Objective sputum colour assessment and clinical outcomes in bronchiectasis: data from the European Bronchiectasis Registry (EMBARC).

BACKGROUND: A validated 4-point sputum colour chart can be used to objectively evaluate the levels of airway inflammation in bronchiectasis patients. In the European Bronchiectasis Registry (EMBARC), we tested whether sputum colour would be associated with disease severity and clinical outcomes. METHODS: We used a prospective, observational registry of adults with bronchiectasis conducted in 31 countries. Patients who did not produce spontaneous sputum were excluded from the analysis. The Murray sputum colour chart was used at baseline and at follow-up visits. Key outcomes were frequency of exacerbations, hospitalisations for severe exacerbations and mortality during up to 5-year follow-up. RESULTS: 13 484 patients were included in the analysis. More purulent sputum was associated with lower forced expiratory volume in 1 s (FEV1), worse quality of life, greater bacterial infection and a higher bronchiectasis severity index. Sputum colour was strongly associated with the risk of future exacerbations during follow-up. Compared to patients with mucoid sputum (reference group), patients with mucopurulent sputum experienced significantly more exacerbations (incident rate ratio (IRR) 1.29, 95% CI 1.22-1.38; p<0.0001), while the rates were even higher for patients with purulent (IRR 1.55, 95% CI 1.44-1.67; p<0.0001) and severely purulent sputum (IRR 1.91, 95% CI 1.52-2.39; p<0.0001). Hospitalisations for severe exacerbations were also associated with increasing sputum colour with rate ratios, compared to patients with mucoid sputum, of 1.41 (95% CI 1.29-1.56; p<0.0001), 1.98 (95% CI 1.77-2.21; p<0.0001) and 3.05 (95% CI 2.25-4.14; p<0.0001) for mucopurulent, purulent and severely purulent sputum, respectively. Mortality was significantly increased with increasing sputum purulence, hazard ratio 1.12 (95% CI 1.01-1.24; p=0.027), for each increment in sputum purulence. CONCLUSION: Sputum colour is a simple marker of disease severity and future risk of exacerbations, severe exacerbations and mortality in patients with bronchiectasis.

Effects of triple therapy on disease burden in patients of GOLD groups C and D: results from the observational COPD cohort COSYCONET.

BACKGROUND: Randomized controlled trials described beneficial effects of inhaled triple therapy (LABA/LAMA/ICS) in patients with chronic obstructive pulmonary disease (COPD) and high risk of exacerbations. We studied whether such effects were also detectable under continuous treatment in a retrospective observational setting. METHODS: Data from baseline and 18-month follow-up of the COPD cohort COSYCONET were used, including patients categorized as GOLD groups C/D at both visits (n = 258). Therapy groups were defined as triple therapy at both visits (triple always, TA) versus its complement (triple not always, TNA). Comparisons were performed via multiple regression analysis, propensity score matching and inverse probability weighting to adjust for differences between groups. For this purpose, variables were divided into predictors of therapy and outcomes. RESULTS: In total, 258 patients were eligible (TA: n = 162, TNA: n = 96). Without adjustments, TA patients showed significant (p < 0.05) impairments regarding lung function, quality of life and symptom burden. After adjustments, most differences in outcomes were no more significant. Total direct health care costs were reduced but still elevated, with inpatient costs much reduced, while costs of total and respiratory medication only slightly changed. CONCLUSION: Without statistical adjustment, patients with triple therapy showed multiple impairments as well as elevated treatment costs. After adjusting for differences between treatment groups, differences were reduced. These findings are compatible with beneficial effects of triple therapy under continuous, long-term treatment, but also demonstrate the limitations encountered in the comparison of controlled intervention studies with observational studies in patients with severe COPD using different types of devices and compounds.

Reduced anticoagulation strategy is associated with a lower incidence of intracerebral hemorrhage in COVID-19 patients on extracorporeal membrane oxygenation.

