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The prevalence of anti-SARS-CoV-2 antibodies in people with cystic fibrosis (CF) is largely unknown. We carried out a cross-sectional study between March and June 2021 with the aim of estimating the seroprevalence of anti-SARS-CoV-2 antibodies in two CF centres in Northern Italy. Total serum anti-SARS-CoV-2 (spike) antibodies levels were measured and values ≥0.8 U/mL were considered positive. Among 434 patients aged >12 years, 64 patients had a positive result (14.7%, 95% CI: 11.5–18.4), 36 (56.3%) without experiencing any COVID-19-related symptoms. Three out of 49 transplanted patients tested positive with an odds ratio for a positive result among transplanted as compared to non-transplanted patients of 0.35 (95% CI: 0.07–1.14). No significant differences were observed between sexes, age groups, socioeconomic status and lung disease severity. In conclusion, SARS-CoV-2 has infected a relatively high proportion of our patients but in most cases the infection was asymptomatic.

Background: Bronchiectasis is a heterogeneous, neglected disease with few multicentre studies exploring the causes, severity, microbiology, and treatment of the disease across Europe. This aim of this study was to describe the clinical characteristics of bronchiectasis and compare between different European countries. Methods: EMBARC is an international clinical research network for bronchiectasis. We report on a multicentre, prospective, observational, non-interventional, cohort study (the EMBARC registry) conducted across 27 European countries and Israel. Comprehensive clinical data were collected from adult patients (aged ≥18 years) at baseline and annual follow-up visits using electronic case report form. Data from individual countries were grouped into four regions (the UK, northern and western Europe, southern Europe, and central and eastern Europe according to modified EU EuroVoc classification). Follow-up data were used to explore differences in exacerbation frequency between regions using a negative binomial regression model. Findings: Between Jan 12, 2015, and April 12, 2022, 16 963 individuals were enrolled. Median age was 67 years (IQR 57–74), 10 335 (60·9%) participants were female and 6628 (39·1%) were male. The most common cause of bronchiectasis in all 16 963 participants was post-infective disease in 3600 (21·2%); 6466 individuals (38·1%) were classified as idiopathic. Individuals with bronchiectasis experienced a median of two exacerbations (IQR 1–4) per year and 4483 (26·4%) patients had a hospitalisation for exacerbation in the previous year. When examining the percentage of all isolated bacteria, marked differences in microbiology were seen between countries, with a higher frequency of Pseudomonas aeruginosa and lower Haemophilus influenzae frequency in southern Europe, compared with higher H influenzae in the UK and northern and western Europe. Compared with other regions, patients in central and eastern Europe had more severe bronchiectasis measured by the Bronchiectasis Severity Index (51·3% vs 35·1% in the overall cohort) and more exacerbations leading to hospitalisations (57·9% vs 26·4% in the overall cohort). Overall, patients in central and eastern Europe had an increased frequency of exacerbations (adjusted rate ratio [RR] 1·12, 95% CI 1·01–1·25) and a higher frequency of exacerbations leading to hospitalisations (adjusted RR 1·71, 1·44–2·02) compared with patients in other regions. Treatment of bronchiectasis was highly heterogeneous between regions. Interpretation: Bronchiectasis shows important geographical variation in causes, microbiology, severity, and outcomes across Europe. Funding: European Union–European Federation of Pharmaceutical Industries and Associations Innovative Medicines Initiative. Translations: For the Arabic, French, German, Greek, Hebrew, Irish, Russian and Spanish translations of the abstract see Supplementary Materials section.

Over the last decades aggressive interventions have been successful to improve nutritional outcomes in people with cystic fibrosis (CF). As a result, with improvement of life expectancy and new CFTR modulators, overweight and obesity are progressively becoming a source of concern for adult population and in developed countries.This was a multicenter, observational, cross-sectional study of 321 adults with CF at three large CF centers in Italy. Patients were divided into three groups according to BMI classes, overweight and obesity (OW) group including patients with BMI ≥25 kg/mWe demonstrated that prevalence of OW in adults with CF in Italy is 22%. OW status is independently associated with male sex (OR 3.520, P = 0.001), pancreatic sufficiency (OR 2.873, P = 0.014) and older age at diagnosis (1.015, P = 0.042). BMI correlated with ppFEV1 (r = 0.337; P0.0001) with median ppFEV1 significantly higher in patients with OW than comparisons. We also reported preliminary data on unfavorable cardiovascular risk factors in a subgroup of patients, where median blood levels [IQR] of cholesterol and systemic hypertension [%] were significantly higher in the OW group than in the NW and UW.People with CF and OW is a relevant patient group that might deserve better definition and proper clinical management.

