European Respiratory Journal

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ISSN / EISSN : 0903-1936 / 1399-3003
Published by: European Respiratory Society (ERS) (10.1183)
Total articles ≅ 13,540
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Sara M. Mensink-Bout, Evelien R. van Meel, Johan C. de Jongste, , Adrien M. Aubert, Jonathan Y. Bernard, Ling-Wei Chen, Cyrus Cooper, Sarah R. Crozier, Wojciech Hanke, et al.
European Respiratory Journal; https://doi.org/10.1183/13993003.01315-2021

Abstract:
Rationale Severe fetal malnutrition has been related to an increased risk of respiratory diseases later in life, but evidence for the association of a suboptimal diet during pregnancy with respiratory outcomes in childhood is conflicting. We aimed to examine whether a pro-inflammatory or low-quality maternal diet during pregnancy was associated with child's respiratory health. Methods We performed an individual participant meta-analysis among 18 326 mother-child pairs from seven European birth cohorts. Maternal pro-inflammatory and low-quality diet were estimated by energy-adjusted Dietary Inflammatory Index (E-DIITM) and Dietary Approaches to Stop Hypertension (DASH) scores. Preschool wheezing and school-age asthma were measured by questionnaires and lung function by spirometry. Results After adjustment for lifestyle and sociodemographic factors, we observed that a higher maternal E-DII score (a more pro-inflammatory diet) during pregnancy was associated only with a lower FVC in children (Z-score difference (95% confidence interval (CI)): −0.05 (−0.08, −0.02), per IQR increase). No linear associations of the maternal E-DII or DASH score with child's wheezing or asthma were observed. When exploratively examining the extremes, a very low DASH score (<10th percentile) (a very low dietary quality) was associated with an increased risk of preschool wheezing and a low FEV1/FVC (z-score <−1.64) (OR (95% CI) 1.20 (1.06, 1.36), 1.40 (1.06, 1.85), compared to ≥10th percentile), with corresponding population attributable risk fractions of 1.7% and 3.3%. Conclusion Main results from this individual participant data meta-analysis do not support the hypothesis that maternal pro-inflammatory or low-quality diet in pregnancy are related to respiratory diseases in childhood.
, Valliappan Muthu, , Sahajal Dhooria, Kuruswamy Thurai Prasad, Mandeep Garg, Ashutosh Nath Aggarwal, Arunaloke Chakrabarti
European Respiratory Journal; https://doi.org/10.1183/13993003.01787-2021

Abstract:
Whether a combination of glucocorticoid and antifungal triazole is superior to glucocorticoid alone, in reducing exacerbations, in patients with allergic bronchopulmonary aspergillosis (ABPA) remains unknown. We aimed to compare the efficacy and safety of prednisolone-itraconazole combination versus prednisolone monotherapy in ABPA. We randomised subjects with treatment-naïve acute-stage ABPA complicating asthma to receive either prednisolone alone (four months) or a combination of prednisolone and itraconazole (four and six months, respectively). The primary outcomes were exacerbation rates at 12 months and glucocorticoid-dependent ABPA within 24 months of initiating treatment. The key secondary outcomes were response rates and percentage decline in serum total IgE at six weeks, time to first ABPA exacerbation, and treatment-emergent adverse effects (AE). We randomised 191 subjects to receive either prednisolone (n=94) or prednisolone-itraconazole combination (n=97). The one-year exacerbation rate was 33% and 20.6% in the prednisolone and the prednisolone-itraconazole arms, respectively (p=0.054). None of the participants progressed to glucocorticoid-dependent ABPA. All the subjects experienced a composite response at 6-weeks, along with a decline in serum total IgE (mean decline, 47.6% versus 45.5%). The mean time to first ABPA exacerbation (417 days) was not different between the groups. None of the participants required modification of therapy due to AE. There was a trend towards a decline in ABPA exacerbations at 1-year with the prednisolone-itraconazole combination than prednisolone monotherapy. A three-arm trial comparing itraconazole and prednisolone monotherapies with their combination, preferably in a multicentric design, is required to define the best treatment strategy for acute-stage ABPA.
, Sandrah P. Eckel, Kiros Berhane, , Patrick Muchmore, Noa Ben-Ari Molshatzki, Edward B. Rappaport, William S. Linn, Rima Habre, Frank D. Gilliland
European Respiratory Journal; https://doi.org/10.1183/13993003.00705-2021

