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Abstract Background The most commonly applied treatment for acute exacerbations of chronic obstructive pulmonary disease (AECOPD) is a 5-day course of high-dose systemic corticosteroids. However, this treatment has not been shown to reduce mortality and can potentially have serious side effects. Recent research has shown that, presumably, only a subgroup of COPD patients identifieable by blood eosinophil count benefit from a rescue course of prednisolone. By applying a biomarker-guided strategy, the aim of this study is to determine whether it is possible to reduce the use of systemic corticosteroids in AECOPD without influencing the outcome. Methods This is an ongoing prospective multicenter randomized controlled open label trial comprising 320 patients with AECOPD recruited from four hospitals in Denmark. The patients are randomized 1:1 to either standard care or eosinophil-guided corticosteroid-sparing therapy where prednisolone is not administered if the daily blood sampling reveals an eosinophil level below 0.3 × 109 cells/L. The primary endpoint is length of hospital stay within 14 days after recruitment. The secondary endpoints are treatment failure, 30-day mortality rate, COPD related re-admission rate, change in FEV1, and a number of adverse effect measures obtained within 3 months after the index hospitalisation date related to corticosteroid usage. Discussion This will be a very large RCT providing knowledge about the effectiveness of individualized biomarker-guided corticosteroid therapy in hospitalised patients with AECOPD. Trial registration Clinicaltrials.gov, NCT02857842 , 02-august-2016. Clinicaltrialregister.eu: Classification Code: 10,010,953, 02-marts-2016.

Abstract Background Increased lung macrophage numbers in COPD may arise from upregulation of blood monocyte recruitment into the lungs. CCR5 is a monocyte chemokine receptor regulated by interleukin-6 (IL-6); the concentration of CCR5 ligands are known to be elevated in COPD lungs. The objective of this study was to investigate mechanisms of monocyte recruitment to the lung in COPD, including the role of CCR5 signalling. Methods Ninety one COPD patients, 29 smokers (S) and 37 non-smokers (NS) underwent sputum induction, plasma sampling (to measure IL-6 and soluble IL-6 receptor [sIL-6R] by immunoassay), monocyte characterization (by flow cytometry) and monocyte isolation for cell migration and quantitative polymerase chain reaction studies. Lung tissue was used for immunohistochemistry. Results Plasma IL-6 and sIL-6R levels were increased in COPD. Greater proportions of COPD CD14++CD16+ monocytes expressed CCR5 compared to controls. Monocyte stimulation with IL-6 and sIL-6R increased CCR5 gene expression. COPD monocytes demonstrated impaired migration towards sputum supernatant compared to NS (% migration, 4.4 vs 11.5, respectively; p

Chronic obstructive lung disease: Variations in disease progression Patients with chronic obstructive pulmonary disease (COPD) who suffer from frequent exacerbations do not necessarily persist with such severity over time. Exacerbations in COPD are defined by worsening respiratory symptoms that result in changes to treatment, hospitalization and, at worst, death. However, clarity is needed on whether frequent exacerbations is a stable feature of some patients’ disease. Mette Reilev at the University of Southern Denmark and co-workers followed, over 10 years, 19,752 COPD patients living in Denmark who suffered at least one exacerbation in 2003. By 2004, 60% of patients were classed as infrequent or non-exacerbators, rising to 68% by 2012. Very few patients remained “frequent exacerbators”, suggesting the rate of exacerbations changes considerably over time. This could hold implications for COPD treatment and challenge assumptions made about disease progression.

Background Elevated eosinophils in COPD is recognized as a potential risk factor for exacerbations, but the prognostic role of elevated eosinophils during exacerbations of COPD is unclear. We investigated short-term and long-term outcomes in patients with exacerbations of eosinophilic phenotype, compared with patients with low blood eosinophils. Methods A single-centre retrospective study of all patients admitted for a COPD exacerbation to Bispebjerg University Hospital in 2010–2011 was established by linking inpatient data with national patient and prescription registries, with a three-year follow-up period. Elevated eosinophils were defined as a blood eosinophil level at admission of ≥0.30 × 109 cells/L. Results A total of 811 patients were included; 13.2% had an eosinophilic exacerbation. The eosinophilic group had less need for non-invasive ventilation, shorter inpatient stay, and lower in-hospital mortality, compared to the non-eosinophilic group. However, the eosinophilic and non-eosinophilic groups showed similar risks of readmission (incidence rate ratio[95], 0.99 [0.73–1.36]). Three-year mortality was high in both groups, although lower in the eosinophilic group (40% vs. 54%, p = 0.006). Conclusions COPD exacerbations in patients with high blood eosinophil have a better short-term prognosis without higher risk of subsequent exacerbation. Eosinophilic exacerbations have also a lower three-year mortality.

