Direct antivirals working against the novel coronavirus: azithromycin (DAWn-AZITHRO), a randomized, multicenter, open-label, adaptive, proof-of-concept clinical trial of new antivirals working against SARS-CoV-2-azithromycin trial.

BACKGROUND: The rapid emergence and the high disease burden of the novel coronavirus SARS-CoV-2 have created a medical need for readily available drugs that can decrease viral replication or blunt the hyperinflammatory state leading to severe COVID-19 disease. Azithromycin is a macrolide antibiotic, known for its immunomodulatory properties. It has shown antiviral effect specifically against SARS-CoV-2 in vitro and acts on cytokine signaling pathways that have been implicated in COVID-19. METHODS: DAWn-AZITHRO is a randomized, open-label, phase 2 proof-of-concept, multicenter clinical trial, evaluating the safety and efficacy of azithromycin for treating hospitalized patients with COVID-19. It is part of a series of trials testing promising interventions for COVID-19, running in parallel and grouped under the name DAWn-studies. Patients hospitalized on dedicated COVID wards are eligible for study inclusion when they are symptomatic (i.e., clinical or radiological signs) and have been diagnosed with COVID-19 within the last 72 h through PCR (nasopharyngeal swab or bronchoalveolar lavage) or chest CT scan showing typical features of COVID-19 and without alternate diagnosis. Patients are block-randomized (9 patients) with a 2:1 allocation to receive azithromycin plus standard of care versus standard of care alone. Standard of care is mostly supportive, but may comprise hydroxychloroquine, up to the treating physician's discretion and depending on local policy and national health regulations. The treatment group receives azithromycin qd 500 mg during the first 5 consecutive days after inclusion. The trial will include 284 patients and recruits from 15 centers across Belgium. The primary outcome is time from admission (day 0) to life discharge or to sustained clinical improvement, defined as an improvement of two points on the WHO 7-category ordinal scale sustained for at least 3 days. DISCUSSION: The trial investigates the urgent and still unmet global need for drugs that may impact the disease course of COVID-19. It will either provide support or else justify the discouragement of the current widespread, uncontrolled use of azithromycin in patients with COVID-19. The analogous design of other parallel trials of the DAWN consortium will amplify the chance of identifying successful treatment strategies and allow comparison of treatment effects within an identical clinical context. TRIAL REGISTRATION: EU Clinical trials register EudraCT Nb 2020-001614-38 . Registered on 22 April 2020.

Early integrated palliative care in chronic heart failure and chronic obstructive pulmonary disease: protocol of a feasibility before-after intervention study.

BACKGROUND: Patients with chronic heart failure (CHF) and patients with chronic obstructive pulmonary disease (COPD) are amenable to integrated palliative care (PC); however, despite the recommendation by various healthcare organizations, these patients have limited access to integrated PC services. In this study, we present the protocol of a feasibility prospective study that aims to explore if an "early integrated PC" intervention can be performed in an acute setting (cardiology and pulmonology wards) and whether it will have an effect on (i) the satisfaction of care and (ii) the quality of life and the level of symptom control of CHF/COPD patients and their informal caregivers. METHODS: A before-after intervention study with three phases, (i) baseline phase where the control group receives standard care, (ii) training phase where the personnel is trained on the application of the intervention, and (iii) intervention phase where the intervention is applied, will be carried out in cardiology and pulmonology wards in the University Hospital Leuven for patients with advanced CHF/COPD and their informal caregivers. Eligible patients (both control and intervention group) and their informal caregivers will be asked to complete the Palliative Outcome Scale, the CANHELP Lite, and the Advance Care Planning Questionnaire at the inclusion moment and 3 months after hospital discharge. DISCUSSION: The present study will assess the feasibility of carrying out PC-focused studies in acute wards for CHF/COPD patients and draw lessons for the further integration of PC alongside standard treatment. Further, it will measure the quality of life and quality of care of patients and thus shed light on the care needs of this population. Finally, it will evaluate the potential efficacy of the "early integrated palliative care" by comparing against existing practices. TRIAL REGISTRATION: Current Controlled Trials ISRCTN24796028 (date of registration August 30, 2018).

