Bronchial thermoplasty in severe asthma: a real-world study on efficacy and gene profiling.

BACKGROUND: Bronchial thermoplasty (BT) is an effective treatment in severe asthma. How to select patients who more likely benefit from BT is an unmet clinical need. Moreover, mechanisms of BT efficacy are still largely unknown. We sought to determine BT efficacy and to identify potential mechanisms of response. METHODS: This retrospective cohort study evaluated clinical outcomes in 27 patients with severe asthma: 13 with T2-high and 14 with T2-low endotype. Expression levels of 20 genes were compared by real-time PCR in bronchial biopsies performed at the third BT session versus baseline. Clinical response was measured based on Asthma Control Questionnaire (ACQ) score < 1.5, asthma exacerbations < 2, oral corticosteroids reduction of at least 50% at 12 months post-BT. Patients were classified as responders when they had at least 2 of 3 outcome measures. RESULTS: 81% of patients were defined as responders. BT induced a reduction in alpha smooth muscle actin (ACTA2) and an increase in CD68, fibroblast activation protein-alpha (FAP), alpha-1 and alpha-2 type I collagen (COL1A1, COL1A2) gene expression in the majority of patients. A higher reduction in ubiquitin carboxy-terminal-hydrolase L1 (PGP9.5) mRNA correlated with a better response based on Asthma Quality of Life Questionnaire (AQLQ). Lower changes in CD68 and FAP mRNAs correlated with a better response based on ACQ. Lower levels of occludin (OCLN), CD68, connective tissue growth factor (CTGF), higher levels of secretory leukocyte protease inhibitor (SLPI) and lower changes in CD68 and CTGF mRNAs were observed in patients who had less than 2 exacerbations post-BT. Lower levels of COL1A2 at baseline were observed in patients who had ACQ < 1.5 at 12 months post-BT. CONCLUSIONS: BT is effective irrespective of the asthma endotypes and seems associated with airway remodelling. Quantification of OCLN, CD68, CTGF, SLPI, COL1A2 mRNAs could be useful to identify patients with better results. TRIAL REGISTRATION: The study protocol was approved by the Local Ethics Committee (Azienda USL-IRCCS of Reggio Emilia-Comitato Etico Area Vasta Nord of Emilia Romagna; protocol number: 2019/0014076) and all the patients provided written informed consent before participating in the study.

Inflammatory burden and persistent CT lung abnormalities in COVID-19 patients.

Inflammatory burden is associated with COVID-19 severity and outcomes. Residual computed tomography (CT) lung abnormalities have been reported after COVID-19. The aim was to evaluate the association between inflammatory burden during COVID-19 and residual lung CT abnormalities collected on follow-up CT scans performed 2-3 and 6-7 months after COVID-19, in severe COVID-19 pneumonia survivors. C-reactive protein (CRP) curves describing inflammatory burden during the clinical course were built, and CRP peaks, velocities of increase, and integrals were calculated. Other putative determinants were age, sex, mechanical ventilation, lowest PaO2/FiO2 ratio, D-dimer peak, and length of hospital stay (LOS). Of the 259 included patients (median age 65 years; 30.5% females), 202 (78%) and 100 (38.6%) had residual, predominantly non-fibrotic, abnormalities at 2-3 and 6-7 months, respectively. In age- and sex-adjusted models, best CRP predictors for residual abnormalities were CRP peak (odds ratio [OR] for one standard deviation [SD] increase = 1.79; 95% confidence interval [CI] = 1.23-2.62) at 2-3 months and CRP integral (OR for one SD increase = 2.24; 95%CI = 1.53-3.28) at 6-7 months. Hence, inflammation is associated with short- and medium-term lung damage in COVID-19. Other severity measures, including mechanical ventilation and LOS, but not D-dimer, were mediators of the relationship between CRP and residual abnormalities.

Predictive factors of clinical outcomes in patients with COVID-19 treated with tocilizumab: A monocentric retrospective analysis.

