Publications by authors named "Paola Rogliani"

300 Publications

Validation of the risk stratification score in idiopathic pulmonary fibrosis: study protocol of a prospective, multi-centre, observational, 3-year clinical trial.

BMC Pulm Med 2021 Dec 4;21(1):396. Epub 2021 Dec 4.

Division of Respirology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.

Background: Idiopathic pulmonary fibrosis (IPF) is characterized by a poor prognosis, with a progressive decline in lung function and considerable variability in the disease's natural history. Besides lung transplantation (LTx), the only available treatments are anti-fibrosing drugs, which have shown to slow down the disease course. Therefore, predicting the prognosis is of pivotal importance to avoid treatment delays, which may be fatal for patients with a high risk of progression. Previous studies showed that a multi-dimensional approach is practical and effective in the development of a reliable prognostic score for IPF. In the RIsk Stratification scorE (RISE), physiological parameters, an objective measure of patient-reported dyspnea and exercise capacity are combined to capture different domains of the complex pathophysiology of IPF.

Methods: This is an observational, multi-centre, prospective cohort study, designed to reflect common clinical practice in IPF. A development cohort and a validation cohort will be included. Patients newly diagnosed with IPF based on the ATS/ERS criteria and multi-disciplinary discussion will be included in the study. A panel of chest radiologists and lung pathologists will further assess eligibility. At the first visit (time of diagnosis), and every 4-months, MRC dyspnea score, pulmonary function tests (FEV, FVC and DLCO), and 6-min walking distance will be recorded. Patients will be prospectively followed for 3 years. Comorbidities will be considered. The radiographic extent of fibrosis on HRCT will be recalculated at a 2-year interval. RISE, Gender-Age-Physiology, CPI and Mortality Risk Scoring System will be calculated at 4-month intervals. Longitudinal changes of each variable considered will be assessed. The primary endpoint is 3-year LTx-free survival from the time of diagnosis. Secondary endpoints include several, clinically-relevant information to ensure reproducibility of results across a wide range of disease severity and in concomitance of associated pulmonary hypertension or emphysema.

Discussion: The objective of this study is to validate RISE as a simple, straightforward, inexpensive and reproducible tool to guide clinical decision making in IPF, and potentially as an endpoint for future clinical trials.

Trial Registration: U.S National Library of Medicine Clinicaltrials.gov, trial n. NCT02632123 "Validation of the risk stratification score in idiopathic pulmonary fibrosis". Date of registration: December 16th, 2015.
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http://dx.doi.org/10.1186/s12890-021-01753-7DOI Listing
December 2021

Rationale and Clinical Use of Bronchodilators in Adults with Bronchiectasis.

Drugs 2021 Nov 26. Epub 2021 Nov 26.

Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy.

Currently, there is much controversy surrounding the therapeutic approach to pulmonary function abnormalities in patients with bronchiectasis and, consequently, whether and when to use bronchodilators in these patients. National and international guidelines on the treatment of bronchiectasis in adults do not recommend the routine use of bronchodilators because there is no evidence that a significant response to a bronchodilator or the presence or hyperresponsiveness of the airway are good predictors of future effective clinical response. However, some guidelines recommend them in the presence of airway obstruction and/or special conditions, which vary according to the guideline in question, although there are no recommendations on optimal dosing and bronchodilator treatment combined with or without inhaled corticosteroids. Nonetheless, in contrast with guideline recommendations, bronchodilators are overused in real-world patients with bronchiectasis even in the absence of airway obstruction, as demonstrated by analysis of national and international registries. This overuse can be explained by the awareness of the existence of a solid pharmacological rationale that supports the use of bronchodilators in the presence of chronic airway obstruction independent of its aetiology. We performed a systematic review of the literature and were able to verify that there are no randomised controlled trials (apart from a small study with methodological limitations and a very recent trial involving a not-very-large number of patients), or any long-term observational studies on the short- or long-term effect of bronchodilators in patients with bronchiectasis. Therefore, we believe that it is essential and even urgent to evaluate the effects of bronchodilators in these patients with appropriately designed studies.
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http://dx.doi.org/10.1007/s40265-021-01646-3DOI Listing
November 2021

Acute effect of oxygen therapy on exercise tolerance and dyspnea perception in ILD patients.

Monaldi Arch Chest Dis 2021 Oct 11. Epub 2021 Oct 11.

Respiratory Medicine, Tor Vergata Hospital Foundation, Rome; Respiratory Medicine, Department of Experimental Medicine, Tor Vergata University, Rome.

Ambulatory oxygen therapy (AOT) is commonly prescribed in Interstitial Lung Disease (ILD) patients, with the aim of reducing dyspnea and increasing exercise tolerance. Despite its frequent use and a reasonable physiological rationale, there is a lack of evidence supporting the effect of AOT on improving dyspnea during exercise. Moreover, dyspnea encompasses distinct sensory (intensity, quality) and affective (anxiety, fear) components with different underlying neurophysiological mechanisms. The aim of this study was to evaluate the effect of oxygen supplementation on exercise tolerance and dyspnea in ILD patients with exercise induced hypoxia (EIH). Forty-seven ILD patients performed a six minute walk test (6MWT) on room air (RA) and with oxygen supplementation (Ox). The 6MWT distance (6MWD) was significantly greater with oxygen supplementation (RA: 242±143 m vs Ox: 345±106 m p<0,01). With oxygen supplementation, the overall dyspnea and anxiety significantly decreased both at rest (1,1±1,4 Borg Unit (BU) vs 0,4±0,9BU , p.<0.01, and 1,1±1,6BU vs 0,5±1,3 BU, p.<0.05, respectively) and at the end of exercise (5,1±2,6 BU vs 3,7±2,5 BU, p.<0.001 and 3,4 ±2,9 vs 2,5 ±2,8, p.<0.01, respectively) despite a greater walked distance. In ILD patients with EIH, oxygen supplementation increases the exercise tolerance and reduces overall dyspnea perception and the anxiety component of breathlessness.
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http://dx.doi.org/10.4081/monaldi.2021.1925DOI Listing
October 2021

Impact of long-acting muscarinic antagonists on small airways in asthma and COPD: A systematic review.

Respir Med 2021 Oct 5;189:106639. Epub 2021 Oct 5.

Department of Medicine and Surgery, Respiratory Disease and Lung Function Unit, University of Parma, Parma, Italy.