BACKGROUND: Optimal anticoagulation strategies for COVID-19 patients with the acute respiratory distress syndrome (ARDS) on venovenous extracorporeal membrane oxygenation (VV ECMO) remain uncertain. A higher incidence of intracerebral hemorrhage (ICH) during VV ECMO support compared to non-COVID-19 viral ARDS patients has been reported, with increased bleeding rates in COVID-19 attributed to both intensified anticoagulation and a disease-specific endotheliopathy. We hypothesized that lower intensity of anticoagulation during VV ECMO would be associated with a lower risk of ICH. In a retrospective, multicenter study from three academic tertiary intensive care units, we included patients with confirmed COVID-19 ARDS requiring VV ECMO support from March 2020 to January 2022. Patients were grouped by anticoagulation exposure into higher intensity, targeting anti-factor Xa activity (anti-Xa) of 0.3-0.4 U/mL, versus lower intensity, targeting anti-Xa 0.15-0.3 U/mL, cohorts. Mean daily doses of unfractionated heparin (UFH) per kg bodyweight and effectively measured daily anti-factor Xa activities were compared between the groups over the first 7 days on ECMO support. The primary outcome was the rate of ICH during VV ECMO support. RESULTS: 141 critically ill COVID-19 patients were included in the study. Patients with lower anticoagulation targets had consistently lower anti-Xa activity values over the first 7 ECMO days (p < 0.001). ICH incidence was lower in patients in the lower anti-Xa group: 4 (8%) vs 32 (34%) events. Accounting for death as a competing event, the adjusted subhazard ratio for the occurrence of ICH was 0.295 (97.5% CI 0.1-0.9, p = 0.044) for the lower anti-Xa compared to the higher anti-Xa group. 90-day ICU survival was higher in patients in the lower anti-Xa group, and ICH was the strongest risk factor associated with mortality (odds ratio [OR] 6.8 [CI 2.1-22.1], p = 0.001). CONCLUSIONS: For COVID-19 patients on VV ECMO support anticoagulated with heparin, a lower anticoagulation target was associated with a significant reduction in ICH incidence and increased survival.

How Much Should be Invested in Lung Care Across the WHO European Region? Applying a Monetary Value to Disability-Adjusted Life-Years Within the International Respiratory Coalition's Lung Facts.

OBJECTIVES: The International Respiratory Coalition's Lung Facts web resource provides the latest data on a range of lung conditions covering the World Health Organization's European Region, informed by the Global Burden of Disease studies: https://international-respiratory-coalition.org/lung-facts/ . Within Lung Facts, disability-adjusted life-years (DALYs) are monetised based on gross domestic product (GDP) per capita. We describe the conceptual and empirical basis for using monetised DALYs to inform negotiations with policymakers to invest in lung care across the World Health Organization European region. METHODS: We reflect on the existing debate and research evidence regarding the X value in an X*GDP per capita framework to monetise DALYs, with a focus on if 1*GDP per capita is conceptually and practically appropriate. Using an asthma case study, Global Burden of Disease study 2019 DALY estimates per country are presented. Gross domestic product per capita are converted to international dollars using purchasing power parity (Int$2019). RESULTS: Using 1*GDP per capita, the estimated monetised asthma DALY burden, for example, in Kyrgyzstan or Germany is: across the whole population, $44,860,483 or $9,264,767,882, respectively; per 100,000 people, $731,600 or $10,208,317, respectively. CONCLUSIONS: Our indicative monetised DALY estimates can enable informed discussions with policy and decision makers, to guide financial investment in alleviating the burden of lung conditions. We suggest 1*GDP per capita as a benchmarked value forms a starting point for negotiation with policymakers for investing in lung care, by scaling the estimated lung condition DALY burden to the resource available in each country to tackle the burden.

Risk Assessment for Patients with Chronic Respiratory Conditions in the Context of the SARS-CoV-2 Pandemic Statement of the German Respiratory Society with the Support of the German Association of Chest Physicians.