, David Drummond, Clément Pontoizeau, Laura Aoust, Maria-Margarita Hurtado Nedelec, Jamel El Benna, Elsa Gachelin, Caroline Perisson, Clémentine Vigier, Manuel Schiff, et al.
European Respiratory Journal; https://doi.org/10.1183/13993003.01554-2021

Abstract:
Introduction Pulmonary alveolar proteinosis related to mutations in the methionine tRNA synthetase (MARS1) gene is a severe, early-onset disease that results in death before the age of 2 years in one-third of patients. It is associated with a liver disease, growth failure and systemic inflammation. As methionine supplementation in yeast models restored normal enzymatic activity of the synthetase, we studied the tolerance, safety and efficacy of daily oral methionine supplementation in patients with severe and early disease. Methods Four patients received methionine supplementation and were followed for respiratory, hepatic, growth, and inflammation-related outcomes. Their course was compared to those of historical controls. Reactive oxygen species (ROS) production by patient monocytes before and after methionine supplementation was also studied. Results Methionine supplementation was associated with respiratory improvement, clearance of the extracellular lipoproteinaceous material, and discontinuation of whole-lung lavage in all patients. The three patients who required oxygen or non-invasive ventilation could be weaned off within 60 days. Liver dysfunction, inflammation, and growth delay also improved or resolved. At a cellular level, methionine supplementation normalised the production of reactive oxygen species by peripheral monocytes. Conclusion Methionine supplementation was associated with important improvements in children with pulmonary alveolar proteinosis related to mutations in the MARS1 gene. This study paves the way for similar strategies for other tRNA synthetase deficiencies.
Elena Chesov, Dumitru Chesov, , Sönke Andres, Christian Utpatel, Ivan Barilar, Ana Donica, , Stefan Niemann, Christoph Lange, et al.
European Respiratory Journal; https://doi.org/10.1183/13993003.00621-2021

Abstract:
Rationale Bedaquiline has been classified as a Group A drug for the treatment of multidrug-resistant tuberculosis (MDR-TB) by the World Health Organization, however globally emerging resistance threatens the effectivity of novel MDR-TB treatment regimens. Objectives We analysed pre-existing and emerging bedaquiline resistance in bedaquiline-based MDR-TB therapies, and risk factors associated with treatment failure and death. Methods In a cross-sectional cohort study, we employed patient data, whole genome sequencing (WGS) and phenotyping of Mycobacterium tuberculosis complex (MTBC) isolates. We could retrieve baseline isolates from 30.5% (62/203) of all MDR-TB patients who received bedaquiline between 2016 and 2018 in the Republic of Moldova. This includes 26 patients for whom we could also retrieve a follow-up isolate. Measurements and Main Results At baseline, all MTBC isolates were susceptible to bedaquiline. Among 26 patients with available baseline and follow-up isolates, 4/26 (15.3%) patients harbored strains which acquired bedaquiline resistance under therapy, while 1/26 (3.8%) patients was re-infected with a second bedaquiline resistant strain. Treatment failure and death were associated with cavitary disease (p=0.011), and any additional drug prescribed in the bedaquiline containing regimen with WGS-predicted resistance at baseline (p=0.012, OR 1.92 per unit increase, 95%CI 1.15–3.21). Conclusions MDR-TB treatments based on bedaquiline require a functional background regimen to achieve high cure rates and to prevent the evolution of bedaquiline resistance. Novel MDR-TB therapies with bedaquiline require timely and comprehensive drug resistance monitoring.
, Jutta Beier, Carol Astbury, Maria G. Belvisi, Carla A. Da Silva, Alexandra Jauhiainen, Eulalia Jimenez, Alejhandra Lei, Sofia Necander, , et al.
European Respiratory Journal; https://doi.org/10.1183/13993003.00972-2021

