International audienceSummaryBackground Neuraminidase inhibitors were widely used during the 2009–10 influenza A H1N1 pandemic, but evidence for their effectiveness in reducing mortality is uncertain. We did a meta-analysis of individual participant data to investigate the association between use of neuraminidase inhibitors and mortality in patients admitted to hospital with pandemic influenza A H1N1pdm09 virus infection. Methods We assembled data for patients (all ages) admitted to hospital worldwide with laboratory confirmed or clinically diagnosed pandemic influenza A H1N1pdm09 virus infection. We identified potential data contributors from an earlier systematic review of reported studies addressing the same research question. In our systematic review, eligible studies were done between March 1, 2009 (Mexico), or April 1, 2009 (rest of the world), until the WHO declaration of the end of the pandemic (Aug 10, 2010); however, we continued to receive data up to March 14, 2011, from ongoing studies. We did a meta-analysis of individual participant data to assess the association between neuraminidase inhibitor treatment and mortality (primary outcome), adjusting for both treatment propensity and potential confounders, using generalised linear mixed modelling. We assessed the association with time to treatment using time-dependent Cox regression shared frailty modelling. Findings We included data for 29 234 patients from 78 studies of patients admitted to hospital between Jan 2, 2009, and March 14, 2011. Compared with no treatment, neuraminidase inhibitor treatment (irrespective of timing) was associated with a reduction in mortality risk (adjusted odds ratio [OR] 0·81; 95% CI 0·70–0·93; p=0·0024). Compared with later treatment, early treatment (within 2 days of symptom onset) was associated with a reduction in mortality risk (adjusted OR 0·48; 95% CI 0·41–0·56; p<0·0001). Early treatment versus no treatment was also associated with a reduction in mortality (adjusted OR 0·50; 95% CI 0·37–0·67; p<0·0001). These associations with reduced mortality risk were less pronounced and not significant in children. There was an increase in the mortality hazard rate with each day's delay in initiation of treatment up to day 5 as compared with treatment initiated within 2 days of symptom onset (adjusted hazard ratio [HR 1·23] [95% CI 1·18–1·28]; p<0·0001 for the increasing HR with each day's delay). Interpretation We advocate early instigation of neuraminidase inhibitor treatment in adults admitted to hospital with suspected or proven influenza infection. Funding F Hoffmann-La Roche

SummaryBackgroundHigh-volume prescribing of antibiotics in primary care is a major driver of antibiotic resistance. Education of physicians and patients can lower prescribing levels, but it frequently relies on highly trained staff. We assessed whether internet-based training methods could alter prescribing practices in multiple health-care systems.MethodsAfter a baseline audit in October to December, 2010, primary-care practices in six European countries were cluster randomised to usual care, training in the use of a C-reactive protein (CRP) test at point of care, in enhanced communication skills, or in both CRP and enhanced communication. Patients were recruited from February to May, 2011. This trial is registered, number ISRCTN99871214.ResultsThe baseline audit, done in 259 practices, provided data for 6771 patients with lower-respiratory-tract infections (3742 [55·3%]) and upper-respiratory-tract infections (1416 [20·9%]), of whom 5355 (79·1%) were prescribed antibiotics. After randomisation, 246 practices were included and 4264 patients were recruited. The antibiotic prescribing rate was lower with CRP training than without (33% vs 48%, adjusted risk ratio 0·54, 95% CI 0·42–0·69) and with enhanced-communication training than without (36% vs 45%, 0·69, 0·54–0·87). The combined intervention was associated with the greatest reduction in prescribing rate (CRP risk ratio 0·53, 95% CI 0·36–0·74, p<0·0001; enhanced communication 0·68, 0·50–0·89, p=0·003; combined 0·38, 0·25–0·55, p<0·0001).InterpretationInternet training achieved important reductions in antibiotic prescribing for respiratory-tract infections across language and cultural boundaries.FundingEuropean Commission Framework Programme 6, National Institute for Health Research, Research Foundation Flanders.