Assessing the risk for specific patient groups to suffer from severe courses of COVID-19 is of major importance in the current SARS-CoV-2 pandemic. This review focusses on the risk for specific patient groups with chronic respiratory conditions, such as patients with asthma, chronic obstructive pulmonary disease, cystic fibrosis (CF), sarcoidosis, interstitial lung diseases, lung cancer, sleep apnea, tuberculosis, neuromuscular diseases, a history of pulmonary embolism, and patients with lung transplants. Evidence and recommendations are detailed in exemplary cases. While some patient groups with chronic respiratory conditions have an increased risk for severe courses of COVID-19, an increasing number of studies confirm that asthma is not a risk factor for severe COVID-19. However, other risk factors such as higher age, obesity, male gender, diabetes, cardiovascular diseases, chronic kidney or liver disease, cerebrovascular and neurological disease, and various immunodeficiencies or treatments with immunosuppressants need to be taken into account when assessing the risk for severe COVID-19 in patients with chronic respiratory diseases.

Economic analysis of ceftaroline fosamil for treating community-acquired pneumonia in Spain.

Background: Adults admitted to hospital with community-acquired pneumonia (CAP) impose significant burden upon limited hospital resources. To achieve early response and possibly early discharge, thus reducing hospital expenditure, the choice of initial antibiotic therapy is pivotal.Methods: A cost-consequences model was developed to evaluate ceftaroline fosamil (CFT) as an alternative to other antibiotic therapies (ceftriaxone, co-amoxiclav, moxifloxacin, levofloxacin) for the empiric treatment of hospitalized adults with moderate/severe CAP (PORT score III-IV) from the perspective of the Spanish National Health System (NHS).Findings: Compared with ceftriaxone, the model predicted an increase in the number of CFT-treated patients discharged early (PDE) (30.6% vs. 26.1%) while decreasing initial antibiotic failures (3.8% vs. 7.6%). For patients with pneumococcal pneumonia, CFT was cost-saving vs. ceftriaxone (by 1.2%) and significantly increased PDE (32.1% vs. 24.6%). CFT resulted in cost-saving vs. levofloxacin, due lower initial antibiotic therapy costs and increased PDE (30.6% vs. 14.9%). Moxifloxacin and co-amoxiclav early response rate of 53.63% and 54.24% resulted in cost neutrality vs. CFT, with direct comparison hampered by the significantly different early response criteria utilized in the literature.Conclusions: Despite a higher unit cost, CFT is a reasonable alternative to other agents for adults hospitalized with moderate/severe CAP, given the projected higher PDE achieved with similar or lower total costs.

Valuing antibiotics: The role of the hospital clinician.

The global public health threat of antibiotic-resistant infections as well as the lack of new treatments in clinical development is a critical issue. Reasons for this include diminished commercial incentives for pharmaceutical companies to develop new antibiotics, which part-reflects a shift in antibiotic marketing paradigm from broad deployment to targeted therapy in relatively small patient populations. Such changes are encouraged by antimicrobial stewardship (AMS). Other factors include a lack of recognition in the traditional assessment of new antibiotics by regulators, health technology assessors and payers of the broad range of benefits of new agents, particularly their value to health care, economies and society. Recognising the seriousness of the situation, there have been recent changes and proposals by regulators for modification of the assessment process to accommodate a broader range of acceptable data supporting new drug applications. There is also increasing recognition by some payers of the societal benefit of new antibiotics and the need for financial incentives for those developing high-priority antibiotics. However, progress is slow, with recent publications focusing on industry and strategic perspectives rather than clinical implications. In this opinion piece, we therefore focus on clinicians and the practical steps they can take to drive and contribute to increasing awareness and understanding of the value of antibiotics. This includes identifying and gathering appropriate alternative data sources, educating on AMS and prescribing habits, and contributing to international antibiotic susceptibility surveillance models.

Quantitation of Perfused Lung Volume Using Hybrid SPECT/CT Allows Refining the Assessment of Lung Perfusion and Estimating Disease Extent in Chronic Thromboembolic Pulmonary Hypertension.

