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Francesco Menzella,1 Matteo Fontana,1 Marco Contoli,2 Patrizia Ruggiero,1 Carla Galeone,1 Silvia Capobelli,1 Anna Simonazzi,1 Chiara Catellani,1 Chiara Scelfo,1 Claudia Castagnetti,1 Francesco Livrieri,1 Nicola Facciolongo1 1Pulmonology Unit, Arcispedale Santa Maria Nuova, Azienda USL – IRCCS di Reggio Emilia, Reggio Emilia, Italy; 2Respiratory Section, Department of Translational Medicine, University of Ferrara, Ferrara, ItalyCorrespondence: Francesco Menzella, Pulmonology Unit, Arcispedale Santa Maria Nuova, Azienda USL – IRCCS di Reggio Emilia, Reggio Emilia, Italy, Tel +39 0522 296073, Email fmenzella@gmail.comPurpose: 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.Keywords: severe allergic asthma, biologics, omalizumab, exacerbations, side effects, oral corticosteroids

Francesco Menzella,1 Carla Galeone,1 Mirco Lusuardi,2 Anna Simonazzi,1 Claudia Castagnetti,1 Patrizia Ruggiero,1 Nicola Facciolongo1 1Department of Medical Specialties, Pneumology Unit, Arcispedale Santa Maria Nuova – IRCCS, Azienda USL di Reggio Emilia, Reggio Emilia, 2Unit of Respiratory Rehabilitation, Azienda USL di Reggio Emilia, S. Sebastiano Hospital, Correggio, Italy Abstract: Severe asthma affects between 5% and 10% of patients with asthma worldwide and requires best standard therapies at maximal doses, but there is a subgroup of patients refractory to all treatments. We share a case report of a 53-year-old woman with a history of severe allergic asthma that progressively worsened over the years despite the best therapy. She had been hospitalized 35 times, including nine admissions to the respiratory intensive care unit due to severe exacerbations. To rule out other possible diagnoses, several investigations were performed, such as computed tomography scan of the chest and neck, fiberoptic laryngoscopy, antineutrophil cytoplasmic antibodies, and complete blood cell count. The patient was first treated with omalizumab, which was completely ineffective, and then with bronchial thermoplasty (BT), again without clinical benefit. The situation remained critical for about 3 months during the last hospitalization, but in February 2017, the Italian Medicines Agency approved the treatment of severe refractory eosinophilic asthma with mepolizumab (Nucala®). Given a blood eosinophil count of 300 cells/µL, our patient was started on 100 mg mepolizumab treatment. After the second administration, symptoms improved progressively, with a reduction in the number and severity of exacerbations, so the patient could finally be discharged from hospital. At follow-up, it was possible to reduce and then suspend oral corticosteroids by continuing only with inhaled corticosteroids/long-acting beta-agonists and montelukast. No further asthmatic exacerbations occurred; symptom control and quality of life improved significantly. To our knowledge, this is the first case of a patient unresponsive to omalizumab and BT but with excellent clinical response to mepolizumab. She is also the first patient to be treated with an anti-IL5 agent in Italy in a real-life clinical setting. The availability of new effective biological agents will allow many patients to resume as normal a life as possible, with a positive outcome also from a social and economic point of view. Keywords: severe asthma, omalizumab, bronchial thermoplasty, mepolizumab, exacerbation, eosinophilia

Francesco Menzella,1 Carla Galeone,1 Francesca Bertolini,2 Claudia Castagnetti,1 Nicola Facciolongo1 1Department of Medical Specialties, Pneumology Unit, IRCCS- Arcispedale Santa Maria Nuova, Reggio Emilia, Italy; 2Department of Animal Science, Iowa State University, Ames, IA, USA Abstract: The increasing understanding of the molecular biology and the etiopathogenetic mechanisms of asthma helps in identification of numerous phenotypes and endotypes, particularly for severe refractory asthma. For a decade, the only available biologic therapy that met the unmet needs of a specific group of patients with severe uncontrolled allergic asthma has been omalizumab. Recently, new biologic therapies with different mechanisms of action and targets have been approved for marketing, such as mepolizumab. Other promising drugs will be available in the coming years, such as reslizumab, benralizumab, dupilumab and lebrikizumab. Moreover, since 2010, bronchial thermoplasty has been successfully introduced for a limited number of patients. This is a nonpharmacologic endoscopic procedure which is considered a promising therapy, even though several aspects still need to be clarified. Despite the increasing availability of new therapies, one of the major problems of each treatment is still the identification of the most suitable patients. This sudden abundance of therapeutic options, sometimes partially overlapping with each other, increases the importance to identify new biomarkers useful to guide the clinician in selecting the most appropriate patients and treatments, without forgetting the drug-economic aspects seen in elevated direct cost of new therapies. The aim of this review is, therefore, to update the clinician on the state of the art of therapies available for refractory asthma and, above all, to give useful directions that will help understand the different choices that sometimes partially overlap and to dispel the possible doubts that still exist. Keywords: severe asthma, phenotypes, monoclonal antibodies, IL-5, bronchial thermoplasty, biomarkers

Summary: Background: Even if horses strictly depend on the gut microbiota for energy homeostasis, only a few molecular studies have focused on its characterisation and none on the perinatal gut microbial colonisation process. Objectives: To explore the perinatal colonisation process of the foal gut microbial ecosystem and the temporal dynamics of the ecosystem assembly during the first days of life. Study design: Longitudinal study. Methods: Thirteen Standardbred mare‐foal pairs were included in the study. For each pair, at delivery we collected the mare amniotic fluid, faeces and colostrum, and the foal meconium. Milk samples and faeces of both mare and foal were also taken longitudinally, until day 10 post‐partum. Samples were analysed by means of next‐generation sequencing of the 16S rRNA gene on Illumina MiSeq. Results: Our findings suggest that microbial components derived from the mare symbiont communities establishes in the foal gut since fetal life. After birth, an external transmission route of mare microorganisms takes place. This involves a rapid and dynamic process of assembling the mature foal gut microbiome, in which the founder microbial species are derived from both the milk and the gut microbial ecosystems of the mare. Main limitations: The inability to discriminate between live and dead cells, the possible presence of contaminating bacteria in low biomass samples (e.g. meconium and amniotic fluid), the limits of the phylogenetic assignment down to species level, and the presence of unassigned operational taxonomic units. Conclusions: Our data highlight the importance of mare microbiomes as a key factor for the establishment of the gut microbial ecosystem of the foal. [ABSTRACT FROM AUTHOR]