The CORE syndrome: an overlap of severe asthma, obstructive sleep apnea, rhinosinusitis, and esophageal reflux.

PURPOSE: Asthma, obstructive sleep apnea (OSA), rhinosinusitis, and esophageal reflux are conditions that may overlap, forming a syndrome known as CORE. Whenever clinical remission of severe asthma (SA) is not achieved, it is essential to investigate the presence of comorbidities, in particular the presence of OSA that may lead to the diagnosis of CORE syndrome. METHODS: The study was conducted on naive patients with SA and concomitant rhinosinusitis and esophageal reflux, referred to our institute since 2018. Patients who did not experience clinical remission were investigated for OSA through a home sleep apnea test. Subsequently, for those diagnosed with OSA, continuous positive airway pressure (CPAP) was proposed and was re-evaluated after 12 months. RESULTS: Six patients with CORE syndrome were enrolled. The mean apnea-hypopnea index (AHI) was 33.25 ± 20.13 events/h, oxygen desaturation index (ODI) was 28.95 ± 19.95 events/h, and time in bed with SaO2 < 90% (T90) was 26.40 ± 27.22% for which continuous positive airway pressure (CPAP) treatment was proposed but only 3 out of 6 patients accepted. After 12 months, all CPAP-treated patients manifested a significant reduction in daytime sleepiness (ESS score was 6.33 ± 3.8), an improvement in ACT score (+ 8 (+ 32%), + 9 (+ 36%), and + 14 (+ 56%) points), a discontinuation of oral corticosteroids (OCS), an absence of exacerbations, and an improvement of lung function leading to clinical remission of asthma. CONCLUSION: Whenever facing SA patients, non-responders to therapy, it is important to suspect the presence of CORE syndrome; in particular, the detection and subsequent treatment of OSA would seem to improve the outcome of such patients.

Role of BAL and Serum Krebs von den Lungen-6 (KL-6) in Patients with Pulmonary Fibrosis.

Background: Interstitial lung diseases (ILDs) encompass a diverse group of disorders affecting the lung interstitium, leading to inflammation, fibrosis, and impaired respiratory function. Currently, the identification of new diagnostic and prognostic biomarkers for ILDs turns out to be necessary. Several studies show the role of KL-6 in various types of interstitial lung disease and suggest that serum KL-6 levels can be used as a prognostic marker of disease. The aim of this study was to analyze KL-6 expression either in serum or bronchoalveolar lavage samples in order to: (i) make a serum vs. BAL comparison; (ii) better understand the local behavior of fibrosis vs. the systemic one; and (iii) evaluate any differences in patients with progressive fibrosis (PPF) versus patients with non-progressive fibrosis (nPPF). Methods: We used qRT-PCR to detect KL-6 expression both in serum and BAL samples. Mann-Whitney's U test was used to compare the differential expression between groups. Results: In serum, KL-6 is more highly expressed in PPF than in non-progressive fibrosis (p = 0.0295). This difference is even more significant in BAL (p < 0.001). Therefore, it is clear that KL-6 values are related to disease progression. Significant differences were found by making a comparison between BAL and serum. KL-6 was markedly higher in serum than BAL (p = 0.0146). Conclusions: This study identifies KL-6 as a promising biomarker for the severity of the fibrosing process and disease progression in ILDs, with significantly higher levels observed in PPF compared to nPPF. Moreover, the marked difference in KL-6 levels between serum and BAL emphasizes its potential diagnostic and prognostic relevance, providing enlightening insights into both the local and systemic aspects of ILDs.

Clinical Remission in Patients Affected by Severe Eosinophilic Asthma on Dupilumab Therapy: A Long-Term Real-Life Study.