Background With increasing longevity and quality of life in adults with Cystic fibrosis (CF), growing maternity rates are reported. Women with severe CF are becoming pregnant, with unpredictable maternal and fetal outcomes. Aim To determine how baseline disease severity, pancreatic insufficiency (PI) and Pseudomonas aeruginosa (PA) infection affect fertility, the pregnancy course, delivery, neonatal outcome, and subsequent disease progression. Methods A multicenter-retrospective cohort study. Data on patients that had been pregnant between 1986-2018 was collected from ten CF centers worldwide. Disease severity [mild or moderate-severe (mod-sev)] was defined according to forced expiratory volume % predicted in 1 second (FEV1) and body mass index (BMI). Three time periods were compared, 12 months prior to conception, the pregnancy itself and the 12 months thereafter. Results Data was available on 171 pregnancies in 128 patients aged 18-45 years; 55.1% with mod-sev disease, 43.1% with PI and 40.3% with PA. Women with mod-sev disease had more CF-related complications during and after pregnancy and delivered more preterm newborns. However, FEV1 and BMI decline were no different between the mild and mod-sev groups. A more rapid decline in FEV1 was observed during pregnancy in PI and PA infected patients, though stabilizing thereafter. PI was associated with increased risk for small for gestational age infants. Conclusion Baseline disease severity, PA infection and PI have an adverse impact on infant outcomes, but do not impact significantly on disease progression during and after pregnancy. Consequently, pregnancies in severe CF patients can have a good prognosis.

In 2019, the American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA) issued a substantial revision of the 2007 guideline on community-acquired pneumonia (CAP). Despite the fact that generalization of infectious disease guidelines is limited because of substantial geographic differences in microbiologic etiology and antimicrobial resistance, the ATS/IDSA guideline is frequently applied outside the United States. Therefore, this project aimed to give a perspective on the ATS/IDSA CAP recommendations related to the management of CAP outside the United States. For this, an expert panel composed of 14 international key opinion leaders in the field of CAP from 10 countries across five continents, who were not involved in producing the 2019 guideline, was asked to subjectively name the five most useful changes, the recommendation viewed most critically, and the recommendation that cannot be applied to their respective region. There was no formal consensus process, and the article reflects different opinions. Recommendations welcomed by most of the international pneumonia experts included the abandonment of the concept of “health-care-associated pneumonia,” the more restrictive indication for empiric macrolide treatment in outpatients, the increased emphasis on microbiologic diagnostics, and addressing the use of corticosteroids. Main criticisms included the somewhat arbitrary choice of a 25% resistance threshold for outpatient macrolide monotherapy. Experts from areas with elevated mycobacterial prevalence particularly opposed the recommendation of fluoroquinolones, even as an alternative.

Background Community-acquired pneumonia (CAP) guidelines have improved the treatment and outcomes of patients with CAP, primarily by standardization of initial empirical therapy. But current society-published guidelines exclude immunocompromised patients. Research Question There is no consensus regarding the initial treatment of immunocompromised patients with suspected CAP. Study Design and Methods This consensus document was created by a multidisciplinary panel of 45 physicians with experience in the treatment of CAP in immunocompromised patients. The Delphi survey methodology was used to reach consensus. Results The panel focused on 21 questions addressing initial management strategies. The panel achieved consensus in defining the population, site of care, likely pathogens, microbiologic workup, general principles of empirical therapy, and empirical therapy for specific pathogens. Interpretation This document offers general suggestions for the initial treatment of the immunocompromised patient who arrives at the hospital with pneumonia.

The pathophysiology of the severe complications of COVID-19 is still unclear. We report preliminary data providing evidence of complement activation in patients with COVID-19 with different degrees of respiratory failure.

Background Recruitment manoeuvres generate a transient increase in trans-pulmonary pressure that could open collapsed alveoli. Recruitment manoeuvres might generate very high inspiratory airflows. We evaluated whether recruitment manoeuvres could displace respiratory secretions towards the distal airways and impair gas exchange in a porcine model of bacterial pneumonia. Methods We conducted a prospective randomised study in 10 mechanically ventilated pigs. Pneumonia was produced by direct intra-bronchial introduction of Pseudomonas aeruginosa. Four recruitment manoeuvres were applied randomly: extended sigh (ES), maximal recruitment strategy (MRS), sudden increase in driving pressure and PEEP (SI-PEEP), and sustained inflation (SI). Mucus transport was assessed by fluoroscopic tracking of radiopaque disks before and during each recruitment manoeuvre. The effects of each RM on gas exchange were assessed 15 min after the intervention. Results Before recruitment manoeuvres, mucus always cleared towards the glottis. Conversely, mucus was displaced towards the distal airways in 28.6% ES applications and 50% of all other recruitment manoeuvres (P=0.053). Median mucus velocity was 1.26 mm min−1 [0.48–3.89] before each recruitment manoeuvre, but was reversed (P=0.007) during ES [0.10 mm min−1 [-0.04–1.00]], MRS [0.10 mm min−1 [-0.4–0.48]], SI-PEEP [0.02 mm min−1 [-0.14–0.34]], and SI [0.10 mm min−1 [-0.63–0.75]]. When PaO2 failed to improve after recruitment manoeuvre, mucus was displaced towards the distal airways in 68.7% of the cases, compared with 31.2% recruitment manoeuvres associated with improved PaO2 (odds ratio: 4.76 (95% confidence interval: 1.13–19.97). Conclusions Recruitment manoeuvres dislodge mucus distally, irrespective of airflow generated by different recruitment manoeuvres. Further investigation in humans is warranted to corroborate these pre clinical findings, as there may be limited benefits associated with lung recruitment in pneumonia.

