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Claudia Crimi,1 Raffaele Campisi,1 Santi Nolasco,2 Sebastian Ferri,3,4 Giulia Cacopardo,5 Pietro Impellizzeri,2 Maria Provvidenza Pistorio,2 Evelina Fagone,2 Corrado Pelaia,6 Enrico Heffler,3,4 Nunzio Crimi1,2 1Respiratory Medicine Unit, A.O.U. Policlinico “G. Rodolico - San Marco”, Catania, Italy; 2Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy; 3Personalized Medicine, Asthma and Allergy - IRCCS Humanitas Research Hospital, Rozzano, Italy; 4Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, MI, Italy; 5Respiratory Intensive Care Unit, ARNAS Civico General Hospital, Palermo, Italy; 6Department of Medical and Surgical Sciences, University “Magna Graecia”, Catanzaro, ItalyCorrespondence: Claudia CrimiRespiratory Medicine Unit, A.O.U. Policlinico “G. Rodolico - San Marco”, Catania, ItalyEmail dott.claudiacrimi@gmail.comIntroduction: Type 2-high severe asthma (T2-SA) is often associated with several comorbidities. To this extent, the coexistence of T2-SA and bronchiectasis (BE) is considered an emerging phenotype.Methods: We performed a prospective observational multicentre study, including T2-SA patients. Chest HRCT confirmed the presence of BE. Data on exacerbations, pulmonary function, Asthma Control Test (ACT), chronic mucus hypersecretion (CMH), chronic rhinosinusitis (CRS), oral corticosteroid (OCS) dosage, eosinophils in peripheral blood and FeNO were recorded. The Bhalla score was used for radiological assessment of T2-SA+BE patients and the Bronchiectasis Severity Index (BSI) was calculated.Results: A total of 113 patients (mean age 55 ± 11 years, 59.3% female) were enrolled. Co-presence of BE was confirmed in 50/113 (44.2%) patients who identified the T2-SA+BE group. CRS and CRSwNP were more prevalent in T2-SA+BE vs T2-SA [respectively, 42/50 (84%) vs 37/63 (58.7%), p = 0.004 and 27/50 (54%) vs 27/63 (42.9%), p = 0.0165]. Furthermore, T2-SA+BE patients reported more CMH compared to T2-SA [29/50 (58%) vs 15/63 (23.8%), p = 0.0004], were more frequently on chronic OCSs intake [28/50 (56%) vs 22/63 (34.9%), p = 0.0357] and experienced more exacerbations/year [10 (4– 12) vs 6 (4– 12), p = 0.0487]. In a multivariate logistic regression model, the presence of CRS, CMH and daily OCS intake were associated with BE presence with a 78% (95% CI: 69– 88) accuracy. Median Bhalla score was 18.3 (16– 20) (Mild radiological severity). Median BSI was 6 (4– 8) and only 6/50 (12%) had a BSI score ≥ 9. Significant inverse linear relationship between BSI and ACT (r = − 0.6095, p < 0.0001), FEV1% (r = − 0.3297, p = 0.0353) and FEV1 mL (r = − 0.4339, p = 0.0046) were found.Conclusion: Type 2 inflammation could have a causative role in BE development. Chest HRCT is mandatory when a diagnosis of T2-SA is made, especially in presence of CRS, CMH and chronic OCS intake. Early BE detection may be crucial to improve T2-SA patients’ outcomes.Keywords: type 2 inflammation, severe asthma, bronchiectasis, chest-CT scan, phenotype

Corrado Pelaia,1 Nicola Lombardo,2 Maria Teresa Busceti,1 Giovanna Piazzetta,2 Claudia Crimi,3 Cecilia Calabrese,4 Alessandro Vatrella,5 Girolamo Pelaia1 1Department of Health Sciences, Magna Graecia University of Catanzaro, Catanzaro, Italy; 2Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, Catanzaro, Italy; 3Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy; 4Department of Translational Medical Sciences, Luigi Vanvitelli University of Campania, Naples, Italy; 5Department of Medicine, Surgery and Dentistry, University of Salerno, Salerno, ItalyCorrespondence: Corrado PelaiaDepartment of Health Sciences, Magna Graecia University of Catanzaro, Catanzaro, ItalyTel + 39 0961 364-7007Email pelaia.corrado@gmail.comBackground: Having been approved for biological treatment of atopic dermatitis, dupilumab has also been recently licensed as add-on therapy for severe asthma and nasal polyposis. With regard to the latter diseases, few real-life clinical investigations have been carried out to date.Objective: The primary end point of this single-center observational study was to evaluate in a real-life setting the short-term therapeutic effects of dupilumab in patients with severe asthma and nasal polyposis.Methods: At baseline and after 4 weeks of add-on therapy with dupilumab, several clinical and functional parameters were assessed in 20 patients with severe asthma and nasal polyposis, including both allergic and nonallergic subjects.Results: After 4 weeks of treatment with dupilumab, all patients experienced remarkable improvement in both severe