Small airway disease is recognized as a cardinal pathological process of chronic obstructive pulmonary disease (COPD), and recently small airways have been recognized as a major site of airflow obstruction also in asthmatic patients. The transversal involvement of small airways in COPD and asthma has warranted research efforts to identify therapeutic strategies able to unlock the small airway compartment. The mainstay of COPD treatment is represented by long-acting β-adrenoceptor agonists (LABAs) and long-acting muscarinic antagonists (LAMAs). In asthma, the efficacy of LAMAs administered add-on to inhaled corticosteroids (ICSs) or ICS/LABA combinations has been investigated only in recent years. The aim of this systematic review was to examine the current literature concerning the impact of LAMAs on small airways and their lung deposition in both COPD and asthma. LAMAs administered either alone or in combination induced an effective bronchorelaxant effect of small airways, however the effectiveness of respiratory medications not only relies on the selected drug, but also on the employed inhalation device and patient's adherence. Tiotropium delivered via Respimat® SMI achieved a superior drug deposition in the peripheral lung compared to HandiHaler® dry powder inhaler and metered-dose inhalers (MDIs). The use of co-suspension™ delivery technology for MDIs and the introduction of the eFlow® nebulizer to deliver glycopyrronium improved aerosol drug delivery to the peripheral lung, by achieving uniform distribution of drug particles. This systematic review provides a synthesis of current literature concerning the impact of LAMAs on small airways and an insight on LAMAs distribution within the lung.
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http://dx.doi.org/10.1016/j.rmed.2021.106639DOI Listing
October 2021

The Impact of Monoclonal Antibodies on Airway Smooth Muscle Contractility in Asthma: A Systematic Review.

Biomedicines 2021 Sep 21;9(9). Epub 2021 Sep 21.

Respiratory Disease and Lung Function Unit, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy.

Airway hyperresponsiveness (AHR) represents a central pathophysiological hallmark of asthma, with airway smooth muscle (ASM) being the effector tissue implicated in the onset of AHR. ASM also exerts pro-inflammatory and immunomodulatory actions, by secreting a wide range of cytokines and chemokines. In asthma pathogenesis, the overexpression of several type 2 inflammatory mediators including IgE, IL-4, IL-5, IL-13, and TSLP has been associated with ASM hyperreactivity, all of which can be targeted by humanized monoclonal antibodies (mAbs). Therefore, the aim of this review was to systematically assess evidence across the literature on mAbs for the treatment of asthma with respect to their impact on the ASM contractile tone. Omalizumab, mepolizumab, benralizumab, dupilumab, and tezepelumab were found to be effective in modulating the contractility of the ASM and preventing the AHR, but no available studies concerning the impact of reslizumab on the ASM were identified from the literature search. Omalizumab, dupilumab, and tezepelumab can directly modulate the ASM in asthma, by specifically blocking the interaction between IgE, IL-4, and TSLP, and their receptors are located on the surface of ASM cells. Conversely, mepolizumab and benralizumab have prevalently indirect impacts against AHR by targeting eosinophils and other immunomodulatory effector cells promoting inflammatory processes. AHR has been suggested as the main treatable trait towards precision medicine in patients suffering from eosinophilic asthma, therefore, well-designed head-to-head trials are needed to compare the efficacy of those mAbs that directly target ASM contractility specifically against the AHR in severe asthma, namely omalizumab, dupilumab, and tezepelumab.
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http://dx.doi.org/10.3390/biomedicines9091281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8468486PMC
September 2021

SMART for the treatment of asthma: A network meta-analysis of real-world evidence.

Respir Med 2021 Nov 7;188:106611. Epub 2021 Sep 7.

Department of Medicine and Surgery, Respiratory Disease and Lung Function Unit, University of Parma, Parma, Italy.

A large proportion of asthmatic patients are treated with protocols resulting from data obtained by randomized controlled trials (RCTs) for which they would not have been eligible. Therefore, the aim of this study was to undertake a quantitative synthesis on real-world evidence comparing single inhaled corticosteroid (ICS)/formoterol maintenance and reliever therapy (SMART) and maintenance ICS/long-acting β-adrenoceptor agonist (LABA) + as-needed short-acting β-adrenoceptor agonist (SABA). A network meta-analysis of real-world studies was performed to compare SMART with ICS/LABA + as-needed SABA therapies in asthmatic patients. The surface under the cumulative ranking curve analysis was used to rank efficacy. The posterior probability distribution was reported as 95% credible interval (95%CrI). Data of 11,360 asthmatic patients were extracted from 6 studies. SMART including an ICS at medium-dose (MD) was more effective than MD ICS/LABA FDC + as-needed SABA (RR 0.54 95%CrI 0.42-0.69; P < 0.001) and low-dose (LD) SMART (RR 0.82 95%CrI 0.70-0.95; P < 0.05) against severe asthma exacerbation. MD SMART improved the Asthma Control Questionnaire score more than MD ICS/LABA FDC + as-needed SABA (delta effect -0.33 95%CrI -0.62 to -0.01; P < 0.05). The efficacy rank was: MD SMART > LD SMART > ICS + LABA free combination + as-needed SABA > ICS/LABA FDC + as-needed SABA > MD ICS/LABA FDC + as-needed SABA. The findings of this network meta-analysis of real-world evidence, and concordance with the effect estimates resulting from previous meta-analyses of RCTs, suggest that SMART may represent the preferred therapeutic option to reduce the risk of severe exacerbation in adults with moderate to severe asthma.
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http://dx.doi.org/10.1016/j.rmed.2021.106611DOI Listing
November 2021

Which LABA/LAMA should be chosen in COPD patients in real life?

Pulm Pharmacol Ther 2021 Sep 13;71:102076. Epub 2021 Sep 13.

Institute of Clinical Physiology, National Research Council, Pisa, Italy.

Background: Given COPD heterogeneity, we do not know if some LABA/LAMAs are more suitable for some COPD phenotypes. This real-life database study aimed to evaluate retrospectively the 4 LABA/LAMA effectiveness and highlight possible specificities that could better guide us in choosing the right LABA/LAMA to be used.

Methods: We searched for subjects (1,779) adherent to umeclidinium/vilanterol (UM/VI), indacaterol/glycopyrronium (IND/GLY), aclidinium/formoterol (ACLI/FOR) and tiotropium/olodaterol (TIO/OLO) treatments in our prescribing/dispensing database. Prescriptions for systemic corticosteroids (SC), antibiotics and salbutamol during one year of LABA/LAMA treatment were analyzed.