Background. Nowadays, highly selective biological drugs offer the possibility of treating severe type 2 asthma. However, in the real-life setting, it is crucial to confirm the validity of the chosen biological treatment by evaluating the achievement of clinical remission. Study purpose. The main aims of this real-life study were to evaluate the efficacy of dupilumab in terms of clinical, functional, and inflammatory outcomes at 6, 12, 18, and 24 months of treatment and to estimate the percentage of patients achieving partial or complete clinical remission at 12 and 24 months of treatment. In addition, we attempted to identify whether baseline clinical characteristics of patients could be associated with clinical remission at 24 months of treatment. Materials and methods. In this observational prospective study, 20 outpatients with severe uncontrolled eosinophilic asthma were prescribed dupilumab and followed-up after 6, 12, 18, and 24 months of treatment. At each patient visit, the need for oral corticosteroids (OCS) and corticosteroid required dose, number of exacerbations during the previous year or from the previous visit, asthma control test (ACT) score, pre-bronchodilator forced expiratory volume in the 1st second (FEV1), fractional exhaled nitric oxide at a flow rate of 50 mL/s (FeNO50), and blood eosinophil count were assessed. Results. The number of OCS-dependent patients was reduced from 10 (50%) at baseline to 5 (25%) at one year (T12) and 2 years (T24). The average dose of OCS required by patients demonstrated a significant reduction at T12 (12.5 ± 13.75 mg vs. 2.63 ± 3.94 mg, p = 0.015), remaining significant even at T24 (12.5 ± 13.75 mg vs. 2.63 ± 3.94 mg, p = 0.016). The number of exacerbators showed a statistically significant decrease at T24 (10 patients, 50% vs. 3 patients, 15%, p = 0.03). The mean number of exacerbations demonstrated a statistically significant reduction at T24 (1.45 ± 1.58 vs. 0.25 ± 0.43, p = 0.02). The ACT score improved in a statistically significant manner at T12 (15.30 ± 4.16 vs. 21.40 ± 2.35, p < 0.0001), improving further at T24 (15.30 ± 4.16 vs. 22.10 ± 2.59, p < 0.0001). The improvement in pre-bronchodilator FEV1 values reached statistical significance at T24 (79.5 ± 14.4 vs. 87.7 ± 13.8, p = 0.03). The reduction in flow at the level of the small airways (FEF25-75%) also demonstrated an improvement, although it did not reach statistical significance either at T12 or T24. A total of 11 patients (55%) showed clinical remission at T12 (6 complete + 5 partial) and 12 patients (60%) reached clinical remission at T24 (9 complete + 3 partial). Only obesity was associated with a negative odds ratio (OR) for achieving clinical remission at T24 (OR: 0.03, 95% CI: 0.002-0.41, p = 0.004). No other statistically significant differences in baseline characteristics emerged between patients who reached clinical remission at T24 and the group of patients who did not achieve this outcome. Conclusion. Dupilumab appears to be an effective drug in promoting achievement of clinical remission in patients with severe uncontrolled eosinophilic asthma. The achievement of clinical remission should be continuously evaluated during treatment. Further studies are needed to clarify whether certain baseline clinical characteristics can help predict dupilumab favorable outcomes.

Mortality in obstructive sleep apnea syndrome (OSAS) and overlap syndrome (OS): The role of nocturnal hypoxemia and CPAP compliance.

BACKGROUND: Obstructive sleep apnea syndrome (OSAS) and chronic obstructive pulmonary disease (COPD) are two chronic diseases that afflict many individuals worldwide with negative effects on health that may overlap in Overlap Syndrome (OS). The aim of our study was to investigate the differences in mortality between OSAS alone and OS and the risk factors involved. METHODS: The study was conducted on patients with OSAS or OS diagnosis that completed 15-year follow-up between 2005 and 2023. Of these, the clinical, functional, sleep and survival data were registered and analysed. Risk factors were found by regression analysis. RESULTS: 501 patients (428 OSAS and 73 OS) were enrolled. Patients with OS had higher mortality than OSAS (p < 0,001). The morality risk factors for the overall population found were age >65 years (odds ratio (OR) = 10.69 (95%CI 3,85-29,69), p < 0,001) and low forced-expiratory volume in 1-s (FEV1) (OR = 10.18 (95%CI 2,32-44,68), p = 0,002). In patients with OSAS, age and nocturnal hypoxemia (NH) (OR = 2.41 (95%CI 1,07-5,41), p = 0,03) were risk factors, while adherence to nighttime positive airway pressure (PAP) reduced mortality (OR = 0,36 (95%CI 0,15-0,83), p = 0,017). Multivariate analysis confirmed age and FEV1 as risk factors in OS. Conversely, the risk factors for the overall population under 65 years were NH, which is confirmed in patients with OSAS alone (OR = 4,72 (95%CI 1,07-20,77), p = 0,04) in whom, on the other hand, PAP compliance reduced the mortality risk. CONCLUSIONS: The study suggests that NH is a risk factor for all-cause mortality in sleep disorders by excluding the age; conversely, nighttime PAP improves the survival.

