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SARS-CoV-2 pandemic has contributed to implement telemedicine, allowing clinicians to follow the patient remotely, therefore minimizing the risk of any exposure to positive COVID-19 patients. We summarize the approaches adopted to treat and monitor severe asthmatic patients during the lockdown phase of the pandemic. Our experience supports the strategy that every effort should be made to minimize patient contact with the health-care system, planning a pathway that allows patients to receive appropriate medical care and continue the biological therapies, thus preventing the loss of disease control and acute severe exacerbations.

Experimental studies indicate that airway calibre increases the sensitivity of the afferents involved in the cough reflex but it has proved difficult to demonstrate that airway calibre increases the sensitivity of the afferents involved in the cough reflex. Therefore, bronchodilators might have a role, although rather minor, in the treatment of cough. However, although bronchodilators represent the standard of care in the treatment of airway obstruction associated with asthma or COPD, controversy persists regarding the mechanism(s) by which these agents alleviate cough. Furthermore, the available evidence indicates that the effects of bronchodilators on cough are rather inconsistent in humans and casts doubt on the appropriateness of the common practice of using bronchodilators in the treatment of patients with cough without any other evidence of airway obstruction. Regrettably, appropriate long-term trials specifically aimed at evaluating the clinical efficacy of bronchodilators in pathologic cough have not yet been performed. Therefore, properly executed clinical studies of bronchodilators in various types of acute and chronic pathologic cough are required.

Background Asthma considerably impairs patients' quality of life and increases healthcare costs. Severity, morbidity, and degree of disease control are the major drivers of its clinical and economic impact. National scientific societies are required to monitor the application of international guidelines and to adopt strategies to improve disease control and better allocate resources. Aim to provide a detailed picture of the characteristics of asthma patients and modalities of asthma management by specialists in Italy and to develop recommendations for the daily management of asthma in a specialist setting. Method: A quantitative research program was implemented. Data were collected using an ad hoc questionnaire developed by a group of specialists selected by the Italian Pneumology Society/Italian Respiratory Society. Results The records of 557 patients were analyzed. In the next few years, specialists are expected to focus their activity patients with more severe disease and will be responsible for selection of patients for personalized biological therapy; however, only 20% of patients attending Italian specialist surgery can be considered severe. In 84.4% of cases, the visit was a follow-up visit requested in 82.2% of cases by the specialist him/herself. The Asthma Control Test is used only in 65% of patients. When available, a significant association has been observed between the test score and asthma control as judged by the physician, although concordance was only moderate (κ = 0.68). Asthma was considered uncontrolled by the specialist managing the case in 29.1% of patients; nevertheless, treatment was not stepped up in uncontrolled or partly controlled patients (modified in only 37.2% of patients). Conclusions The results of this survey support re-evaluation of asthma management by Italian specialists. More resources should be made available for the initial visit and for more severely ill patients. In addition, more extensive use should be made of validated tools, and available drugs should be used more appropriately.

Background The prevalence of idiopathic pulmonary fibrosis (IPF) is increasing every year. Pirfenidone and nintedanib were approved for treatment of IPF in 2014, but they received only a conditional recommendation for use and, thus, to date no drugs are strongly recommended for IPF. The aim of this study was to assess the effectiveness and safety of the currently approved drugs for IPF and N -acetylcysteine (NAC), the most debated drug in the last update of guidelines for IPF treatment. Methods RCTs in IPF were identified searching from databases of published and unpublished studies. The influence of pirfenidone, nintedanib and NAC on clinical outcomes, safety, and mortality was assessed via pair-wise meta-analysis. Results Ten papers (3847 IPF patients; 2254 treated; 1593 placebo) were included in this study. Our results showed that both pirfenidone and nintedanib, but not NAC, were significantly effective in reducing FVC decline and the risk of FVC ≥10% decline in percent predicted over 12 months. Nintenadib significantly protected against the risk of acute exacerbation and mortality. Pirfenidone and nintedanib showed a similar and good safety profile, whereas NAC provided a signal for increased adverse events. Conclusions The rank of effectiveness emerging from this meta-analysis represents an indirect indicator of potential differences between currently approved doses of pirfenidone and nintedanib. Direct comparisons are necessary to assess this matter, and well designed bench-to-bedside studies would permit to understand the potential of combined, sequential, or adjunctive treatment regimens in which perhaps NAC may have a role for specific clusters of IPF patients.