Results: A better adherence was found in individuals taking IND/GLY (10.42 ± 1.86 packages/year) compared with UM/VI (10.09 ± 1.9; p = 0.008), ACLI/FOR (9.8 ± 1.8; p = 0.001) and TIO/OLO (10.1 ± 2.1; p = 0.047). The number of patients that were prescribed at least one package of SC/year and their package numbers/year were similar in males/females, across age groups and in "non-frequent exacerbators" with the 4 LABA/LAMAs. More SC were taken by frequent exacerbators, whereas fewer SC/antibiotic packages were prescribed to subjects aged >80 years with all treatments. In patients treated with ACLI/FOR or TIO/OLO, lower risks to having antibiotic prescriptions were observed when UM/VI (0.698[0.516-0.945] and 0.696[0.491-0.985; p = 0.020 and p = 0.041) and IND/GLY (0.597[0.445-0.802] and 0.595[0.423-0.836]; p = 0.001 and p = 0.003) were considered as landmarks. Lower risks for salbutamol prescriptions were detected with UM/VI (0.678[0.480-0.958]; p = 0.027) and TIO/OLO (0.585[0.365-0.937]; p = 0.026) when ACLI/FOR was used as a reference.

Conclusion: According to our retrospective database study, each LABA/LAMA could have a specific efficacy profile in COPD that might be considered for personalized therapy. However, head-to-head targeted trials aimed to assess the impact of different LABA/LAMAs on COPD are needed to confirm/disprove such results.
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http://dx.doi.org/10.1016/j.pupt.2021.102076DOI Listing
September 2021

Multi-walled carbon nanotubes induce airway hyperresponsiveness in human bronchi by stimulating sensory C-fibers and increasing the release of neuronal acetylcholine.

Expert Rev Respir Med 2021 11 16;15(11):1473-1481. Epub 2021 Sep 16.

Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy.

Objectives: The potential of multi-walled carbon nanotubes (MWCNTs) in inducing airway hyperresponsiveness (AHR) was investigated in human airways.

Methods: Human isolated bronchi were exposed to MWCNTs and the contractility to electrical field stimulation (EFS) was measured. Neuronal acetylcholine (ACh) and cyclic adenosine monophosphate (cAMP) were quantified. Some tissues were desensitized by consecutive administrations of capsaicin.

Results: MWCNTs (100 ng/ml - 100 µg/ml) induced AHR (overall contractile tone vs. negative control: +83.43 ± 11.13%, P < 0.01). The potency was significantly (P < 0.05) greater when airways were stimulated at low frequency (EFS) then at medium-to-high frequencies (EFS and EFS) (delta potency: +2.13 ± 0.74 and +2.40 ± 0.65 logarithms, respectively). In capsaicin-desensitized airways, the AHR to MWCNTs 100 ng/ml was abolished. MWCNTs increased the release of ACh, an effect prevented by capsaicin-desensitization (-90.17 ± 18.59%, P < 0.05). MWCNTs did not alter the level of cAMP.

Conclusion: MWCNTs administered at low concentrations elicit AHR in human airways by activating sensory C-fibers and, in turn, increasing the release of neuronal ACh. Our results suggest that work is required to understand the impact of MWCNTs in patients at risk of AHR, such as those suffering from chronic obstructive respiratory disorders.
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http://dx.doi.org/10.1080/17476348.2021.1979395DOI Listing
November 2021

An Overview of the Safety and Efficacy of Monoclonal Antibodies for the Chronic Obstructive Pulmonary Disease.

Biologics 2021 27;15:363-374. Epub 2021 Aug 27.

Chair of Pharmacology, Department of Experimental Medicine, University of Campania Luigi Vanvitelli, Naples, Italy.

Several mAbs have been tested or are currently under clinical evaluation for the treatment of COPD. They can be subdivided into those that aim to block specific pro-inflammatory and pro-neutrophilic cytokines and chemokines, such as TNF-α, IL-1β, CXCL8 and IL-1β, and those that act on T2-mediated inflammation, respectively, by blocking IL-5 and/or its receptor, preventing IL-4 and IL-13 signaling, affecting IL-33 pathway and blocking TSLP. None of these approaches has proved to be effective, probably because in COPD there is no dominant cytokine or chemokine and, therefore, a single mAb cannot be effective on all pathways. With a more in-depth understanding of the numerous pheno/endotypic pathways that play a role in COPD, it may eventually be possible to identify those specific patients in whom some of these cytokines or chemokines might predominate. In this case, it will be possible to implement a personalized treatment, but the use of each mAb will only be reserved for a very limited number of subjects.
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http://dx.doi.org/10.2147/BTT.S295409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8407524PMC
August 2021

Use of Thiols in the Treatment of COVID-19: Current Evidence.

Lung 2021 08 27;199(4):335-343. Epub 2021 Aug 27.

Unit of Pharmacology, Department of Experimental Medicine, University of Campania "Luigi Vanvitelli, Naples, Italy.

There is a possible role for oxidative stress, a state characterized by an altered balance between the production of free radicals or reactive oxygen species (ROS) and antioxidant defences, in coronavirus disease 2019 (COVID-19), the genesis of which is quite complex. Excessive oxidative stress could be responsible for the alveolar damage, thrombosis, and red blood cell dysregulation observed in COVID-19. Apparently, deficiency of glutathione (GSH), a low-molecular-weight thiol that is the most important non-enzymatic antioxidant molecule and has the potential to keep the cytokine storm in check, is a plausible explanation for the severe manifestations and death in COVID-19 patients. Thiol drugs, which are considered mucolytic, also possess potent antioxidant and anti-inflammatory properties. They exhibit antibacterial activity against a variety of medically important bacteria and may be an effective strategy against influenza virus infection. The importance of oxidative stress during COVID-19 and the various pharmacological characteristics of thiol-based drugs suggest a possible role of thiols in the treatment of COVID-19. Oral and intravenous GSH, as well as GSH precursors such as N-acetylcysteine (NAC), or drugs containing the thiol moiety (erdosteine) may represent a novel therapeutic approach to block NF-kB and address the cytokine storm syndrome and respiratory distress observed in COVID-19 pneumonia patients.
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http://dx.doi.org/10.1007/s00408-021-00465-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8390541PMC
August 2021

Controversy surrounding the Sputnik V vaccine.

Respir Med 2021 10 10;187:106569. Epub 2021 Aug 10.

Unit of Pharmacology, Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.