The main characteristics of mechanically ventilated ARDS patients affected with COVID-19, and the adherence to lung-protective ventilation strategies are not well known. We describe characteristics and outcomes of confirmed ARDS in COVID-19 patients managed with invasive mechanical ventilation (MV). Methods: This is a multicenter, prospective, observational study in consecutive, mechanically ventilated patients with ARDS (as defined by the Berlin criteria) affected with with COVID-19 (confirmed SARS-CoV-2 infection in nasal or pharyngeal swab specimens), admitted to a network of 36 Spanish and Andorran intensive care units (ICUs) between March 12 and June 1, 2020. We examined the clinical features, ventilatory management, and clinical outcomes of COVID-19 ARDS patients, and compared some results with other relevant studies in non-COVID-19 ARDS patients. Results: A total of 742 patients were analysed with complete 28-day outcome data: 128 (17.1%) with mild, 331 (44.6%) with moderate, and 283 (38.1%) with severe ARDS. At baseline, defined as the first day on invasive MV, median (IQR) values were: tidal volume 6.9 (6.3-7.8) ml/kg predicted body weight, positive end-expiratory pressure 12 (11-14) cmH 2 O. Values of respiratory system compliance 35 (27-45) ml/cmH 2 O, plateau pressure 25 (22-29) cmH 2 O, and driving pressure 12 (10-16) cmH 2 O were similar to values from non-COVID-19 ARDS patients observed in other studies. Recruitment maneuvers, prone position and neuromuscular blocking agents were used in 79%, 76% and 72% of patients, respectively. The risk of 28-day mortality was lower in mild ARDS [hazard ratio (RR) 0.56 (95% CI 0.33-0.93), p = 0.026] and moderate ARDS [hazard ratio (RR) 0.69 (95% CI 0.47-0.97), p = 0.035] when compared to severe ARDS. The 28-day mortality was similar to other observational studies in non-COVID-19 ARDS patients. Conclusions: In this large series, COVID-19 ARDS patients have features similar to other causes of ARDS, compliance with lung-protective ventilation was high, and the risk of 28-day mortality increased with the degree of ARDS severity.

Objectives To analyse the characteristics and predictors of death in hospitalized patients with coronavirus disease 2019 (COVID-19) in Spain. Methods A retrospective observational study was performed of the first consecutive patients hospitalized with COVID-19 confirmed by real-time PCR assay in 127 Spanish centres until 17 March 2020. The follow-up censoring date was 17 April 2020. We collected demographic, clinical, laboratory, treatment and complications data. The primary endpoint was all-cause mortality. Univariable and multivariable Cox regression analyses were performed to identify factors associated with death. Results Of the 4035 patients, male subjects accounted for 2433 (61.0%) of 3987, the median age was 70 years and 2539 (73.8%) of 3439 had one or more comorbidity. The most common symptoms were a history of fever, cough, malaise and dyspnoea. During hospitalization, 1255 (31.5%) of 3979 patients developed acute respiratory distress syndrome, 736 (18.5%) of 3988 were admitted to intensive care units and 619 (15.5%) of 3992 underwent mechanical ventilation. Virus- or host-targeted medications included lopinavir/ritonavir (2820/4005, 70.4%), hydroxychloroquine (2618/3995, 65.5%), interferon beta (1153/3950, 29.2%), corticosteroids (1109/3965, 28.0%) and tocilizumab (373/3951, 9.4%). Overall, 1131 (28%) of 4035 patients died. Mortality increased with age (85.6% occurring in older than 65 years). Seventeen factors were independently associated with an increased hazard of death, the strongest among them including advanced age, liver cirrhosis, low age-adjusted oxygen saturation, higher concentrations of C-reactive protein and lower estimated glomerular filtration rate. Conclusions Our findings provide comprehensive information about characteristics and complications of severe COVID-19, and may help clinicians identify patients at a higher risk of death.