Endoscopic advanced imaging of the respiratory tract: exploring probe-based confocal laser endomicroscopy in emphysema.

: Probe-based confocal laser endomicroscopy (pCLE) was performed in 15 patients with emphysema and 15 healthy subjects to visualise small airways in a direct and dynamic way. Morphometry shows that the median cross-sectional area of the alveolar openings at the level of the alveolar ducts is significantly larger in emphysema (7.2×104 µm2) as compared with healthy subjects (5.2×104 µm2) (p=0.0002). Normalised autofluorescence intensity histograms show a decrease in median autofluorescence intensity (mAFI) in emphysema (p=0.001). mAFI correlates well with Tiffeneau index (r=0.66, p=0.007, 95% CI 0.21 to 0.88). Autofluorescence intensity in emphysema correlates with corresponding data of CT-based quantification. pCLE-based morphometry and autofluorescence intensity analysis in emphysema is able to detect regional changes inside the 'quiet zone'. TRIAL REGISTRATION NUMBER: Results, NCT01204970.

Elevated GDF-15 contributes to pulmonary inflammation upon cigarette smoke exposure.

The molecular mechanisms underlying the pathogenesis of chronic obstructive pulmonary disease (COPD) are still unclear, however signaling pathways associated with lung development, such as the transforming growth factor (TGF)-ß superfamily, could be implicated in COPD. Growth differentiation factor (GDF)-15, a member of the TGF-ß superfamily, is involved in inflammation, mucus secretion, and cachexia. We analyzed the pulmonary expression of GDF-15 in smokers and patients with COPD, in cigarette smoke (CS)-exposed cultures of primary human bronchial epithelial cells (pHBECs), and in CS-exposed mice. Next, we exposed GDF-15 KO and control mice to air or CS and evaluated pulmonary inflammation. GDF-15 levels were higher in sputum supernatant and lung tissue of patients with COPD and smokers without COPD compared with never smokers. Immunohistochemistry revealed GDF-15 staining in the airway epithelium. Increased expression and secretion of GDF-15 was confirmed in vitro in CS-exposed pHBECs compared with air-exposed pHBECs. Similarly, GDF-15 levels were increased in lungs of CS-exposed mice. Importantly, GDF-15 deficiency attenuated the CS-induced pulmonary inflammation. These results suggest that increased GDF-15-as observed in lungs of smokers and patients with COPD-contributes to CS-induced pulmonary inflammation.

Thrombosis of an Arteria Lusoria with Secondary Subclavian Steal Syndrome and Swallowing Difficulties.

We report a case of an arteria lusoria causing swallowing difficulties known as dysphagia lusoria. Although the presence of an arteria lusoria is quite common, dysphagia lusoria is relatively rare. Interestingly, our patient also presented with a concurrent aneurysmal dilatation, known as a Kommerell's diverticulum, at the aortic origin. Complete thrombosis of the artery and flow reversal in the right cervical artery resulting in an asymptomatic subclavian steal syndrome was also seen. No underlying primary pro-thrombotic defects were identified but due to the presence of locally advanced prostate cancer, a paraneoplastic phenomenon was suspected.

Quality and reproducibility of spirometry in COPD patients in a randomized trial (UPLIFT®).

BACKGROUND: This study explores spirometry quality and reproducibility in the Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT(®)) trial. METHODS: Four-year, randomized, double-blind, placebo-controlled, multicenter trial in 5993 patients with chronic obstructive pulmonary disease. Within-test variability of pre- and post-bronchodilator forced expiratory volume in 1 s (FEV(1)) was compared across study visits. Between-test variability of best pre- or post-FEV(1) values between two visits 6 months apart was compared at the start, middle and end of the trial. RESULTS: Three or more acceptable maneuvers were obtained in 93% of visits. Within-test variability of pre- and post-FEV(1) (mean standard deviation: 0.092 and 0.098 L) decreased during the trial. Between-test variability also decreased: pre-FEV(1) (visit 3-5 = 0.141 ± 0.138 L; visit 9-11 = 0.129 ± 0.121 L; visit 17-19 = 0.121 ± 0.122 L); post-FEV(1) (0.139 ± 0.140, 0.126 ± 0.123, 0.121 ± 0.122 L, respectively), and was dependent on age, sex, smoking status and disease stage, but not on bronchodilator response or study treatment. CONCLUSION: Spirometry quality in UPLIFT(®) was good and improved during the trial. Between-test variability across patient subgroups suggests that relevant cut-offs for individual disease monitoring are difficult to establish. TRIAL REGISTRATION NUMBER: NCT00144339.