The Sputnik V COVID-19 vaccine is a member of the so-called vector vaccines and uses two different vectors (Ad26 priming and Ad5 boost) to reduce the risk of a reduction in the effectiveness of the vaccination. Real life data indicate an efficacy of the vaccine above 97%. Low cost and no need for ultra-cold storage temperature temperatures are other pluses of the Sputnik V vaccine. However, there are also several important shortcomings that must be considered such as the possible reduction of its immunogenicity in the presence of very high Ad5 neutralizing antibody titres and the decrease with age of the antibody titres neutralizing the virus. Furthermore, there is emerging documentation that Sputnik V has a reduced neutralizing capacity against the Beta variant and all variants with the spike protein carrying the E484K substitution. Nevertheless, due to its characteristics, Sputnik V could be another useful means of satisfying the need for mass vaccination. However, it is imperative to document the efficacy and safety of the Sputnik V vaccine in individuals with high pre-existing anti-Ad26 and Ad5-neutralizing antibody titres and in those under the age of 18 or older than 60 years and be certain that Sputnik V does not cause the rare development of immune thrombotic thrombocytopenia. It is hoped that the now widespread use of this vaccine will generate a large pragmatic real-world study with data accessible to anyone interested in verifying them.
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http://dx.doi.org/10.1016/j.rmed.2021.106569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8352655PMC
October 2021

Indacaterol, glycopyrronium, and mometasone: Pharmacological interaction and anti-inflammatory profile in hyperresponsive airways.

Pharmacol Res 2021 10 5;172:105801. Epub 2021 Aug 5.

Department of Medicine and Surgery, Respiratory Disease and Lung Function Unit, University of Parma, Parma, Italy.

LABA/ICS and LABA/LAMA/ICS combinations elicit beneficial effects in asthma. Specific evidence concerning the impact of combining indacaterol acetate (IND), glycopyrronium bromide (GLY), and mometasone furoate (MF) on human airway hyperresponsiveness (AHR) and airway inflammation is still missing. The aim of this study was to characterize the synergy of IND/MF and IND/GLY/MF combinations, both once-daily treatments for asthma, in hyperresponsive airways. Passively sensitized human medium and small airways were stimulated by histamine and treated with IND/MF (molar ratio: 100/45, 100/90) and IND/GLY/MF (molar ratio: 100/37/45, 100/37/90). The effect on contractility and airway inflammation was tested. Drug interaction was assessed by Bliss Independence equation and Unified Theory. IND/MF 100/90 elicited middle-to-very strong synergistic relaxation in medium and small airways (+≈20-30% vs. additive effect, P < 0.05), for IND/MF 100/45 the synergy was middle-to-very strong in small airways (+≈20% vs. additive effect, P < 0.05), and additive in medium bronchi (P > 0.05 vs. additive effect). IND/GLY/MF 100/37/45 and 100/37/90 induced very strong synergistic relaxation in medium and small airways (+≈30-50% vs. additive effect, P < 0.05). Synergy was related with significant (P < 0.05) reduction in IL-4, IL-5, IL-6, IL-9, IL-13, TNF-α, TSLP, NKA, SP, and non-neuronal ACh, and enhancement in cAMP. IND/MF and IND/GLY/MF combinations synergistically interact in hyperresponsive medium and small airways and modulate the levels of cytokines, neurokinins, ACh, and intracellular cAMP. The concentrations of MF in the combinations modulate the effects in the target tissue.
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http://dx.doi.org/10.1016/j.phrs.2021.105801DOI Listing
October 2021

Pulmonary Rehabilitation in Noncystic Fibrosis Bronchiectasis.

Respiration 2021 Aug 5:1-9. Epub 2021 Aug 5.

Division of Respiratory Medicine, Department of Emergency Medicine, University Hospital Policlinico Tor Vergata, Rome, Italy.

Background: Current guidelines for the treatment of noncystic fibrosis bronchiectasis (NCFB) recommend pulmonary rehabilitation (PR), but to date, there are few studies that have proven its effectiveness.

Objective: The main objective of this study was to examine the effect of PR on pulmonary function tests and exercise capacity.

Method: The aim of this study was to systematically review the effects of PR in NCFB on (1) forced expiratory volume in the first second (FEV1) and (2) exercise capacity evaluated by the 6-min walk test (6MWT) and the incremental shuttle walk test (ISWT). This meta-analysis was undertaken according to PRISMA recommendations.

Results: This pair-wise meta-analysis included data obtained from studies that enrolled 529 NCFB patients. The FEV1 assessment after PR between the active and control group did not show any significant increase (FEV1 difference 0.084 mL; CI: -0.064, +0.233; p = 0.264), and there was an increasing trend (188 mL; CI: -0 to 0.009, +0.384) at the limits of statistical significance (p = 0.061). Walked distance showed a significant increase in the PR group compared to the control group (ISWT distance difference 070.0 m; CI: 55.2, 84.8; p < 0.001), and this finding was confirmed before and after PR both by the ISWT (68.85 m greater than baseline; CI: 40.52, 97.18; p < 0.001) and by the 6MWT (37.7 m greater than baseline; CI: 20.22, 55.25; p < 0.001).

Conclusions: PR improves exercise tolerance in NCFB patients, but it has a modest impact on respiratory function.
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http://dx.doi.org/10.1159/000517527DOI Listing
August 2021

Oral Corticosteroids Dependence and Biologic Drugs in Severe Asthma: Myths or Facts? A Systematic Review of Real-World Evidence.

Int J Mol Sci 2021 Jul 1;22(13). Epub 2021 Jul 1.

Respiratory Disease and Lung Function Unit, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy.

Airway inflammation represents an important characteristic in asthma, modulating airflow limitation and symptom control, and triggering the risk of asthma exacerbation. Thus, although corticosteroids represent the cornerstone for the treatment of asthma, severe patients may be dependent on oral corticosteroids (OCSs). Fortunately, the current humanised monoclonal antibodies (mAbs) benralizumab, dupilumab, mepolizumab, omalizumab, and reslizumab have been proven to induce an OCS-sparing effect in randomized controlled trials (RCTs), thus overcoming the problem of OCS dependence in severe asthma. Nevertheless, a large discrepancy has been recognized between selected patients enrolled in RCTs and non-selected asthmatic populations in real-world settings. It is not possible to exclude that the OCS-sparing effect of mAbs resulting from the RCTs could be different than the real effect resulting in clinical practice. Therefore, we performed a systematic review and correlation analysis to assess whether mAbs are effective in eliciting an OCS-sparing effect and overcoming the OCS dependence in severe asthmatic patients in real-world settings. Overall, real-world studies support the evidence that OCS dependence is a real condition that, however, can be found only in a small number of really severe asthmatic patients. In most patients, the dependence on OCS can be related to modifying factors that, when adequately modulated, may lead to a significant reduction or suspension of OCS maintenance. Conversely, in severe asthmatics in whom OCS resistance is proved by a high daily dose intake, mAbs allow reversion of the OCS dependence, leading to the suspension of OCS therapy in most patients or >50% reduction in the daily OCS dose.
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http://dx.doi.org/10.3390/ijms22137132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269277PMC
July 2021

Sex differences in excessive oral corticosteroid exposure in poor adherent adult asthmatics overusing short-acting β-2 agonists.

