Graphical Abstract Highlights d Severe COVID-19 patients display immune dysregulation or macrophage activation syndrome d Severe respiratory failure is associated with a major decrease of HLA-DR on CD14 monocytes d CD4 cell and NK cell cytopenias are characteristics of severe COVID-19 d IL-6 blocker Tocilizumab partially rescues SARS-CoV-2associated immune dysregulation

IMPORTANCE Severe acute respiratory syndrome coronavirus 2 infection has evolved into a global pandemic. Low-dose colchicine combines anti-inflammatory action with a favorable safety profile. OBJECTIVE To evaluate the effect of treatment with colchicine on cardiac and inflammatory biomarkers and clinical outcomes in patients hospitalized with coronavirus disease 2019 (COVID-19). DESIGN, SETTING, AND PARTICIPANTS In this prospective, open-label, randomized clinical trial (the Greek Study in the Effects of Colchicine in COVID-19 Complications Prevention), 105 patients hospitalized with COVID-19 were randomized in a 1:1 allocation from April 3 to April 27, 2020, to either standard medical treatment or colchicine with standard medical treatment. The study took place in 16 tertiary hospitals in Greece. INTERVENTION Colchicine administration (1.5-mg loading dose followed by 0.5 mg after 60 min and maintenance doses of 0.5 mg twice daily) with standard medical treatment for as long as 3 weeks. MAIN OUTCOMES AND MEASURES Primary end points were (1) maximum high-sensitivity cardiac troponin level; (2) time for C-reactive protein to reach more than 3 times the upper reference limit; and (3) time to deterioration by 2 points on a 7-grade clinical status scale, ranging from able to resume normal activities to death. Secondary end points were (1) the percentage of participants requiring mechanical ventilation, (2) all-cause mortality, and (3) number, type, severity, and seriousness of adverse events. The primary efficacy analysis was performed on an intentionto-treat basis. RESULTS A total of 105 patients were evaluated (61 [58.1%] men; median [interquartile range] age, 64 [54-76] years) with 50 (47.6%) randomized to the control group and 55 (52.4%) to the colchicine group. Median (interquartile range) peak high-sensitivity cardiac troponin values were 0.0112 (0.0043-0.0093) ng/mL in the control group and 0.008 (0.004-0.0135) ng/mL in the colchicine group (P = .34). Median (interquartile range) maximum C-reactive protein levels were 4.5 (1.4-8.9) mg/dL vs 3.1 (0.8-9.8) mg/dL (P = .73), respectively. The clinical primary end point rate was 14.0% in (continued) Key Points Question Is the receipt of colchicine among patients hospitalized with symptomatic coronavirus disease 2019 associated with clinical benefit? Findings In this randomized clinical trial of 105 patients, the rate of the primary clinical end point (clinical deterioration) was higher in the control group than in the colchicine group, and the time to clinical deterioration was shorter in the control group than in the colchicine arm. No difference was observed in the primary biochemical end point (highsensitivity troponin concentration), but patients in the colchicine group had a smaller increase in dimerized plasma fragment D compared with patients in the control group. Meaning The hypothesis-generating findings of this study suggest a role for colchicine in the treatment of patients with coronavirus disease 2019.

A A s si im mp pl le e m me et th ho od d t to o d de et te ec ct t e ex xp pi ir ra at to or ry y f fl lo ow w l li im mi it ta at ti io on n d du ur ri in ng g s sp po on nt ta an ne eo ou us s b br re ea at th hi in ng g N.G. Koulouris*, P. Valta*, A. Lavoie*, C. Corbeil**, M. Chassé**, J. Braidy**, J. Milic-Emili*A simple method to detect expiratory flow limitation during spontaneous breathing. N.G. Koulouris, P. Valta, A. Lavoie, C. Corbeil, M. Chassé, J. Braidy, J. Milic-Emili. ERS Journals Ltd 1995. ABSTRACT: Patients with severe chronic obstructive pulmonary disease (COPD) often exhale along the same flow-volume curve during quiet breathing as during a forced expiratory vital capacity manoeuvre, and this has been taken as indicating flow limitation at rest. To obtain such curves, a body plethysmograph and the patient's co-operation are required. We propose a simple technique which does not entail these requirements. It consists in applying negative pressure at the mouth during a tidal expiration (NEP). Patients in whom NEP elicits an increase in flow throughout the expiration are not flow-limited. In contrast, patients in whom application of NEP does not elicit an increase in flow during most or part of the tidal expiration are considered as flowlimited. Using this technique, 26 stable COPD patients were studied sitting and supine.Eleven patients were flow-limited both seated and supine, eight were flow-limited only when supine, and seven were not flow-limited either seated or supine. Only 5 of 19 patients who were flow-limited seated and/or supine had severe ventilatory impairment (forced expiratory volume in one second (FEV 1 ) <40% predicted).We conclude that the NEP technique provides a simple, rapid, and reliable method for detection of expiratory flow limitation in spontaneously breathing subjects, which does not require the patient's co-operation, and can be applied in different body positions both at rest and during muscular exercise. Our results also indicate a high prevalence of flow limitation in COPD patients at rest, particularly when supine. Eur Respir J., 1995, 8, 306-313 It has long been suggested that patients with severe chronic obstructive pulmonary disease (COPD) may exhibit expiratory flow limitation at rest, as reflected by the fact that they breathe tidally along or above their maximum expiratory flow-volume curves [1][2][3]. The effects of expiratory flow limitation may be partly compensated by breathing at lung volumes higher than the relaxation volume of the respiratory system [3]. The latter condition, which is termed dynamic pulmonary hyperinflation, is associated with intrinsic positive endexpiratory pressure (PEEPi) [4]. The combined effects of increased flow resistance, dynamic hyperinflation and PEEPi place a severe burden on the inspiratory muscles of COPD patients [5][6][7], and may also contribute to dyspnoea [8].Though dynamic hyperinflation is the hallmark of expiratory flow limitation, the prevalence and clinical significance of this phenomenon have not been adequa...