COPD awareness survey: do Belgian pulmonary physicians comply with the GOLD guidelines 2010?

Chronic Obstructive Pulmonary Disease (COPD) is underestimated, underdiagnosed and often under-treated in the general population. A survey of 17 structured questions, delivered to all Belgian pulmonary physicians (PPs) (116 responses), evaluated diagnosis and treatment strategies in accordance with the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines 2010 and assessed opinions about the importance of diurnal variation of COPD symptoms. All COPD diagnoses (37% new cases) were spirometry confirmed. Main diagnostic parameters were symptoms (99%), external risk factors (99%), clinical examination (97%), exacerbations (96%) and patient mobility (96%). FEV1 (forced expiratory volume in 1s) (97%) or FEV1/FVC (ratio of FEV1 to forced vital capacity) (93%) were used most to assess diagnosis and severity. The 3 most important therapeutic objectives were symptom relief, preventing exacerbations, and improving quality of life; if these were not reached, the preferred strategy (60% of PPs) was adding another medication. Treatment strategies varied with COPD stage: short-acting beta2-agonists (90%) and short-acting anti-cholinergics (59%) were used for GOLD I disease, whereas for higher stages long-acting beta2-agonists (36-48%) and long-acting anti-cholinergics (79%) were given with inhaled corticosteroids (21-67%). Symptoms were perceived to vary throughout the day, affecting quality of life (97%) and mobility (89%). In particular, respiratory symptoms were more severe in the morning (51-92%), leading PPs to adapt treatment (69%). This survey demonstrated that management of COPD by PPs in Belgium is generally in line with the GOLD guidelines 2010 and that they perceive morning symptoms as being frequent and having an impact on patient's life.

Rehabilitation and acute exacerbations.

Recent evidence indicates that acute exacerbations of chronic obstructive pulmonary disease aggravate the extrapulmonary consequences of the disease. Skeletal muscle dysfunction, a sustained decrease in exercise tolerance, enhanced symptoms of depression and fatigue are reported. Avoidance of physical activities is likely to be a key underlying mechanism and increases the risk of new exacerbations. Pulmonary rehabilitation is an intervention targeting these systemic consequences. Exercise strategies need to be adapted to the increased feelings of dyspnoea and fatigue. This review aims to describe the systemic consequences of acute exacerbations and compiles evidence for the feasibility and effectiveness of different rehabilitation strategies to counteract these consequences during and/or immediately after the acute phase of the exacerbation. Resistance training and neuromuscular electrical stimulation have been applied safely in frail, hospitalised patients and have the potential to prevent muscle atrophy. Comprehensive pulmonary rehabilitation, including general exercise training, can be implemented immediately after the exacerbation, leading to a reduction in hospital admissions and an increase in exercise tolerance and quality of life. Self-management strategies play a crucial role in changing disease-related health behaviour and preventing hospital admissions.

The TERT-CLPTM1L locus for lung cancer predisposes to bronchial obstruction and emphysema.

Clinical studies suggest that bronchial obstruction and emphysema increase susceptibility to lung cancer. We assessed the possibility of a common genetic origin and investigated whether the lung cancer susceptibility locus on chromosome 5p15.33 increases the risk for bronchial obstruction and emphysema. Three variants in the 5p15.33 locus encompassing the TERT and CLPTM1L genes were genotyped in 777 heavy smokers and 212 lung cancer patients. Participants underwent pulmonary function tests and computed tomography of the chest, and completed questionnaires assessing smoking behaviour. The rs31489 C-allele correlated with reduced forced expiratory volume in 1 s (p=0.006). Homozygous carriers of the rs31489 C-allele exhibited increased susceptibility to bronchial obstruction (OR 1.82, 95% CI 1.24-2.69; p=0.002). A similar association was observed for diffusing capacity of the lung for carbon monoxide (p=0.004). Consistent with this, CC-carriers had an increased risk of emphysema (OR 2.04, 95% CI 1.41-2.94; p=1.73 × 10(-4)) and displayed greater alveolar destruction. Finally, CC-carriers also had an increased risk for lung cancer (OR 1.90, 95% CI 1.21-2.99; p=0.005), and were more susceptible to developing both lung cancer and bronchial obstruction than lung cancer alone (OR 2.11, 95% CI 1.04-4.26; p=0.038). The rs31489 variant on 5p15.33 is associated with bronchial obstruction, presence and severity of emphysema, and lung cancer.