Minerva Med 2021 Jul 16. Epub 2021 Jul 16.

Institute of Clinical Physiology, National Research Council, Pisa, Italy.

Background: We know that excessive short-acting β2-agonists (SABA) use in asthma may be associated to high exacerbation risks. We studied whether such excessive SABA consumption is connected with different higher oral corticosteroid (OC) prescriptions in the two sexes.

Methods: In our prescribing database, we searched subjects aged 18-40 years that were prescribed at least one SABA package/year and/or at least two ICS or two ICS/LABA boxes/year to identify asthmatics. Their OC prescriptions/year were also examined. Subjects were divided into 4 groups according to SABA packages/year prescribed (0, 1-2,3-6 and ≥7), considering sexes separately.

Results: Individuals recruited were 9,102. Subjects with at least one OC prescription were higher in each group and were females (p<0.001). The OC packages/year number was also more elevated in women especially those with >7 SABA prescriptions/year (0.96 in males vs 2.64 in females, p<0.001). 94.7%/93.6% males/females, who never used SABA, took at least one ICS/LABA (mean 5.84/5.48 packages/year), while the subject percentage adhering to ICS/LABA dropped to 28-47% (mean 0.94-3.82 packages/year) in those who used SABA (p<0.001). Higher SABA prescriptions were associated with an increasing OC dispensation (β=0.057,p<0.0001). We observed also a greater risk of using >3 OC packages/year in subjects with 3-6 (OR:2.98[95%CI:2.19-4.06],p<0.001) and ≥7 (OR:3.49[95%CI:2.39-5.10],p<0.001) SABA prescriptions compared to those that never used SABA. Besides, we found that using ICS (OR:0.51[95%CI:0.35-0.75], p<0.001) or ICS/LABA (OR:0.07[95%CI:0.05-0.09],p<0.001) may significantly reduce SABA prescriptions.

Conclusions: Poor adherence to maintenance treatment appears to associated with excessive SABA prescriptions that may lead to a higher OC consumption particularly noticeable in women.
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http://dx.doi.org/10.23736/S0026-4806.21.07645-XDOI Listing
July 2021

Atherogenic Dyslipidemia on Admission Is Associated With Poorer Outcome in People With and Without Diabetes Hospitalized for COVID-19.

Diabetes Care 2021 09 12;44(9):2149-2157. Epub 2021 Jul 12.

Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy

Objective: Identifying metabolic factors associated with critical disease can help to improve management of patients hospitalized for coronavirus disease 2019 (COVID-19). High triglycerides and low HDL levels characterize the atherogenic dyslipidemia closely related to insulin resistance and diabetes. We examined associations of atherogenic dyslipidemia detected on admission with outcome of COVID-19 during hospitalization.

Research Design And Methods: We retrospectively analyzed clinical reports of 118 consecutive patients hospitalized for COVID-19 in Rome, Italy, between March and May 2020. Clinical characteristics, inflammation markers, and glucose and lipid metabolism parameters at admission were collected. Critical disease was defined as in-hospital death or need for endotracheal intubation. Associations were tested using logistic regression analysis.

Results: Patients with critical COVID-19 ( = 43) were significantly older than those with noncritical disease ( = 75) and presented higher levels of fasting glucose, triglycerides, C-reactive protein, interleukin-6, procalcitonin, and d-dimer ( < 0.01 for all), whereas HDL levels were lower ( = 0.003). Atherogenic dyslipidemia was more frequent in patients with critical COVID-19 (46 vs. 24%, = 0.011), as well as diabetes (37 vs. 19%, = 0.026), and significantly associated with death or intubation (odds ratio 2.53 [95% CI 1.16-6.32], = 0.018). Triglycerides were significantly associated with selected inflammatory biomarkers ( < 0.05 for all) and poorer outcome of COVID-19 during hospitalization in both the overall population and the subgroup with atherogenic dyslipidemia.

Conclusions: Atherogenic dyslipidemia detected on admission can be associated with critical in-hospital course of COVID-19. Further investigations are needed to elucidate the hypothetical role of insulin resistance and related lipid abnormalities in severe acute respiratory syndrome coronavirus 2 pathogenesis. Assessment of lipid profile should be encouraged in patients hospitalized for COVID-19.
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http://dx.doi.org/10.2337/dc20-2838DOI Listing
September 2021

Current long-acting muscarinic antagonists for the treatment of asthma.

Expert Opin Pharmacother 2021 Dec 15;22(17):2343-2357. Epub 2021 Jul 15.

Respiratory Medicine Unit, University Hospital "Tor Vergata", Rome, Italy.

Introduction: The role of long-acting muscarinic antagonists (LAMAs) is well established in uncontrolled asthma, but not in milder stages.

Areas Covered: This review examines the main randomized controlled trials (RCTs) that have investigated LAMAs administered as monotherapy or in combination to asthmatic patients, according to the different phenotypes. It offers an overview of the role of LAMAs or their fixed dose combinations (FDCs) in the treatment across all the different stages of asthma.

Expert Opinion: Tiotropium is now widely recognized as treatment for moderate to severe uncontrolled asthma (step 4-5) in adults and children. The most recent new evidence is: a) in adults, three different LAMA/long-acting β-agonist (LABA)/inhaled corticosteroid (ICS) FDCs have been recently approved, extending the treatment options for these patients; b) therapy with LAMAs does not depend on patient's Th2 status and justifies the indication regardless of patient's phenotyping; c) in the milder stages, the high variability of response to LAMAs and the lack of a good phenotyping of patients represents the main obstacle in prescribing LAMAs. A better characterization of parasympathetic tone activity could improve LAMAs prescription.
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http://dx.doi.org/10.1080/14656566.2021.1952182DOI Listing
December 2021

Medium-dose ICS-containing FDCs reduce all-cause mortality in COPD patients: an in-depth analysis of dual and triple therapies.

Expert Rev Respir Med 2021 Jul 31:1-9. Epub 2021 Jul 31.

Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy.

Objectives: The recent publication of additional data retrieval for patients missing week 52 vital status in the original analyses of the ETHOS study provides the urgent need of updating previous network meta-analyses (NMA) to produce stronger evidence on mortality in patients receiving dual and triple FDCs according with the level of ICS dose.