Background Animal models and few clinical reports suggest the involvement of the complement system in the onset of severe manifestations of coronavirus disease-2019 (COVID-19). However, complement contribution to endotheliopathy and hypercoagulability has not been elucidated yet. Objective To evaluate the association among complement activation, endothelial damage and disease severity or activity in COVID-19 patients. Methods In this single-centre cohort study, 148 patients with COVID-19 of different severity were evaluated upon hospital admission and 30 days later. Markers of complement activation (SC5b-9 and C5a) and endothelial perturbation (von Willebrand factor [vWF], tissue-type plasminogen activator [t-PA], plasminogen activator inhibitor-1 [PAI-1], soluble thrombomodulin [sTM], and soluble endothelial selectin [sE-selectin]) were measured in plasma. Results The patients had high plasma levels of SC5b-9 and C5a (p = 0.0001 for both) and vWF, t-PA and PAI-1 (p = 0.0001 for all). Their SC5b-9 levels correlated with those of vWF (r = 0.517, p = 0.0001) and paralleled disease severity (severe vs mild p = 0.0001, severe vs moderate p = 0.026 and moderate vs mild p = 0.001). The levels of sE-selectin were significantly increased only in the patients with severe disease. After 30 days, plasma SC5b-9, C5a and vWF levels had significantly decreased (p = 0.0001 for all), and 43% of the evaluated patients had normal levels. Conclusions Complement activation is boosted during the progression of COVID-19 and dampened during remission, thus indicating its role in the pathophysiology of the disease. The association between complement activation and the biomarkers of endothelial damage suggests that complement may contribute to tissue injury and could be the target of specific therapy.

COVID-19, the novel coronavirus pandemic, has already spread around the globe affecting more than 18 million people. As previously observed with other coronaviruses, SARS-CoV-2 deeply dysregulate the immune system eliciting respiratory failure and a state of systemic hyperinflammation in severely ill individuals. Immunotherapy is often used to downgrade the detrimental effects of the disease sustained by high-level of cytokines. Those treatments, however, are known to undermine patients’ ability to contain tuberculosis (TB) infection. This study aims to describe interferon-γ release assay (IGRA) results in severe COVID-19 patients eligible for immunosuppressive treatment. Aggregate data were gathered from five hospitals in Milan, Italy, from March 1 to May 15, 2020 and retrospectively analyses. Results were summarized using absolute frequencies and percentages and compared using a two-sided Chi-squared test. Overall, 462 COVID-19 patients were eligible for immunosuppressive therapy, among which 335 were tested using IGRA testing. More than one-third of them (122/335; 36.4%) had an indeterminate IGRA result because of insufficient immune response to mitogen control, 19 (5.7%) tested positive and 194 (57.9) negative. The majority of patients with lymphocytopenia (i.e., total lymphocyte count [TLC] below 1000 cells/mm3) had indeterminate IGRAs (81/155; 52.3%). The proportion becomes even higher in patients with severe lymphocytopenia (i.e., TLC, Highlights • So far, no data on the effect of COVID-19 and anti-IL-1/-6 agents in TB progression. • IGRA indeterminate was associated to severe lymphocytopenia in COVID-19 patients. • Patients with indeterminate IGRA treated with anti-IL-1/-6 were more likely to die. • A monitoring program is needed to avoid late diagnosis and poor outcome of TB.

