Ulla Møller Weinreich

The established and future biomarkers of malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is an asbestos-related cancer with a median survival of 12months. The MPM incidence is 1-6/100,000 and is increasing as a result of historic asbestos exposure in industrialized countries and continued use of asbestos in developing countries. Lack of accurate biomarkers makes diagnosis, prognostication and treatment prediction of MPM challenging. The aim of this review is to identify the front line of MPM biomarkers with current or potential clinical impact. Literature search using the PubMed and PLoS One databases, the related-articles function of PubMed and the reference lists of associated publications until April 26th 2015 revealed a plethora of candidate biomarkers. The current gold standard of MPM diagnosis is a combination of two positive and two negative immunohistochemical markers in the epithelioid and biphasic type, but sarcomatous type do not have specific markers, making diagnosis more difficult. Mesothelin in serum and pleural fluid may serve as adjuvant diagnostic with high specificity but low sensitivity. Circulating proteomic and microRNA signatures, fibulin-3, tumor cell gene-ratio test, transcriptomic, lncRNA, glycopeptides, pleural fluid FISH assay, hyaluronate/N-ERC mesothelin and deformability cytometry may be important future markers. Putative predictive markers for pemetrexed-platinum are tumor TS and TYMS, for vinorelbine the ERCC1, beta-tubuline class III and BRCA1. Mutations of the BAP1 gene are potential markers of MPM susceptibility. In conclusion, the current status of MPM biomarkers is not satisfactory but encouraging as more sensitive and specific non-invasive markers are emerging. However, prospective validation is needed before clinical application.

Bacterial colonisation of lower airways in health and chronic lung disease.

Background:  To evaluate the colonisation rate and type in different groups of patients with chronic lung diseases, bronchial lavage (BL) fluid was investigated for bacteria.

Design, and participant enrollment, of a randomized controlled trial evaluating effectiveness and cost-effectiveness of a community-based case management intervention, for patients suffering from COPD

License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php Open Access Journal of Clinical Trials 2015:7 53–62 Open Access Journal of Clinical Trials Dovepress

The effect of comorbidities on COPD assessment: a pilot study

Introduction Patients with chronic obstructive pulmonary disease (COPD) frequently suffer from comorbidities. COPD severity may be evaluated by the Global initiative for chronic Obstructive Lung Disease (GOLD) combined risk assessment score (GOLD score). Spirometry, body plethysmography, diffusing capacity of the lung for carbon monoxide (DLCO), and high-resolution computed tomography (HR-CT) measure lung function and elucidate pulmonary pathology. This study assesses associations between GOLD score and measurements of lung function in COPD patients with and without (≤1) comorbidities. It evaluates whether the presence of comorbidities influences evaluation by GOLD score of COPD severity, and questions whether GOLD score describes morbidity rather than COPD severity. Methods In this prospective study, 106 patients with stable COPD were included. Patients treated for lung cancer were excluded. Demographics, oxygen saturation (SpO2), modified Medical Research Council Dyspnea Scale, COPD exacerbations, and comorbidities were recorded. Body plethysmography and DLCO were measured, and HR-CT performed and evaluated for emphysema and airways disease. COPD severity was stratified by the GOLD score. Correlation analyses: 1) GOLD score, 2) emphysema grade, and 3) airways disease and lung function parameters, described by: forced expiratory volume in the first second in percent of expected value (FEV1%), inspiratory capacity (IC%), total lung volume (TLC%), IC/TLC, and SpO2. Correlation analyses between subgroups and hierarchical cluster analysis were performed. Results Significant associations were found between GOLD score and both emphysema grade (correlation coefficients [cc]: −0.2, P=0.03) and lung function parameters (cc: −0.5 to −0.7, P-values all <0.001) weakened in patients with >1 comorbidity (cc: −0.4 to −0.5, P-values all 0.001). Significant differences between subgroups were found in GOLD score and both FEV1% (cc: −0.2, P=0.02) and IC/TLC (cc: −0.2, P=0.02). Comorbidities were associated with GOLD score and composite measures in hierarchical cluster analysis. Conclusion The presence of comorbidities influences the relationship between GOLD score and lung function measurements. GOLD score may be more representative of morbidity than of COPD severity.

Diffusion capacity of the lung for carbon monoxide – A potential marker of impaired gas exchange or of systemic deconditioning in chronic obstructive lung disease?