Methods: A NMA was performed to compare the effect of ICS/LABA/LAMA, ICS/LABA, and LABA/LAMA FDCs administered via the same inhaler device in COPD patients. The number need to treat (NNT) was also calculated.

Results: When considering on-treatment all-cause of death (analyzed patients: 18,864), MD ICS/LABA/LAMA and MD ICS/LABA FDCs significantly reduced the risk of mortality vs. LABA/LAMA FDC (RR 0.59 95%CrI 0.35-0.97 and 0.61 95%CrI 0.38-0.99 respectively, P < 0.05); NNT ranged between 123 and 129. MD ICS/LABA/LAMA FDC also significantly reduced the risk of adjudicated cardiovascular mortality vs. LABA/LAMA FDC (RR 0.44 95%CI 0.19-0.97, P < 0.05). Low-dose (LD) ICS/LABA FDC did not significantly modulate mortality.

Conclusion: MD ICS/LABA/LAMA and MD ICS/LABA FDCs were effective in reducing on-treatment all-cause of death, with MD ICS/LABA/LAMA FDC being effective also against adjudicated cardiovascular mortality. The protection against mortality was related with the level of ICS dose in the FDCs.
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http://dx.doi.org/10.1080/17476348.2021.1951237DOI Listing
July 2021

Assessment of self-reported and objective daytime sleepiness in adult-onset myotonic dystrophy type 1.

J Clin Sleep Med 2021 Dec;17(12):2383-2391

Department of Neurology, Tor Vergata University of Rome, Rome, Italy.

Study Objectives: Excessive daytime sleepiness (EDS) in myotonic dystrophy type 1 is mostly of central origin but it may coexist with sleep-related breathing disorders. However, there is no consensus on the sleep protocols to be used, assessments vary, and only a minority of patients are regularly tested or are on treatment for EDS. Our study presents data on self-reported and objective EDS in adult-onset myotonic dystrophy type 1.

Methods: Sixty-three patients with adult-onset DM1 were subjected to EDS-sleep assessments (polysomnography, Multiple Sleep Latency Test, Epworth Sleepiness Scale). Correlation coefficients were computed to assess the relationship between sleep and sleepiness test results, fatigue, and quality of life.

Results: 33% and 48% of patients had EDS based, respectively, on the Epworth Sleepiness Scale and the Multiple Sleep Latency Test, with a low concordance between these tests (k = 0.19). Thirteen patients (20%) displayed 2 or more sleep-onset rapid eye movement periods on Multiple Sleep Latency Test. Patients having EDS by Multiple Sleep Latency Test had a shorter disease duration ( < .05), higher total sleep time and sleep efficiency and lower wake after sleep onset on polysomnography. Patients with self-reported EDS reported significantly higher fatigue score compared with patients without EDS ( < .05). No other difference was found in demographic, clinical, and respiratory features.

Conclusions: EDS test results are contradictory, making treatment options difficult. Combining quantitative tests and self-reported scales may facilitate physicians in planning EDS care with patients and families.

Citation: Sansone VA, Proserpio P, Mauro L, et al. Assessment of self-reported and objective daytime sleepiness in adult-onset myotonic dystrophy type 1. . 2021;17(12):2383-2391.
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http://dx.doi.org/10.5664/jcsm.9438DOI Listing
December 2021

Ceiling effect of beclomethasone/formoterol/glycopyrronium triple fixed-dose combination in COPD: A translational bench-to-bedside study.

Pulm Pharmacol Ther 2021 08 12;69:102050. Epub 2021 Jun 12.

Department of Medicine and Surgery, Respiratory Disease and Lung Function Unit, University of Parma, Parma, Italy. Electronic address:

Background: Currently, data on the possible synergy of adding a LAMA to ICS/LABA combination are missing and no studies assessed whether triple therapy may induce ceiling bronchodilator effect. A translational study was performed to investigate the interaction between glycopyrronium bromide (GB) and beclomethasone dipropionate (BDP)/formoterol fumarate (FF) combination in human isolated airways and the effect on FEV and small airway resistance of BDP/FF/GB in COPD.

Methods: The interaction of adding GB to BDP/FF combination was tested in vitro in medium and small airways via Bliss, Loewe, and Highest Single Agent models. The peak and trough effect on FEV and R5-R19 of salbutamol on top of BDP/FF/GB 100/6/12.5 μg FDC via extrafine formulation was investigated in severe COPD patients after two weeks of treatment.

Results: GB plus BDP/FF elicited significant synergistic bronchorelaxation in medium and small isolated airways (overall maximal effect: +32% vs. additive effect). No significant (P > 0.05) improvement in R5-R19 was detected when salbutamol was administered on top of BDP/FF/GB 100/6/12.5 μg FDC (peak -0.12 ± 0.22 cmHO/L/s, trough -0.23 ± 0.25 cmHO/L/s). Salbutamol significantly (P < 0.01) increased FEV when administered on top of triple FDC (peak +145 ± 119 ml, trough +221 ± 111 ml).

Conclusion: The synergistic interaction detected in vitro when adding GB to BDP/FF combination may lead to ceiling bronchorelaxation of small airways in vivo, an effect that may improve hyperinflation in subjects with small airway disease and, thus, explain the substantial clinical benefits of triple combination therapy administered via extrafine formulation in severe COPD patients.

Study Registration: ISRCTN94089001.
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http://dx.doi.org/10.1016/j.pupt.2021.102050DOI Listing
August 2021

Incidence of pneumomediastinum in COVID-19: A single-center comparison between 1st and 2nd wave.

Respir Investig 2021 Sep 28;59(5):661-665. Epub 2021 May 28.

Tor Vergata Polyclinic, Department of Surgery, Units of Thoracic Surgery and Breast Surgery, Floor 7A, Viale Oxford 81, 00133, Rome, Italy.

In this study, we compared the incidence of pneumomediastinum in coronavirus disease (COVID-19) patients during the ascending phases of the 1st and 2nd epidemic waves. Crude incidence was higher during the 2nd wave at a quasi-significant level (0.68/1000 vs. 2.05/1000 patient-days, p = 0.05). When restricting the analysis to patients who developed pneumomediastinum during noninvasive ventilation, the difference became clearly significant (0.17/1000 vs 1.36/1000 patient-days, p = 0.039). At logistic regression, predisposing factors (p = 0.031), and COVID-19 radiological severity (p = 0.019) were independently associated with pneumomediastinum. Mortality in patients with pneumomediastinum was 87.5%. However, pneumomediastinum seemed to be related to a generally worse disease presentation in hospitalized patients during the 2nd wave, rather than to a separate pattern of disease.
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http://dx.doi.org/10.1016/j.resinv.2021.04.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8162722PMC
September 2021

Step-up and step-down approaches in the treatment of asthma.