MiRNA and Exosomal miRNA as New Biomarkers Useful to Phenotyping Severe Asthma.

Severe asthma (SA) is a chronic inflammatory disease of the airways. Due to the extreme heterogeneity of symptoms, new biomarkers are currently needed. MiRNAs are non-coding RNAs that negatively regulate gene expression at the post-transcriptional level. In biological fluids, miRNAs are contained within exosomes, vesicles capable of giving miRNAs considerable stability and resistance to degradation by RNAses. The main function attributed to the exosomes is intercellular communication. The goal of our study was to analyze intracellular and exosomal miRNAs in order to demonstrate their potential use as non-invasive biomarkers of asthma by showing, in particular, their role in SA. We detected miRNAs by qRT-PCR in both serum and serum-derived-exosomes of asthmatic patients and healthy controls. The levels of almost all analyzed intracellular miRNAs (miR-21, miR-223, and let-7a) were greater in asthmatic patients vs. healthy control, except for miR-223. In detail, miR-21 was greater in SA, while let-7a increased in mild-to-moderate asthma. On the other hand, in exosomes, all analyzed miRNAs were higher in SA. This study identified a series of miRNAs involved in SA, highlighting their potential role in asthma development and progression. These results need validation on a larger cohort.

Intermittent Hypoxia Mediates Cancer Development and Progression Through HIF-1 and miRNA Regulation

Introduction: There is still a debate for the link between obstructive sleep apnoea (OSA) and cancer. The mechanisms underlying this causality are poorly understood. Several miRNAs are involved in cancer development and progression with expression being influenced by hypoxia. The aims of this work were (i) to compare miRNAs expression in controls versus patients affected by OSA without or with cancer (ONCO-OSA) and (ii) in colorectal cancer cells exposed to intermittent hypoxia (IH), to evaluate miRNAs impact on tumor progression in vitro. Methods: We detected miRNAs by qRT-PCR in patients’ sera and in CaCo2 cells exposed to 2–32h of IH with or without acriflavine (ACF), a HIF-1 inhibitor. Viability and transwell invasion test were applied to investigate the proliferation and migration of CaCo2 exposed to IH and treated with miRNA inhibitors or acriflavine. HIF-1α activity was evaluated in CaCo2 cells after IH. Results: The levels of miR-21, miR-26a and miR-210 increased in OSA and ONCO-OSA patients compared to controls. MiR-23b increased in ONCO-OSA patients, and miR-27b and miR-145 increased in OSA but not ONCO-OSA patients. MiR-21, miR-26a, miR-23b and miR-210 increased in cells after IH. IH stimulated cell proliferation and migration. This effect was reduced after either miRNA inhibition or acriflavine treatment. MiRNA inhibition reduces HIF-1α gene expression. Conversely, acriflavine reduced the expression of these miRNAs. Conclusions: We identified a signature of miRNAs, induced by the IH environment. They could be implicated in cancer development and progression through a regulatory loop involving HIF-1. (AU)

Intermittent Hypoxia Mediates Cancer Development and Progression Through HIF-1 and miRNA Regulation.

INTRODUCTION: There is still a debate for the link between obstructive sleep apnoea (OSA) and cancer. The mechanisms underlying this causality are poorly understood. Several miRNAs are involved in cancer development and progression with expression being influenced by hypoxia. The aims of this work were (i) to compare miRNAs expression in controls versus patients affected by OSA without or with cancer (ONCO-OSA) and (ii) in colorectal cancer cells exposed to intermittent hypoxia (IH), to evaluate miRNAs impact on tumor progression in vitro. METHODS: We detected miRNAs by qRT-PCR in patients' sera and in CaCo2 cells exposed to 2-32h of IH with or without acriflavine (ACF), a HIF-1 inhibitor. Viability and transwell invasion test were applied to investigate the proliferation and migration of CaCo2 exposed to IH and treated with miRNA inhibitors or acriflavine. HIF-1α activity was evaluated in CaCo2 cells after IH. RESULTS: The levels of miR-21, miR-26a and miR-210 increased in OSA and ONCO-OSA patients compared to controls. MiR-23b increased in ONCO-OSA patients, and miR-27b and miR-145 increased in OSA but not ONCO-OSA patients. MiR-21, miR-26a, miR-23b and miR-210 increased in cells after IH. IH stimulated cell proliferation and migration. This effect was reduced after either miRNA inhibition or acriflavine treatment. MiRNA inhibition reduces HIF-1α gene expression. Conversely, acriflavine reduced the expression of these miRNAs. CONCLUSIONS: We identified a signature of miRNAs, induced by the IH environment. They could be implicated in cancer development and progression through a regulatory loop involving HIF-1.