Early risk stratification for complications and death related to Coronavirus disease 2019 (COVID-19) infection is needed. Because many patients with COVID-19 who developed acute respiratory distress syndrome have diffuse alveolar inflammatory damage associated with microvessel thrombosis, we aimed to investigate a common clinical tool, the CHA(2)DS(2)-VASc, to aid in the prognostication of outcomes for COVID-19 patients. We analyzed consecutive patients from the multicenter observational CORACLE registry, which contains data of patients hospitalized for COVID-19 infection in 4 regions of Italy, according to data-driven tertiles of CHA(2)DS(2)-VASc score. The primary outcomes were inpatient death and a composite of inpatient death or invasive ventilation. Of 1045 patients in the registry, 864 (82.7%) had data available to calculate CHA(2)DS(2)-VASc score and were included in the analysis. Of these, 167 (19.3%) died, 123 (14.2%) received invasive ventilation, and 249 (28.8%) had the composite outcome. Stratification by CHA(2)DS(2)-VASc tertiles (T1: ≤1; T2: 2 to 3; T3: ≥4) revealed increases in both death (8.1%, 24.3%, 33.3%, respectively; p

Background Myocardial injury is frequent among patients hospitalized with coronavirus disease-2019 (COVID-19) and is associated with a poor prognosis. However, the mechanisms of myocardial...

To investigate the association between time to active sitting position and clinical features in people with COVID-19 admitted to intensive care unit (ICU) and referred to physiotherapists.Prospective study conducted in the largest temporary ICU in Lombardy (Italy) between April 2020 and June 2021. All individuals with COVID-19 who received physiotherapy were included. Multivariable Cox proportional hazard model was fitted to explore the statistical association between active sitting position and characteristics of patients referred to physiotherapists, also accounting for the different multidisciplinary teams responsible for patients.284 individuals over 478 (59.4%) had access to physiotherapy, which was performed for a median of 8 days, without difference between multidisciplinary teams (P = 0.446). The active sitting position was reached after a median of 18 (IQR: 10.0-32.0) days. Sex was the only characteristic associated with the time to active sitting position, with males showing a reduced hazard by a factor of 0.65 (95% CI: 0.48-0.87; P = 0.0042) compared to females. At ICU discharge, nearly 50% individuals increased Manchester Mobility Score by 3 points. During physiotherapy no major adverse event was recorded.Individuals with COVID-19 take long time to reach active sitting position in ICU, with males requiring longer rehabilitation than females.

Graphical abstract, PhotoAcoustic Imaging (PAI) is a biomedical imaging modality currently under evaluation in preclinical and clinical settings. In this work, ICG is coupled to an integrin binding vector (ICG-RGD) to combine the good photoacoustic properties of ICG and the favourable αvβ3-binding capabilities of a small RGD cyclic peptidomimetic. ICG-RGD is characterized in terms of physicochemical properties, biodistribution and imaging performance. Tumor uptake was assessed in subcutaneous xenograft mouse models of human glioblastoma (U-87MG, high αvβ3 expression) and epidermoid carcinoma (A431, low αvβ3 expression). ICG and ICG-RGD showed high PA signal in tumors already after 15 min post-injection. At later time points the signal of ICG rapidly decreased, while ICG-RGD showed sustained uptake in U-87MG but not in A431 tumors, likely due to the integrin-mediated retention of the probe. In conclusion, ICG-RGD is a novel targeted contrast agents for PAI with superior biodistribution, tumor uptake properties and diagnostic value compared to ICG.

A high treatment burden with nebulised therapies in cystic fibrosis (CF) patients is the major limitation for treatment compliance; moreover, studies on treatment compliance with inhaled antibiotics are limited. This study assessed compliance to TOBIThis longitudinal, multicentre, cohort study included 2 follow-up (FU) visits: FU-1 at 3-months±15-days from the baseline visit and FU-2 at the end of third TIP cycle (or 6-months after enrolment, whichever occurred first). The effect of TIP on quality-of-life (QoL) and treatment satisfaction were evaluated using Cystic Fibrosis Questionnaire-Revised (CFQ-R) and Treatment Satisfaction Questionnaire for Medication (TSQM), respectively. Overall compliance to treatments was assessed using ITA-CFq.Eighty-two patients (mean age, 24.8 ± 7.9 years), including 22 paediatric patients (age,18 years), were enrolled in the study; 56 (68.3%) patients, including 17 paediatric patients, completed the study. At baseline, the mean compliance score to aerosol antibiotic treatment was 7.8 ± 3.2; upon introducing TIP, the compliance score improved to 9.4 ± 1.2 at the FU-1 and thereafter remained stable at 9.5 ± 1.2. TSQM was higher for the convenience domain (74.2 ± 17.1 at enrolment and slightly improved to 77.8 ± 15.9 at FU-2) following TIP initiation. No substantial effect of TIP was observed on the QoL when measured using the revised CFQ-R. The safety profile was in line with previous findings.TIP was convenient to use and led to improved treatment adherence in CF patients with chronic Pa-infection.

