative? A comparative analysis with the National Lung Cancer Audit.

OBJECTIVES: Healthcare systems increasingly recognise the importance of service users' perspectives for improving care organisation and delivery. The English Cancer Patient Experience Survey (CPES) is carried out annually, however, its representativeness within cancer types is unknown. We have explored if the CPES results are representative of people with lung cancer. MATERIALS AND METHODS: We linked cancer registry data across multiple sources to assess how CPES represents sociodemographic and clinical characteristics of the National Lung Cancer Audit population, accounting for post-sampling mortality bias. Multivariable logistic regression was used to compare people included and not included in CPES. RESULTS: Of 240,375 people diagnosed (2009-2015), 15,967 (7 %) were included in CPES. Gender and ethnicity were reasonably represented, as were sociodemographic and clinical groupings, although more received anti-cancer treatment (96 % of CPES respondents vs. 56 % of patients nationally; adjusted odds ratio = 10.3, 95 % confidence interval 9.4-11.2 for any anti-cancer treatment) with chemotherapy most over-represented, followed by surgery and then radiotherapy. CPES under-represented older, more socioeconomically deprived, and certain clinical groups, including those with worse performance status, multiple comorbidities, and diagnosis via emergency presentation. CONCLUSION: CPES includes patients across the sociodemographic and clinical spectrum indicating its value for research and service planning. Unbalanced representation of incident lung cancer cases is a limitation that must be considered in context of using CPES findings to implement service changes. Although half the national lung cancer population who received no anti-cancer treatment do not have their experiences represented, the strength of this dataset is in providing detailed comparisons of patient experiences across different treatment groups.

Genome-Wide Association Study of Susceptibility to Idiopathic Pulmonary Fibrosis.

Rationale: Idiopathic pulmonary fibrosis (IPF) is a complex lung disease characterized by scarring of the lung that is believed to result from an atypical response to injury of the epithelium. Genome-wide association studies have reported signals of association implicating multiple pathways including host defense, telomere maintenance, signaling, and cell-cell adhesion.Objectives: To improve our understanding of factors that increase IPF susceptibility by identifying previously unreported genetic associations.Methods: We conducted genome-wide analyses across three independent studies and meta-analyzed these results to generate the largest genome-wide association study of IPF to date (2,668 IPF cases and 8,591 controls). We performed replication in two independent studies (1,456 IPF cases and 11,874 controls) and functional analyses (including statistical fine-mapping, investigations into gene expression, and testing for enrichment of IPF susceptibility signals in regulatory regions) to determine putatively causal genes. Polygenic risk scores were used to assess the collective effect of variants not reported as associated with IPF.Measurements and Main Results: We identified and replicated three new genome-wide significant (P < 5 × 10-8) signals of association with IPF susceptibility (associated with altered gene expression of KIF15, MAD1L1, and DEPTOR) and confirmed associations at 11 previously reported loci. Polygenic risk score analyses showed that the combined effect of many thousands of as yet unreported IPF susceptibility variants contribute to IPF susceptibility.Conclusions: The observation that decreased DEPTOR expression associates with increased susceptibility to IPF supports recent studies demonstrating the importance of mTOR signaling in lung fibrosis. New signals of association implicating KIF15 and MAD1L1 suggest a possible role of mitotic spindle-assembly genes in IPF susceptibility.

Overlap of Genetic Risk between Interstitial Lung Abnormalities and Idiopathic Pulmonary Fibrosis.