We carried out a comprehensive microbiological study of the upper and lower airways in patients with severe exacerbations of chronic obstructive pulmonary disease (COPD) requiring mechanical ventilation in order to describe microbial patterns and analyze their clinical significance. Quantitative cultures of tracheobronchial aspirates (TBAs), bronchoscopically retrieved protected specimen brush (PSB) and bronchoalveolar lavage fluid (BALF) at admission to the ICU and after 72 h, as well as serology for bacteria and respiratory viruses were performed. Fifty patients (mean age 68 +/- 8, 46 males) were studied prospectively. Potentially pathogenic microorganisms (PPMs) and/or a positive serology were present in 36 of 50 (72%) patients, including 12 (33%) polymicrobial cases. Only six (12%) had no pathogen in any sample in the absence of antimicrobial pretreatment. Microbial patterns corresponded to community-acquired pathogens (Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis) in 19 of 34 (56%) and to gram-negative enteric bacilli (GNEB), Pseudomonas, and Stenotrophomonas spp. in 15 of 34 (44%) of isolates. Chlamydia pneumoniae and respiratory viruses were found in 18% and 16% of investigations, respectively. Repeated investigation after 72 h in 19 patients with PPMs in the initial investigation revealed eradication of virtually all isolates of community-acquired pathogens and GNEB but persistence of three of five Pseudomonas spp. and both Stenotrophomonas spp. as well as the emergence of new GNEB, Pseudomonas and Stenotrophomonas spp. Clinical parameters neither predicted the presence of PPMs nor of GNEB and Pseudomonas/Stenotrophomonas spp. Nevertheless, severe pneumonia attributable to initially isolated pathogens occurred in two patients with severe COPD exacerbation. We conclude that pathogens were more frequently present than previously reported. The rate of GNEB and Pseudomonas/Stenotrophomonas spp. isolates was high. The presence of pathogens was clinically unpredictable. Thus, in this population of patients with severe exacerbations of COPD, it may be advisable to obtain respiratory samples and to treat according to diagnostic results. Further studies are warranted to clarify this issue.

Objective To describe variation in antibiotic prescribing for acute cough in contrasting European settings and the impact on recovery. Design Cross sectional observational study with clinicians from 14 primary care research networks in 13 European countries who recorded symptoms on presentation and management. Patients followed up for 28 days with patient diaries. Setting Primary care. Participants Adults with a new or worsening cough or clinical presentation suggestive of lower respiratory tract infection. Main outcome measures Prescribing of antibiotics by clinicians and total symptom severity scores over time. Results 3402 patients were recruited (clinicians completed a case report form for 99% (3368) of participants and 80% (2714) returned a symptom diary). Mean symptom severity scores at presentation ranged from 19 (scale range 0 to 100) in networks based in Spain and Italy to 38 in the network based in Sweden. Antibiotic prescribing by networks ranged from 20% to nearly 90% (53% overall), with wide variation in classes of antibiotics prescribed. Amoxicillin was overall the most common antibiotic prescribed, but this ranged from 3% of antibiotics prescribed in the Norwegian network to 83% in the English network. While fluoroquinolones were not prescribed at all in three networks, they were prescribed for 18% in the Milan network. After adjustment for clinical presentation and demographics, considerable differences remained in antibiotic prescribing, ranging from Norway (odds ratio 0.18, 95% confidence interval 0.11 to 0.30) to Slovakia (11.2, 6.20 to 20.27) compared with the overall mean (proportion prescribed: 0.53). The rate of recovery was similar for patients who were and were not prescribed antibiotics (coefficient −0.01, P<0.01) once clinical presentation was taken into account.