Benralizumab in Patients with Severe Eosinophilic Asthma: A Multicentre Real-Life Experience.

BACKGROUND: Mepolizumab and benralizumab are monoclonal antibodies directed against anti-IL-5 and anti-IL5R, respectively, and their use reduces the exacerbation rate and maintains oral corticosteroid requirements in severe eosinophilic asthma. Previous studies have tested the therapeutic switch between two biologics with excellent results, further demonstrating the heterogeneity of asthmatic disease and the complexity of the therapeutic choice. It remains unclear if such patients may improve following a switch from mepolizumab to benralizumab. AIMS: Within a multicentre real-life setting, we decided to evaluate the potential effectiveness of a therapeutic switch to benralizumab in patients with severe eosinophilic asthma initially treated with mepolizumab, who experienced sub-optimal responses. The secondary aim was to identify the clinical factors associated with a better response to benralizumab. METHODS: We retrospectively assessed patients with severe eosinophilic asthma treated at six Italian specialist centres, who were switched from mepolizumab to benralizumab following a sub-optimal response, defined as a partial or total lack of clinical remission (i.e., frequent severe exacerbations and/or poorly controlled symptoms and/or higher OCS daily use in patients with a poor or moderate response in the global evaluation of treatment effectiveness scale), after at least 12 months of treatment. RESULTS: Twenty-five patients were included in the analysis (mean age 56.76 ± 11.97 years, 65% female). At 6 months of treatment with benralizumab, the ACT score was significantly higher than the ACT score with mepolizumab (20.24 ± 3.38 vs. 16.77 ± 3.48, p < 0.0001); the mean number of daily SABA inhalations was significantly lower after 6 months and 12 months of treatment with benralizumab than that after treatment with mepolizumab; OCS intake and the prednisone median dosage at 6 months of treatment with benralizumab were significantly lower than those with mepolizumab. Benralizumab treatment resulted in a marked improvement in asthma control, suppressed blood eosinophil levels and reduction in the number of exacerbations in the subgroup of patients with severe eosinophilic asthma and nasal polyposis. CONCLUSIONS: Patients diagnosed with severe eosinophilic asthma who experience a partial response to mepolizumab could benefit from switching to benralizumab, and even more those who have nasal polyposis.

Benralizumab Effectiveness in Severe Eosinophilic Asthma with Co-Presence of Bronchiectasis: A Real-World Multicentre Observational Study.

Introduction: The co-presence of bronchiectasis (BE) in severe eosinophilic asthma (SEA) is common. Data about the effectiveness of benralizumab in patients with SEA and BE (SEA + BE) are lacking. Aim: The aim of this study was to evaluate the effectiveness of benralizumab and remission rates in patients with SEA compared to SEA + BE, also according to BE severity. Methods: We conducted a multicentre observational study, including patients with SEA who underwent chest high-resolution computed tomography at baseline. The Bronchiectasis Severity Index (BSI) was used to assess BE severity. Clinical and functional characteristics were collected at baseline and after 6 and 12 months of treatment. Results: We included 74 patients with SEA treated with benralizumab, of which 35 (47.2%) showed the co-presence of bronchiectasis (SEA + BE) with a median BSI of 9 (7-11). Overall, benralizumab significantly improved the annual exacerbation rate (p < 0.0001), oral corticosteroids (OCS) consumption (p < 0.0001) and lung function (p < 0.01). After 12 months, significant differences were found between SEA and SEA + BE cohorts in the number of exacerbation-free patients [64.1% vs. 20%, OR 0.14 (95% CI 0.05-0.40), p < 0.0001], the proportion of OCS withdrawal [-92.6% vs. -48.6, p = 0.0003], and the daily dose of OCS [-5 mg (0 to -12.5) vs. -12.5 mg (-7.5 to -20), p = 0.0112]. Remission (zero exacerbations + zero OCS) was achieved more frequently in the SEA cohort [66.7% vs. 14.3%, OR 0.08 (95% CI 0.03-0.27), p < 0.0001]. Changes in FEV1% and FEF25-75% were inversely correlated with BSI (r = -0.36, p = 0.0448 and r = -0.41, p = 0.0191, respectively). Conclusions: These data suggest that benralizumab exerts beneficial effects in SEA with or without BE, although the former achieved less OCS sparing and fewer respiratory-function improvements.