Abstract:
Background Navafenterol (AZD8871) belongs to a new class of bronchodilator, the single-molecule muscarinic antagonist and beta agonist (MABA), being developed for the treatment of chronic obstructive pulmonary disease (COPD). This study aimed to evaluate the efficacy, pharmacokinetics and safety of navafenterol versus placebo and an active comparator treatment for moderate-to-severe COPD. Methods This phase 2a, randomised, multicentre (Germany and UK), double-blind, double-dummy, three-way complete crossover study (ClinicalTrials.gov identifier: NCT03645434) compared 2 weeks’ treatment of once-daily navafenterol 600 µg via inhalation with placebo and a fixed-dose combination bronchodilator (umeclidinium/vilanterol [UMEC/VI]; 62.5 µg/25 µg) in participants with moderate-to-severe COPD. The primary outcome was change from baseline in trough FEV1 on day 15. Secondary endpoints included: change from baseline in peak FEV1; change from baseline in breathlessness, cough and sputum scale (BCSS); change from baseline in COPD assessment tool (CAT); adverse events; and pharmacokinetics. Results Seventy-three participants were randomised. After 14 days, trough FEV1 was significantly improved with navafenterol compared with placebo (least-squares [LS] mean difference 0.202 L; p<0.0001). There was no significant difference in FEV1 between navafenterol and UMEC/VI (LS mean difference −0.046 L; p=0.075). COPD symptoms (CAT and BCSS) showed significantly greater improvements with both active treatments versus placebo (all p<0.005). Novel objective monitoring (VitaloJAK) showed that cough was reduced with both active treatments compared with placebo. Safety profiles were similar across the treatment groups and no serious adverse events were reported in the navafenterol treatment period. Conclusion Once-daily navafenterol was well tolerated, improved lung function and reduced COPD-related symptoms, similar to an established once-daily fixed-dose combination bronchodilator.
Marija Gredic, Cheng-Yu Wu, Stefan Hadzic, Oleg Pak, , Baktybek Kojonazarov, Siddartha Doswada, Astrid Weiss, Andreas Weigert, Andreas Guenther, et al.
European Respiratory Journal; https://doi.org/10.1183/13993003.01153-2021

Abstract:
Pulmonary hypertension (PH) is a common complication of chronic obstructive pulmonary disease (COPD), associated with increased mortality and morbidity. Intriguingly, pulmonary vascular alterations have been suggested to drive emphysema development. We previously identified inducible nitric oxide synthase (iNOS) as an essential enzyme for development and reversal of smoke-induced PH and emphysema, and showed that iNOS expression in bone-marrow-derived cells drives pulmonary vascular remodelling, but not parenchymal destruction. In this study, we aimed to identify the iNOS-expressing cell type driving smoke-induced PH and to decipher pro-proliferative pathways involved. To address this question we used 1) myeloid cell-specific iNOS knockout mice in chronic smoke exposure, 2) co-cultures of macrophages and pulmonary artery smooth muscle cells (PASMC) to decipher underlying signalling pathways. Myeloid cell-specific iNOS knockout prevented smoke-induced PH but not emphysema in mice. Moreover, iNOS deletion in myeloid cells ameliorated the increase in expression of CD206, a marker of M2 polarisation, on interstitial macrophages. Importantly, the observed effects on lung macrophages were hypoxia-independent, as these mice developed hypoxia-induced PH. In vitro, smoke-induced PASMC proliferation in co-cultures with M2-polarised macrophages could be abolished by iNOS deletion in phagocytic cells, as well as by ERK inhibition in PASMC. Crucially, CD206-positive and iNOS-positive macrophages accumulated in proximity of remodelled vessels in the lungs of COPD patients, as shown by immunohistochemistry. In summary, our results demonstrate that iNOS deletion in myeloid cells confers protection against PH in smoke-exposed mice and provide evidence for an iNOS-dependent communication between M2-like macrophages and PASMC in underlying pulmonary vascular remodelling.
Kevin R. Flaherty, Athol U. Wells, , Anand Devaraj, , Luca Richeldi, Simon L.F. Walsh, , Dirk Koschel, Teng Moua, et al.
European Respiratory Journal; https://doi.org/10.1183/13993003.04538-2020