Rationale: Interstitial lung abnormalities (ILAs) are associated with the highest genetic risk locus for idiopathic pulmonary fibrosis (IPF); however, the extent to which there are unique associations among individuals with ILAs or additional overlap with IPF is not known.Objectives: To perform a genome-wide association study (GWAS) of ILAs.Methods: ILAs and a subpleural-predominant subtype were assessed on chest computed tomography (CT) scans in the AGES (Age Gene/Environment Susceptibility), COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease [COPD]), Framingham Heart, ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points), MESA (Multi-Ethnic Study of Atherosclerosis), and SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study) studies. We performed a GWAS of ILAs in each cohort and combined the results using a meta-analysis. We assessed for overlapping associations in independent GWASs of IPF.Measurements and Main Results: Genome-wide genotyping data were available for 1,699 individuals with ILAs and 10,274 control subjects. The MUC5B (mucin 5B) promoter variant rs35705950 was significantly associated with both ILAs (P = 2.6 × 10-27) and subpleural ILAs (P = 1.6 × 10-29). We discovered novel genome-wide associations near IPO11 (rs6886640, P = 3.8 × 10-8) and FCF1P3 (rs73199442, P = 4.8 × 10-8) with ILAs, and near HTRE1 (rs7744971, P = 4.2 × 10-8) with subpleural-predominant ILAs. These novel associations were not associated with IPF. Among 12 previously reported IPF GWAS loci, five (DPP9, DSP, FAM13A, IVD, and MUC5B) were significantly associated (P < 0.05/12) with ILAs.Conclusions: In a GWAS of ILAs in six studies, we confirmed the association with a MUC5B promoter variant and found strong evidence for an effect of previously described IPF loci; however, novel ILA associations were not associated with IPF. These findings highlight common genetically driven biologic pathways between ILAs and IPF, and also suggest distinct ones.

Factors influencing treatment selection and 30-day mortality after chemotherapy for people with small-cell lung cancer: An analysis of national audit data.

BACKGROUND: Thirty-day mortality after treatment for lung cancer is a measure of unsuccessful outcome and where treatment should have been avoided. Guidelines recommend offering chemotherapy to individuals with small-cell lung cancer (SCLC) who have poorer performance status (PS) because of its high initial response rate. However, this comes with an increased risk of toxicity and early death. We quantified real-world 30-day mortality in SCLC after chemotherapy, established the factors associated with this and compared these with the factors that influence receipt of chemotherapy. METHODS: We used linked national English data sets to define the factors associated with both receiving chemotherapy and 30-day mortality after chemotherapy. RESULTS: We identified 3715 people diagnosed with SCLC, of which 2235 (60.2%) received chemotherapy. There were 174 (7.8%) deaths within 30 days of chemotherapy. The adjusted odds of receiving chemotherapy decreased with older age, worsening PS and increasing comorbidities. Thirty-day mortality was independently associated with poor PS [PS 2 vs PS 0, adjusted odds ratio (OR) 3.75, 95% confidence interval (CI) 1.71-8.25] and stage (extensive vs limited adjusted OR 1.68, 95% CI 1.03-2.74) but in contrast was not associated with increasing age. Both chemotherapy administration and 30-day mortality varied by hospital network. CONCLUSIONS: To reduce variation in chemotherapy administration, predictors of 30-day mortality could be used as an adjunct to improve suboptimal patient selection. We have quantified 30-day mortality risk by the two independently associated factors, PS and stage, so that patients and clinicians can make better informed decisions about the potential risk of early death after chemotherapy.

Are working practices of lung cancer nurse specialists associated with variation in peoples' receipt of anticancer therapy?

OBJECTIVES: Treatment choices for people with lung cancer may be influenced by contact and engagement with lung cancer nurse specialists (LCNSs). We investigated how service factors, LCNS workload, and LCNS working practices may influence the receipt of anticancer treatment. MATERIALS AND METHODS: English National Lung Cancer Audit data and inpatient Hospital Episode Statistics for 109,079 people with lung cancer surviving 30 days from diagnosis were linked along with LCNS workforce census data and a bespoke nationwide LCNS survey. Multinomial logistic regression was used to determine adjusted relative risk ratios (RRRs) for receipt of anticancer therapies associated with LCNS assessment, LCNS workforce composition, caseload, LCNS reported working practices, treatment facilities at the patients' attending hospitals, and the size of the lung cancer service. RESULTS: Assessment by an LCNS was the strongest independent predictor for receipt of anticancer therapy, with early LCNS assessments being particularly associated with greater receipt of surgery (RRR 1.85, 95%CI 1.63-2.11). For people we considered clinically suitable for surgery, receipt was 55%. Large LCNS caseloads were associated with decreased receipt of surgery among suitable patients (RRR 0.71, 95%CI 0.51-0.97) for caseloads >250 compared to ≤150. Reported LCNS working practices were associated with receipt of surgery, particularly provision of psychological support (RRR 1.60, 95%CI 1.02-2.51) and social support (RRR 1.56, 95%CI 1.07-2.28). CONCLUSION: LCNS assessment, workload, and working practices are associated with the likelihood of patients receiving anticancer therapy. Enabling and supporting LCNSs to undertake key case management interventions offers an opportunity to improve treatment uptake and reduce the apparent gap in receipt of surgery for those suitable.