Real-life effects of dupilumab in patients with severe type 2 asthma, according to atopic trait and presence of chronic rhinosinusitis with nasal polyps.

Background: The efficacy of dupilumab as biological treatment of severe asthma and chronic rhinosinusitis with nasal polyps (CRSwNP) depends on its ability to inhibit the pathophysiologic mechanisms involved in type 2 inflammation. Objective: To assess in a large sample of subjects with severe asthma, the therapeutic impact of dupilumab in real-life, with regard to positive or negative skin prick test (SPT) and CRSwNP presence or absence. Methods: Clinical, functional, and laboratory parameters were measured at baseline and 24 weeks after the first dupilumab administration. Moreover, a comparative evaluation was carried out in relation to the presence or absence of SPT positivity and CRSwNP. Results: Among the 127 recruited patients with severe asthma, 90 had positive SPT, while 78 reported CRSwNP. Compared with the 6 months preceding the first dupilumab injection, asthma exacerbations decreased from 4.0 (2.0-5.0) to 0.0 (0.0-0.0) (p < 0.0001), as well as the daily prednisone intake fell from 12.50 mg (0.00-25.00) to 0.00 mg (0.00-0.00) (p < 0.0001). In the same period, asthma control test (ACT) score increased from 14 (10-18) to 22 (20-24) (p < 0.0001), and sino-nasal outcome test (SNOT-22) score dropped from 55.84 ± 20.32 to 19.76 ± 12.76 (p < 0.0001). Moreover, we observed relevant increases in forced expiratory volume in one second (FEV1) from the baseline value of 2.13 L (1.62-2.81) to 2.39 L (1.89-3.06) (p < 0.0001). Fractional exhaled nitric oxide (FeNO) values decreased from 27.0 ppb (18.0-37.5) to 13.0 ppb (5.0-20.0) (p < 0.0001). These improvements were quite similar in subgroups of patients characterized by SPT negativity or positivity, and CRSwNP absence or presence. No statistically significant correlations were detected between serum IgE levels, baseline blood eosinophils or FeNO levels and dupilumab-induced changes, with the exception of FEV1 increase, which was shown to be positively correlated with FeNO values (r = 0.3147; p < 0.01). Conclusion: Our results consolidate the strategic position of dupilumab in its role as an excellent therapeutic option currently available within the context of modern biological treatments of severe asthma and CRSwNP, frequently driven by type 2 airway inflammation.

Inhaled Medications in Chronic Respiratory Diseases: Analysis of Real-Life Use in Puglia (Apulia), Italy.

BACKGROUND: Chronic respiratory diseases (CRDs) are common diseases with a heterogeneous distribution worldwide. Due to their impact on disability, weight assistance and pharmaceutical spending, they represent an important global burden for national health systems. However, few studies have investigated the use and consumption of inhaled drugs in real life in patients with CRDs. OBJECTIVE: This study aimed to investigate the real-life consumption of health care resources of main CRDs through an analysis of the administrative databases of the local health authority (ASL) in the Puglia region (Italy). METHODS: The present study is an observational study that longitudinally reviewed the administrative and health databases associated with patients' consumption of health resources between 2017 and 2018. RESULTS: The first important finding is a marked underestimation of the true incidence of CRDs despite the search for disease-specific exemption codes. Another important result is that the real-life consumption of inhaled drugs among these patients is well below the minimum acceptable values for adherence. The most commonly used inhaled drugs, for which at least one pack was withdrawn, were inhaled steroids (61.6%), followed by the ICS/LABA combination (43.7%) and LABAs (32.4%). However, less than one-third of patients (31%) withdrew at least three packages of ICS or ICS/LABA during the year, while the percentage was reduced to less than 15% for other combinations. Another alarming finding is that only 8.4% of patients taking CRDs drugs reported at least one spirometry during the study period. CONCLUSIONS: The wide availability of computerized systems may be an important tool for increasing therapeutic adherence and optimizing the resources of health systems in the diagnosis, treatment and management of patients with CRDs.

[Inclusion of vaccination into clinical pathways for COPD and asthma: current challenges and future perspectives in Italy]. / La vaccinazione dei pazienti con BPCO e Asma nei PDTA in Italia: gap da colmare e prospettive future.