asthma and nasal polyposis. In particular, asthma-control test and sinonasal outcome test 22 scores had significantly increased (p< 0.0001) and decreased (p< 0.0001), respectively. Oral corticosteroid intake got to zero within 4 weeks (p< 0.0001). Moreover, in week 4, significant increases were detected with regard to both prebronchodilator forced expiratory volume in the first second (p< 0.01) and forced vital capacity (FVC; p< 0.05). At the same time point, dupilumab had significantly reduced residual volume (p< 0.0001) and total lung capacity (p< 0.001), whereas it had enhanced forced midexpiratory flow of 25%– 75% FVC (p< 0.01) and peak expiratory flow (p< 0.01). After 4 weeks of treatment, dupilumab had also lowered levels of fractional exhaled nitric oxide (p< 0.0001).Conclusion: The results of this real-life study suggest that dupilumab can be utilized in both allergic and nonallergic patients with severe asthma and nasal polyposis as a valuable add-on biological therapy with rapid onset of action.Keywords: severe asthma, nasal polyposis, interleukin 4 receptor, dupilumab

Raffaele Campisi,1 Claudia Crimi,1 Santi Nolasco,2 Bianca Beghè,3 Leonardo Antonicelli,4 Gabriella Guarnieri,5 Nicola Scichilone,6 Morena Porto,2 Luigi Macchia,7 Giulia Scioscia,8 Maria Pia Foschino Barbaro,8 Alberto Papi,9 Nunzio Crimi1,2 1Respiratory Medicine Unit, A.O.U. Policlinico “G. Rodolico -San Marco”, Catania, Italy; 2Department of Clinical and Experimental Medicine, Section of Respiratory Diseases, University of Catania, Catania, Italy; 3Respiratory Medicine Unit, Department of Medicine, University of Modena and Reggio Emilia, Modena, Italy; 4Allergy Unit, Department of Internal Medicine, Ancona University Hospital, Ancona, Italy; 5Department of Cardiac, Thoracic and Vascular Sciences, University-City Hospital of Padova, Padova, Italy; 6University of Palermo, PROMISE Department, University of Palermo, Palermo, Italy; 7Department of Emergency and Organ Transplantation, School and Chair of Allergology and Clinical Immunology, University of Bari, Bari, Italy; 8Department of Medical and Surgical Sciences, Institute of Respiratory Diseases, University of Foggia, Foggia, Italy; 9Respiratory Medicine Unit, S. Anna University Hospital, Ferrara, ItalyCorrespondence: Claudia CrimiRespiratory Medicine Unit, A.O.U. Policlinico “G. Rodolico - San Marco”, Catania, ItalyEmail dott.claudiacrimi@gmail.comIntroduction: Dupilumab is a monoclonal antibody targeting IL-4Rα recently licensed for severe asthma (SA). A Named Patients Program (NPP) was created in Italy before its commercial availability for SA patients with no other available therapeutic options. We aimed to assess the real-world effectiveness of dupilumab in patients with SA and unmet needs.Methods: We performed a multicentre retrospective study, including SA patients admitted to the NPP treated with dupilumab for 12 months. Data on the number of exacerbations, Asthma Control Test (ACT), pre-bronchodilator FEV1%, oral corticosteroids (OCSs) use, FeNO and eosinophils count in peripheral blood were recorded at baseline and after 3, 6, and 12 months.Results: We included 18 SA patients (mean age 53.3± 12.4 years, 66.7% female). Eleven (61.1%) were OCSs dependent. Five patients (27.8%) received previous anti-IgE and/or anti-IL-5 agents. A significant improvement in ACT score (from 15.7± 5.1 to 18.8± 4.8, p=0.023), OCSs intake [10 (5– 25) mg/day to 0 (0– 5) mg/day, p=0.0333] and FeNO [from 25 (20– 80) ppb to 21 (10.9– 55.3) ppb, p=0.0190] was already detected after 3 months of treatment. After 12 months, a statistically significant decrease in the number of exacerbations from 2 (0– 3) to 0 (0– 1) (p< 0.0068) and increase in FEV1% from 73.5± 19.5% to 87.1± 19.2% (p=0.0407) and ACT to a mean value of 22.4± 1.7 (p< 0.0001) and the interruption of OCSs in all the patients (p< 0.0001) was observed. A transient increase in the eosinophil count was observed in five patients (above 1000 cells/μL in 2 cases) after 3 months, without any clinical effect.Conclusion: Dupilumab improved all the explored clinical outcomes after 12 months, and the transient hypereosinophilia did not modify treatment response. These real-world data confirm the results reported in randomized controlled trials and provide an important opportunity to characterize the clinical impact of the treatment in a non-trial setting. Further real-world studies with a larger cohort of patients are needed to confirm these findings.Keywords: severe asthma, Named Patient Program, oral corticosteroids, real-world, dupilumab

