Biochemical analysis of catecholamine and cortisol for the evaluation of the fetal distress in third trimester stillbirths.

BACKGROUND: Stress hormones like catecholamine and cortisol are thought to reflect the magnitude of physical stress in adults and were studied in relationship to the cause of death and agony time. Intrauterine distress, intrapartum events, and modes of delivery can affect the fetal endocrine stress response, as reflected by biochemical analyses. The aim of the present study was to evaluate the role of catecholamines and cortisol as markers of ante-mortem fetal distress. The role of cortisol as a marker of circadian timing of delivery was also assessed. METHODS: A 2-year prospective cohort-comparison inclusion of stillbirths and newborns took place with collection of antemortem data, labor parameters, neonatal outcome, post-mortem data and blood samples. Stillbirths were classified as acute or chronic on the basis of a multidisciplinary evaluation. Heart blood of stillbirths and cord blood of newborns were analyzed by high pressure liquid chromatography (HPLC) for adrenaline and noradrenaline and by immunoassay for cortisol determination. RESULTS: Fifteen stillbirths and 46 newborns, as a comparison group, delivered by spontaneous vaginal birth, elective, and emergency cesarean sections were included. Stillbirths' main cause of death was cord thrombosis. Levels of adrenaline and noradrenaline (median: 14,188 pg/ml and 230.5 pg/ml, respectively) were significantly higher (p < 0.001) in stillbirths than in newborns and were also higher in acute compared to chronic distress. Cortisol levels were significantly higher (p < 0.05) in spontaneous vaginal delivery (median: 18.2 µg/dl) compared to elective cesarean sections (median: 3.8 µg/dl). No difference in cortisol concentrations was detected between newborns delivered at morning and at afternoon/evening. CONCLUSION: Our results suggest that the biochemical measurement of adrenaline and noradrenaline levels might reflect a marked physical stress response during the process of death in stillbirths. On the contrary, the elevation of cortisol levels could mirror the elevation in maternal cortisol level during vaginal delivery. For the post-mortem evaluation of stillbirths, the analysis of CA levels could provide additional data on the duration of distress, useful to integrate the forensic diagnosis.

Biologics and Bronchial Thermoplasty for severe refractory asthma treatment: From eligibility criteria to real practice. A cross-sectional study.

The increasing knowledge on immuno-inflammatory pathways allowed the development of new therapeutic options in the field of severe refractory asthma (SRA). It is therefore very important to accurately identify phenotypes and endotypes of patients potentially eligible for innovative treatments. The aim of this study was to describe a cohort of patients affected by SRA referring to the Pneumology Unit of Azienda USL di Reggio Emilia/IRCCS in Reggio Emilia, Italy. It is an observational cross-sectional study, investigating the proportion of subjects with eligibility criteria for biological treatments (omalizumab, mepolizumab, benralizumab) and non-pharmacological treatment (bronchial thermoplasty, BT). We enrolled 137 patients with SRA referring to the centre from June 1st, 2017 to June 30th, 2019. The results of this study showed that 125 (91%) of patients were eligible for at least one biologic and 94 (69%) were eligible for BT. Only 6 (4%) of patients had no criteria for any available SRA treatments. Among biologics, there were only 11 (8%) patients resulting in overlap between omalizumab, mepolizumab and benralizumab, and 22 (16%) overlap of patients when BT was included. Considering eligibility criteria for BT, only 6 (4%) patients had inclusion criteria for BT, instead in real life 28% of patients were treated with BT. The major comorbidities were: bronchiectasis, chronic rhinosinusitis with nasal polyps (CRSwNP), gastro-esophageal reflux disease (GERD), and eosinophilic granulomatosis with polyangiitis (EGPA). The prevalence of bronchiectasis was much higher in the mepolizumab (45%) and benralizumab (43%) groups than in omalizumab (1%) and BT (7%), p < 0,001; CRSwNP and GERD were equally present and EGPA was only present in the mepolizumab group. Overall, our population was eligible for biologicals in almost all cases, and a significant percentage of patients showed the presence of an overlap of allergic and eosinophilic endotypes. This implies the possibility of different therapeutic options and reiterates the need for a correct characterization of patients. This study confirmed how the identification of inflammatory endotypes and phenotypes represent a key role in the selection of the right therapy for the right patient.