OBJECTIVES: to describe the importance given to vaccination as a preventive measure in the clinical pathways (CPWs) of patients affected by chronic obstructive pulmonary disease (COPD) and asthma in the Italian regional healthcare services. DESIGN: a comparative analysis was conducted to assess the presence/absence of vaccination recommendations among the available regional CPWs for the management of COPD and asthma. SETTING AND PARTICIPANTS: all the regional CPWs for COPD and asthma available in the "Fondazione ReS" database between 2008 and 2019 have been analysed. MAIN OUTCOME MEASURES: the role attributed to vaccination was assessed in terms of type of recommended vaccinations, management step indicated for administration, vaccination schedules, healthcare professionals involved in the vaccination pathway, potential contraindications, use of indicators for the monitoring of the offer. RESULTS: thirteen CPWs for COPD and only 3 for asthma were published between 2008 and 2019. Twelve of the CPWs for COPD included recommendation for influenza vaccination, 11 of which including also pneumococcal vaccination. The most recent CPW also contained recommendations for measles-mumps-rubella, varicella, Herpes Zoster, and tetanus-diphtheria-acellular pertussis vaccinations. Two of the CPWs related to asthma in adults recommended influenza vaccination. All CPWs provided for the vaccination recommendations during the patient follow-up step. CONCLUSIONS: Italian CPWs still pay little attention to the topic of vaccinations in patients with COPD and asthma. CPWs are required to be updated in the future being compliant with the national immunization schedule recommendations.

A consumer wearable device for tracking sleep respiratory events.

PURPOSE: The diagnosis of obstructive sleep apnea (OSA) is instrument, operator, and time-dependent and therefore requires long waiting times. In recent decades, technological development has produced useful devices to monitor the health status of the population, including sleep. Therefore, the aim of this study was to evaluate a wearable device (WD) in a group of individuals at high risk of OSA. METHODS: The study was conducted on consecutive subjects with high risk of OSA assessed by sleep questionnaires and clinical evaluation. All subjects performed cardio-respiratory monitoring (CRM) and WD simultaneously on a single night, after which the parameters of the two sleep investigations were compared. RESULTS: Of 20 individuals enrolled, 60% were men and mean age was 57.3 ± 10.7 years. The apnea-hypopnea index (AHI) for the CRM was 23.1 ± 19.6 events·h-1 while it was 10.3 ± 8.3 events·h-1 for the WD. Correlation analysis between the results of the two investigations showed r = 0.19 (p = 0.40) for AHI and r = 0.4076 (p = 0.07) for sO2%. The accuracy for different stages of OSA severity was 70% in OSA cases and 60% in moderate to severe cases with sensitivity and specificity varying a great deal. CONCLUSION: Small and low-cost devices may prove to be a valuable resource to reduce costs and waiting times for a sleep investigation in suspected OSA. However, diagnosis of sleep apnea requires valid and reliable instruments, so validation tests are necessary before a device can be commercialized.

Obstructive sleep apnoea-hypopnoea syndrome: state of the art.

Obstructive sleep apnoea-hypopnoea syndrome (OSAHS) is an extremely common sleep-related breathing disorder (SRBD) characterised by complete or partial collapse of the upper airways. These nocturnal phenomena cause high-frequency hypoxemic desaturations (or intermittent hypoxia, IH) during sleep and alterations in gas exchange. The result of IH is the development or worsening of cerebro-cardio-vascular, metabolic and other diseases, which cause a high risk of death. Hence, OSAHS is a multifactorial disease affecting several organs and systems and presenting with various clinical manifestations involving different medical branches. Although it has been estimated that about one billion individuals worldwide are affected by OSAHS, this SRBD remains underestimated also due to misinformation regarding both patients and physicians. Therefore, this review aims to provide information on the main symptoms and risk factors for the detection of individuals at risk of OSAHS, as well as to present the diagnostic investigations to be performed and the different therapeutic approaches. The scientific evidence reported suggest that OSAHS is an extremely common and complex disorder that has a large impact on the health and quality of life of individuals, as well as on healthcare expenditure. Moreover, given its multifactorial nature, the design and implementation of diagnostic and therapeutic programmes through a multidisciplinary approach are necessary for a tailor-made therapy for each patient.