BACKGROUND: We evaluated the feasibility of perfusion SPECT/CT for providing quantitative data for estimation of perfusion defect extent in chronic thromboembolic pulmonary hypertension (CTEPH). METHODS: Thirty patients with CTEPH underwent Tc-human serum albumin lung perfusion SPECT/CT. Perfusion defects were quantified using 3 different methods: (1) visual, semiquantitative scoring of perfusion defect extent in each lung segment, (2) threshold-based segmentation of perfused lung volumes, and (3) threshold-based segmentation of perfused lung volumes divided by segmented lung volumes at CT (perfusion index). Imaging findings were correlated with right-sided heart catheterization results and N-terminal pro-B-type natriuretic peptide. Receiver operating characteristic analysis was performed to identify SPECT thresholds for mean pulmonary arterial pressure (PAPm) greater than 50 mm Hg. RESULTS: Assessment of lung perfusion provided similar results using all 3 methods. The perfusion defect score correlated with PAPm (rs = 0.60, P = 0.0005) and was associated with serum levels of N-terminal pro-B-type natriuretic peptide (rs = 0.37, P = 0.04). Perfused lung volume (40% threshold, rs = -0.48, P = 0.007) and perfusion index (40% threshold, rs = -0.50, P = 0.005) decreased as PAPm increased. Receiver operating characteristic analysis showed that perfusion defect score (sensitivity, 88%; specificity, 77%; area under the curve [AUC] = 0.89, P = 0.001), perfused lung volume (sensitivity, 88%; specificity, 64%; AUC = 0.80, P = 0.01), and perfusion index (sensitivity, 88%; specificity, 64%; AUC = 0.82, P = 0.009) could identify patients with PAPm of greater than 50 mm Hg. CONCLUSIONS: Quantitative analysis of perfusion defects at SPECT is feasible, provides a measure of disease severity, and correlates with established clinical parameters. Quantitation of perfusion SPECT may refine the diagnostic approach in CTEPH providing a quantitative imaging biomarker, for example, for therapy monitoring.

Burden of pneumococcal community-acquired pneumonia in adults across Europe: A literature review.

BACKGROUND: The burden of community-acquired pneumonia (CAP) caused by Streptococcus pneumoniae (pneumococcus) among adults in Europe is poorly defined. METHODS: Structured searches of PubMed were conducted to identify the incidence of pneumococcal CAP among adults across Europe. RESULTS: The overall incidence rates for CAP was 68-7000 per 100,000 and the incidence in hospitalised CAP cases of all causes was 16-3581 per 100,000. In general the incidence of CAP increased consistently with age. Available data indicated higher burdens of pneumococcal CAP caused in groups with more comorbidities. Most cases of pneumococcal CAP (30%-78%) were caused by serotypes covered by PCV13 vaccine; the incidence of PCV13-related pneumonia decreased after the introduction of childhood vaccination. CONCLUSIONS: We observed a high burden adult pneumococcal CAP in Europe despite use of the 23-valent pneumococcal polysaccharide vaccine, particularly in elderly patients with comorbidities. CAP surveillance presented wide variations across Europe. Pneumococcal CAP has to be monitored very carefully due to the possible effect of current vaccination strategies.

Trade-off between benefits, harms and economic efficiency of low-dose CT lung cancer screening: a microsimulation analysis of nodule management strategies in a population-based setting.

BACKGROUND: In lung cancer screening, a nodule management protocol describes nodule assessment and thresholds for nodule size and growth rate to identify patients who require immediate diagnostic evaluation or additional imaging exams. The Netherlands-Leuvens Screening Trial and the National Lung Screening Trial used different selection criteria and nodule management protocols. Several modelling studies have reported variations in screening outcomes and cost-effectiveness across selection criteria and screening intervals; however, the effect of variations in the nodule management protocol remains uncertain. This study evaluated the effects of the eligibility criteria and nodule management protocols on the benefits, harms and cost-effectiveness of lung screening scenarios in a population-based setting in Germany. METHODS: We developed a modular microsimulation model: a biological module simulated individual histories of lung cancer development from carcinogenesis onset to death; a screening module simulated patient selection, screening-detection, nodule management protocols, diagnostic evaluation and screening outcomes. Benefits included mortality reduction, life years gained and averted lung cancer deaths. Harms were costs, false positives and overdiagnosis. The comparator was no screening. The evaluated 76 screening scenarios included variations in selection criteria and thresholds for nodule size and growth rate. RESULTS: Five years of annual screening resulted in a 9.7-12.8% lung cancer mortality reduction in the screened population. The efficient scenarios included volumetric assessment of nodule size, a threshold for a volume of 300 mm3 and a threshold for a volume doubling time of 400 days. Assessment of volume doubling time is essential for reducing overdiagnosis and false positives. Incremental cost-effectiveness ratios of the efficient scenarios were 16,754-23,847 euro per life year gained and 155,287-285,630 euro per averted lung cancer death. CONCLUSIONS: Lung cancer screening can be cost-effective in Germany. Along with the eligibility criteria, the nodule management protocol influences screening performance and cost-effectiveness. Definition of the thresholds for nodule size and nodule growth in the nodule management protocol should be considered in detail when defining optimal screening strategies.