Background To date there is emerging clinical evidence to add long-acting anti-muscarinic agents (LAMAs) with inhaled corticosteroid (ICSs) in asthma, but the pharmacological rationale that supports the use of such a combination has not yet been explained. The aim of this study was to pharmacologically investigate the interaction between the ICS beclomethasone and the LAMA glycopyrronium on the human airway smooth muscle (ASM) tone. Methods We investigated the rapid non-genomic bronchorelaxant effect of beclomethasone and glycopyrronium, administered alone and in combination, in human isolated bronchi and bronchioles. Experiments were carried out also in passively sensitized airways and the pharmacological analysis of drug interaction was performed by Bliss Independence method. Results The acute administration of beclomethasone and glycopyrronium induced a significant relaxation of passively sensitized ASM pre-contracted with histamine, by causing submaximal/maximal inhibition of the contractile tone in both medium bronchi and bronchioles. Beclomethasone was characterized by a rapid non-genomic and epithelium independent bronchorelaxant effect. In passively sensitized airways, this effect seemed to be dependent by the activation of a Gsα – cyclic adenosine monophosphate (cAMP) – protein kinase A cascade. While no synergistic interaction was detected in non-sensitized bronchi, the beclomethasone/glycopyrronium combination synergistically enhanced the relaxation of passively sensitized medium and small bronchi. The synergistic interaction between beclomethasone and glycopyrronium was associated with an increase of cAMP concentrations. Conclusions Our study provides for the first time the pharmacological rationale for combining low doses of an ICS plus a LAMA.

The major influencing factors on persistent asthma control are the selected treatment(s), the drug delivery route and patient's adherence to therapy, together with the influence of lifestyle (i.e. sedentary habit), comorbid conditions and specific asthma phenotypes. Inhaled corticosteroids (ICS) in combination with a long-acting β2-agonist (LABA) are the gold standard for management of persistent asthma, with maximal local targeting and minimal systemic side effects. Several innovative inhaler devices have been developed for effective local drug administration and good patient compliance to therapy. Recently, a new ICS/LABA fixed combination, formulated with fluticasone propionate (FP) and formoterol fumarate (FF), has been proposed for maintenance treatment of asthma in adults and adolescent patients. FP/FF combines the anti-inflammatory and bronchodilating properties of powerful compounds in a single inhaler. Its pharmacological characteristics allow rapid speed of onset and dosage flexibility required for step-up and step-down strategies, improving adherence to treatment of asthmatic patients. The efficacy of the FP/FF fixed combination at all dosages in controlling asthma symptoms and the reduced rate of discontinuation have been demonstrated by all randomized trials conducted so far.

COPD is a preventable and treatable disease associated with an enhanced chronic inflammatory response. In addition to chronic inflammation other mechanisms have been proposed that is likely to be involved in the development and progression of COPD. Recent evidence in the literature suggests a role for the inflammasome in the airway inflammation observed in COPD. Inflammasomes are intracellular multiprotein complexes that facilitate the autoactivation of the proinflammatory caspase-1 that in response to specific signals induces ultimately the release of the mature form of the inflammatory cytokines IL-1β and IL-18. In stable COPD was observed a higher production of IL-1, with levels further increases during exacerbations. IL-1 is strongly expressed by macrophage-monocyte. It seems that the activity of IL-1β in the lung induces a phenotype with typical characteristics of COPD consisting of lung inflammation, emphysema, and airway fibrosis. COPD could benefit from a targeted approach to the suppression of the inflammatory response, although an effective anti-inflammatory treatment is not yet available. Canakinumab, an anti-IL-1β monoclonal antibody, that binds to human IL-1β with high specificity and neutralizes its signaling, resulting in suppression of inflammation in patients with disorders of autoimmune origin, has been recently evaluated in inflammatory conditions such as COPD.

