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Severe asthma affects about 10% of the population with asthma and is characterized by low lung function and a high count of blood leukocytes, mainly eosinophils. Various definitions are used in clinical practice and in the literature to identify asthma remission: clinical remission, inflammatory remission, and complete remission. This work highlights a consensus for asthma remission using a Delphi method. In the context of the Severe Asthma Network Italy, which accounts for 57 severe asthma centers and more than 2,200 patients, a board of six experts drafted a list of candidate statements in a questionnaire, which has been revised to minimize redundancies and ensure clear and consistent wording for the first round (R1) of the analysis. Thirty-two statements were included in the R1 questionnaire and then submitted to a panel of 80 experts, which used a 5-point Likert scale to measure agreement regarding each statement. Then, an interim analysis of R1 data was performed, and items were discussed and considered to produce a consistent questionnaire for round 2 (R2) of the analysis. Then, the board set the R2 questionnaire, which included only important topics. Panelists were asked to vote on the statements in the R2 questionnaire afterward. During R2, the criteria of complete clinical remission (the absence of the need for oral corticosteroids, symptoms, exacerbations or attacks, and pulmonary function stability) and those of partial clinical remission (the absence of the need for oral corticosteroids, and two of three criteria: the absence of symptoms, exacerbations or attacks, and pulmonary stability) were confirmed. This Severe Asthma Network Italy Delphi analysis defined a valuable and independent tool that is easy to use, to test the efficacy of different treatments in patients with severe asthma enrolled into the SANI registry.

Introduction:Chronic obstructive pulmonary disease (COPD) is a complex respiratory disorder, whose medical and socioeconomic burden as one of the main causes of morbidity and mortality is increasing worldwide. COPD pathophysiology includes chronic airway/lung inflammation and progressive airflow limitation. Therefore, anti-inflammatory and bronchodilator agents are key players in COPD treatment.Areas covered:This review article discusses the complementary molecular interactions connecting the respective mechanisms of action of inhaled corticosteroids (ICS) and long-acting β2-adrenergic agonists (LABAs). Moreover, attention is also focused on clinical trials, which have shown that ICS/LABA combinations are very effective in improving COPD symptoms and lung function, being also able to significantly reduce disease exacerbations.Expert opinion:In selected subgroups of COPD patients, ICS/LABA combinations represent a very useful therapeutic approach for this widespread chronic respiratory disease. In addition to the well-known fixed-dose drug associations such as fluticasone propionate/salmeterol xinafoate and budesonide/formoterol fumarate, other newly developed ICS/LABA combinations are currently emerging as very interesting pharmacological options for COPD treatment.

Introduction:Mounting evidence indicates that endothelial dysfunction and oxidative stress play crucial roles in the pathophysiology of COVID-19 and Long-COVID.Hypothesis:We hypothesized that a supplementation combining L-Arginine (to improve endothelial function) and Vitamin C (to reduce oxidation) could have beneficial effects on Long-COVID symptoms.Methods:We designed a nationwide multicenter clinical study, in which a survey assessing several symptoms that have been previously associated with Long-COVID was administered to COVID-19 survivors; the subjective perception of the tolerance to the effort was measured as well, trough the Borg scale. Patients were divided in two groups, with a 2:1 ratio: the first group included patients treated with L-Arginine + Vitamin C, whereas the second group was treated with multivitaminic combinations (alternative treatment). Before administering the survey, patients completed 30 days of treatment.Results:1590 patients were initially enrolled, of which 1390 successfully completed the study. Following a 30-day treatment with L-Arginine + Vitamin C, the survey revealed that patients in this treatment group had significantly lower scores compared to the other group. There were no other significant differences between the two groups. Furthermore, when examining the subjective perception of the tolerance to the effort (modified Borg scale), we observed a significantly lower value (p<0.0001) in the L-Arginine + Vitamin C patients compared to the alternative-treatment arm.Conclusions:Our findings indicate for the first time that the supplementation with L-Arginine + Vitamin C has favorable effects in Long-COVID, in terms of reducing its typical symptoms and improving the perceived tolerance to effort.

Objective:In critically ill patients, glycaemic variability (GV) was reported as a better predictor of mortality than mean blood glucose level (BGL). We compared the ability of different GV indices and mean BGLs to predict mortality and intensive care unit-acquired infections in a population of ICU patients.

Chronic rhinosinusitis with nasal polyps (CRSwNP) affects around 60% of patients with severe eosinophilic asthma (SEA). Benralizumab was recently approved for SEA add-on treatment.