The effect of bacterial colonization of the bronchi on the progress of airflow limitation is not well known. Therefore, the pattern of airway inflammation in smokers and patients with stable chronic obstructive pulmonary disease (COPD) and its relation to bronchial microbial colonization was assessed.Eight nonsmoking and 18 smoking controls as well as 52 patients with COPD (28 mild, 11 moderate and 13 severe) were studied. All subjects were investigated by means of flexible bronchoscopy including protected specimen brush and bronchoalveolar lavage (BAL) sampling. Differential cell counts, cytokine (interleukin (IL)-1b, IL-6, IL-8, IL-10 and tumour necrosis factor-a (TNF-a) concentrations and microbial patterns were determined in BAL fluid.Forced expiratory volume in one second (FEV1) % of the predicted value was inversely correlated with pack-yrs of cigarette smoking (r=-0.47, p<0.0001), the percentage of neutrophil (r=-0.56, p<0.0001) and IL-6 (r=-0.37, p=0.01) and IL-8 concentration (r=-0.43, p=0.004) in BAL fluid. Accordingly, pk-yrs of cigarette smoking (r=0.39, p=0.01) and IL-8 (r=0.69, p<0.0001) and TNFa (r=0.4, p<0.005) were positively correlated with the percentage of neutrophils in BAL fluid. Smoking controls and COPD patients were mainly colonized in the bronchial tree (33%) by community endogenous potentially pathogenic micro-organisms (PPMs). Colonization rates and patterns of PPMs were not affected by severity of airflow obstruction. The presence of PPMs was significantly associated with higher percentages of neutrophils (33.210.4% versus 10.13.5%, p=0.02) and TNF-a concentration (29.910.8 versus 6.32.1 pg . mL -1 , p=0.01) in BAL fluid.In conclusion, bronchial neutrophilia is a key inflammatory pattern in chronic obstructive pulmonary disease patients. Bronchial colonization with potentially pathogenic micro-organisms may represent an independent stimulus for additional airway inflammation.

In contrast to the healthy population, distal airway bacterial colonization may occur in patients with chronic lung diseases, who often have altered pulmonary defences. However, the information dealing with this issue is insufficient and is based mainly on nonspecific samples, such as sputum cultures.Using quantitative cultures of bronchoscopic protected specimen brush (PSB) and bronchoalveolar lavage (BAL) samples, we studied the bacterial colonization of distal airways in 16 healthy subjects, 33 patients with bronchogenic carcinoma, 18 with chronic obstructive pulmonary disease (COPD), 17 with bronchiectasis, and 32 with a long-term tracheostomy due to laryngeal carcinoma. All patients were without exacerbation, and free from antibiotic treatment at least 1 month before the study protocol. Thresholds for quantitative cultures to define colonization were ≥10 2 colony-forming units (cfu)·mL -1 for PSB and ≥10 3 cfu·mL -1 for BAL.Only one healthy subject was colonized by a potential pathogenic microorganism (PPM) (Staphylococcus aureus 4×10 2 cfu·mL -1 in a PSB culture). Colonization was observed in 14 (42%) bronchogenic carcinoma patients (19 non-PPMs, and 10 PPMs); in 15 (83%) COPD patients (22 non-PPMs and 7 PPMs); in 15 (88%) bronchiectasis patients (20 non-PPMs and 13 PPMs); and in 15 (47%) long-term tracheostomy patients (5 non-PPMs and 13 PPMs). The two most frequent nonPPMs isolated in all groups studied were Streptococcus viridans and Neisseria spp. Haemophilus spp., Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis were the most frequent PPMs isolated in bronchogenic carcinoma, COPD, bronchiectasis and long-term tracheostomized patients, respectively. Pseudomonas aeruginosa colonization was infrequent in all the groups.Our results show that distal airway bacterial colonization is a frequent feature in stable patients with chronic lung diseases and also in patients with long-term tracheostomy. However, the pattern of colonization differs among groups studied. The knowledge of different colonization patterns may be important for future antibiotic prophylactic strategies and for the empirical antibiotic regimens when exacerbations occur in these patients.