Introduction Patients with coronavirus disease (COVID-19) and pneumonitis often have hypoxemic respiratory failure and a need of supplementary oxygen. Guidelines recommend controlled oxygen, for most patients with a recommended interval of SpO2 between 92 and 96%. We aimed to determine if closed-loop control of oxygen was feasible in patients with COVID-19 and could maintain SpO2 in the specified interval. Methods Patients were prospectively enrolled in an observational study on a medical ward dedicated to patients with COVID-19. Closed-loop controlled oxygen was delivered by O2matic® which can deliver 0–15 liters/min and adjusts flow every second based on 15 seconds averaging of SpO2 measured by pulse oximetry. Lung function parameters were measured at admission. Results Fifteen patients (six women, nine men) participated in the study. Average age was 72 years. Lung function was severely impaired with FEV1, FVC and PEF reduced to approximately 50%. The average stay on the ward was 3.2 days and O2matic was used on average for 66 hours, providing 987 hours of observation. O2matic maintained SpO2 in the desired interval for 82.9% of the time. Time with SpO2 > 2% below interval was 5.1% and time with SpO2 > 2% above interval was 0.6%. Conclusion Closed-loop control of oxygen to patients with COVID-19 is feasible and can maintain SpO2 in the specified interval in the majority of time. Closed-loop automated control could be of particular benefit for patients in isolation with decreased visibility, surveillance and monitoring. Further studies must examine the clinical benefits.

Randomised controlled trials (RCTs) evaluating the management of acute exacerbations of chronic obstructive pulmonary disease (COPD) report heterogeneous outcome measures, thus rendering their results incomparable, complicating their translation into clinical practice. As a first step in the development of a core outcome set that will aim to homogenise outcome measures in future RCTs, we assessed the outcomes reported in recent relevant RCTs and systematic reviews. We conducted a methodological systematic review (https://www.crd.york.ac.uk/prospero/ registration number CRD42016052437) of RCTs and systematic reviews on COPD exacerbation management indexed on Medline and PubMed during the last decade. We evaluated their methodology, specifically focusing on the reported outcome measures. Based on 123 RCTs and 38 systematic reviews, we found significant variability in the outcomes reported and in their definition. Mortality, which was assessed in 82% of the included trials, was the most frequently assessed outcome, followed by the rate of treatment success or failure (63%), adverse events (59%), health status, symptoms and quality of life (59%), lung function (47%), and duration of exacerbations (42%). The significant heterogeneity in the selection and definition of outcome measures in RCTs and systematic reviews limits the interpretability and comparability of their results, and warrants the development of a core outcome set for COPD exacerbations management.