Significant improvement in lung function and asthma control after benralizumab treatment for severe refractory eosinophilic asthma.

Severe eosinophilic asthma is a complex disease and much effort has been made to fully understand its mechanisms. Bronchial remodeling and loss of lung function are important features in asthma, however their key aspects are not completely clear, especially the impact that biological drugs may have on them. One of the key cytokines involved in the pathophysiology of eosinophilic asthma is interleukin-5 (IL-5), which plays a very important role together with other type 2 cytokines and chemokines in the development, transmigration and persistence of eosinophils into airways, such as eotaxin-2 and 3, thymic stromal lymphopoietin (TSLP), IL-33, as well as IL-4 and IL-13. Several monoclonal antibodies have been developed against this cytokine (mepolizumab, reslizumab) or its receptor (benralizumab). Data on the improvement of respiratory function in patients who undergo benralizumab treatment are scarce and partly conflicting. Real-life studies may play a crucial role in clarifying this important aspect. The aim of this retrospective observational real-world study was to evaluate the effect of benralizumab on lung function improvement, exacerbation rate, oral corticosteroids (OCS) reduction and asthma control questionnaire (ACQ) score before and after six months of treatment with benralizumab in a cohort of 20 consecutive patients with severe refractory asthma (SRA) treated at the Pneumology Unit of Local Health Authority, Reggio Emilia, Italy. Add-on therapy with benralizumab allowed to completely suspend OCS in 19 out of 20 patients. Notably, the number of moderate/severe exacerbations dropped significantly (p < 0,0001); as well as an improvement in ACQ score (p < 0,0001). The most relevant data concern respiratory function: the average pre-bronchodilator FEV1 increased by 21.3% (+680 ml) compared to baseline (p = 0,0006). Moreover, the improvement in morning PEF (+66,6 l/min) confirmed the benefit of benralizumab (p = 0,02). The improvement in respiratory function was significantly higher in patients with blood eosinophilia greater than 500 cells/µL and chronic rhinosinusitis with nasal polyps (CRSwNP). This study underlies a noticeable improvement in respiratory function, much higher than what has been observed in literature so far. This aspect, together with the others aforementioned, should be considered when choosing a treatment option in the context of precision medicine.

Long-Term Outcomes after Surgical Resection for Synchronous or Metachronous Hepatic and Pulmonary Colorectal Cancer Metastases.

BACKGROUND/AIMS: At present, benefits of surgical resection and appropriate selection criteria in patients affected by both hepatic and pulmonary metastases of colorectal cancer (CRC) are under discussion. Our analysis focused on a surgical series of such patients and our final aim consisted in identifying potential prognostic factors. METHODS: Eighty-five patients undergoing resection of both hepatic and pulmonary metastases at 2 Healthcare Institutions from January 1993 to June 2015 were retrospectively reviewed as concerned clinical information, surgical notes and pathological features. Patient, treatment, and outcome variables were analyzed by use of log-rank tests, Cox regression, and Kaplan-Meier methods. RESULTS: Liver turned out as the first site of metastasis in 75% patients, lung in 13% patients, and both sites in 12% patients. Multiple hepatic metastases were detected in 67% patients and pulmonary metastases in 31% patients. Two hundred eighteen surgical interventions were performed (mean 2.56 for each patient). Overall survival (OS) rates at 3-, 5-, and 10-year follow-up from colorectal resection were 94, 79, and 38% respectively. Median OS was 8.31 years. Survival turned out significantly longer for patients with disease-free interval (DFI) exceeding 1 year between first metastasectomy and diagnosis of second metastases and in patients affected by metachronous pulmonary metastases. CONCLUSIONS: Surgical resection of both hepatic and pulmonary metastases of CRC represents a safe and effective treatment. It might lead to rewarding long-term survival rates in high selected patients. Shorter DFIs between first metastasectomy and diagnosis of second metastases can determine worse prognoses. In addition, poor outcomes could be predicted also for patients affected by synchronously detected pulmonary CRC metastases, although further confirmatory analyses are strongly required.