Real life experience of molnupiravir as a treatment of SARS-CoV-2 infection in vaccinated and unvaccinated patients: a letter on its effectiveness at preventing hospitalization.

BACKGROUND: The SARS-CoV-2 pandemic has prompted clinicians to develop an early and effective treatment of viral infections. To date, vaccines, monoclonal antibodies, and antivirals are the cornerstone of therapy for SARS-CoV-2. AIFA approved the prescription of molnupiravir on 30/12/2021. Molnupiravir is a prodrug that causes the accumulation of errors in the viral genome. METHODS: We prescribed molnupiravir to a total of 74 patients in a range between 26 and 96 years old and followed-up them for 30 days. 10 patients affected by idiopathic pulmonary fibrosis (IPF) were treated. RESULTS: The follow-up showed that all of the treated patients presented a regression of symptoms. No patients were hospitalized and/or showed sequelae after the infection by SARS-CoV-2, even though the examined population was older and with more co-morbidities than other patients treated with different antivirals. CONCLUSION: Molnupiravir is safe and well-tolerated by patients with high-risk of progression to severe COVID. No patients were hospitalized or showed sequelae, including all patients affected by IPF.

Imaging Profile After Treatment with Tocilizumab in COVID-19: A Case Series.

INTRODUCTION: COVID-19 is a pandemic disease, mainly affecting the respiratory tract, triggering an inflammatory cascade complicated by multiorgan failure up to death. Among the tested medications for this disease, tocilizumab appears to act directly on the inflammatory cascade, improving COVID-19 outcomes. For this reason, we have tested the efficacy of tocilizumab on lung damage using chest computed tomography (CT). CASE PRESENTATION: The study was conducted on twenty-one hospitalised COVID-19 patients between March-June 2020. Patients were divided into 2 groups according to the therapies administered (TCZ group= treatment with tocilizumab and NTZ group= other therapies). At admission, TCZ group presented worse laboratory test values, respiratory profile (PaO2/FiO2 ratio: 145.37±38.16 mmHg vs 257.9±95.3 mmHg of NTZ group, P<0.01) and radiological signs (multifocal opacity at chest-X-ray: 88% vs 23% of NTZ group, P<0.01). After performing chest CT during the clinical recovery, the scans of the 2 groups were compared and we observed that some features (e.g., ground glass opacity, consolidation and parenchymal bands) were less marked in the TCZ group. CONCLUSION: In our study, patients treated with tocilizumab presented a worse overall clinical and radiological profile at admission, but the control CT showed a similar imaging profile to patients treated with standard therapy. Based on this evidence, we may suggest that tocilizumab plays an important role in COVID-19 patients in reducing lung inflammation.

Clinical Evaluation and Management of Overlap Syndrome (OS) and Obesity Hypoventilation Syndrome (OHS).

Background and Aim: Sleep-disordered breathing (SDB) is an extremely common disorder with a high impact on morbidity and mortality. The purpose of this study was to compare overlap syndrome (OS) and obesity hypoventilation syndrome (OHS) and to highlight and understand the differences between them. Material and Methods: The study was conducted retrospectively on 132 subjects selected by consecutive sampling from those attending our unit for suspected SDB. After clinical evaluation as well as functional and sleep investigations, the population was divided according to diagnosis in OS and OHS; then, the clinical parameters of two groups were compared with different statistical analysis. Results: The subjects with OHS were younger and reported higher rated daytime sleepiness (p = 0.005). In addition, they presented more nocturnal respiratory events (apnea-hypopnea index (AHI) 63.61 ± 22.79 events·h−1 vs. AHIOS 42.21 ± 22.91 events·h−1, p < 0.0001) at the sleep investigation as worse gas exchange during sleep leading to a higher percentage of nocturnal hypoxemia (p < 0.0001). In contrast, subjects with OS had more an impaired respiratory function. With regard to night-time ventilatory therapy, more subjects with OS were effectively treated with continuous positive airway pressure (CPAP) (p = 0.011), while more OHS were treated with auto-adjusting PAP (APAP) (14% vs. 1%, p = 0.008). Conclusions: The present study tried to establish a framework for OS and OHS because proper management of the two disorders would reduce their burden on healthcare.

The Burden of Respiratory Alterations during Sleep on Comorbidities in Obstructive Sleep Apnoea (OSA).