Abstract Background Modern combination antiretroviral therapy (cART) has improved survival for people living with HIV (PLWHIV). Non-AIDS comorbidities have replaced opportunistic infections as leading causes of mortality and morbidity, and are becoming a key health concern as this population continues to age. The aim of this study is to estimate the prevalence and incidence of non-AIDS comorbidity among PLWHIV in Denmark in the cART era and to determine risk factors contributing to the pathogenesis. The study primarily targets cardiovascular, respiratory, and hepatic non-AIDS comorbidity. Methods/design The Copenhagen comorbidity in HIV-infection (COCOMO) study is an observational, longitudinal cohort study. The study was initiated in 2015 and recruitment is ongoing with the aim of including 1500 PLWHIV from the Copenhagen area. Follow-up examinations after 2 and 10 years are planned. Uninfected controls are derived from the Copenhagen General Population Study (CGPS), a cohort study including 100,000 uninfected participants from the same geographical region. Physiological and biological measures including blood pressure, ankle-brachial index, electrocardiogram, spirometry, exhaled nitric oxide, transient elastography of the liver, computed tomography (CT) angiography of the heart, unenhanced CT of the chest and upper abdomen, and a number of routine biochemical analysis are uniformly collected in participants from the COCOMO study and the CGPS. Plasma, serum, buffy coat, peripheral blood mononuclear cells (PBMC), urine, and stool samples are collected in a biobank for future studies. Data will be updated through periodical linking to national databases. Discussion As life expectancy for PLWHIV improves, it is essential to study long-term impact of HIV and cART. We anticipate that findings from this cohort study will increase knowledge on non-AIDS comorbidity in PLWHIV and identify targets for future interventional trials. Recognizing the demographic, clinical and pathophysiological characteristics of comorbidity in PLWHIV may help inform development of new guidelines and enable us to move forward to a more personalized HIV care. Trial registration ClinicalTrials.gov: NCT02382822 .

A number of scientific questions cannot be tested in a laboratory, clinic or clinical trial setting. In many cases, observational data can be used to test such hypotheses. This article illustrates how epidemiology can contribute and shows the different ways of using observational data through three approaches: 1) prospective cohort study design; 2) time series analysis; and 3) a nested case–control design in pharmacoepidemiology. In a prospective cohort study design, three cohorts were merged to study lung function decline, testing the importance of different trajectories of lung function decline for developing chronic obstructive pulmonary disease (COPD). Using these three well-described cohorts it was documented that maximally attained lung function in early adulthood is as important as excess decline in forced expiratory volume in 1 s for the development of COPD. Time series analysis is used to examine exposures and disease over time. In a recent review of cardiovascular disease some interesting associations, and not least lack of associations, were presented. Assessing effects of drugs in database studies is challenging. In a nested case–control design in a large cohort study, statins were found to reduce the risk of COPD exacerbations. These findings will be discussed. Observational data from large databases, as well as carefully collected data in cohort studies, can be used to test hypotheses that may not be addressed in a traditional experimental setting.

It is crucial that randomized controlled trials (RCTs) on the management of coronavirus disease 2019 (COVID-19) evaluate the outcomes that are critical to patients and clinicians, to facilitate relevance, interpretability, and comparability. This methodological systematic review describes the outcomes evaluated in 415 RCTs on the management of COVID-19, that were registered with ClinicalTrials.gov, by 5 May 2020, and the instruments used to measure these outcomes. Significant heterogeneity was observed in the selection of outcomes and instruments. Mortality, adverse events and treatment success or failure are only evaluated in 64.4%, 48.4% and 43% of the included studies, respectively, while other outcomes are selected less often. Studies focusing on more severe presentations (hospitalized patients or requiring intensive care) most frequently evaluate mortality (72.5%) and adverse events (55.6%), while hospital admission (50.8%) and viral detection/load (55.6%) are most frequently assessed in the community setting. Outcome measurement instruments are poorly reported and heterogeneous. Follow-up does not exceed one month in 64.3% of these earlier trials, and long-term COVID-19 burden is rarely assessed. The methodological issues identified could delay the introduction of potentially life-saving treatments in clinical practice. Our findings demonstrate the need for greater consistency, to enable decision makers to compare and contrast studies.

The impact of prior treatment on results of clinical trials in chronic obstructive pulmonary disease (COPD) has been debated. We used data from the Study to Understand Mortality and Morbidity in COPD Trial to examine the impact of prior treatment on the effects of randomised study drugs on mortality and exacerbations. We used data on 16 417 patients with moderate COPD and heightened cardiovascular risk and information on prior medications to examine the effects of fluticasone furoate (FF), vilanterol (VI) and combined FF/VI compared to placebo on moderate and severe exacerbation as well as mortality. The study was event-driven with a median study exposure of 1.8 years. This study was registered with ClinicalTrials.gov, number NCT01313676. There were no consistent associations between treatment prior to study entry and the effects of FF, VI or FF/VI on exacerbations during the study. However, patients taking inhaled corticosteroids and one or more bronchodilators prior to study entry seemed to have a better effect of active treatments than of placebo on mortality (hazard ratio for FF/VI 0.65, 95% CI 0.48–0.89). Survival in those randomised to placebo was independent of treatment prior to study enrolment. Prior treatment appears to affect treatment effects on mortality but not exacerbations in a randomised controlled trial of patients with COPD and heightened cardiovascular risk.