OBJECTIVE: The aim of this retrospective observational study is to analyse clinical, serological and radiological predictors of outcome in patients with COVID-19 pneumonia treated with tocilizumab, providing clinical guidance to its use in real-life. METHOD: This is a retrospective, monocentric observational cohort study. All consecutive patients hospitalized between February the 11th and April 14th 2020 for severe COVID-19 pneumonia at Reggio Emilia AUSL and treated with tocilizumab were enrolled. The patient's clinical status was recorded every day using the WHO ordinal scale for clinical improvement. Response to treatment was defined as an improvement of one point (from the status at the beginning of tocilizumab treatment) during the follow-up on this scale. Bivariate association of main patients' characteristics with outcomes was explored by descriptive statistics and Fisher or Kruskal Wallis tests (respectively for qualitative or quantitative variables). Each clinically significant predictor was checked by a loglikelihood ratio test (in univariate logistic models for each of the considered outcomes) against the null model. RESULTS: A total of 173 patients were included. Only hypertension, the use of angiotensin-converting enzyme inhibitors, PaO2/FiO2, respiratory rate and C-reactive protein were selected for the multivariate analysis. In the multivariable model, none of them was significantly associated with response. CONCLUSIONS: Evaluating a large number of clinical variables, our study did not find new predictors of outcome in COVID19 patients treated with tocilizumab. Further studies are needed to investigate the use of tocilizumab in COVID-19 and to better identify clinical phenotypes which could benefit from this treatment.

Efficacy and safety of EBUS-TBNA under conscious sedation with meperidine and midazolam.

BACKGROUND: According to the guidelines, endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) is the technique of choice for the diagnosis of mediastinal involvement in lung cancer; it is also useful for other mediastinal malignancies and benign pathology. Nevertheless, there is still discussion about whether to perform it under general anesthesia or under conscious sedation. METHODS: We retrospectively analyzed the data of all patients who underwent EBUS-TBNA under conscious sedation with up to 1 mg/kg of meperidine and up to 0.15 mg/kg of midazolam in the Interventional Pulmonology Unit of the Azienda USL-IRCCS Santa Maria Nuova of Reggio Emilia during 2 consecutive years. Demographic data, indication for the procedure, duration, number of lymph node sampled, number of passes per station, diagnostic yield, drugs dosage, questionnaire score, and complications were collected. RESULTS: A total of 302 patients underwent EBUS-TBNA, and 68% of the patients were males and the mean age was 65 ± 13 years old. The average duration of procedures was 24.4 minutes and the mean dosage of drugs was 4.32 ± 1.52 mg for midazolam and 50.86 ± 13.71 mg for meperidine. The mean number of lymph nodes sampled per patient was 1.75 ± 0.82, and each patient received an average of 4.71 ± 1.78 passes. A total of 90.7% of patients completed the procedures, 85% had adequate samples, and 94.4% of patients declared with Likert's questionnaire that they strongly agree to repeat the test if necessary. CONCLUSION: EBUS-TBNA performed under conscious sedation with meperidine and midazolam is feasible and well-tolerated and has a similar diagnostic yield of that reported in literature.

Real world effectiveness of benralizumab on respiratory function and asthma control.

BACKGROUND: Biological drugs have been recognized as a breakthrough in the treatment of severe refractory asthma. This retrospective real-life observational study aims to evaluate the effect of add-on benralizumab on lung function, exacerbation rate, oral corticosteroids (OCS) reduction and asthma control questionnaire (ACQ) score after 52-weeks. METHODS: In this observational study, a cohort of 18 patients with severe eosinophilic asthma (SEA) according to the ERS / ATS and GINA 2020 classifications, with reference to the Pulmonology Unit of the Azienda USL - IRCCS, Reggio Emilia, Italy, were enrolled from 1 September 2019 to 31 August 2020. For each patient, the following data were collected: demographic data (age, sex, age of onset of asthma, history of smoking and atopy); comorbidity; clinical data (lung function, exacerbations, emergency room visits and hospitalizations); asthma control questionnaire (ACQ); biomarkers (blood eosinophil count and total serum IgE); asthma control drugs as high-dose inhaled corticosteroids / long-acting beta-adrenoceptor agonists (ICS / LABA), long-acting muscarinic antagonists (LAMA), leukotriene receptor antagonists (LTRA), theophylline, OCS. The benralizumab 30 mg treatment schedule was based on the currently recommended dosing regimen. RESULTS: After end-of-treatment (EOT), a complete weaning of all patients from OCS was confirmed. After 26 weeks, the number of exacerbations decreased from 2.90 to 0.05 (p<0.0001), hospitalizations and ACQ score decreased from 3.37 to 0.97 (p<0.0001). At EOT, the number of exacerbations was unchanged, while no hospitalizations had occurred. Overall, lung function markedly improved over the study period. After 52 weeks, the increase in FEV1 from baseline was 26,8% (p=0.0002). The subset of patients with nasal polyposis (NP) had an increase of nearly 50% (1008 ml) and patients with blood eosinophils count (BEC) greater than 500 cells / µl showed an increase of 68% (1081 ml) in FEV1 at EOT. CONCLUSIONS: The notable improvement in respiratory function is a significant result in this study and it is much higher than what has emerged to date. This result, together with the OCS sparing effect and the excellent clinical control of asthma, makes benralizumab a reliable and safe therapeutic option for SEA.