The aim of this study has been to evaluate the efficacy of the IL-5 receptor blocker benralizumab on chronic rhinosinusitis with nasal polyposis (CRSwNP), associated with severe eosinophilic allergic asthma. Ten patients with severe eosinophilic allergic asthma and CRSwNP were enrolled. Sino-nasal outcome test (SNOT-22), numerical rating scale (NRS), endoscopic nasal polyp score, Lund Mackey CT (computed tomography) score, and blood eosinophil count were measured at baseline and after 24 weeks of treatment with benralizumab. All the above clinical, endoscopic, imaging, and hematological parameters significantly improved after 24 weeks of treatment with benralizumab. In particular, SNOT-22 decreased from 61.10 ± 17.20 to 26.30 ± 19.74 (P< 0.001), NRS decreased from 7.20 ± 1.55 to 3.40 ± 2.22 (P< 0.001), the endoscopic polyp nasal score decreased from 4.20 ± 1.32 to 2.50 ± 1.78 (P< 0.001), the Lund-Mackay CT score decreased from 16.60 ± 5.50 to 6.90 ± 5.99 (P< 0.001), and blood eosinophil count decreased from 807.3 ± 271.1 cells/μL to 0 cells/μL (P< 0.0001). These results strongly suggest that benralizumab exerted a very effective therapeutic action on CRSwNP associated with severe asthma, thus improving nasal symptoms and decreasing polyp size.

Bronchial hyperresponsiveness and airway infiltration with eosinophils and T lymphocytes are key features of asthma. In particular, CD4+T cells are currently believed to play a pivotal role as initiators and coordinators of the asthmatic inflammatory response and, therefore, they represent a crucial target of corticosteroid treatment. The aim of the present investigation is thus to evaluate, in patients with mild asthma, the effects of inhaled corticosteroid therapy on the following parameters: (i) functional state of CD4+T cells; (ii) airway eosinophilia; (iii) bronchial hyperresponsiveness to methacholine. The study was completed by twenty asthmatic, atopic subjects, subdivided into two groups of ten and treated for 12 weeks with either inhaled budesonide (200 μg twice daily) or terbutaline alone (500 μg twice daily), respectively. Expression of CD4+T cell activation markers was measured in induced sputum at baseline and after 1, 4, 8 and 12 weeks of treatment by flow cytometry, which showed a down-regulation of HLA-DR and CD25 surface proteins in the budesonide group, compared with the control group; these differences resulted as being statistically significant through weeks 4–12. Budesonide also induced a quick, sharp reduction in the percentage of eosinophils detectable in induced sputum, as well as a more gradual progressive improvement in airway hyperresponsiveness to methacholine. Therefore, in addition to assessing various indices of bronchial inflammation, flow cytometry can be reliably applied to induced sputum in order to monitor, even in mildly symptomatic patients, the effects of anti-asthma treatments on T cell activation.

Non-typeable Haemophilus influenzae(NTHi) is one of the most frequently involved pathogens in bacterial exacerbations of chronic obstructive pulmonary disease (COPD). In the airways, the main tissue target of NTHi is bronchial epithelium, where this pathogen can further amplify the inflammatory and structural changes induced by proinflammatory cytokines such as tumour necrosis factor-α (TNF-α). Therefore, the aim of this study is to investigate, in primary cultures of human bronchial epithelial cells, the effects of NTHi on signal transduction pathways, apoptotic events and chemokine production activated by TNF-α. Moreover, we also evaluated the effects exerted on such cellular and molecular phenomena by a corticosteroid drug. p38 mitogen-activated protein kinase (MAPK) phosphorylation was analyzed by Western blotting, using an anti-phospho-p38 MAPK monoclonal antibody. Apoptosis was assayed by active caspase-3 expression. Interleukin-8 (IL-8/CXCL8) was detected in cell-free culture supernatants by ELISA. TNF-α induced a significant increase in p38 MAPK phosphorylation. NTHi was able to potentiate the stimulatory actions of TNF-α on caspase-3 expression and, to a lesser extent, on IL-8 secretion. These effects were significantly (P <0.01) inhibited by a pharmacological pre-treatment with budesonide. These results suggest that TNF-a is able to stimulate, via activation of p38 MAPK signalling pathway, IL-8 release and airway epithelial cell apoptosis; the latter effect can be markedly potentiated by NTHi. Furthermore, budesonide can be very effective in preventing, through inhibition of p38 MAPK phosphorylation, both structural and proinflammatory changes elicited in bronchial epithelium by TNF-α and NTHi.

Postoperative organ failures commonly occur after major abdominal surgery, increasing the utilization of resources and costs of care. Tissue hypoxia is a key trigger of organ dysfunction. A therapeutic strategy designed to detect and reverse tissue hypoxia, as diagnosed by an increase of oxygen extraction (O2ER) over a predefined threshold, could decrease the incidence of organ failures. The primary aim of this study was to compare the number of patients with postoperative organ failure and length of hospital stay between those randomized to conventional vs a protocolized strategy designed to maintain O2ER < 27%.