Asthma and chronic obstructive pulmonary disease (COPD) have overlapping clinical features and share pathobiological mechanisms but are often considered distinct disorders. Prospective, observational studies across asthma, COPD and asthma–COPD overlap are limited. NOVELTY is a global, prospective observational 3-year study enrolling ∼12 000 patients ≥12 years of age from primary and specialist clinical practices in 19 countries (ClinicalTrials.gov identifier: NCT02760329). NOVELTY's primary objectives are to describe patient characteristics, treatment patterns and disease burden over time, and to identify phenotypes and molecular endotypes associated with differential outcomes over time in patients with a diagnosis/suspected diagnosis of asthma and/or COPD. NOVELTY aims to recruit real-world patients, unlike clinical studies with restrictive inclusion/exclusion criteria. Data collected at yearly intervals include clinical assessments, spirometry, biospecimens, patient-reported outcomes (PROs) and healthcare utilisation (HCU). PROs and HCU will also be collected 3-monthly via internet/telephone. Data will be used to identify phenotypes and endotypes associated with different trajectories for symptom burden, clinical progression or remission and HCU. Results may allow patient classification across obstructive lung disease by clinical outcomes and biomarker profile, rather than by conventional diagnostic labels and severity categories. NOVELTY will provide a rich data source on obstructive lung disease, to help improve patient outcomes and aid novel drug development.

Cigarette smoke (CS) is the main cause of chronic obstructive pulmonary disease. Surfactant protein D (SP-D) is an important anti-inflammatory protein that regulates host immune defense in the lungs. Here, we investigated the role of SP-D in a murine model of CS-induced inflammation. Pulmonary SP-D localization and abundance was compared between smoker and non-smoker individuals. For in vivo studies, wildtype, and SP-D-deficient mice were exposed to CS for either 12 weeks or 3 days. Moreover, the effect of therapeutic administration of recombinant fragment of human SP-D on the acute CS-induced changes was evaluated. Pulmonary SP-D appeared with heterogenous expression in human smokers, while mouse lung SP-D was uniformly upregulated after CS exposure. We found that SP-D-deficient mice were more susceptible to CS-induced macrophage-rich airway inflammation. SP-D deficiency influenced local pro-inflammatory cytokine levels, with increased CCL3 and interleukin-6 but decreased CXCL1. Furthermore, CS exposure caused significant upregulation of pro-inflammatory ceramides and related ceramide synthase gene transcripts in SP-D-deficient mice compared to wildtype littermates. Administration of recombinant fragment of human SP-D (rfhSP-D) alleviated CS-induced macrophage infiltration and prevented induction of ceramide synthase gene expression. Finally, rfhSP-D treatment attenuated CS-induced human epithelial cell apoptosis in vitro. Our results indicate that SP-D deficiency aggravates CS-induced lung inflammation partly through regulation of ceramide synthesis and that local SP-D enrichment rescues CS-induced inflammation.

Challenges in the differentiation of the aetiology of acute exacerbations of chronic obstructive pulmonary disease (AECOPD) have led to significant overuse of antibiotics. Serum procalcitonin, released in response to bacterial infections, but not viral infections, could possibly identify AECOPD requiring antibiotics. In this meta-analysis we assessed the clinical effectiveness of procalcitonin-based protocols to initiate or discontinue antibiotics in patients presenting with AECOPD. Based on a prospectively registered protocol, we reviewed the literature and selected randomised or quasi-randomised trials comparing procalcitonin-based protocols to initiate or discontinue antibiotics versus standard care in AECOPD. We followed Cochrane and GRADE (Grading of Recommendations, Assessment, Development and Evaluation) guidance to assess risk of bias, quality of evidence and to perform meta-analyses. We included eight trials evaluating 1062 patients with AECOPD. Procalcitonin-based protocols decreased antibiotic prescription (relative risk (RR) 0.56, 95% CI 0.43–0.73) and total antibiotic exposure (mean difference (MD) −3.83, 95% CI (−4.32–−3.35)), without affecting clinical outcomes such as rate of treatment failure (RR 0.81, 0.62–1.06), length of hospitalisation (MD −0.76, −1.95–0.43), exacerbation recurrence rate (RR 0.96, 0.69–1.35) or mortality (RR 0.99, 0.58–1.69). However, the quality of the available evidence is low to moderate, because of methodological limitations and small overall study population. Procalcitonin-based protocols appear to be clinically effective; however, confirmatory trials with rigorous methodology are required.