The role of systemic corticosteroids in severe asthma and new evidence in their management and tapering.

INTRODUCTION: Based on the latest literature evidence, between 30% and 60% of adults with severe refractory asthma (SRA) are systemic corticosteroid (SCS) dependent. There are numerous therapeutic options in asthma, which are often not effective in severe forms. In these cases, SCS should be considered, but it is increasingly recognized that their regular use is often associated with significant and potentially serious adverse events. AREAS COVERED: The aim of this article is to provide an update about the recent and significant literature on SCS and to establish their role in the management of SRA. We summarized the most important and recent evidence and we provided useful indications for clinicians. EXPERT OPINION: There is now strong evidence supporting the increased risk of comorbidities and complications with long-term SCS therapies, regardless of the dose. New evidence on SCS tapering and withdrawal will allow to define protocols to address SCS management with greater safety and effectiveness, after starting efficient steroid-sparing strategies. In the next 5years, it will be necessary to implement corrective actions to address these unmet needs, to reduce the inappropriate use of SCS by maximizing the application of more innovative and effective therapies.

The pharmacoeconomics of the state-of-the-art drug treatments for asthma: a systematic review.

Asthma is a chronic disease characterized by significant morbidities and mortality, with a large impact on socio-economic resources and a considerable burden on health-care systems. In the standard care of asthma, inhaled corticosteroids (ICS) associated with long-acting ß-adrenoceptor agonists (LABA) are a reliable and often cost-effective choice, especially if based on the single inhaler therapy (SIT) strategy; however, in a subset of patients it is not possible to reach an adequate asthma control. In these cases, it is possible to resort to other pharmacologic options, including corticosteroids (OCS) or biologics. Unfortunately, OCS are associated with important side effects, whilst monoclonal antibodies (mAbs) allow excellent results, even if far more expensive. Up to now, the economic impact of asthma has not been compared with equivalent indicators in several studies. In fact, a significant heterogeneity of the cost analysis is evident in literature, for which the assessment of the real cost-effectiveness of asthma therapies is remarkably complex. To maximize the cost-effectiveness of asthma strategies, especially of biologics, attention must be paid on phenotyping and identification of predictors of response. Several studies were included, involving comparative analysis of drug treatments for asthma, comparative analysis of the costs and consequences of therapies, measurement and evaluation of direct drug costs, and the reduction of health service use. The initial research identified 389 articles, classified by titles and abstracts. A total of 311 articles were excluded as irrelevant and 78 articles were selected. Pharmacoeconomic studies on asthma therapies often report conflicting data also due to heterogeneous indicators and different populations examined. A careful evaluation of the existing literature is extremely important, because the scenario is remarkably complex, with an attempt to homogenize and interpret available data. Based on these studies, the improvement of prescriptive appropriateness and the reduction of the use of healthcare resources thanks to controller medications and to innovative therapies such as biologics partially reduce the economic burden of these treatments. A multidisciplinary stakeholder approach can also be extremely helpful in deciding between the available options and thus optimizing healthcare resources.

A Real-World Evaluation of Clinical Outcomes of Biologicals and Bronchial Thermoplasty for Severe Refractory Asthma (BIOTERM).