Pulmonary rehabilitation (PR) remains grossly underutilised by suitable patients worldwide. We investigated whether home-based maintenance tele-rehabilitation will be as effective as hospital-based maintenance rehabilitation and superior to usual care in reducing the risk for acute chronic obstructive pulmonary disease (COPD) exacerbations, hospitalisations and emergency department (ED) visits.Following completion of an initial 2-month PR programme this prospective, randomised controlled trial (between December 2013 and July 2015) compared 12 months of home-based maintenance tele-rehabilitation (n=47) with 12 months of hospital-based, outpatient, maintenance rehabilitation (n=50) and also to 12 months of usual care treatment (n=50) without initial PR.In a multivariate analysis during the 12-month follow-up, both home-based tele-rehabilitation and hospital-based PR remained independent predictors of a lower risk for 1) acute COPD exacerbation (incidence rate ratio (IRR) 0.517, 95% CI 0.389-0.687, and IRR 0.635, 95% CI 0.473-0.853), respectively, and 2) hospitalisations for acute COPD exacerbation (IRR 0.189, 95% CI 0.100-0.358, and IRR 0.375, 95% CI 0.207-0.681), respectively. However, only home-based maintenance tele-rehabilitation and not hospital-based, outpatient, maintenance PR was an independent predictor of ED visits (IRR 0.116, 95% CI 0.072-0.185).Home-based maintenance tele-rehabilitation is equally effective as hospital-based, outpatient, maintenance PR in reducing the risk for acute COPD exacerbation and hospitalisations. In addition, it encounters a lower risk for ED visits, thereby constituting a potentially effective alternative strategy to hospital-based, outpatient, maintenance PR.

Increasing evidence indicates that chronic inflammatory and immune responses play key roles in the development and progression of COPD. Recent data provide evidence for a role in the NLRP3 inflammasome in the airway inflammation observed in COPD. Cigarette smoke activates innate immune cells by triggering pattern recognition receptors (PRRs) to release “danger signal”. These signals act as ligands to Toll-like receptors (TLRs), triggering the production of cytokines and inducing innate inflammation. In smokers who develop COPD there appears to be a specific pattern of inflammation in the airways and parenchyma as a result of both innate and adaptive immune responses, with the predominance of CD8+ and CD4+ cells, and in the more severe disease, with the presence of lymphoid follicles containing B lymphocytes and T cells. Furthermore, viral and bacterial infections interfere with the chronic inflammation seen in stable COPD and exacerbations via pathogen-associated molecular patterns (PAMPs). Finally, autoimmunity is another novel aspect that may play a critical role in the pathogenesis of COPD. This review is un update of the currently discussed roles of inflammatory and immune responses in the pathogenesis of COPD.

Serological, molecular and phylogenetic analyses of a recently imported case of Middle East respiratory syndrome coronavirus (MERS-CoV) in Greece are reported. Although MERS-CoV remained detectable in the respiratory tract secretions of the patient until the fourth week of illness, viraemia was last detected 2 days after initiation of triple combination therapy with pegylated interferon, ribavirin and lopinavir/ritonavir, administered from Day 13 of illness. Phylogenetic analysis of the virus showed close similarity with other human MERS-CoVs from the recent Jeddah outbreak in Saudi Arabia. Immunoglobulin G (IgG) titres peaked 3 weeks after the onset of illness, whilst IgM levels remained constantly elevated during the follow-up period (second to fifth week of illness). Serological testing confirmed by virus neutralisation assay detected an additional case that was a close contact of the patient.

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These results show that eosinophil infiltration was present in the nasal mucosa of asthmatic patients even in the absence of rhinitis, and add further support to the hypothesis that asthma and rhinitis are clinical expressions of the same disease entity.