Costs and outcomes of the German disease management programme (DMP) for chronic obstructive pulmonary disease (COPD)-A large population-based cohort study.

INTRODUCTION: To curb costs and improve health outcomes in chronic obstructive pulmonary disease (COPD), a nationwide disease management programme (DMP) was introduced in Germany in 2005. Yet, its effectiveness has not been comprehensively evaluated. OBJECTIVE: To examine the effects of the German COPD DMP over three years on costs and health resource utilisation from the payer perspective, process quality, morbidity and mortality. METHODS: A retrospective, population-based cohort study design is applied, using administrative data. After eliminating differences in observable characteristics between the DMP and the control group with entropy balancing, difference-in-difference estimators were computed to account for time-invariant unobservable heterogeneity. RESULTS: 215,104 individuals were included into the analysis of whom 25,269 were enrolled in the DMP. DMP patients had a reduced mortality hazard ratio (0.89, 95%CI: 0.84-0.94) but incurred excess costs of €553 per year. DMP enrolees reveal higher healthcare utilisation with larger shares of individuals being hospitalised (3.14%), consulting an outpatient clinic due to exacerbations (11.13%) and pharmaceutical prescriptions (2.78). However, average length of hospitalisation due to COPD fell by 0.49 days, adherence to medication guidelines as well as indicators for morbidity improved. CONCLUSION: The German COPD DMP achieved significant improvements in mortality, morbidity and process quality, but at higher costs. Given the low ICER per life year gained, DMP COPD may constitute a cost-effective option to promote COPD population health.

Lung transplantation in the spotlight: Reasons for high-cost procedures.

BACKGROUND: Hospital treatment costs of lung transplantation are insufficiently analyzed. Accordingly, it remains unknown, whether current Diagnosis Related Groups, merely accounting for 3 ventilation time intervals and length of hospital stay, reproduce costs properly, even when an increasing number of complex recipients are treated. Therefore, in this cost determination study, actual costs were calculated and cost drivers identified. METHODS: A standardized microcosting approach allowed for individual cost calculations in 780 lung transplant patients taken care of at Hannover Medical School and University of Munich from 2009 to 2013. A generalized linear model facilitated the determination of characteristics predictive for inpatient costs. RESULTS: Lung transplantation costs varied substantially by major diagnosis, with a mean of €85,946 (median €52,938 ± 3,081). Length of stay and ventilation time properly reproduced costs in many cases. However, complications requiring prolonged ventilation or reinterventions were identified as additional significant cost drivers, responsible for high costs. CONCLUSIONS: Diagnosis Related Groups properly reproduce actual lung transplantation costs in straightforward cases, but costs in complex cases may remain underestimated. Improved grouping should consider major diagnosis, a higher gradation of ventilation time, and the number of reinterventions to allow for more reasonable reimbursement.

Prognostic assessment in COPD without lung function: the B-AE-D indices.