BACKGROUND: The important progress made on asthma phenotyping encouraged the development of new therapeutic strategies, such as monoclonal antibodies (mAbs) and bronchial thermoplasty (BT). The aim of this study is to compare patients diagnosed with severe refractory asthma (SRA) who are currently being treated with omalizumab, mepolizumab, benralizumab or BT and to evaluate the efficacy of these treatments over a 12-month observation period. METHODS: Overall, 199 consecutive patients with SRA were included. The cohort was selected referring to the eligibility criteria for all available biologics and BT. RESULTS: Among 32 patients treated with benralizumab, we found a 16.7% reduction in hospitalizations, a 66.6% reduction in exacerbations (p = 0.0001) and the greater improvement in FEV1 (+ 37.4%, p < 0.0001). Among omalizumab group (54 patients), there was a 85.7% (p = 0.012) reduction in hospitalizations and a 88.8% (p < 0.0001) reduction in exacerbations. In the mepolizumab group (83 patients), we found a 89.5% (p = 0.02) reduction in hospitalizations and a 92.1% (p < 0.0001) reduction in exacerbations. BT subgroup (30 patients) showed a 93.7% (p = 0.001) reduction in hospitalizations and a 73.5% (p < 0.0001) reduction in exacerbations. The best results in terms of OCS sparing effect were obtained by BT (- 76%, p < 0.0001) and mepolizumab (- 90.2%, p = 0.002). Omalizumab showed the highest percentage of super responder patients. CONCLUSION: To our knowledge, this is the first study to compare all marketed mAbs with BT, ending in more comprehensive and applicable results to clinical practice. All biologics, to varying degrees, reduced hospitalizations, exacerbations, and OCS use. The starting point for patients in the BT group was worse regarding hospitalizations, exacerbations and OCS, but despite this, even this non-pharmacological option obtained positive results, comparable to biologics.

Successful treatment with benralizumab in a patient with eosinophilic granulomatosis with polyangiitis refractory to mepolizumab.

INTRODUCTION: Eosinophilic granulomatosis with polyangiitis (EGPA) is characterized by necrotizing eosinophilic granulomatous inflammation that frequently involves the respiratory tract (90% of cases). Asthma in EGPA is systematically severe and often refractory to common treatment, it is corticosteroid resistant and can often anticipate the onset of systemic vasculitis by many years. A release of cytokines necessary for the activation, maturation and survival of eosinophils, such as IL-4, IL-5 and IL-13 occurs in the activated Th-2 phenotype. In particular, IL-5 level is high in active EGPA and its inhibition has become a key therapeutic target. Oral glucocorticoids (OCS) are effective treatment options but unfortunately, frequent relapses occur in many patients and they lead to frequent side effects. As for now, there are currently no official recommendations on doses and treatment schedules in the management of EGPA. CASE PRESENTATION: In this article, we describe the case of a man with EGPA, severe asthma and chronic rhinosinusitis with nasal polyps (CRSwNP), with poor asthma and CRSwNP control despite OCS and mepolizumab treatment. Respiratory and vasculitis symptoms improved markedly after therapeutic switch to benralizumab. During the treatment, in addition to clinical effects, we witnessed a depletion of blood eosinophils, as well as an improvement in both pulmonary function tests, CT scan and skin lesions present initially. CONCLUSIONS: While there are many studies confirming the efficacy of benralizumab in EGPA, the most interesting aspect of our report is that efficacy was confirmed in a patient previously unresponsive to mepolizumab, known to be effective in EGPA.

Interventional pulmonology during COVID-19 pandemic: current evidence and future perspectives.

COVID-19, caused by SARS-CoV-2 infection, has become increasingly prevalent worldwide, reaching a pandemic stage in March 2020. The organization of health care services had to change because of this new disease, with the need to reallocate staff and materials, besides changing management protocols. A very important challenge is not to expose patients and health care workers to the risk of infection and not to waste personal protective equipment (PPE). In the field of interventional pulmonology, various aspects related to COVID-19 must be taken into great consideration. Although bronchoscopy is not a first-line test for patients with suspected SARS-CoV-2 infection, it has a role in selected cases and it can be useful for differential diagnosis. However, bronchoscopy is an aerosol-generating procedure, that's why its unjustified use could contribute to propagate the virus. For this reason, the utility of each procedure must be carefully evaluated, the patient has to be properly investigated before the procedure, which has to be performed with specific precautions, including adequate PPE. In this review, we summarize the knowledge and the principal statements about endoscopic activity in COVID-19 period, in both diagnosis of COVID-19 and management of patients. How to safely perform both bronchoscopic and pleural-related procedures (thoracoscopy, pleural biopsy and drainage of pleural effusions) is described with the aim to help the staff to decide when and how performing a procedure. We also highlight how interventional pulmonology could help in matter of complications related to COVID-19.

