Background Elevated proinflammatory cytokines are associated with greater COVID-19 severity. We aimed to assess safety and efficacy of sarilumab, an interleukin-6 receptor inhibitor, in patients with severe (requiring supplemental oxygen by nasal cannula or face mask) or critical (requiring greater supplemental oxygen, mechanical ventilation, or extracorporeal support) COVID-19. Methods We did a 60-day, randomised, double-blind, placebo-controlled, multinational phase 3 trial at 45 hospitals in Argentina, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Russia, and Spain. We included adults (≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and pneumonia, who required oxygen supplementation or intensive care. Patients were randomly assigned (2:2:1 with permuted blocks of five) to receive intravenous sarilumab 400 mg, sarilumab 200 mg, or placebo. Patients, care providers, outcome assessors, and investigators remained masked to assigned intervention throughout the course of the study. The primary endpoint was time to clinical improvement of two or more points (seven point scale ranging from 1 [death] to 7 [discharged from hospital]) in the modified intention-to-treat population. The key secondary endpoint was proportion of patients alive at day 29. Safety outcomes included adverse events and laboratory assessments. This study is registered with ClinicalTrials.gov , NCT04327388 ; EudraCT, 2020-001162-12; and WHO, U1111-1249-6021. Findings Between March 28 and July 3, 2020, of 431 patients who were screened, 420 patients were randomly assigned and 416 received placebo (n=84 [20%]), sarilumab 200 mg (n=159 [38%]), or sarilumab 400 mg (n=173 [42%]). At day 29, no significant differences were seen in median time to an improvement of two or more points between placebo (12·0 days [95% CI 9·0 to 15·0]) and sarilumab 200 mg (10·0 days [9·0 to 12·0]; hazard ratio [HR] 1·03 [95% CI 0·75 to 1·40]; log-rank p=0·96) or sarilumab 400 mg (10·0 days [9·0 to 13·0]; HR 1·14 [95% CI 0·84 to 1·54]; log-rank p=0·34), or in proportions of patients alive (77 [92%] of 84 patients in the placebo group; 143 [90%] of 159 patients in the sarilumab 200 mg group; difference −1·7 [−9·3 to 5·8]; p=0·63 vs placebo; and 159 [92%] of 173 patients in the sarilumab 400 mg group; difference 0·2 [−6·9 to 7·4]; p=0·85 vs placebo). At day 29, there were numerical, non-significant survival differences between sarilumab 400 mg (88%) and placebo (79%; difference +8·9% [95% CI −7·7 to 25·5]; p=0·25) for patients who had critical disease. No unexpected safety signals were seen. The rates of treatment-emergent adverse events were 65% (55 of 84) in the placebo group, 65% (103 of 159) in the sarilumab 200 mg group, and 70% (121 of 173) in the sarilumab 400 mg group, and of those leading to death 11% (nine of 84) were in the placebo group, 1...

Chronic airway infection is a key aspect of the pathogenesis of bronchiectasis. A growing interest has been raised on non-tuberculous mycobacteria (NTM) infection. We aimed at describing the clinical characteristics, diagnostic process, therapeutic options and outcomes of bronchiectasis patients with pulmonary NTM (pNTM) disease. This was a prospective, observational study enrolling 261 adult bronchiectasis patients during the stable state at the San Gerardo Hospital, Monza, Italy, from 2012 to 2015. Three groups were identified: pNTM disease; chronic P. aeruginosa infection; chronic infection due to bacteria other than P. aeruginosa. NTM were isolated in 32 (12%) patients, and among them, a diagnosis of pNTM disease was reached in 23 cases. When compared to chronic P. aeruginosa infection, patients with pNTM were more likely to have cylindrical bronchiectasis and a “tree-in-bud” pattern, a history of weight loss, a lower disease severity and a lower number of pulmonary exacerbations. Among pNTM patients who started treatment, 68% showed a radiological improvement, and 37% achieved culture conversion without recurrence, while 21% showed NTM isolation recurrence. NTM isolation seems to be a frequent event in bronchiectasis patients, and few parameters might help to suspect NTM infection. Treatment indications and monitoring still remain an important area for future research.