Background: Increasing evidence is available about the presence of increased serum concentration of immunoglobulin (Ig) free light chains (FLCs) in both atopic and non‐atopic inflammatory diseases, including severe asthma, providing a possible new biomarker of disease. Methods: We analyzed clinical and laboratory data, including FLCs, obtained from a cohort of 79 asthmatic subjects, clinically classified into different GINA steps. A control group of 40 age‐matched healthy donors (HD) was considered. Particularly, HD have been selected according to the absence of monoclonal components (in order to exclude paraproteinemias), were tested for total IgE (that were in the normal ranges) and were negative for aeroallergens specific IgE. Moreover, no abnormality of common inflammatory markers (i.e., erythrocyte sedimentation rate and C‐reactive protein) was detectable. Results: FLC‐k levels were significantly increased in the asthmatic population, compared to the control group. Despite the absence of statistically significant differences in FLC‐λ levels, the FLC‐k/FLC‐λ ratio displayed remarkable differences between the two groups. A positive correlation between FLC‐κ and FLC‐λ levels was found. FLC‐ λ level displayed a significant negative correlation with the FEV1 value. Moreover, the FLC‐κ /FLC‐ λ ratio was negatively correlated with the SNOT‐22 score and a positive correlation was observed between FLCs and Staphylococcus Aureus IgE enterotoxins sensitization. Conclusions: Our findings confirmed the role of FLCs in asthma as a potential biomarker in an inflammatory disease characterized by different endotypes and phenotypes. In particular, FLC‐κ and FLC‐k/FLC‐λ ratio could be a qualitative indicator for asthma, while FLC‐λ levels could be a quantitative indicator for clinical severity parameters. [ABSTRACT FROM AUTHOR]

Corrado Pelaia,1 Claudia Crimi,2 Alida Benfante,3 Maria Filomena Caiaffa,4 Cecilia Calabrese,5 Giovanna Elisiana Carpagnano,6 Domenico Ciotta Jnr,7 Maria D’Amato,8 Luigi Macchia,9 Santi Nolasco,2 Girolamo Pelaia,1 Simona Pellegrino,7 Nicola Scichilone,3 Giulia Scioscia,10 Giuseppe Spadaro,11 Giuseppe Valenti,12 Alessandro Vatrella,7 Nunzio Crimi2 1Department of Health Sciences, University “Magna Graecia” of Catanzaro, Catanzaro, Italy; 2Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy; 3Department of Biomedicine and Internal and Specialistic Medicine, University of Palermo, Palermo, Italy; 4Allergology and Clinical Immunology Unit, University of Foggia, Foggia, Italy; 5Department of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, Foggia, Italy; 6Department of Basic Medical Sciences, Neuroscience and Sense Organs, Section of Respiratory Disease, University “Aldo Moro” of Bari, Bari, Italy; 7Department of Medicine, Surgery and Dentistry, University of Salerno, Salerno, Italy; 8Division of Pneumology, “V. Monaldi” University Hospital, Naples, Italy; 9Allergology and Clinical Immunology Unit, University “Aldo Moro” of Bari, Bari, Italy; 10Department of Medical and Surgical Sciences, Institute of Respiratory Diseases, University of Foggia, Foggia, Italy; 11Allergology and Immunology Unit, University “Federico II” of Naples, Naples, Italy; 12Allergology and Pulmonology Unit, Provincial Outpatient Center of Palermo, Palermo, ItalyCorrespondence: Corrado PelaiaDepartment of Health Sciences, University “Magna Graecia” of Catanzaro, Catanzaro, ItalyTel + 39 0961 3647007Email pelaia.corrado@gmail.comBackground: Benralizumab can be utilized as add-on biological treatment of severe eosinophilic asthma. However, so far only a few real-life studies have been published with regard to the use of this anti-IL-5 receptor humanized monoclonal antibody.Objective: The primary aim of this multicenter observational investigation has been to assess the therapeutic effects of benralizumab in patients with severe uncontrolled, corticosteroid refractory eosinophilic asthma. The secondary objective was to evaluate the efficacy of benralizumab with regard to positive or negative skin prick test (SPT).Methods: Clinical, functional, and laboratory parameters were evaluated in order to verify the therapeutic actions of benralizumab in atopic and non atopic subjects with difficult-to-treat eosinophilic asthma. Moreover, a comparative evaluation was carried out in relation to the presence or absence of SPT positivity.Results: After 6 months of add-on biological therapy with benralizumab, our 111 patients experienced a marked improvement of their severe eosinophilic asthma, expressed by significant changes in asthma exacerbation rate, prednisone