Pneumonia and Invasive Pneumococcal Diseases: The Role of Pneumococcal Conjugate Vaccine in the Era of Multi-Drug Resistance.

Streptococcus pneumoniae related diseases are a leading cause of morbidity and mortality, especially in children and in the elderly population. It is transmitted to other individuals through droplets and it can spread to other parts of the human host, causing a wide spectrum of clinical syndromes, affecting between 10 and 100 cases per 100,000 people in Europe and the USA. In order to reduce morbidity and mortality caused by this agent, pneumococcal vaccines have been developed over the years and have shown incredible effectiveness in reducing the spread of this bacterium and the development of related diseases, obtaining a significant reduction in mortality, especially in developing countries. However, considerable problems are emerging mainly due to the replacement phenomenon, multi-drug resistance, and the high production costs of conjugated vaccines. There is still a debate about the indications given by various countries to different age groups; this is one of the reasons for the diffusion of different serotypes. To cope with these problems, significant efforts have been made in the research field to further improve vaccination serotypes coverage. On the other hand, an equally important commitment by health care systems to all age group populations is needed to improve vaccination coverage.

Immunological Aspects Related to Viral Infections in Severe Asthma and the Role of Omalizumab.

Viral respiratory infections are recognized risk factors for the loss of control of allergic asthma and the induction of exacerbations, both in adults and children. Severe asthma is more susceptible to virus-induced asthma exacerbations, especially in the presence of high IgE levels. In the course of immune responses to viruses, an initial activation of innate immunity typically occurs and the production of type I and III interferons is essential in the control of viral spread. However, the Th2 inflammatory environment still appears to be protective against viral infections in general and in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections as well. As for now, literature data, although extremely limited and preliminary, show that severe asthma patients treated with biologics don't have an increased risk of SARS-CoV-2 infection or progression to severe forms compared to the non-asthmatic population. Omalizumab, an anti-IgE monoclonal antibody, exerts a profound cellular effect, which can stabilize the effector cells, and is becoming much more efficient from the point of view of innate immunity in contrasting respiratory viral infections. In addition to the antiviral effect, clinical efficacy and safety of this biological allow a great improvement in the management of asthma.

Effectiveness of noninvasive ventilation in COVID-19 related-acute respiratory distress syndrome.

INTRODUCTION: During this long COVID-19 pandemic outbreak, continuous positive airway pressure (CPAP) and noninvasive ventilation (NIV) are being widely used to treat patients with moderate to severe acute respiratory failure (ARF). As for now, data on the efficacy of NIV in COVID-19 acute respiratory distress syndrome (ARDS) are lacking, and for this reason it is extremely important to accurately determine the outcomes of this strategy. This study aimed to evaluate clinical data and outcomes of NIV in patients with COVID-19 ARDS. MATHERIALS AND METHODS: Seventy-nine consecutive patients with sudden worsening of respiratory failure were evaluated. All patients (71% male) had a confirmed SARS-CoV-2 infection and signs, symptoms and radiological findings compatible with COVID-19 pneumonia and all of them underwent a trial of NIV. Primary outcomes were NIV success and failure defined by intubation and mortality rate. Secondary outcome was the duration of NIV. RESULTS: NIV was successful in 38 (48.1%) patients (Table 1). EOT was necessary in 21 patients (26.6%). Death occurred in 20 patients (25.3%). In the group of patients having failed a trial with NIV and then being intubated, compared to those who continued NIV, there was no higher mortality rate. By evaluating the ICU survival outcome of the subgroup of patients intubated after NIV, 57% of the patients were discharged and 43% died. CONCLUSION: Previous studies conducted on patients undergoing invasive mechanical ventilation showed higher mortality rate than the present study. Our data showed that NIV can avoid intubation in almost half of the patients. Therefore, this data could reassure clinicians who would consider using NIV in COVID-19 ARDS-related treatment.

May 2020: Is It Always COVID-19 No Matter What?