Expert Rev Respir Med 2021 09 7;15(9):1159-1168. Epub 2021 Jun 7.

Division of Respiratory Medicine, University Hospital "Tor Vergata", Rome, Italy.

Significant intraindividual and temporal variability in symptom control is a feature of asthma that requires careful monitoring and the need to periodically review and adjust therapy. Both NHLBI/NAEPP and GINA offer helpful algorithms for a stepping approach to asthma. The problems arisen in applying the stepwise approach to the treatment of asthma proposed by NHLBI/NAEPP and GINA algorithms and their possible alternatives. The current therapeutic stepping approach to asthma, which takes into account lung function, symptoms and quality of life, is certainly useful, but it does not consider the underlying mechanisms. Furthermore, patient's overestimation or underestimation of the severity of the disease and differences in the opinions on the level of asthma control required between patients and physicians and also between physicians in both primary care and specialist settings are common and may negatively affect asthma control and future risks. A reassessment of the conventional stepping approach to management of asthma is now needed. A pragmatic approach that sets therapeutic goals for each individual and associates them with the treatable traits of asthma which, when therapeutically targeted, will in many cases help to achieve the goals, seems more reasonable than the present stepping approach.
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http://dx.doi.org/10.1080/17476348.2021.1935245DOI Listing
September 2021

Management of COPD patients during COVID: difficulties and experiences.

Expert Rev Respir Med 2021 08 19;15(8):1025-1033. Epub 2021 May 19.

Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.

: The role of COPD in COVID-19 is not yet well understood. However, there is increasing evidence showing that COPD patients with COVID-19 have a higher risk of presenting a serious infection, a greater likelihood of requiring ICU support, and a higher mortality than other groups.: In this article, we address some critical questions on COVID-19 as they pertain to COPD. In particular, we discuss whether the usual algorithms of pharmacological and non-pharmacological management in COPD still apply.: Patients with COPD must continue their regular therapy, regardless of whether they are affected by COVID-19. Corticosteroids reduce mortality in COVID-19 patients in need of supportive oxygen therapy or invasive mechanical ventilation. It is essential that a COPD patient who has tested positive for SARS-CoV-2 is closely followed over time because any delay in diagnosis and initiation of appropriate therapy could negatively affect his/her prognosis. However, we still do not know if COVID-19 infection occurs and evolves differently in each of the recognized COPD phenotypes and, therefore, whether it needs a different management. There are other open questions concerning COVID-19 and COPD that need to be considered. Future studies are absolutely necessary to answer these questions.
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http://dx.doi.org/10.1080/17476348.2021.1929176DOI Listing
August 2021

Disputes over the production and dissemination of misinformation in the time of COVID-19.

Respir Med 2021 06 29;182:106380. Epub 2021 Mar 29.

Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.

Ultimate coronavirus disease 2019 (COVID-19) mitigation and crisis resolution is dependent on trustworthy data and actionable information. At present time, there is still no cure for COVID-19, although some treatments are being used in severe illness. Regrettably, as the SARS-CoV-2 virus spreads, the lack of cure has been accompanied by an increasing amount of medical misinformation. In particular, there is a lot of misinformation about how to treat patients who have tested positive for SARS-CoV-2 and who are asymptomatic or have mild symptoms and for whom management at home is deemed appropriate. In this editorial, we highlight the risks deriving from this misinformation, which often arises from the publication of studies that are not conceptually and methodologically accurate.
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http://dx.doi.org/10.1016/j.rmed.2021.106380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006495PMC
June 2021

Dexamethasone in Patients Hospitalized with COVID-19: Whether, When and to Whom.

J Clin Med 2021 Apr 10;10(8). Epub 2021 Apr 10.

Respiratory Disease and Lung Function Unit, Department of Medicine and Surgery, University of Parma, 43125 Parma, Italy.

A clinical interpretation of the Randomized Evaluation of COVID-19 Therapy (RECOVERY) study was performed to provide a useful tool to understand whether, when, and to whom dexamethasone should be administered during hospitalization for COVID-19. A post hoc analysis of data published in the preliminary report of the RECOVERY study was performed to calculate the person-based number needed to treat (NNT) and number needed to harm (NNH) of 6 mg dexamethasone once daily for up to 10 days vs. usual care with respect to mortality. At day 28, the NNT of dexamethasone vs. usual care was 36.0 (95%CI 24.9-65.1, < 0.05) in all patients, 8.3 (95%CI 6.0-13.1, < 0.05) in patients receiving invasive mechanical ventilation, and 34.6 (95%CI 22.1-79.0, < 0.05) in patients receiving oxygen only (with or without noninvasive ventilation). Dexamethasone increased mortality compared with usual care in patients not requiring oxygen supplementation, leading to a NNH value of 26.7 (95%CI 18.1-50.9, < 0.05). NNT of dexamethasone vs. usual care was 17.3 (95%CI 14.9-20.6) in subjects <70 years, 27.0 (95%CI 18.5-49.8) in men, and 16.2 (95%CI 13.2-20.8) in patients in which the onset of symptoms was >7 days. Dexamethasone is effective in male subjects < 70 years that require invasive mechanical ventilation experiencing symptoms from >7 days and those patients receiving oxygen without invasive mechanical ventilation; it should be avoided in patients not requiring respiratory support.
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http://dx.doi.org/10.3390/jcm10081607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069656PMC
April 2021

Factors Influencing the Efficacy of COVID-19 Vaccines: A Quantitative Synthesis of Phase III Trials.

Vaccines (Basel) 2021 Apr 1;9(4). Epub 2021 Apr 1.

Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome "Tor Vergata", 00133 Rome, Italy.