PUREAIR protocol: randomized controlled trial of intensive pulmonary rehabilitation versus standard care in patients undergoing surgical resection for lung cancer.

BACKGROUND: Non-small cell lung cancer is the most common type of lung cancer. Surgery is proven to be the most effective treatment in early stages, despite its potential impact on quality of life. Pulmonary rehabilitation, either before or after surgery, is associated with reduced morbidity related symptoms and improved exercise capacity, lung function and quality of life. METHODS: We describe the study protocol for the open-label randomized controlled trial we are conducting on patients affected by primary lung cancer (stages I-II) eligible for surgical treatment. The control group receives standard care consisting in one educational session before surgery and early inpatient postoperative physiotherapy. The treatment group receives, in addition to standard care, intensive rehabilitation involving 14 preoperative sessions (6 outpatient and 8 home-based) and 39 postoperative sessions (15 outpatient and 24 home-based) with aerobic, resistance and respiratory training, as well as scar massage and group bodyweight exercise training. Assessments are performed at baseline, the day before surgery and one month and six months after surgery. The main outcome is the long-term exercise capacity measured with the Six-Minute Walk Test; short-term exercise capacity, lung function, postoperative morbidity, length of hospital stay, quality of life (Short Form 12), mood disturbances (Hospital Anxiety and Depression Scale) and pain (Numeric Rating Scale) are also recorded and analysed. Patient compliance and treatment-related side effects are also collected. Statistical analyses will be performed according to the intention-to-treat approach. T-test for independent samples will be used for continuous variables after assessment of normality of distribution. Chi-square test will be used for categorical variables. Expecting a 10% dropout rate, assuming α of 5% and power of 80%, we planned to enrol 140 patients to demonstrate a statistically significant difference of 25 m at Six-Minute Walk Test. DISCUSSION: Pulmonary Resection and Intensive Rehabilitation study (PuReAIR) will contribute significantly in investigating the effects of perioperative rehabilitation on exercise capacity, symptoms, lung function and long-term outcomes in surgically treated lung cancer patients. This study protocol will facilitate interpretation of future results and wide application of evidence-based practice. TRIAL REGISTRATION: ClinicalTrials.gov Registry n. NCT02405273 [31.03.2015].

Endobronchial ultrasound-guided transbronchial needle aspiration under conscious sedation with meperidine and midazolam.

Endobronchial Ultrasound guided transbronchial needle aspiration (EBUS-TBNA) is usually performed under general anesthesia or deep sedation with drugs such as Propofol that, at least in Italy, can be administered only by an anesthesiologist. Aim of the study was to assess conscious sedation feasibility, safety and tolerability using Meperidine and Midazolam as administered by Pulmonologist and relevant impact on the efficiency of the sampling procedures.All patients undergoing EBUS-TBNA from February 2013 to July 2014 were examined retrospectively. Efficiency using Meperidine and Midazolam during EBUS-TBNA has been assessed: completion of lymph-nodal sampling, sampling adequacy, diagnostic yield, cough during endoscopic procedure complications and need for procedure repetition with Anesthesiology assistance. Patient satisfaction and cost/effectiveness were also evaluated. One hundred and thirty-four consecutive patients were considered; 97.7% completed the procedure. In 96.9% of cases the prefixed program of lymph-nodal sampling was accomplished. Sampling adequacy was 92,4%. Diagnostic yield was 55%. In 94.7% of cases cough was absent or did not interfere with EBUS-TBNA. The need to repeat the endoscopic procedure occurred in 6 cases but only in 2 the presence of an Anesthesiologist was required. Patient satisfaction was very high, with 95.9% of subjects reporting they would "definitely return". A 27% cost reduction was calculated. EBUS-TBNA under conscious sedation using Meperidine and Midazolam prescribed and administered by pulmonologist without the Anesthesiologist assistance, revealed to be a safe, well tolerated and cost saving procedure. The efficiency of sampling was good, apart from a relatively low diagnostic yield due to different expertise of operators.

Soluble Epidermal Growth Factor Receptors (sEGFRs) in Cancer: Biological Aspects and Clinical Relevance.