intake, daily use of short-acting β2-adrenergic agonists (SABA), asthma control test (ACT) score, asthma quality of life questionnaire (AQLQ) score (56 patients), forced expiratory volume in one second (FEV1), forced vital capacity (FVC), blood eosinophil count, blood basophil count (59 patients), and fractional exhaled nitric oxide (FeNO) levels (39 patients). In addition, significantly more effective outcomes were detected in patients with positive SPT, when compared to subjects with negative SPT, only in regard to asthma exacerbation number, ACT score, and daily SABA utilization. No significant correlation was found between serum IgE concentrations and each of all measured parameters.Conclusion and Clinical Relevance: Taken together, the results of this real-world study indicate that in both allergic and non-allergic subjects benralizumab can be used as a valuable pharmacotherapeutic option for add-on biological therapy of severe eosinophilic asthma, regardless of SPT positivity or negativity.Keywords: severe eosinophilic asthma, allergic and non-allergic phenotypes, asthma exacerbations, IL-5 receptor, benralizumab

Claudia Crimi,1 Enrico Heffler,2 Teresa Augelletti,2 Raffaele Campisi,1 Alberto Noto,3 Carlo Vancheri,4 Nunzio Crimi2 1Respiratory Medicine Unit, AOU “Policlinico-Vittorio Emanuele”, Catania, Italy; 2Respiratory Medicine Unit, Department of Clinical and Experimental Medicine, AOU “Policlinico-Vittorio Emanuele”, University of Catania, Catania, Italy; 3Anesthesia and Intensive Care Unit, AOU Policinico “G. Martino”, Messina, Italy; 4Regional Referral Centre for Rare Lung Diseases, A.O.U. “Policlinico-Vittorio Emanuele”, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy Background: Pulmonary rehabilitation (PR) may improve respiratory symptoms and skeletal muscle strength in patients with COPD. We aimed to evaluate changes in ultrasound (US) measurements of diaphragmatic mobility and thickness after PR in COPD patients and to test its correlation with PR outcomes.Methods: Twenty-five COPD patients were enrolled and underwent a diaphragm US assessment before and after a 12-week PR program.Results: We found a correlation between the intraindividual percentage of change in the diaphragmatic length of zone of apposition at functional residual capacity (ΔLzapp%) and the change in 6-minute walking distance (6MWD) after PR (rho=0.49, P=0.02). ΔLzapp% was significantly higher in patients with improved 6MWD and COPD Assessment Test (CAT) score (mean rank=12.03±2.57 vs 6.88±4.37; P=0.02). A ΔLzapp% of ≥10% was able to discriminate among patients with improved 6MWD, with a sensitivity of 83% and a specificity of 74%. The area under the receiver operating characteristic curve for ΔLzapp% was 0.83. A cutoff value of ≥9% of ΔLzapp% had a positive predictive value in discriminating a reduction in ≥2 points of CAT score after PR, with a sensitivity and a specificity of 80% and 62%, respectively.Conclusion: Diaphragm US assessment represents a useful prognostic marker of PR outcomes in COPD patients. Keywords: diaphragm ultrasound, COPD, pulmonary rehabilitation

Cristina Santonocito,1 Alberto Noto,2 Claudia Crimi,3 Filippo Sanfilippo1 1Department of Anesthesia and Intensive Care, IRCCS-ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), Palermo, Italy; 2Department of Anesthesia and Intensive Care, Messina University, Messina, Italy; 3Department of Respiratory Medicine, AOU “Policlinico-Vittorio Emanuele”, University of Catania, Catania, Italy Abstract: The use of remifentanil in clinical practice offers several advantages and it is used for a wide range of procedures, ranging from day-surgery anesthesia to more complex procedures. Nonetheless, remifentanil has been consistently linked with development of opioid-induced hyperalgesia (OIH), which is described as a paradoxical increase in sensitivity to painful stimuli that develops after exposure to opioid treatment. The development of OIH may cause several issues, delaying recovery after surgery and preventing timely patient’s discharge. Moreover, it causes patient’s discomfort with higher pain scores, greater use of analgesics, and associated side effects. Remifentanil is the opioid most convincingly associated with OIH, and hereby we provide a review of remifentanil-induced hyperalgesia, describing both the underlying mechanisms involved and the available studies investigating experimental and clinical pharmacologic approaches aiming at reducing its incidence and degree. Keywords: opioid-induced hyperalgesia, pain, opioid consumption, opioid tolerance