Novel insights into the aetiology of granulomatosis with polyangiitis-a case-control study using the Clinical Practice Research Datalink.

Objectives: We aimed to provide insights into the aetiology of granulomatosis with polyangiitis (GPA), by conducting a large case-control study using a general population-based, prospectively collected database of healthcare records. Methods: We compared all incident cases of GPA in the Clinical Practice Research Datalink 1990-2014, with up to 10 age-, sex- and general practice-matched controls. We identified potential risk factors, recorded numbers of cases and controls exposed to each, and calculated odds ratios (ORs) using conditional logistic regression. Our main analysis excluded data recorded during 1 year before diagnosis, to prevent early symptoms being mistaken for risk factors. Results: We identified 757 people with GPA and matched 7546 controls. People with GPA were five times more likely to have a previous diagnosis of bronchiectasis (OR = 5.1, 95% CI: 2.7, 9.4; P < 0.0001), and these effects remained stable in diagnoses recorded >5 years prior to diagnosis. People with GPA were two to three times more likely than controls to have previous diagnoses of autoimmune diseases or chronic renal impairment, and these effects also remained stable >5 years prior to diagnosis. People with GPA were more likely to have a diagnosis of pulmonary fibrosis (OR = 5.7, 95% CI: 1.7, 19.5; P = 0.01) and sinus infections (OR = 2.7, 95% CI: 1.8, 4.2; P < 0.0001) recorded in the 3 years before diagnosis, but not before this. We also found former smoking, some medications and higher socio-economic status significantly, but less strongly, associated. Conclusion: We found novel long-term associations between GPA and pre-existing bronchiectasis and autoimmune diseases.

Cardiovascular Outcomes after a Respiratory Tract Infection among Adults with Non-Cystic Fibrosis Bronchiectasis: A General Population-based Study.

RATIONALE: Studies suggest that adults with bronchiectasis are at increased risk of cardiovascular comorbidities. OBJECTIVES: We aimed to quantify the relative risk of incident cardiovascular events after a respiratory tract infection among adults with bronchiectasis. METHODS: Using UK electronic primary care records, we conducted a within-person comparison using the self-controlled case series method. We calculated the relative risk of first-time cardiovascular events (either first myocardial infarction or stroke) after a respiratory tract infection compared with the individual's baseline risk. RESULTS: Our cohort consisted of 895 adult men and women with non-cystic fibrosis bronchiectasis with a first myocardial infarction or stroke and at least one respiratory tract infection. There was an increased rate of first-time cardiovascular events in the 91-day period after a respiratory tract infection (incidence rate ratio, 1.56; 95% confidence interval, 1.20-2.02). The rate of a first cardiovascular event was highest in the first 3 days after a respiratory tract infection (incidence rate ratio, 2.73; 95% confidence interval, 1.41-5.27). CONCLUSIONS: These data suggest that respiratory tract infections are strongly associated with a transient increased risk of first-time myocardial infarction or stroke among people with bronchiectasis. As respiratory tract infections are six times more common in people with bronchiectasis than the general population, the increased risk has a disproportionately greater impact in these individuals. These findings may have implications for including cardiovascular risk modifications in airway infection treatment pathways in this population.