[COPD and bone metabolism: a clinical update]. / BPCO et métabolisme osseux: une mise à jour clinique.

Increasing evidence indicates that COPD and osteoporosis are strongly linked. Both diseases share common risk factors like age, smoking and inactivity but the typical presence in COPD of systemic inflammation, vitamin D deficiency and the frequent use of corticosteroids catalyse ongoing bone resorption. Osteoporosis in its turn may lead to vertebral compression fractures with a consequent further decline of forced vital capacity and forced expiratory volume in one second. In addition, fragility fractures in disabled COPD patients may cause further immobility and increased morbidity. Prevention and treatment of osteoporosis in COPD should therefore be based on population specific risk assessments which combine measures of bone mineral density and clinical factors. Unfortunately, intervention studies specifically designed for patients with COPD are currently lacking and no specific guidelines have yet been established. Hence, a rigorous application of the current treatment guidelines with respect to osteoporosis in general would already be a major step forward in the treatment of COPD.

Exercise training and pulmonary rehabilitation: new insights and remaining challenges.

Pulmonary rehabilitation is now regarded as an evidence-based treatment for symptomatic patients with chronic obstructive pulmonary disease. It has been shown to enhance exercise tolerance, improve symptoms and health-related quality of life, and reduce exacerbations in patients with recurrent exacerbations. In this article we review the mechanisms through which exercise training results in beneficial effects. We also review three challenges that currently remain: 1) the fine tuning of exercise training and multidisciplinary programmes; 2) the timing of rehabilitation; and 3) efforts to enhance the accessibility and adherence to pulmonary rehabilitation programmes. Further research is needed in order to apply the now well-established principles of pulmonary rehabilitation to unusual patient populations, or patient populations that are unlikely to participate in conventional outpatient programmes.

Mucoactive therapy in COPD.

It has been shown that mucus hypersecretion is associated with greater susceptibility for chronic obstructive pulmonary disease (COPD), excess forced expiratory volume in 1 s decline, hospitalisations and excess mortality. The effects of mucoactive drugs on outcomes have been reviewed in several meta-analyses, the largest one including 26 studies. 21 studies were performed in patients with chronic bronchitis and five in patients with COPD. The majority of these trials were performed with N-acetylcysteine (n = 13) and carbocysteine (n = 3). Overall, there was a significant reduction in exacerbations (0.05 per patient per month) and the number of days with disability (0.56 days per patient per month). Mucolytics were well tolerated and the number of adverse events was lower than with placebo (odds ratio 0.78). In the largest and best designed study with N-acetylcysteine in 523 patients with COPD, the reduction in exacerbations was only observed in patients not taking inhaled corticosteroids. In addition, a 374 mL reduction in functional residual capacity was found. A recent large study (n = 709) with high-dose carbocysteine (1,500 mg·day⁻¹) demonstrated a significant effect on exacerbations (25% reduction) and also reported an improvement in health-related quality of life (-4.06 units in St George's Respiratory Questionnaire). It is unclear what the mechanisms underlying these effects may be and which phenotypes benefit from this treatment. On the basis of this evidence mucoactive drugs may deserve consideration in the long-term treatment of COPD.

Contributing to shipping container security: can passive sensors bring a solution?