Several composite markers have been proposed for risk assessment in chronic obstructive pulmonary disease (COPD). However, choice of parameters and score complexity restrict clinical applicability. Our aim was to provide and validate a simplified COPD risk index independent of lung function.The PROMISE study (n=530) was used to develop a novel prognostic index. Index performance was assessed regarding 2-year COPD-related mortality and all-cause mortality. External validity was tested in stable and exacerbated COPD patients in the ProCOLD, COCOMICS and COMIC cohorts (total n=2988).Using a mixed clinical and statistical approach, body mass index (B), severe acute exacerbations of COPD frequency (AE), modified Medical Research Council dyspnoea severity (D) and copeptin (C) were identified as the most suitable simplified marker combination. 0, 1 or 2 points were assigned to each parameter and totalled to B-AE-D or B-AE-D-C. It was observed that B-AE-D and B-AE-D-C were at least as good as BODE (body mass index, airflow obstruction, dyspnoea, exercise capacity), ADO (age, dyspnoea, airflow obstruction) and DOSE (dyspnoea, obstruction, smoking, exacerbation) indices for predicting 2-year all-cause mortality (c-statistic: 0.74, 0.77, 0.69, 0.72 and 0.63, respectively; Hosmer-Lemeshow test all p>0.05). Both indices were COPD specific (c-statistic for predicting COPD-related 2-year mortality: 0.87 and 0.89, respectively). External validation of B-AE-D was performed in COCOMICS and COMIC (c-statistic for 1-year all-cause mortality: 0.68 and 0.74; c-statistic for 2-year all-cause mortality: 0.65 and 0.67; Hosmer-Lemeshow test all p>0.05).The B-AE-D index, plus copeptin if available, allows a simple and accurate assessment of COPD-related risk.

[CAPNETZ. The competence network for community-acquired pneumonia (CAP)]. / CAPNETZ. Das Kompetenzzentrum für ambulant erworbene Pneumonie.

CAPNETZ is a medical competence network for community-acquired pneumonia (CAP), which was funded by the German Ministry for Education and Research. It has accomplished seminal work on pneumonia over the last 15 years. A unique infrastructure was established which has so far allowed us to recruit and analyze more than 11,000 patients. The CAPNETZ cohort is the largest cohort worldwide and the results obtained relate to all relevant aspects of CAP management (epidemiology, risk stratification via biomarkers or clinical scores, pathogen spectrum, pathogen resistance, antibiotic management, prevention and health care research). Results were published in more than 150 journals and informed the preparation and update of the national S3-guideline. CAPNETZ was also the foundation for further networks like the Pneumonia Research Network on Genetic Resistance and Susceptibility for the Evolution of Severe Sepsis) (PROGRESS), the Systems Medicine of Community Acquired Pneumonia Network (CAPSyS) and SFB-TR84 (Sonderforschungsbereich - Transregio 84). The main recipients (Charité Berlin, University Clinic Ulm and the Hannover Medical School) founded the CAPNETZ foundation and transferred all data and materials rights to this foundation. Moreover, the ministry granted the CAPNETZ foundation the status of being eligible to apply for research proposals and receive research funds. Since 2013 the CAPNETZ foundation has been an associated member of the German Center for Lung Research (DZL). Thus, a solid foundation has been set up for CAPNETZ to continue its success story.

Hospital Incidence and Mortality Rates of Sepsis.

BACKGROUND: Sepsis, the most severe manifestation of acute infection, poses a major challenge to health care systems around the world. To date, adequate data on the incidence and mortality of sepsis in Germany have been lacking. METHODS: Nationwide case-related hospital DRG statistics for the years 2007-2013 were used to determine the in-hospital incidence and mortality of sepsis. Cases were identified on the basis of the clinical and pathogen-based ICD-10 codes for sepsis. The statistical evaluation was standardized for age and sex and carried out separately for each age group. RESULTS: The number of cases of sepsis rose by an average of 5.7% per year, from 200 535 in 2007 to 279 530 in 2013, corresponding to an increase in the adjusted in-hospital incidence from 256 to 335 cases per 100 000 persons per year. The percentage of patients with severe sepsis rose from 27% to 41%. The in-hospital mortality of sepsis fell over the same period by 2.7%, to 24.3%. In 2013, 67 849 persons died of sepsis in German hospitals (or died of another disease, but also had sepsis). The incidence was highest in the youngest and oldest age groups, and the in-hospital mortality rose nearly linearly with age from age 40 onward. CONCLUSION: Sepsis and death from sepsis are markedly more common in Germany than previously assumed, and they are on the rise. Sepsis statistics should become a standard component of federal statistical reports on public health, as well as of hospital statistics. Preventive measures and evidencebased treatment should be implemented across the nation.