International experts suggest tailoring antibiotic duration in community-acquired pneumonia (CAP) according to patients' characteristics. We aimed to assess the effectiveness of an individualized approach to antibiotic duration based on time in which CAP patients reach clinical stability during hospitalization. In a multicenter, non-inferiority, randomized, controlled trial hospitalized adult patients with CAP reaching clinical stability within 5 days after hospitalization were randomized to a standard vs. individualized antibiotic duration. In the Individualized group, antibiotics were discontinued 48 h after the patient reached clinical stability, with at least five days of total antibiotic treatment. Early failure within 30 days was the primary composite outcome. 135 patients were randomized to the Standard group and 125 to the Individualized group. The trial was interrupted by the safety committee because of an apparent inferiority of the Individualized group over the Standard treatment: 14 (11.2%) patients in the Individualized group experienced early failure vs. 10 (7.4%) patients in the Standard group, p = 0.200, at the intention-to-treat analysis. 30-day mortality rate was four-time higher in the Individualized group than the Standard group. Shortening antibiotic duration according to patients' characteristics still remains an open question.

Purpose We hereby report our real-life experience with extracorporeal photopheresis (ECP) for CLAD. Methods This was an observational retrospective study on LuTx adult patients who received a diagnosis of chronic lung allograft dysfunction (CLAD) from January 2008 to December 2018. They were referred to an ECP Service on a regional basis. Both automated closed and open loop devices were used. Results Over the period considered, 42 patients were diagnosed with CLAD, 10 (24%) restrictive allograft syndrome (RAS) and 32 BOS. Of those 42, 6 individuals were considered ineligible to initiate ECP due to their excessively compromised conditions; they all died soon after (less than 6 months). The rest (36 patients) were scheduled to receive ECP treatments. Median time from CLAD diagnosis to ECP initiation was 2 (1; 4) months. Median rate of FEV1 decline in the first 6 months was -13 mL/month; however, 11 (31%) did not respond (FEV1 decreased > 10% from ECP initiation). 14 (38%) patients were hospitalized at least once for respiratory infection. The majority of treated patients (21, 58%) reported a good quality of life and worked or were fit to work. 6 patients died, 5 of CLAD-related death. 3 individuals received a re-transplant, and 2 continued with ECP even afterwards. Given also that the majority of patients at our centre are affected by cystic fibrosis (24, 58% of this cohort), one of the major problems with performing ECP was represented by the lack of good vascular access; 4 patients needed a long term catheter insertion. In one of these patients early termination of treatment was decided after a sepsis due to S. epidermidis starting from her Tesio access. No other significant adverse event occurred. No difference was observed between closed and open loop devices. Conclusion Our data seem to further support the efficacy and safety of ECP to treat CLAD, not only in terms of pulmonary function but also of survival and quality of life. Vascular access related problems were the major issue. Several limits to be acknowledged: retrospective nature, single centre, no control group.

Background: Bronchiectasis is predominantly a neutrophilic inflammatory disease. There are no established therapies that directly target neutrophilic inflammation because of a lack of understanding of the underlying mechanisms leading to severe disease. Neutrophil extracellular trap (NET) formation is a mode of host defence that has been implicated in multiple inflammatory diseases. Methods: We conducted a series of UK and international studies to investigate the role of NETs in disease severity and treatment response in bronchiectasis. Nano LC/MS-MS was used to identify proteomic markers associated with disease severity, defined using the bronchiectasis severity index (BSI) (n=40). These were validated in two cohorts (n=175 and n=275) using a validated immunoassay to measure NETs. 20 patients with acute exacerbations of bronchiectasis were treated with intravenous antibiotics for 14 days and proteomics used to identify proteins associated with treatment response. Two studies of long-term macrolide treatment, one in bronchiectasis and a post-hoc analysis of the AMAZES trial in asthma, investigated the effect of macrolide treatment on NETs. Findings: 96 proteins were differentially expressed in sputum between severe and mild bronchiectasis. The most abundant and most discriminating were proteins known to be NET proteins. This was validated in two observational cohorts where sputum NETs were associated with BSI, quality of life, lung function, future risk of hospital admissions and mortality. Antibiotic treatment in 20 patients was associated with 23 significantly down-regulated and 16 up-regulated proteins, with the “neutrophil degranulation” pathway being most strongly implicated in response. Patients with Pseudomonas aeruginosa infection had a blunted proteomic and clinical response to treatment. Treatment with low dose azithromycin was associated with a significant reduction in NETs in sputum over 12 months in both bronchiectasis and asthma. Interpretation: NETs are identified as a key marker of disease severity and treatment response in bronchiectasis. Funding: Supported by the Scottish Government Chief Scientist Office (Senior Clinical Fellowship to JDC) and British Lung Foundation through the BLF Chair of Respiratory Research. Supported by the European Bronchiectasis Network (EMBARC), a European Respiratory Society Clinical Research Collaboration. Declaration of Interests: None to declare Ethics Approval Statement: The studies were approved by local research ethics committees and patients provided informed consent.