Illicit trafficking of fissionable material in container cargoes is recognized as a potential weakness in Nuclear Security. Triggered by the attacks of 11 September 2001, measures were undertaken to enhance maritime security in extension to the Safety Of Life At Sea Convention and in line with the US Container Security Initiatives. Effective detection techniques are needed that allow the inspector to intercept illicit trafficking of nuclear weapons components or components of other nuclear explosive devices. Many security measures focus on active interrogation of the container content by X-ray scan, which might be extended with the newly developed tagged neutron inspection system. Both active interrogation techniques can, with the current huge volume of container traffic, only be applied to a limited number of selected containers. The question arises whether a passive detection technique can offer an alternative solution. This study investigates if containers equipped with a small passive detector will register during transport the neutron irradiation by fissionable material such as plutonium in a measurable way. In practice, 4/5 of the containers are about 1/8 filled with hydrogenous material and undergo a typical 2 months route. For this reference case, it was found that the most compatible passive detector would be an activation foil of iridium. Monte-Carlo simulations showed that for the reference case the activity of a 250 microm thin foil with 6 cm(2) cross-section would register 1.2 Bq when it is irradiated by a significant quantity of Reactor-Grade PuO(2). However this activity drops with almost two orders of magnitude for other fillings and other isotopic compositions and forms of the Pu-source. The procedure of selecting the target material for Pu detection is detailed with the theoretical methods, in order to be useful for other applications. Moreover the value of such additional passive sensors for securing maritime container transport is situated within the global framework of the First, Second and Third Line of Defense against illicit trafficking.

Drug impurity profiling: Method optimization on dissimilar chromatographic systems: Part I: pH optimization of the aqueous phase.

The use of dissimilar chromatographic systems in drug impurity profiling can be very advantageous. Screening a new-drug impurity mixture on those systems not only enhances the chance that all impurities are revealed, but also allows choosing a suited system for further method development. In this paper several strategies were evaluated to predict the optimal pH (of the buffer used in the mobile phase) from the screening results. Four or five dissimilar stationary phases were screened at four pH values (between 2.5 and 9.4), in order to obtain maximal information about the composition of the sample and to select one column for the subsequent optimization. Different linear models (straight lines, 2nd and 3rd degree polynomials) based on these experiments were tested for their ability to predict the retention times (t(R)) of the impurities at intermediate pH values. The predicted t(R) values were then used to calculate minimal resolutions and eventually to select an optimal pH at which the highest minimal resolution is predicted. None of the applied models is accurate enough to predict correctly which peaks are worst separated at the indicated optimal pH. However, the best strategy (applying a second degree polynomial describing the t(R) measured at 3 consecutive screening pH values) did succeed in indicating an optimal pH at which a good separation of the impurities is obtained. Unfortunately, the resulting separation quality is not or only slightly better than the best separation obtained during screening. Therefore, it can be concluded that the most (time-) efficient approach to develop an impurity profile of a new drug is to screen it on four or five dissimilar columns at four different pH values and to retain the best screening conditions (without making predictions for intermediate conditions) for further optimization of the organic modifier composition of the mobile phase, and occasionally the temperature and the gradient. This is at least the case when the profiles have a complexity similar to those studied.

Metabolic syndrome in the elderly: an overview of the evidence.

We reviewed the literature concerning the prevalence and correlates of metabolic syndrome (MetS) in older adults and assessed the impact of MetS with regard to life expectancy and comorbidity in the elderly (aged 65 years and over). Using the PubMed database and the Cochrane Library, we found 16 eligible studies, of which 8 were prospective cohort studies, 7 cross-sectional studies, and 1 a case-control study. The World Health Organisation (WHO) and National Cholesterol Education Program (NCEP) are the most popular definitions to describe MetS experienced by the elderly. The prevalence of metabolic syndrome in an elderly population varied from 11% to 43% (median 21%) according to the WHO, and 23% to 55 % (median 31%) according to NCEP. Obesity and hypertension are the most prevalent individual components. MetS in an elderly population is a proven risk factor for cardiovascular (CV) morbidity, especially stroke and coronary heart disease (CHD), and mortality. Preventing and treating MetS would be useful in preventing disability and promoting normal aging. Results from the different studies of elderly population-based cohorts provide support for earlier investigations in middle-aged populations to prevent MetS components. In conclusion, it is possible to say that the results from the different elderly study populations link the presence of the MetS with the development of cardiovascular disease (CVD) and functional disability, and further underscore the importance of recognising and treating its individual components, particularly high blood pressure.