Gas exchange impairment is primarily caused by ventilation–perfusion mismatch in chronic obstructive pulmonary disease (COPD), where diffusing capacity of the lungs for carbon monoxide (DLCO) remains the clinical measure. This study investigates whether DLCO: (1) can predict respiratory impairment in COPD, that is, changes in oxygen and carbon dioxide (CO2); (2) is associated with combined risk assessment score for COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) score); and (3) is associated with blood glucose and body mass index (BMI). Fifty patients were included retrospectively. DLCO; arterial blood gas at inspired oxygen (FiO2) = 0.21; oxygen saturation (SpO2) at FiO2 = 0.21 (SpO2 21) and FiO2 = 0.15 (SpO2 15) were registered. Difference between arterial and end-tidal CO2 (ΔCO2) was calculated. COPD severity was stratified according to GOLD score. The association between DLCO, SpO2, ΔCO2, GOLD score, blood glucose, and BMI was investigated. Multiple regression showed association between DLCO and GOLD score, BMI, and glucose level (R 2 = 0.6, p < 0.0001). Linear and multiple regression showed an association between DLCO and SpO2 21 (R 2 = 0.3, p = 0.001 and p = 0.03, respectively) without contribution from SpO2 15 or ΔCO2. A stronger association between DLCO and GOLD score than between DLCO and SpO2 could indicate that DLCO is more descriptive of systemic deconditioning than gas exchange in COPD patients. However, further larger studies are needed. A weaker association is seen between DLCO and SpO2 21 without contribution from SpO2 15 and ΔCO2. This could indicate that DLCO is more descriptive of systemic deconditioning than gas exchange in COPD patients. However, further larger studies are needed.

Chronic obstructive pulmonary disease as comorbidity in patients admitted to a university hospital: a cross-sectional study

Chronic obstructive pulmonary disease (COPD) is a common disease, especially among smokers. The disease is underdiagnosed, and patients often suffer from comorbidities. The aims of this study were to elucidate the prevalence of COPD as comorbidity in a university hospital setting, to characterise patients demographically, to investigate comorbidities in patients suffering from COPD and lastly, to analyse whether CODP as comorbidity influenced the length of stay.

Trends in assisted ventilation and outcome for obstructive pulmonary disease exacerbations: A nationwide study

Background Non-invasive ventilation (NIV) has been used for decades in treatment of exacerbations of chronic obstructive pulmonary disease (COPD). The impact of the changing use of assisted ventilation in acute exacerbations on outcomes has not been fully elucidated and we aimed to describe these changes in the Danish population and describe their consequences for mortality. Methods A register-based study was conducted of a cohort of 12,847 patients admitted for acute exacerbation of COPD (AECOPD) from 2004 through 2011, treated with invasive mechanical ventilation (IMV) or NIV for the first time. Age, sex, in-hospital mortality rates, time to death or readmission for AECOPD were established and changes over time tracked. Results The number of admissions for AECOPD where assisted ventilation was used was 1,130 in 2004 and had increased by 145% in 2011. First time ventilations increased by 88%. This was mainly due to an increase in use of NIV accounting for 36% of the total number of assisted ventilations in 2004 and 67% in 2011. The number of IMV with or without NIV treatments remained constant. The mean age of NIV patients increased from 71.5 to 73.6 years, but remained constant at 70.0 years in IMV patients. Mortality rates both in hospital and after discharge for patients receiving NIV remained constant throughout the period. In-hospital mortality following IMV increased from 30% to 38%, but mortality after discharge remained stable. Conclusion Assisted ventilation has been increasingly used in a broader spectrum of AECOPD patients since the introduction of NIV. The changes in treatment strategies have been followed by shifts in in-hospital mortality rates following IMV.

Association between hemoglobin and prognosis in patients admitted to hospital for COPD

Low concentrations of hemoglobin have previously been demonstrated in many patients with COPD. There is evidence of anemia as a prognostic factor in acute exacerbations, but the detailed relationship between concentrations of hemoglobin and mortality is not known. A register-based cohort of patients admitted for the first time to Danish hospitals for acute exacerbations of COPD from 2007 through 2012 was established. Age, sex, comorbidities, medication, renal function, and concentrations of hemoglobin were retrieved. Sex-specific survival analyses were fitted for different rounded concentrations of hemoglobin. The cohort encompassed 6,969 patients. Hemoglobin below 130 g/L was present in 39% of males and below 120 g/L in 24% of females. The in-hospital mortality rates for patients with hemoglobin below or above these limits were 11.6% and 5.4%, respectively. After discharge, compared to hemoglobin 130 g/L, the hazard ratio (HR) for males with hemoglobin 120 g/L was 1.45 (95% confidence interval [CI] 1.22–1.73), adjusted HR 1.37 (95% CI 1.15–1.64). Compared to hemoglobin 120 g/L, the HR for females with hemoglobin 110 g/L was 1.4 (95% CI 1.17–1.68), adjusted HR 1.28 (95% CI 1.06–1.53). In conclusion, low concentrations of hemoglobin are frequent in COPD patients with acute exacerbations, and predict long-term mortality.