Purpose The outcome of lung transplantion (LuTx) suffers from a high rejection rate, and there are still huge gaps of knowledge about immune-mediated rejection mechanisms. Acute rejection (AR) can lead to chronic lung allograft dysfunction (CLAD), the main cause of poor survival and low quality of life. The standardized morphologic evaluation of rejection is based on histopathologic diagnostic criteria at a given time-point, but it has a limited prognostic value towards clinical outcome and the likelihood to develop CLAD. We analyzed immune-check point proteins in lung tissues of patients who received a LuTx and who were or were not undergoing rejection in the attempt to define novel immunological markers that could predict rejection. Methods We conducted an observational retrospective study on eight consecutive explanted grafts for chronic rejection and on transbronchial cryobiopsies (TCB) obtained from 24 consecutive patients during the first year LuTx follow-up. A broad spectrum of immunohistochemical analysis was carried out (PD1/CD279, PDL1/CD274, CTLA4/CD152, CD4, CD8, hFoxp3, TIGIT, TOX, B-Cell-Specific Activator Protein). Of those TCB-patients we recorded at least 1 year follow up of survival, infections and rejections (acute and chronic) rate. Results Exhausted (PD1+/TOX+) as well as Treg (PD1+/FOXP3+) lymphocytes were significantly reduced in restrictive allograft syndrome (RAS)-compared to bronchiolitis-obliterans-syndrome (BOS)-rejected lungs. PD1-expressing T-lymphocytes in TCBs correlated (sensitivity 0.69; specificity 1) with the presence of AR and were highly suggestive of CLAD development (sensitivity 0.86; specificity 0.82; overall 10 times higher risk of developing CLAD) at one-year follow-up. Conclusion Results herein for the first time show the importance of immunological checkpoints in the setting of LuTx rejection and indicate that the evaluation of the expression of such proteins could offer a distinct prognostic advantage in monitoring the onset of AR in patients who underwent LuTx. Longitudinal analyses in ampler cohorts will be needed to confirm these data.

The disease burden due to nontuberculous mycobacteria is growing worldwide, consequently to improved diagnostic abilities and an increase in the individuals at risk. Uncertainties exist about the right moment on which start treatment. We investigated the clinical features associated with starting an antimicrobial treatment in patients with nontuberculous mycobacterial lung disease among Italian physicians involved in the field. We found that in real life predictors of starting antimicrobial treatment are quite adherent to international guidelines, with some uncertainties regarding the implication of immunosuppressive drugs.

Pneumococcal pneumonia remains a clear unmet medical need for adults worldwide. Despite advances in vaccine technology, vaccination coverage remains low, putting many people at risk of significant morbidity and mortality. The herd effect seen with paediatric vaccination is not enough to protect all older and vulnerable people in the community, and more needs to be done to increase the uptake of pneumococcal vaccination in adults. Several key groups are at increased risk of contracting pneumococcal pneumonia, and eligible patients are being missed in clinical practice. At present, community-acquired pneumonia costs over €10 billion annually in Europe alone. Pneumococcal conjugate vaccination could translate into preventing 200,000 cases of community-acquired pneumonia every year in Europe alone. This group calls on governments and decision makers to implement consistent age-based vaccination strategies, and for healthcare professionals in daily clinical practice to identify eligible patients who would benefit from vaccination strategies.

Liver plays a key role in controlling body carbohydrate homeostasis by switching between accumulation and production of glucose and this way maintaining constant level of glucose in blood. Increased blood glucose level triggers release of insulin from pancreatic β-cells. Insulin represses hepatic glucose production and increases glucose accumulation. Insulin resistance is the main cause of type 2 diabetes and hyperglycemia. Currently thiazolidinediones (TZDs) targeting transcriptional factor PPARγ are used as insulin sensitizers for treating patients with type 2 diabetes. However, TZDs are reported to be associated with cardiovascular and liver problems and stimulate obesity. Thus, it is necessary to search new approaches to improve insulin sensitivity. A promising candidate is transcriptional factor Prep1, as it was shown earlier it could affect insulin sensitivity in variety of insulin-sensitive tissues. The aim of the present study was to evaluate a possible involvement of transcriptional factor Prep1 in control of hepatic glucose accumulation and production. We created mice with liver-specific Prep1 knockout and discovered that hepatocytes derived from these mice are much more sensitive to insulin, comparing to their WT littermates. Incubation of these cells with 100 nM insulin results in almost complete inhibition of gluconeogenesis, while in WT cells this repression is only partial. However, Prep1 doesn't affect gluconeogenesis in the absence of insulin. Also, we observed that nuclear content of gluconeogenic transcription factor FOXO1 was greatly reduced in Prep1 knockout hepatocytes. These findings suggest that Prep1 may control hepatic insulin sensitivity by targeting FOXO1 nuclear stability.