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is causing a massive outbreak throughout the world. In this period, diseases other than coronavirus disease (COVID-19) have not disappeared; however, it is hard for doctors to diagnose diseases that can mimic the clinical, radiological, and laboratory features of COVID-19, especially rare lung diseases such as acute eosinophilic pneumonia (AEP). We report the clinical case of a young patient who presented to the Emergency Department with respiratory failure and clinical symptoms, radiological aspects, and blood tests compatible with COVID-19; two swabs and a serology test for SARS-CoV-2 were performed, both resulted negative, but the respiratory failure worsened. Peripheral eosinophilia guided us to consider the possibility of a rare disease such as AEP, even if radiology findings were not pathognomonic. Therefore, we decided to perform a flexible bronchoscopy with bronchoalveolar lavage (BAL) at the lingula, which showed the presence of eosinophilia greater than 40%. As a consequence, we treated the patient with high-dose corticosteroids that completely resolved the respiratory symptoms. This case report highlights the difficulty of making alternative diagnoses during the COVID-19 pandemic, especially for rare lung diseases such as AEP, which may have initial characteristics similar to COVID-19.

A Dangerous Consequence of the Recent Pandemic: Early Lung Fibrosis Following COVID-19 Pneumonia - Case Reports.

The outbreak of the novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) started in China in December 2019. COVID-19 patients at presentation show a wide spectrum of clinical and pathological involvement. We report two cases of respiratory insufficiency due to COVID-19 pneumonia that occurred in adults without a history of respiratory diseases. Although these patients improved and were discharged from the acute ward, during the hospitalization they both progressed with a subsequent clinical and radiological worsening, pointing out one of the main concerns for these patients at discharge: the possibility of developing persistent lung abnormalities also in healthy people not having other risk factors. In conclusion, these cases represent two examples of early lung fibrosis in patients with COVID-19 pneumonia with different severity disease evolution and highlight the need for long-term follow-up strategies. The etiology of this fibrosis is under discussion: we suppose that it could be due to either a possible outcome of natural history of lung damage produced by ARDS, or to the lung injury related to high oxygen level or to the lung damage directly induced by viral infection or finally to the autoimmune response. At this moment, it is not possible to predict how many people will have consequences due to COVID-19 pneumonia, and therefore we believe that careful follow-up should be mandatory.

Anti-IL5 Therapies for Severe Eosinophilic Asthma: Literature Review and Practical Insights.

Severe refractory asthma (SRA) still has a high economic and social impact, including a reduction in quality of life (QoL), productivity, a greater risk of exacerbations and emergency department (ED) visits. Another major issue is the need of oral corticosteroids (OCS), often due to a poor response to standard therapies or the lack of indication for currently available biological drugs. A thorough understanding of the immunological pathways and eosinophilopoietic processes allows a correct application of the new pharmacological strategies and leads to better clinical responses. For these unmet needs, several monoclonal antibody (mAb) drugs have been introduced over the past few years. These are mainly available for allergic and especially eosinophilic uncontrolled refractory asthma. As the number of therapeutic options increases, the choice of biological drugs can be made only after careful considerations of the particular asthma endotype, patients' comorbidities and clinical data. The selection of the correct therapeutic option can therefore be guided after a careful evaluation of the particular endotype and phenotype, from the combined evaluation of inflammatory biomarkers, clinical picture and comorbidities. The careful evaluation of all these parameters can therefore help the physician in the optimal management of these complex patients, for whom it is often possible to achieve exceptional results by managing the available options in the best possible way. The aim of this review is to define the positioning of the biological drugs currently available for type 2 asthma, with a special focus on options for eosinophilic asthma in the context of the most recent knowledge of immunological pathways.

Efficacy of tocilizumab in patients with COVID-19 ARDS undergoing noninvasive ventilation.