The identification of molecules that can reliably detect the presence of a tumor or predict its behavior is one of the biggest challenges of research in cancer biology. Biological fluids are intriguing mediums, containing many molecules that express the individual health status and, accordingly, may be useful in establishing the potential risk of cancer, defining differential diagnosis and prognosis, predicting the response to treatment, and monitoring the disease progression. The existence of circulating soluble growth factor receptors (sGFRs) deriving from their membrane counterparts has stimulated the interest of researchers to investigate the use of such molecules as potential cancer biomarkers. But what are the origins of circulating sGFRs? Are they naturally occurring molecules or tumor-derived products? Among these, the epidermal growth factor receptor (EGFR) is a cell-surface molecule significantly involved in cancer development and progression; it can be processed into biological active soluble isoforms (sEGFR). We have carried out an extensive review of the currently available literature on the sEGFRs and their mechanisms of regulation and biological function, with the intent to clarify the role of these molecules in cancer (and other pathological conditions) and, on the basis of the retrieved evidences, speculate about their potential use in the clinical setting.

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.

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.

Efficacy and Safety of Omalizumab Treatment Over a 16-Year Follow-Up: When a Clinical Trial Meets Real-Life.

Purpose: Treatment of severe asthma has made great strides thanks to rapid progress in understanding immune response and inflammatory pathways. This led to the advent of the first biologic for severe allergic asthma (SAA), omalizumab. Although the long-term efficacy and safety of omalizumab has been confirmed, increasingly longer follow-up data can further reinforce this evidence and potentially provide new ones, for example on any loss of efficacy or the appearance of unexpected side effects. This study reports omalizumab treatment-related outcomes after 16 years of follow-up. Patients and Methods: In this real-life retrospective study, an extension of a previous 9-year follow-up study on patients initially recruited in a clinical trial, we enrolled 8 adult patients with SAA followed-up from November 2005 to December 2021. Study subjects were selected based on omalizumab eligibility criteria. Results: Exacerbation rate significantly decreased from 3.6 ± 2.1 events in year before index date to 0.1 ± 0.4 after 32 weeks of treatment (p < 0.0001). Mean annual number of mild-to-moderate exacerbations at 16 years was 0.88 compared with 1.8 in the year before the index date and 1.1 at 32 weeks. No hospitalizations were documented during the 16-year follow-up compared to 0.3 hospitalizations/patient in the year before the index date. Respiratory function also progressively and significantly improved. Regarding patient-reported outcomes (PROs), The AQLQ and ACT significantly improved from baseline throughout the follow-up, particularly up to 9 years of follow-up. During the study, an overall reduction in doses of asthma medications was observed, with a significant OCS-sparing effect. Conclusion: Our study, the longest clinical follow-up on patients treated with anti-IgE, confirms and amplifies the results of the studies carried out so far, as they are maintained over a very long interval of time without drops in efficacy without any type of side effect.

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.

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.

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.

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.

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.

Rehabilitation for lung cancer patients undergoing surgery: results of the PUREAIR randomized trial.

