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.

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 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.

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.

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.

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.

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.

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.

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.

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.

Severe refractory asthma: current treatment options and ongoing research.

Patients with severe asthma have a greater risk of asthma-related symptoms, morbidities, and exacerbations. Moreover, healthcare costs of patients with severe refractory asthma are at least 80% higher than those with stable asthma, mainly because of a higher use of healthcare resources and chronic side effects of oral corticosteroids (OCS). The advent of new promising biologicals provides a unique therapeutic option that could achieve asthma control without OCS. However, the increasing number of available molecules poses a new challenge: the identification and selection of the most appropriate treatment. Thanks to a better understanding of the basic mechanisms of the disease and the use of predictive biomarkers, especially regarding the Th2-high endotype, it is now easier than before to tailor therapy and guide clinicians toward the most suitable therapeutic choice, thus reducing the number of uncontrolled patients and therapeutic failures. In this review, we will discuss the different biological options available for the treatment of severe refractory asthma, their mechanism of action, and the overlapping aspects of their usage in clinical practice. The availability of new molecules, specific for different molecular targets, is a key topic, especially when considering that the same targets are sometimes part of the same phenotype. The aim of this review is to help clarify these doubts, which may facilitate the clinical decision-making process and the achievement of the best possible outcomes.

Acute respiratory failure as presentation of late-onset Pompe disease complicating the diagnostic process as a labyrinth: a case report.

BACKGROUND: Acute respiratory failure can be triggered by several causes, either of pulmonary or extra-pulmonary origin. Pompe disease, or type II glycogen storage disease, is a serious and often fatal disorder, due to a pathological accumulation of glycogen caused by a defective activiy of acid α-glucosidase (acid maltase), a lysosomal enzyme involved in glycogen degradation. The prevalence of the disease is estimated between 1 in 40,000 to 1 in 300,000 subjects. CASE PRESENTATION: This case report describes a difficult diagnosis of late-onset Pompe disease (LOPD) in a 52 year old Caucasian woman with acute respiratory failure requiring orotracheal intubation and subsequent tracheostomy for long-term mechanical ventilation 24 h/day. Despite a complex diagnostic process including several blood tests, bronchoscopy with BAL, chest CT, brain NMR, electromyographies, only a muscle biopsy allowed to reach the correct diagnosis. DISCUSSION: The most frequent presentation of myopathies, including LOPD, is proximal limb muscle weakness. Respiratory related symptoms (dyspnea on effort, reduced physical capacity, recurrent infections, etc.) and respiratory failure are often evident in the later stages of the diseases, but they have been rarely described as the onset symptoms in LOPD. In our case, a third stage LOPD, the cooperation between pulmonologists and neurologists was crucial in reaching a correct diagnosis despite a very complex clinical scenario due to different confounding co-morbidities as potential causes of respiratory failure and an atypical presentation. In this patient, enzyme replacement therapy with infusion of alglucosidase alfa was associated with progressive reduction of ventilatory support to night hours, and recovery of autonomous walking.

Heat-induced necrosis after bronchial thermoplasty: a new concern?

BACKGROUND: Bronchial thermoplasty (BT) is an endoscopic procedure for the treatment of severe refractory asthma, based on the local airways delivery of radio-frequency at 65 °C. Several controlled clinical studies demonstrated the effectiveness of BT on clinical outcomes, particularly the reduction of asthma exacerbations. During procedure or shortly after, significant but transient respiratory adverse events have been reported. CASE REPORT: We describe the case of a male, caucasian, 56-year-old, non-smoker patient with non-allergic severe asthma. A few days after the second BT session performed in the left lower lobe, persistent haemoptysis appeared requiring patient hospitalization. A chest CT scan showed mild varicoid bronchiectasis and distal parenchymal infiltrate in the basal anterior segment of the left lower lobe. At fibreoptic bronchoscopy two small nodular neoformations were observed in sub-segmental areas of the same lobe. Histological examination showed mild non-specific inflammation of bronchial mucosa, and some large fragments of peribronchial pulmonary parenchyma with an area of haemorrhagic necrosis. The patient was treated empirically with co-amoxiclav, azithromycin and prednisone. A new chest CT showed a complete resolution of the parenchymal opacity. Finally, the patient underwent the third session of BT, without recurrence of haemoptysis or radiological changes. DISCUSSION: Bronchial thermoplasty is a generally safe procedure. To our knowledge this is the first report of necrosis of the treated bronchus and haemoptysis complicating BT after the second session. The pulmonary damage was most likely determined by a thermal shock induced by BT. One hypothesis could be a structural fragility of the treated bronchus, possibly related to bronchiectasis. A technical malfunction of the BT controller or the catheter, causing an excessive energy delivery could not be excluded. Adverse events following BT deserve particular attention but should not discourage clinicians from the application of this promising procedure.

Precision Medicine in Targeted Therapies for Severe Asthma: Is There Any Place for "Omics" Technology?

According to the current guidelines, severe asthma still represents a controversial topic in terms of definition and management. The introduction of novel biological therapies as a treatment option for severe asthmatic patients paved the way to a personalized approach, which aims at matching the appropriate therapy with the different asthma phenotypes. Traditional asthma phenotypes have been decomposing by an increasing number of asthma subclasses based on functional and physiopathological mechanisms. This is possible thanks to the development and application of different omics technologies. The new asthma classification patterns, particularly concerning severe asthma, include an increasing number of endotypes that have been identified using new omics technologies. The identification of endotypes provides new opportunities for the management of asthma symptoms, but this implies that biological therapies which target inflammatory mediators in the frame of specific patterns of inflammation should be developed. However, the pathway leading to a precision approach in asthma treatment is still at its beginning. The aim of this review is providing a synthetic overview of the current asthma management, with a particular focus on severe asthma, in the light of phenotype and endotype approach, and summarizing the current knowledge about "omics" science and their therapeutic relevance in the field of bronchial asthma.

Towards precision medicine: The application of omics technologies in asthma management.

Asthma is a chronic obstructive respiratory disease characterised by bronchial inflammation. Its biological and clinical features have been widely explored and a number of pharmacological treatments are currently available. Currently several aspects of asthma pathophysiological background remain unclear, and this is crucial for the traditional asthma phenotype approach as well as for new endotype definition. In this scenario, the identification of new molecular and clinical biomarkers may be helpful in order to better understand the disease, define specific diagnostic tools and highlight relevant novel targets for pharmacology treatments. Omics technologies offer an innovative research tool for addressing the above mentioned goals. However, there is still a lot to do both in the fields of basic research and in the clinical application of these new technologies. Recently, genome-wide association studies, microRNAs and proteomics are contributing to enrich the available data for the identification of new asthma biomarkers. A precise approach to the patient with asthma, particularly with severe uncontrolled asthma, requires new and specific therapeutic targets, but also proper tools able to drive the clinician in tailoring the treatment. On the other hand, treatment response predictors are needed, particularly in the field of biological drugs, whose sustainability implies a correct and precise patient selection. Translating acquired knowledge about omics in clinical practice may address the unmet needs described above, but large-scale studies are required in order to confirm omics relevance and effectiveness in daily practice. Thus in our opinion the application of omics is still lagging in the real-life setting.