Long-term effects of oxygen-enriched high-flow nasal cannula treatment in COPD patients with chronic hypoxemic respiratory failure

Background This study investigated the long-term effects of humidified high-flow nasal cannula (HFNC) in COPD patients with chronic hypoxemic respiratory failure treated with long-term oxygen therapy (LTOT). Patients and methods A total of 200 patients were randomized into usual care ± HFNC. At inclusion, acute exacerbation of COPD (AECOPD) and hospital admissions 1 year before inclusion, modified Medical Research Council (mMRC) score, St George’s Respiratory Questionnaire (SGRQ), forced expiratory volume in 1 second (FEV1), 6-minute walk test (6MWT) and arterial carbon dioxide (PaCO2) were recorded. Patients completed phone interviews at 1, 3 and 9 months assessing mMRC score and AECOPD since the last contact. At on-site visits (6 and 12 months), mMRC, number of AECOPD since last contact and SGRQ were registered and FEV1, FEV1%, PaCO2 and, at 12 months, 6MWT were reassessed. Hospital admissions during the study period were obtained from hospital records. Hours of the use of HFNC were retrieved from the high-flow device. Results The average daily use of HFNC was 6 hours/day. The HFNC group had a lower AECOPD rate (3.12 versus 4.95/patient/year, p<0.001). Modeled hospital admission rates were 0.79 versus 1.39/patient/year for 12- versus 1-month use of HFNC, respectively (p<0.001). The HFNC group had improved mMRC scores from 3 months onward (p<0.001) and improved SGRQ at 6 and 12 months (p=0.002, p=0.033) and PaCO2 (p=0.005) and 6MWT (p=0.005) at 12 months. There was no difference in all-cause mortality. Conclusion HFNC treatment reduced AECOPD, hospital admissions and symptoms in COPD patients with hypoxic failure.

Time to Steady State after Changes in FIO2 in Patients with COPD

Abstract Background: International guidelines recommend that when changing FIO2 in patients with COPD receiving Long-Term Oxygen Therapy (LTOT), 30 minutes should be waited for steady state before measurement of arterial blood gasses. This study evaluates whether 30 minutes is really necessary, as a smaller duration might improve the logistics of care, potentially reducing the time spent by patients at the out-patient clinic. Methods: 12 patients with severe to very severe COPD according to the GOLD guidelines were included. Patients had a median FEV1% of 23% of the predicted value (range 15–64%), median FEV1/FVC 0.43 (range 0.26–0.63), and chronic respiratory failure necessitating LTOT, 1–4 liters/minute, minimum 16 hours/day. Following a FIO2 reduction (wash out), arterial blood gases were measured at 0, 1, 2, 4, 8, 12, 17, 22, 32 and 34 minutes. FIO2 was then increased to baseline levels (wash in) and blood gasses measured at 0, 1, 2, 4, 8, 12, 17, 22, 32, and 34 minutes. Data were analyzed to examine the dynamics of arterial PO2 and saturation (SO2) wash out and wash in by calculating the time constants, tau (ô), and to evaluate the time required to reach values which might be considered clinically stable, defined as PO2 within 0.5 kPa and SO2 within 1% of equilibrium values. Results: For arterial PO2 values of time constants were about 3 minutes and similar for both wash out and wash in. A median of 5 minutes was required to reach clinically stable values of PO2 in both wash out and wash in, with 7–8 minutes sufficient in 75% of patients, and in the worst case 14 minutes. For SO2, values of the time constant were 4.5 and 1.4 minutes for wash out and wash in, respectively. The time required to reach clinically stable values was different in the two phases. For wash out the median time was 7.4 minutes, and in the worst case 15.6 minutes. For wash in the median time was 2.6 minutes and in worst case 6.8 minutes. No significant changes in PCO2 or pH were seen during FIO2 changes. Discussion/Conclusion: This study shows that oxygen equilibration relevant for clinical interpretation requires only 10 minutes following an increase and 16 minutes following a decrease in FIO2. over the range studied.