Abstract:
The primary analysis of the INBUILD trial showed that in subjects with progressive fibrosing interstitial lung diseases (ILDs), nintedanib slowed the decline in forced vital capacity (FVC) over 52 weeks. We report the effects of nintedanib on ILD progression over the whole trial. Subjects with fibrosing ILDs other than idiopathic pulmonary fibrosis, who had ILD progression within the 24 months before screening despite management deemed appropriate in clinical practice, were randomised to receive nintedanib or placebo. Subjects continued on blinded randomised treatment until all subjects had completed the trial. Over the whole trial, mean (sd) exposure to trial medication was 15.6 (7.2) and 16.8 (5.8) months in the nintedanib and placebo groups, respectively. In the nintedanib (n=332) and placebo (n=331) groups, respectively, the proportions of subjects who had ILD progression (absolute decline in FVC ≥10% predicted) or died were 40.4% and 54.7% in the overall population (HR 0.66 [95% CI: 0.53, 0.83]; p=0.0003), and 43.7% and 55.8% among subjects with a usual interstitial pneumonia (UIP)-like fibrotic pattern on high-resolution computed tomography (HRCT) (HR 0.69 [0.53, 0.91]; p=0.009). In the nintedanib and placebo groups, respectively, the proportions who had an acute exacerbation of ILD or died were 13.9% and 19.6% in the overall population (HR 0.67 [95% CI: 0.46, 0.98]; p=0.04), and 15.0% and 22.8% among subjects with a UIP-like fibrotic pattern on HRCT (HR 0.62 [0.39, 0.97]; p=0.03). Based on data from the whole INBUILD trial, nintedanib reduced the risk of events indicating ILD progression.
, , Miquel Ferrer, , Enric Barbeta, Albert Gabarrús, , , Gennaro De Pascale, Stefano Nogas, et al.
European Respiratory Journal; https://doi.org/10.1183/13993003.00620-2021

Abstract:
Ventilator-associated pneumonia is a leading infectious cause of morbidity in critically ill patients; yet current guidelines offer no indications for follow-up cultures. We aimed to evaluate the role of follow-up cultures and microbiological response 3 days after diagnosing ventilator-associated pneumonia as predictors of short- and long-term outcomes. We performed a retrospective analysis of a cohort prospectively collected from 2004 to 2017. Ventilator-associated pneumonia was diagnosed based on clinical, radiographic, and microbiological criteria. For microbiological identification, a tracheobronchial aspirate was performed at diagnosis and repeated after 72 h. We defined three groups when comparing the two tracheobronchial aspirate results: persistence, superinfection, and eradication of causative pathogens. One-hundred-fifty-seven patients were enrolled in the study, among whom microbiological persistence, superinfection, and eradication was present in 67 (48%), 25 (16%), and 65 (41%), respectively, after 72hs. Those with superinfection had the highest mortalities in the intensive care unit (p=0.015) and at 90 days (p=0.036), while also having the fewest ventilation-free days (p=0.024). Multivariable analysis revealed shock at VAP diagnosis (odds ratios [OR] 3.43; 95% confidence interval [CI] 1.25 to 9.40), Staphylococcus aureus isolation at VAP diagnosis (OR 2.87; 95%CI 1.06 to 7.75), and hypothermia at VAP diagnosis (OR 0.67; 95%CI 0.48 to 0.95, per +1°C) to be associated with superinfection. Our retrospective analysis suggests that ventilator-associated pneumonia short-term and long-term outcomes may be associated with superinfection in follow-up cultures. Follow-up cultures may help guiding antibiotic therapy and its duration. Further prospective studies are necessary to verify our findings.
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