BACKGROUND: Surgery for non-small cell lung cancer is proven to be the most effective treatment in early stages, although concerns exist on its negative impact on patients' overall fitness. AIM: To establish whether intensive pulmonary rehabilitation, preoperative and postoperative, improves exercise capacity in patients undergoing lung resection. DESIGN: Single center, unblinded, designed for superiority, 1:1 randomized controlled trial with two parallel arms. SETTING: S. Maria Nuova Hospital of Reggio Emilia (Reggio Emilia, Italy). POPULATION: Patients referred from local lung cancer multidisciplinary team for lung resection. METHODS: Patients were randomized to either standard of care (SC) or SC + intensive perioperative pulmonary rehabilitation (SC+PR). The primary aim was to investigate the effectiveness of pulmonary rehabilitation in improving exercise capacity six months after surgery. Additionally, we wanted to investigate the same effect shortly after surgery (at one month), as well as the overall impact of rehabilitation on lung function, postoperative complications and length of stay, quality of life, mood disturbances and pain. Sample was sized based on the primary outcome assuming a minimal clinically significant difference of 25 meters in exercise tolerance, measured with 6 minutes walking test. RESULTS: The exercise tolerance at 6 months after surgery was significantly higher in patients undertaking PR compared to SC (+48.9 meters vs. -7.5 meters respectively, difference: +56.4 meters, 95% CI: 29.6-83.0, P<0.001) and it showed significantly lower impairment at 1 month after surgery in the intervention group (-3.0 meters vs. -30.1 meters difference: +27.1 meters, 95% CI: 3.4-50.8, P=0.025). No other significant differences between groups were found. CONCLUSIONS: Comparison between groups showed that pulmonary rehabilitation, administered pre and postoperatively, significantly improved exercise capacity at 6 months in patients undergoing lung resection; it also significantly reduced the decrease in exercise tolerance observed 1 month after surgery. CLINICAL REHABILITATION IMPACT: The PUREAIR trial highlights the importance of combined preoperative and postoperative rehabilitation in reducing physical deconditioning in lung cancer patients undergoing surgery. Comprehensive pulmonary rehabilitation improves exercise capacity at 1 and 6 months after surgery. The PUREAIR trial results increase knowledge on comprehensive rehabilitation's outcomes in the first six months after surgery.

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.

Efficacy and steroid-sparing effect of benralizumab: has it an advantage over its competitors?

Severe refractory asthma is characterized by a higher risk of asthma-related symptoms, morbidities, and exacerbations. This disease also determines much greater healthcare costs and deterioration in health-related quality of life (HR-QoL). Another concern, which is currently much discussed, is the high percentage of patients needing regular use of oral corticosteroids (OCS), which can lead to several systemic side effects. Airway eosinophilia is present in the majority of asthmatic patients, and elevated levels of blood and sputum eosinophils are associated with worse control of asthma. Regarding severe refractory eosinophilic asthma, interleukin-5 (IL-5) plays a fundamental role in the inflammatory response, due to the profound effect on eosinophils biology. The advent of the biological therapies provided an effective strategy, even if the increased number of molecules with different targets raised the challenge of choosing the right therapy and avoid overlapping. When considering severe refractory eosinophilic asthma and anti-IL-5 treatments, it is not easy to define which drug to choose between mepolizumab, reslizumab, and benralizumab. In this article, we carried out an indirect comparison among literature data, especially between OCS reduction studies (ZONDA-SIRIUS) and pivotal studies (SIROCCO-MENSA), evaluating whether the clinical efficacy and the steroid-sparing effect of benralizumab may represent an advantage over other compounds. This data could help the clinician in the decision process of treatment choice, within the different available therapeutic options for eosinophilic refractory severe asthma.

A case of chronic eosinophilic pneumonia in a patient treated with dupilumab.

The increasing knowledge on inflammatory pathways has driven the development of targeted biological therapies for severe refractory asthma. Among the recently developed biologics, the fully human monoclonal antibody dupilumab is an interesting therapeutic option, given its ability to inhibit the biological effects of both IL-4 and IL-13. We describe the case of a male, Caucasian, 56-year-old patient with allergic and eosinophilic severe asthma. Given the poor asthma control, he started treatment with add-on dupilumab, and after the tenth injection, he presented with a fever and bilateral pulmonary thickening. A significant increase in blood eosinophilia was also reported. The patient underwent a fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) and transbronchial lung biopsy (TBLB/TBB). BAL revealed eosinophils alveolitis (60%) while TBB showed findings compatible with chronic eosinophilic pneumonia (CEP). After prolonged treatment with oral corticosteroids, the clinical picture improved with resolution of CEP. Since the beginning of dupilumab treatment, simultaneously to a great improvement in asthma control, the patient showed a progressive increase in blood eosinophils count and subsequent onset of clinical-radiological pattern suggestive of CEP. Based on published data, dupilumab may have induced an alteration of the complex immunological pathway of our patient. This pathway is affected by both allergic and eosinophilic asthmatic endotypes, and consequently, the concomitant action of allergenic stimuli and eosinophils may have caused the appearance of eosinophilic pneumonia. To our knowledge, this is the first reported case of CEP as a possible severe side effect of dupilumab administration.