Umme Kolsum, Kay Roy, Cerys Starkey, Zoë Borrill, Nick Truman, Jørgen Vestbo, Dave SinghNorth West Lung Research Centre, University of Manchester, South Manchester University Hospitals Trust, Wythenshawe, Manchester, UKBackground: Many of the systemic manifestations of chronic obstructive pulmonary disease (COPD) are mediated through increased systemic levels of inflammatory proteins. We assessed the long term repeatability of Interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and C-reactive protein (CRP) over one year and examined the relationships between these systemic markers in COPD.Methods: Fifty-eight stable COPD patients completed a baseline and one-year visit. Serum IL-6, plasma CRP, and plasma TNF-α were measured. Repeatability was expressed by intraclass correlation coefficient (Ri) and the Bland–Altman method. Pearson correlations were used to determine the relationships between the systemic markers at both visits.Results: There was moderate repeatability with a very high degree of statistical significance (p ≤ 0.001) between the two visits for all the systemic biomarkers (IL-6, CRP, and TNF-α). CRP was significantly associated with IL-6 at both visits (r = 0.55, p = 0.0001, r = 0.51, p = 0.0002, respectively). There were no other significant associations between the systemic markers at either of the visits.Conclusions: Systemic inflammatory biomarkers IL-6, CRP, and TNF-α were moderately repeatable over a twelve month period in COPD patients. We have also shown that a robust and repeatable association between IL-6 and CRP exists.Keywords: interleukin-6, tumor necrosis factor-α, C-reactive protein, repeatability, COPD

Exacerbations have significant impact on the morbidity and mortality of patients with chronic obstructive pulmonary disease. Most guidelines emphasise prevention of exacerbations by treatment with long-acting bronchodilators and/or anti-inflammatory drugs. Whereas most of this treatment is evidence-based, it is clear that patients differ regarding the nature of exacerbations and are likely to benefit differently from different types of treatment. In this short review, we wish to highlight this, suggest a first step in differentiating pharmacological exacerbation prevention and call for more studies in this area. Finally, we wish to highlight that there are perhaps easier ways of achieving similar success in exacerbation prevention using nonpharmacological tools.

Inflammatory biomarkers predict mortality and hospitalisation in chronic obstructive pulmonary disease (COPD). Yet, it remains uncertain if biomarkers in addition to reflecting disease severity add new prognostic information on severe COPD. We investigated if leukocytes, C-reactive protein (CRP), and vitamin D were independent predictors of mortality and hospitalisation after adjusting for disease severity with an integrative index, the i-BODE index. In total, 423 patients participating in a pulmonary rehabilitation programme, with a mean value of FEV1 of 38% of predicted, were included. Mean followup was 45 months. During the follow-up period, 149 deaths (35%) were observed and 330 patients (78.0%) had at least one acute hospitalisation; 244 patients (57.7%) had at least one hospitalisation due to an exacerbation of COPD. In the analysis (Cox proportional hazards model) fully adjusted for age, sex, and i-BODE index, the hazard ratio for 1 mg/L increase in CRP was 1.02 (P=0.003) and for 1×109/L increase in leukocytes was 1.43 (P=0.03). Only leukocyte count was significantly associated with hospitalisation. Vitamin D was neither associated with mortality nor hospitalisation. Leukocytes and CRP add little information on prognosis and vitamin D does not seem to be a useful biomarker in severe COPD in a clinical setting.