A comprehensive approach to lung function in bronchiectasis ABSTRACT Background: International guidelines recommend simple spirometry for bronchiectasis patients. However, pulmonary pathophysiology of bronchiectasis is very complex and still poorly understood. Our objective was to characterize lung function in bronchiectasis and identify specific functional sub-groups. Methods:This was a multicenter, prospective, observational study enrolling consecutive adults with bronchiectasis during stable sate. Patients underwent body-plethysmography before and after acute bronchodilation testing, diffusing lung capacity (DL CO ) with a 3-year follow up. Air trapping and hyperinflation were a residual volume (RV)>120%predicted and a total lung capacity>120%predicted. Acute reversibility was: ΔFEV 1 ≥12% and 200 ml from baseline (FEV 1rev ) and ΔRV ≥10% reduction from baseline (RV rev ). Sensitivity analyses included different reversibility cutoffs and excluded patients with concomitant asthma or chronic obstructive pulmonary disease.Results: 187 patients were enrolled (median age: 68 years; 29.4% males).Pathophysiological abnormalities often overlapped and were distributed as follows: air trapping (70.2%), impaired DL CO (55.7%), airflow obstruction (41.1%), hyperinflation (15.7%) and restriction (8.0%). 9.7% of patients had normal lung function. RV rev (17.6%) was more frequent than FEV 1rev (4.3%). Similar proportions were found after multiple sensitivity analyses. Compared with non-reversible patients, patients with RV rev had more severe obstruction (mean(SD) FEV 1 %pred: 83.0% (24.4) vs 68.9% (26.2); P=0.02) and air trapping (RV%pred, 151.9% (26.6) vs 166.2% (39.9); P=0.028). Conclusions:Spirometry alone does not encompass the variety of pathophysiological characteristics in bronchiectasis. Air trapping and diffusion impairment, not airflow obstruction, represent the most common functional abnormalities. RV rev is related to worse lung function and might be considered in bronchiectasis' workup and for patients' functional stratification. Demographics

Bronchiectasis is a heterogeneous chronic disease. Heterogeneity characterises bronchiectasis not only in the stable state but also during exacerbations, despite evidence on clinical and biological aspects of bronchiectasis, exacerbations still remain poorly understood.Although the scientific community recognises that bacterial infection is a cornerstone in the development of bronchiectasis, there is a lack of data regarding other trigger factors for exacerbations. In addition, a huge amount of data suggest a primary role of neutrophils in the stable state and exacerbation of bronchiectasis, but the inflammatory reaction involves many other additional pathways. Cole's vicious cycle hypothesis illustrates how airway dysfunction, airway inflammation, infection and structural damage are linked. The introduction of the concept of a “vicious vortex” stresses the complexity of the relationships between the components of the cycle. In this model of disease, exacerbations work as a catalyst, accelerating the progression of disease. The roles of microbiology and inflammation need to be considered as closely linked and will need to be investigated in different ways to collect samples. Clinical and translational research is of paramount importance to achieve a better comprehension of the pathophysiology of bronchiectasis, microbiology and inflammation both in the stable state and during exacerbations.

COVID-19 is a complex and heterogeneous disease. The pathogenesis and the complications of the disease are not fully elucidated, and increasing evidence shows that SARS-CoV-2 causes a systemic inflammatory disease rather than a pulmonary disease. The management of hospitalized patients in COVID-19 dedicated units is advisable for segregation purpose as well as for infection control. In this article we present the standard operating procedures of our COVID-19 high dependency unit of the Policlinico Hospital, in Milan. Our high dependency unit is based on a multidisciplinary approach. We think that the multidisciplinary involvement of several figures can better identify treatable traits of COVID-19 disease, early identify patients who can quickly deteriorate, particularly patients with multiple comorbidities, and better manage complications related to off-label treatments. Although no generalizable to other hospitals and different healthcare settings, we think that our experience and our point of view can be helpful for countries and hospitals that are now starting to face the COVID-19 outbreak.