BACKGROUND: The severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is extremely variable, ranging from asymptomatic patients to those who develop severe acute respiratory distress syndrome (ARDS). As for now, there are still no really effective therapies for coronavirus disease 2019 (COVID-19). Some evidences suggest that tocilizumab (TCZ) may avoid the progression of severe COVID-19. The aim of this retrospective case-control study was to analyze the efficacy and safety of TCZ in patients with COVID-19 ARDS undergoing noninvasive mechanical ventilation (NIV). METHODS: Seventy-nine consecutive patients with severe COVID-19 pneumonia and worsening acute respiratory failure (ARF) were admitted to the Pulmonology Unit of Azienda USL of Reggio Emilia-IRCCS. All patients were inflamed (elevated CRP and IL-6 levels) and received NIV at admission according to the presence of a pO2/FiO2 ratio ≤ 200 mmHg. The possibility of being treated with TCZ depended on the drug availability. The primary outcome was the in-hospital mortality rate. A secondary composite outcome of worsening was represented by the patients who died in the pulmonology unit or were intubated. RESULTS: Out of 79 patients, 41 were treated with TCZ. Twenty-eight patients received intravenous (IV) TCZ and 13 patients received subcutaneous (SC) TCZ. In-hospital overall mortality rate was 38% (30/79 patients). The probabilities of dying and being intubated during the follow-up using Kaplan-Meier method were significantly lower in total patients treated with TCZ compared to those of patients not treated with TCZ (log-rank p value = 0.006 and 0.036, respectively). However, using Cox multivariate analyses adjusted for age and Charlson comorbidity index only the association with the reduced risk of being intubated or dying maintained the significance (HR 0.44, 95%CI 0.22-0.89, p = 0.022). Two patients treated with TCZ developed cavitating lung lesions during the follow-up. CONCLUSIONS: This study shows that TCZ treatment may be effective in COVID-19 patients with severe respiratory impairment receiving NIV. More data on safety are required. Randomized controlled trials are needed to confirm these results.

Etiology of Syncope and Unexplained Falls in Elderly Adults with Dementia: Syncope and Dementia (SYD) Study.

OBJECTIVES: To investigate the etiology of transient loss of consciousness (T-LOC) suspected to be syncope and unexplained falls in elderly adults with dementia. DESIGN: Prospective, observational, multicenter study. SETTING: Acute care wards, syncope units or centers for the diagnosis of dementia. PARTICIPANTS: Individuals aged 65 and older with a diagnosis of dementia and one or more episodes of T-LOC of a suspected syncopal nature or unexplained falls during the previous 3 months were enrolled. MEASUREMENTS: The causes of T-LOC suspected to be syncope and unexplained falls were evaluated using a simplified protocol based on European Society of Cardiology guidelines. RESULTS: Of 357 individuals enrolled, 181 (50.7%) had been referred for T-LOC suspected to be syncope, 166 (46.5%) for unexplained falls, and 10 (2.8%) for both. An initially suspected diagnosis of syncope was confirmed in 158 (87.3%), and syncope was identified as the cause of the event in 75 (45.2%) of those referred for unexplained falls. Orthostatic hypotension was the cause of the event in 117 of 242 (48.3%) participants with a final diagnosis of syncope. CONCLUSION: The simplified syncope diagnostic protocol can be used in elderly people with dementia referred for suspected syncope or unexplained falls. Unexplained falls may mask a diagnosis of syncope or pseudosyncope in almost 50% of cases. Given the high prevalence of orthostatic syncope in participants (~50%), a systematic reappraisal of drugs potentially responsible for orthostatic hypotension is warranted.

The "syncope and dementia" study: a prospective, observational, multicenter study of elderly patients with dementia and episodes of "suspected" transient loss of consciousness.

BACKGROUND AND AIM: Syncope and related falls are one of the main causes and the predominant cause of hospitalization in elderly patients with dementia. However, the diagnostic protocol for syncope is difficult to apply to patients with dementia. Thus, we developed a "simplified" protocol to be used in a prospective, observational, and multicenter study in elderly patients with dementia and transient loss of consciousness suspected for syncope or unexplained falls. Here, we describe the protocol, its feasibility and the characteristics of the patients enrolled in the study. METHODS: Patients aged ≥65 years with a diagnosis of dementia and one or more episodes of transient loss of consciousness during the previous 3 months, subsequently referred to a Geriatric Department in different regions of Italy, from February 2012 to May 2014, were enrolled. A simplified protocol was applied in all patients. Selected patients underwent a second-level evaluation. RESULTS: Three hundred and three patients were enrolled; 52.6% presented with episodes suspected to be syncope, 44.5% for unexplained fall and 2.9% both. Vascular dementia had been previously diagnosed in 53.6% of participants, Alzheimer's disease in 23.5% and mixed forms in 12.6%. Patients presented with high comorbidity (CIRS score = 3.6 ± 2), severe functional impairment, (BADL lost = 3 ± 2), and polypharmacy (6 ± 3 drugs). CONCLUSION: Elderly patients with dementia enrolled for suspected syncope and unexplained falls have high comorbidity and disability. The clinical presentation is often atypical and the presence of unexplained falls is particularly frequent.