BACKGROUND: Obstructive sleep apnoea (OSA) has an important impact on the risk of morbidity and mortality, so we have designed the present study to understand which factor is most involved in the risk of developing a comorbidity between OSA severity and nocturnal hypoxemia. METHODS: A retrospective study was conducted on 617 adult subjects who were referred to our unit for a suspicion of OSA between January 2018 and January 2020. RESULTS: Sleep investigations performed by participants (72% male and obese in 70% of cases) reported an overall mean apnoea-hypopnoea index (AHI) of 44.0 ± 24.8 events·h-1. Overall, 66% were classified as severe OSA and 76% experienced nocturnal hypoxemia. By analysing the burden of OSA severity and nocturnal hypoxemia on the comorbidities risk, multivariate analysis highlighted the predominant role of age and obesity. Accordingly, after the exclusion of the older and obese participants from the analyses, we noticed that severe OSA was related to the risk of hypertension (odds ratio (OR) = 3.0 [95% confidence interval [CI] 1.4-6.2], p = 0.004) as well as nocturnal hypoxemia (OR = 2.6 [95% CI 1.2-5.4], p = 0.01). CONCLUSIONS: The study seems to suggest that in young, non-obese subjects, OSA is a predisposing factor for the risk of developing hypertension.

EVs-miRNA: The New Molecular Markers for Chronic Respiratory Diseases.

Idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), asthma and sleep disorders are chronic respiratory diseases that affect the airways, compromising lung function over time. These diseases affect hundreds of millions of people around the world and their frequency seems to be increasing every year. Extracellular vesicles (EVs) are small-sized vesicles released by every cell in the body. They are present in most body fluids and contain various biomolecules including proteins, lipids, mRNA and non-coding RNA (micro-RNA). The EVs can release their cargo, specifically micro-RNAs (miRNAs), to both neighboring and/or distal cells, playing a fundamental role in cell-cell communication. Recent studies have shown their possible role in the pathogenesis of various chronic respiratory diseases. The expression of miRNAs and, in particular, of miRNAs contained within the extracellular vesicles seems to be a good starting point in order to identify new potential biomarkers of disease, allowing a non-invasive clinical diagnosis. In this review we summarize some studies, present in the literature, about the functions of extracellular vesicles and miRNAs contained in extracellular vesicles in chronic respiratory diseases and we discuss the potential clinical applications of EVs and EVs-miRNAs for their possible use such as future biomarkers.

Adaptive immunity in different CT patterns of active tuberculosis and possible variability according to patients' geographic provenience.

Background: It is still unclear if low lymphocyte levels are directly related to immunological modifications induced by the TB infection or if they depend on the general pre-existing health impairment of affected patients. Our aim was to detect eventual differences in the immunological status of patients with pulmonary TB compared to an age and sex-matched group of hospitalized patients with other bacterial community-acquired pneumonia (CAP). In addition, we tried to assess an association between alterations in the peripheral lymphocyte subsets and the development of different CT patterns of active TB and to discover differences in the immunological status and in the radiological patterns of TB presentation between patients of different geographic proveniences. Methods: This observational study included 48 patients with TB and 48 sex- and age-matched patients affected by other bacterial CAP. The presence of HIV/AIDS, other immunocompromising conditions, and confounding chronic pulmonary comorbidities was excluded. Flow cytometry was performed on all the enrolled subjects at admission, before starting the appropriate antibiotic therapy. Patients with TB also underwent a computed tomography (CT) scan. Results: Patients with TB showed a decrease in the absolute count of all the lymphocyte subsets compared to the CAP group. Only the reduction in the percentage of CD4+ T-lymphocytes was significant, while the percentage of CD8+ T-lymphocytes was significantly increased. Patients presenting exudative forms with atypical locations of TB showed a significant reduction in the absolute count and percentage of CD19+ B-lymphocytes compared to those affected by productive TB forms with the typical location. Despite being younger, our black Sub-Saharan Africans showed a significant reduction in the CD4+ T-lymphocytes compartment and a higher prevalence of atypical and exudative forms of TB compared with white Europeans. Conclusion: Tuberculosis itself may alter peripheral blood lymphocyte subsets compared to other CAP. An impaired CD19+ B-lymphocyte compartment may result in an abnormal exudative response in atypical locations and a suboptimal bacterial control. Other constitutive or environmental causes may influence immunological differences found in patients with TB, particularly in case of different geographic origins. Anyhow, flow cytometry may be of great value in evaluating the immune function of these patients.