Orally inhaled agents are a key therapeutic class for treatment of asthma. Inhaled corticosteroids (ICS) are the most effective anti-inflammatory treatment for asthma thus representing the first-line therapy and bronchodilators complement the effects of ICSs. A significant body of evidence indicates that addition of a β2-agonist to ICS therapy is more effective than increasing the dose of ICS monotherapy. In this paper, pharmacological features of available ICSs and bronchodilators will be reviewed with a focus on fluticasone propionate/formoterol fumarate combination which represents the one of the most powerful ICS acting together with the most rapid active LABA.

Traditionally, nasal oxygen therapy has been delivered at low flows through nasal cannulae. In recent years, nasal cannulae designed to administer heated and humidified air/oxygen mixtures at high flows (up to 60 L/min) have been gaining popularity. These high-flow nasal cannula (HFNC) systems enhance patient comfort and tolerance compared with traditional high-flow oxygenation systems, such as nasal masks and nonrebreathing systems. By delivering higher flow rates, HFNC systems are less apt than traditional oxygenation systems to permit entrainment of room air during patient inspiration. Combined with the flushing of expired air from the upper airway during expiration, these mechanisms assure more reliable delivery of high Fio2 levels. The flushing of upper airway dead space also improves ventilatory efficiency and reduces the work of breathing. HFNC also generates a positive end-expiratory pressure (PEEP), which may counterbalance auto-PEEP, further reducing ventilator work; improve oxygenation; and provide back pressure to enhance airway patency during expiration, permitting more complete emptying. HFNC has been tried for multiple indications, including secretion retention, hypoxemic respiratory failure, and cardiogenic pulmonary edema, to counterbalance auto-PEEP in patients with COPD and as prophylactic therapy or treatment of respiratory failure postsurgery and postextubation. As of yet, very few high-quality studies have been published evaluating these indications, so recommendations regarding clinical applications of HFNC remain tentative.

Pneumococcal infections, including pneumonia and invasive disease, are major sources of morbidity and mortality worldwide. Prevention of the first acquisition of Streptococcus pneumoniae through the use of vaccines represents an effective method to reduce the burden of the disease in both children and adults. Two vaccines are currently available in adults: a pneumococcal polysaccharide vaccine (PPV23) that includes 23 purified capsular polysaccharide antigens and a pneumococcal protein-conjugate vaccine (PCV13) that includes capsular polysaccharide antigens covalently linked to a non-toxic protein. The PPV23 induces a humoral immune response and since it has been licensed has been the subject of debates and controversies. Numerous studies and meta-analyses have shown that PPV23 protects against invasive pneumococcal disease, although there are conflicting data regarding its efficacy for the prevention of pneumonia. Vaccination with PCV13 stimulates good antibody responses as well as mucosal immunity and suppresses colonization. A conjugate vaccine can be expected to have benefits over a polysaccharide vaccine because of the characteristics of a T-cell-dependent response in terms of affinity, maturation of antibodies with repeated exposure, induction of immunological memory and long-lasting immunity. PCV13 has demonstrated all of these characteristics in children and fundamental differences in adults are not expected. The efficacy in adults is currently being investigated and results will be available soon.

Methicillin-resistant Staphylococcus aureus (MRSA) is an important cause of antimicrobial-resistant hospital-acquired infections worldwide and remains a public health priority in Europe. Nosocomial pneumonia (NP) involving MRSA often affects patients in intensive care units with substantial morbidity, mortality and associated costs. A guideline-based approach to empirical treatment with an antibacterial agent active against MRSA can improve the outcome of patients with MRSA NP, including those with ventilator-associated pneumonia. New methods may allow more rapid or sensitive diagnosis of NP or microbiological confirmation in patients with MRSA NP, allowing early de-escalation of treatment once the pathogen is known. In Europe, available antibacterial agents for the treatment of MRSA NP include the glycopeptides (vancomycin and teicoplanin) and linezolid (available as an intravenous or oral treatment). Vancomycin has remained a standard of care in many European hospitals; however, there is evidence that it may be a suboptimal therapeutic option in critically ill patients with NP because of concerns about its limited intrapulmonary penetration, increased nephrotoxicity with higher doses, as well as the emergence of resistant strains that may result in increased clinical failure. Linezolid has demonstrated high penetration into the epithelial lining fluid of patients with ventilator-associated pneumonia and shown statistically superior clinical efficacy versus vancomycin in the treatment of MRSA NP in a phase IV, randomized, controlled study. This review focuses on the disease burden and clinical management of MRSA NP, and the use of linezolid after more than 10 years of clinical experience.