Spectral Entropy (SpEn) is an alternative tool to the bispectral index (BIS) for monitoring depth of hypnosis. SpEn measures response entropy (RE) and state entropy (SE). This open-label prospective study was designed to evaluate SpEn and BIS in 20 patients undergoing elective supratentorial neurosurgery with craniotomy and resection of brain tumors. SpEn and BIS were obtained continuously by Datex Ohmeda M-entropy module S5 (Helsinki, Finland) and Aspect Medical System BIS (Newton), respectively. Total intravenous anesthesia was performed in all patients by Fresenius Vial infusion system (Brezins, France) to maintain a plasma concentration of propofol of 2.5 to 5 μg mL−1and sufentanil of 0.2 to 0.4 ηg mL−1. SpEn, BIS, the estimated propofol effect-site concentrations (Ce), the mean arterial pressure (MAP), and the heart rate (HR) were recorded during 12 specific events induction of anesthesia, patient stop counting, loss of blinking reflex, intubation, mayfield pinning, craniotomy, termination of propofol infusion, recovery of blinking reflex, coughing, limb movement, order execution, and extubation. Stated that prediction probability or PKrepresents an indicator probability to predict correctly the rank order of an arbitrary pair of distinct observed indices of depth of hypnosis (ie, clinical settings and SpEn indices, or BIS, Ce, MAP, HR), PKof BIS, SE, RE, and Ce provided a better depth of hypnosis than MAP and HR; RE being the best for rapidity, SE for sensitivity, and BIS for specificity. There is good correlation between the 3 hypnosis indices and Ce. This study demonstrates that SpEn provides a reproducible hypnosis index for patients undergoing supratentorial neurosurgical procedures.

Mitogen-activated protein kinases (MAPKs) are evolutionary conserved enzymes playing a key role in the transduction of biological signals from cell surface receptors, through the cytoplasm, up to the transcriptional machinery in the nucleus. MAPKs are expressed by alveolar and airway vascular endothelial cells, as well as by bronchial epithelial cells, which actively participate in the inflammatory and immune processes characterizing many lung diseases. We have recently shown, in human pulmonary endothelial cells, that the synthetic glucocorticoid dexamethasone is able to inhibit the phosphorylation-dependent activation of MAPKs induced by oxidative stress and by the pro-inflammatory cytokines interleukin-1β and tumor necrosis factor-α. In primary cultures of human bronchial epithelial cells, our group has also demonstrated that budesonide, a topical corticosteroid widely used as inhaled anti-inflammatory therapy, exerts a potent inhibitory effect on transforming growth factor-β-induced activation of p38, which represents the MAPK subgroup mostly involved in inflammatory processes. Furthermore, other authors have detected an anti-inflammatory action of specific p38 inhibitors in some experimental models of pulmonary inflammation. Therefore, MAPK signalling pathways are emerging as very important, newly recognized targets of anti-inflammatory and immunoregulatory therapies, aimed in particular at controlling the pathogenic events underlying several lung diseases. In this regard, we think that our studies, together with those of other research groups, may contribute to better elucidate the molecular mechanisms responsible for the therapeutic effects of currently available anti-inflammatory agents, as well as to develop novel pharmacological strategies directly targeted at MAPK modulation.

The occurrence of cardiovascular side effects is sometimes associated with the utilization of β-adrenoceptor agonists. The most important causes of these undesirable pharmacologic actions are as follows: (1) direct stimulation of cardiac β-adrenoceptors; (2) reflex activation of adrenergic mechanisms due to peripheral vasodilation; (3) hypokalemia; and (4) hypoxemia. The aim of this study was to evaluate the potential short-term, cardiovascular side effects of salmeterol, a long-acting and highly selective β2-adrenoceptor agonist. Eight volunteer healthy subjects and eight patients with reversible airway obstruction and without cardiovascular alterations were treated with 50 μg of salmeterol twice a day for 3 days and then with 100 μg of salmeterol twice a day for a further 3-day period. The 24-h ECG (Holter) monitoring and measurement of arterial BP, performed on the admission day and on the third and the sixth day of pharmacologic treatment, showed that salmeterol did not produce any significant change in mean heart rate, number of supraventricular and ventricular premature complexes, and BP. Furthermore, no ECG abnormality related to myocardial ischemia was recorded during 24-h Holter monitoring. These data suggest that salmeterol, administered in regular and high doses for a short period, does not cause significant cardiovascular effects in both normal subjects and patients with reversible airway obstruction.