BackgroundMicrofibrillar-associated protein 4 (MFAP4) is a systemic biomarker that is significantly elevated in samples from patients suffering from hepatic cirrhosis. The protein is generally localized to elastic fibers and other connective tissue fibers in the extracellular matrix (ECM), and variation in systemic MFAP4 (sMFAP4) has the potential to reflect diverse diseases with increased ECM turnover. Here, we aimed to validate an enzyme-linked immunosorbent assay (ELISA) for the measurement of sMFAP4 with an emphasis on the robustness of the assay. Moreover, we aimed to determine confounders influencing the basal sMFAP4 variability and the genetic contribution to the basal variation.MethodsThe sandwich ELISA was based on two monoclonal anti-MFAP4 antibodies and was optimized and calibrated with a standard of recombinant MFAP4. The importance of pre-analytical sample handling was evaluated regarding sample tube type, time, and temperature conditions. The mean value structure and variance structure was determined in a twin cohort including 1,417 Danish twins (age 18-67 years) by mixed-effect linear regression modeling.ResultsThe practical working range of the sandwich ELISA was estimated to be 4-75 U/ml. The maximum intra- and inter-assay variation was estimated to be 8.7% and 6.6%, respectively. Sample handling and processing appeared to influence MFAP4 measurements only marginally. The average concentration of sMFAP4 in the serum was 18.9 ± 8.4 (SD) U/ml in the twin cohort (95% CI: 18.5-19.4, median sMFAP4 17.3 U/ml). The mean structure model was demonstrated to include waist-hip ratio, age, and cigarette smoking status in interactions with gender. A relatively low heritability of h(2) = 0.24 was found after applying a model including additive genetic factors and shared and non-shared environmental factors.ConclusionsThe described ELISA provides robust measures of the liver fibrosis marker sMFAP4. The low heritability and the relatively limited basal variation suggest that increased sMFAP4 reflects disease-induced processes.

Microfibrillar-associated protein 4 (MFAP4) is located in the extracellular matrix (ECM). We sought to identify tissues with high levels of MFAP4 mRNA and MFAP4 protein expression. Moreover, we aimed to evaluate the significance of MFAP4 as a marker of cardiovascular disease (CVD) and to correlate MFAP4 with other known ECM markers, such as fibulin-1, osteoprotegerin (OPG), and osteopontin (OPN). Quantitative real-time PCR demonstrated that MFAP4 mRNA was more highly expressed in the heart, lung, and intestine than in other elastic tissues. Immunohistochemical studies demonstrated high levels of MFAP4 protein mainly at sites rich in elastic fibers and within blood vessels in all tissues investigated. The AlphaLISA technique was used to determine serum MFAP4 levels in a clinical cohort of 172 patients consisting of 5 matched groups with varying degrees of CVD: 1: patients with ST elevation myocardial infarction (STEMI), 2: patients with non-STEMI, 3: patients destined for vascular surgery because of various atherosclerotic diseases (stable atherosclerotic disease), 4: apparently healthy individuals with documented coronary artery calcification (CAC-positive), and 5: apparently healthy individuals without signs of coronary artery calcification (CAC-negative). Serum MFAP4 levels were significantly lower in patients with stable atherosclerotic disease than CAC-negative individuals (p

Because chronic obstructive pulmonary disease (COPD) is a heterogeneous condition, the identification of specific clinical phenotypes is key to developing more effective therapies. To explore if the persistence of systemic inflammation is associated with poor clinical outcomes in COPD we assessed patients recruited to the well-characterized ECLIPSE cohort (NCT00292552).Six inflammatory biomarkers in peripheral blood (white blood cells (WBC) count and CRP, IL-6, IL-8, fibrinogen and TNF-α levels) were quantified in 1,755 COPD patients, 297 smokers with normal spirometry and 202 non-smoker controls that were followed-up for three years. We found that, at baseline, 30% of COPD patients did not show evidence of systemic inflammation whereas 16% had persistent systemic inflammation. Even though pulmonary abnormalities were similar in these two groups, persistently inflamed patients during follow-up had significantly increased all-cause mortality (13% vs. 2%, p