Funding: This article is based on the content of a presentation by R.F. Grossman entitled ‘‘Fluoroquinolones: a role in CAP and TB’’, part of the CME symposium entitled ‘‘Fluoroquinolones: CAP, TB and the importance of differential diagnosis’’ at the 15 th International Congress on Infectious Diseases (ICID), Bangkok, Thailand, June 13–16, 2012, which was sponsored by Bayer HealthCare (Germany). The respiratory fluoroquinolones moxifloxacin, gemifloxacin, and high-dose levofloxacin are recommended in guidelines for effective empirical antimicrobial therapy of community-acquired pneumonia (CAP). The use of these antibiotics for this indication in areas with a high prevalence of tuberculosis (TB) has been questioned due to the perception that they contribute both to delays in the diagnosis of pulmonary TB and to the emergence of fluoroquinolone-resistant strains of Mycobacterium tuberculosis. In this review, we consider some of the important questions regarding the potential use of fluoroquinolones for the treatment of CAP where the burden of TB is high. The evidence suggests that the use of fluoroquinolones as recommended for 5-10 days as empirical treatment for CAP, according to current clinical management guidelines, is appropriate even in TB-endemic regions. It is critical to quickly exclude M. tuberculosis as a cause of CAP using the most rapid relevant diagnostic investigations in the management of all patients with CAP. Publisher PDF

Summary Background The effect of time of the first antimicrobial dose (TFAD) on the outcomes of community-acquired pneumonia (CAP) remains a controversy. Methods This was an observational, retrospective study of consecutive adult patients hospitalized with CAP. TFAD was defined as the time in hours from arrival at the emergency department to the intravenous infusion of antimicrobial. All patients received appropriate antibiotic therapy according to available Infectious Diseases Society of America/American Thoracic Society guidelines during the time of our study. Multivariable analysis and a propensity score adjusted methodology were used to measure the association of TFAD with mortality, time to clinical stability (TCS), and length of stay in the hospital (LOS). Results Data of 372 patients with CAP were studied. A total 29 (8.4%) patients died within 30 days of hospitalization. Our propensity-adjusted logistic regression model did not show a significant association between TFAD and mortality ( p =0.148). Patients who died received antimicrobials significantly earlier than survivors: 5.7h vs. 7.5h, respectively ( p =0.04). The LOS and TCS were not significantly affected by the TFAD; the LOS hazard ratio was 0.996 (95% confidence interval 0.97–1.02; p =0.774) and the TCS hazard ratio was 1.01 (95% confidence interval 0.98–1.03; p =0.604). Conclusions TFAD does not seem to be associated with the clinical outcome of patients with CAP. Early TFAD should be considered as an important marker of optimal care of patients with CAP rather than as a factor predicting outcomes.

SummaryInflammation is a double-edged sword in the outcome of pneumonia. On the one hand, an effective and timely inflammatory response is required to eliminate the invading respiratory pathogen. On the other, a toxic and prolonged inflammatory response may result in lung injury and poor outcomes, even in those receiving advanced medical care. This review focuses on recent understanding of the dynamics of the cytokine response, neutrophil activity, and responsiveness to cytokines and neutrophil lifespan as major elements of lung inflammation resulting in favorable or poor outcomes in lung infection primarily due to pneumococcus and influenza virus. Although some progress has been made in our understanding of the molecular mechanisms of the pneumonia inflammation axis composed of cytokines modulating neutrophil activation and neutrophil apoptosis, important questions remain to be answered. The degree of neutrophil activation, generation of reactive oxygen species, and the release of granule antimicrobial peptides play a key role in microbial pathogen clearance; however, prolonged neutrophil activation may contribute to lung injury and poor outcomes in pneumonia. Molecular markers of the mechanisms regulating neutrophil survival and apoptosis may help in the identification of novel therapeutic targets to modulate inflammation by inducing timely neutrophil apoptosis. A major task is to identify the mechanisms of dysregulation in inflammation leading to toxic responses, thereby targeting a biomarker and enabling timely therapies to modulate inflammation.

Clin Microbiol Infect 2012; 18 (Suppl. 5) 37-41 ABSTRACT: Population protection through vaccination against infectious diseases has been one of the major achievements of public health care. The recent H1N1 influenza virus pandemic reopened the discussion on the strategic arrangements for vaccination in the face of spreading infection. Even though vaccination against a pandemic strain is considered to be one of the most effective countermeasures for protecting individuals, the general acceptance of H1N1 influenza vaccination has been low worldwide. The understanding of the potential health risks of the novel influenza A (H1N1) strain, the distrust of vaccinations and concerns about vaccine safety are the main reasons reported by the public for not undergoing vaccination. Concern about vaccine safety and distrust of health authorities are the commonest reasons given for low compliance with vaccination by healthcare workers. Better communication strategies to improve vaccination acceptance by the general population and by healthcare workers are required