To date, there is still a paucity of data from Phase III trials concerning the efficacy of vaccines against COVID-19. Furthermore, no studies investigated the variables that may modulate the efficacy of vaccination. The aim of this analysis was to assess whether there are modifying factors that may potentially influence the clinical efficacy of COVID-19 vaccines. A quantitative synthesis of data from Phase III trials was performed via pairwise and network meta-analyses, along with meta-regression analysis. Data from Phase III trials are currently available only for AZD1222, BNT162b2, mRNA-1237, and Sputnik V. Vaccination resulted to be generally effective (90.0%, 95%CI 72.6-96.4; < 0.001), although the efficacy of AZD1222 (62.1%) introduced a significant level of heterogeneity in the meta-analysis (I 92.17%, < 0.001). No significant modifying factors resulted from the meta-regression analysis. However, considering the mRNA-based vaccines, a trend toward significance ( = 0.081) resulted for age. The network meta-analysis provided the following rank of effectiveness: BNT162b2 ≃ mRNA-1273 > Sputnik V >> AZD1222. In conclusion, no modifying factors seem to modulate the efficacy of vaccines against COVID-19. This quantitative synthesis will need to be updated as soon as further clinical results on the efficacy profile are available from Phase III trials for further licensed COVID-19 vaccines.
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http://dx.doi.org/10.3390/vaccines9040341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065664PMC
April 2021

Quasilobar minimalist lung volume reduction surgery.

Eur J Cardiothorac Surg 2021 09;60(3):598-606

Department of Biostatistics, Tor Vergata University of Rome, Rome, Italy.

Objectives: Our goal was to assess the results and the costs of the quasilobar minimalist (QLM) thoracoscopic lung volume reduction (LVR) surgical method developed to minimize the trauma from the operation and the anaesthesia and to maximize the effect of the lobar volume reduction.

Methods: Forty patients with severe emphysema underwent QLM-LVR that entailed adoption of sole intercostal block analgesia and lobar plication through a single thoracoscopic incision. Results were compared after propensity matching with 2 control groups undergoing non-awake resectional LVR with double-lumen tracheal intubation or awake non-resectional LVR by plication with thoracic epidural anaesthesia. As a result, we had 3 matched groups of 30 patients each.

Results: Baseline forced expiratory volume in 1 s, residual volume, the 6-min walking test and the modified Medical Research Council dyspnoea index were 0.77 ± 0.18, 4.97 ± 0.6, 328 ± 65 and 3.3 ± 0.7, respectively, with no intergroup difference after propensity score matching. The visual pain score was better (P < 0.007), the hospital stay was shorter (P < 0.04) and overall costs were lower (P < 0.04) in the QLM-LVR group than in the control groups. The morbidity rate was lower with QLM-LVR than with non-awake resectional-LVR (P = 0.006). Significant improvements (P < 0.001) occurred in all study groups during the follow-up period. At 24 months, improvements in residual volume and dyspnoea index were significantly better with QLM-LVR (P < 0.04).

Conclusions: QLM-LVR proved safe and showed better perioperative outcomes and lower procedure-related costs than the control groups. Similar clinical benefit occurred at 12 months, but absolute improvements in residual volume and dyspnoea index were better in the QLM-LVR group at 24 months.
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http://dx.doi.org/10.1093/ejcts/ezab174DOI Listing
September 2021

SARS-CoV-2 Neutralizing Antibodies: A Network Meta-Analysis across Vaccines.

Vaccines (Basel) 2021 Mar 5;9(3). Epub 2021 Mar 5.

Respiratory Disease and Lung Function Unit, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy.

: There are no studies providing head-to-head comparison across SARS-CoV-2 vaccines. Therefore, we compared the efficacy of candidate vaccines in inducing neutralizing antibodies against SARS-CoV-2. : A network meta-analysis was performed to compare the peak levels of SARS-CoV-2 neutralizing antibodies across candidate vaccines. Data were reported as standardized mean difference (SMD) since the outcome was assessed via different metrics and methods across the studies. : Data obtained from 836 healthy adult vaccine recipients were extracted from 11 studies. BBIBP-CorV, AZD1222, BNT162b2, New Crown COVID-19, and Sputnik V induced a very large effect on the level of neutralizing antibodies (SMD > 1.3); CoVLP, CoronaVac, NVX-CoV2373, and Ad5-nCoV induced a large effect (SMD > 0.8 to ≤1.3); and Ad26.COV2.S induced a medium effect (SMD > 0.5 to ≤0.8). BBIBP-CorV and AZD122 were more effective ( < 0.05) than Ad26.COV2.S, Ad5-nCoV, mRNA-1237, CoronaVac, NVX-CoV2373, CoVLP, and New Crown COVID-19; New Crown COVID-19 was more effective ( < 0.05) than Ad26.COV2.S, Ad5-nCoV, and mRNA-1237; CoronaVac was more effective ( < 0.05) than Ad26.COV2.S and Ad5-nCoV; and Sputnik V and BNT162b2 were more effective ( < 0.05) than Ad26.COV2.S. In recipients aged ≤60 years, AZD1222, BBIBP-CorV, and mRNA-1237 were the most effective candidate vaccines. : All the candidate vaccines induced significant levels of SARS-CoV-2 neutralizing antibodies, but only AZD1222 and mRNA-1237 were certainly tested in patients aged ≥70 years. Compared with AZD1222, BNT162b and mRNA-1237 have the advantage that they can be quickly re-engineered to mimic new mutations of SARS-CoV-2.
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http://dx.doi.org/10.3390/vaccines9030227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999682PMC
March 2021

New Avenues for Phosphodiesterase Inhibitors in Asthma.

J Exp Pharmacol 2021 15;13:291-302. Epub 2021 Mar 15.

Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy.

Introduction: Phosphodiesterases (PDEs) are isoenzymes ubiquitously expressed in the lungs where they catalyse cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (GMP), which are fundamental second messengers in asthma, thereby regulating the intracellular concentrations of these cyclic nucleotides, their signaling pathways and, consequently, myriad biological responses. The superfamily of PDEs is composed of 11 families with a distinct substrate specificity, molecular structure and subcellular localization. Experimental studies indicate a possible role in asthma mainly for PDE3, PDE4, PDE5 and PDE7. Consequently, drugs that inhibit PDEs may offer novel therapeutic options for the treatment of this disease.

Areas Covered: In this article, we describe the progress made in recent years regarding the possibility of using PDE inhibitors in the treatment of asthma.

Expert Opinion: Many data indicate the potential benefits of PDE inhibitors as an add-on treatment especially in severe asthma due to their bronchodilator and/or anti-inflammatory activity, but no compound has yet reached the market as asthma treatment mainly because of their limited tolerability. Therefore, there is a growing interest in developing new PDE inhibitors with an improved safety profile. In particular, the research is focused on the development of drugs capable of interacting simultaneously with different PDEs, or to be administered by inhalation. CHF 6001 and RPL554 are the only molecules that currently are under clinical development but there are several new agents with interesting pharmacological profiles. It will be stimulating to assess the impact of such agents on individual treatable traits in specially designed studies.
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http://dx.doi.org/10.2147/JEP.S242961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979323PMC
March 2021
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