Skeletal muscle weakness, exercise tolerance and physical activity in adults with cystic fibrosis.

The aim of the present study was to investigate the prevalence of muscle weakness and the importance of physical inactivity in cystic fibrosis (CF), and its relationship to exercise tolerance and muscle strength. Exercise tolerance, skeletal and respiratory muscle strength were studied in a group of 64 adults with CF (age 26+/-8 yrs, FEV(1 % predicted) 65+/-19) and in 20 age-matched controls. Physical activity (PA) was assessed in 20 patients and all controls. Quadriceps muscle weakness was present in 56% of the patients. Peak oxygen uptake and 6-min walking distance were below normal in 89 and 75% of patients, respectively. Respiratory muscle strength was normal. The differences remained after correcting for PA. Quadriceps force was correlated to the 6-min walking distance but not to peak oxygen uptake. "Mild" PA (>3 metabolic equivalents (METS)) and the number of steps overlapped with controls, but CF patients had less moderate PA (>4.8 METS). Moderate PA was related to peak oxygen uptake and quadriceps force. Skeletal muscle weakness and exercise intolerance are prevalent in cystic fibrosis. Physical inactivity is a factor significantly contributing to exercise tolerance and skeletal muscle force in adults with cystic fibrosis, but these impairments are in excess to that expected from physical inactivity only.

The use of metabolising systems for in vitro testing of endocrine disruptors.

Legislation and prospective legislative proposals in for instance the USA, Europe, and Japan require, or may require that chemicals are tested for their ability to disrupt the hormonal systems of mammals. Chemicals found to test positive are considered to be endocrine active substances (EAS) and may be putative endocrine disruptors (EDs). To date, there is still little or no experience with incorporating metabolic and toxicokinetic aspects into in vitro tests for EAS. This is a situation in sharp contrast to genotoxicity testing, where in vitro tests are routinely conducted with and without metabolic capacity. Originally prepared for the Organisation of Economic Cooperation and Development (OECD), this detailed review paper reviews why in vitro assays for EAS should incorporate mammalian systems of metabolism and metabolic enzyme systems, and indicates how this could be done. The background to ED testing, the available test methods, and the role of mammalian metabolism in the activation and the inactivation of both endogenous and exogenous steroids are described. The available types of systems are compared, and the potential problems in incorporating systems in in vitro tests for EAS, and how these might be overcome, are discussed. Lastly, some recommendations for future activities are made.

Inspiratory flow rates at different levels of resistance in elderly COPD patients.

Dry powder inhalers (DPIs) are increasingly replacing metered dose inhalers in elderly chronic obstructive pulmonary disease (COPD) patients. However, most DPIs are dependent on inspiratory flow, which is compromised by the ageing process itself. Using the in-check dial method, the present study compared peak inspiratory flow (PIF) rates in 26 elderly COPD patients and 14 matched control subjects, at a pre-set resistance level of the Aeroliser, Diskus and Turbuhaler inhalers. It was found that the PIF measured by the in-check method positively correlated with the PIF derived from spirometry, forced vital capacity and maximal inspiratory pressure, while a negative, but significant, correlation was observed with age. PIF derived from spirometry and age were independent variables which determined PIF across the device, whereas the presence or absence of COPD was not related. When comparing elderly COPD patients with matched elderly controls no difference could be found in PIF at the different resistances. However, an important number of patients did not reach the recommended flow rate, especially when using the Turbuhaler (30%). In conclusion, the present study demonstrates that, in elderly patients, the ability to generate sufficient inspiratory flow across a dry powder inhaler is compromised, irrespective of the presence of chronic obstructive pulmonary disease.

Listeria pleuritis 1 week after lung transplantation.

Listeria monocytogenes is an important bacterial pathogen in immunocompromised patients, the elderly, pregnant women and transplant patients, but until now it has not been reported in lung transplants. We report the first case of listeriosis in a lung transplant recipient who presented with a pleural effusion 8 days after transplantation. After the introduction of a thorax drain and the administration of intravenous antibiotics during 3 weeks, the patient recovered completely. This case highlights the increased risk for uncommon respiratory infections in lung transplant patients and examines the specific management of listeria pleuritis.