Inhalation is the preferred route of drug administration in chronic respiratory diseases because it optimises delivery of the active compounds to the targeted site and minimises side effects from systemic distribution. The choice of a device should be made after careful evaluation of the patient's clinical condition (degree of airway obstruction, comorbidities), as well as their ability to coordinate the inhalation manoeuvre and to generate sufficient inspiratory flow. These patient factors must be aligned with the specific advantages and limitations of each inhaler when making this important choice. Finally, adherence to treatment is not the responsibility of the patient alone, but should be shared also by clinicians. Clinicians have access to a wide selection of pressurised metered dose inhalers (pMDIs) and dry powder inhalers (DPIs) that can be used effectively when matched to the needs of individual patients; this should be perceived as an opportunity rather than a limitation.

Bronchoscopy is generally a safe procedure, but the induction of anaesthesia can induce bronchospasm. Consequently we investigated the influence of propofol, remifentanil and lidocaine on the tone of the human bronchial smooth muscle. Materials and methods: The influence of propofol, remifentanil and lidocaine on the contractile response of human bronchial smooth muscle to electrical field stimulation (EFS) has been evaluated. The role of capsaicin-sensitive sensory nerves and of inducible nitric oxide synthase has also been assessed. Furthermore, the interaction between these three dugs has been measured by Bliss Independence (BI) theory. Statistical significance (P < 0.05) was assessed by Student's t test or ANOVA. Results: Propofol (1.3 μg ml-1) and lidocaine (1 mg ml-1) reduced the baseline tone of bronchial rings (-14.45 ± 4.53% and -33.40 ± 1.07%, respectively, P < 0.05), whereas remifentanil had not such effect. Aminoguanidine prevented the relaxant effect of propofol. Propofol did not alter the bronchial contractile response to EFS following 30 min of treatment, whereas remifentanil enhanced the bronchial tension (133.83 ± 9.38%, control 101.93 ± 6.82%, P < 0.05 P < 0.05) and lidocaine completely abolished the contractility at 1 mg ml-1 (P < 0.05). The desensitization of capsaicin-sensitive sensory nerves normalized the hyperresponsiveness induced by remifentanil (-26.77 ± 1.68%, P < 0.05). Significant BI antagonism (P < 0.001) was detected for propofol and lidocaine on the bronchial hyperresponsiveness induced by remifentanil. Conclusion: Propofol and remifentanil may be used safely for bronchoscopy, although remifentanil should be associated with propofol or lidocaine to prevent the potential opioid-mediated bronchospasm.

The use of muscarinic receptor antagonists in the treatment of chronic obstructive pulmonary disease (COPD) is well established. More recently, the potential for long-acting muscarinic receptor antagonists (LAMAs) in the treatment of asthma has also been investigated. While LAMAs offer advantages over short-acting muscarinic receptor antagonists, in terms of a reduced dosing frequency, there remains a need for therapies that improve symptom control throughout both the day and night, provide better management of exacerbations and deliver improved health-related quality of life. Furthermore, the potential for unwanted anticholinergic side effects, particularly cardiovascular effects, remains a concern for this class of compounds. Novel LAMAs in clinical development for the treatment of respiratory disease include: aclidinium bromide, NVA237 (glycopyrronium bromide), GP-MDI, EP-101, CHF-5259, umeclidinium bromide, CHF-5407, TD-4208, AZD8683 and V-0162. These compounds offer potential advantages in terms of onset of action, symptom control and safety. In addition, a number of LAMAs are also being developed as combination treatments with long-acting β2-agonists (LABAs) or inhaled glucocorticosteroids, potentially important treatment options for patients who require combination therapy to achieve an optimal therapeutic response as their disease progresses. More recently, compounds such as GSK961081 and THRX-198321 have been identified that combine LAMA and LABA activity in the same molecule, and have the potential to offer the benefits of combination therapy in a single compound. Here, we review novel LAMAs and dual action compounds in clinical development, with a particular focus on how they may address the current unmet clinical needs in the treatment of respiratory disease, particularly COPD.

Background Respiratory tract infections are common and remain a major source of morbidity, mortality and economic cost worldwide, despite advances in modern medicine. One treatment approach is to non-specifically increase the immune response or augment innate defense mechanisms through the use of bacterial lysates. Polyvalent Mechanical Bacterial Lysate (PMBL) is a bacterial lysate made from a wide range of pathogenic bacteria, including all of the most commonly occurring pathogens of the upper and lower respiratory tract obtained by mechanical lysis. Aim To test the available evidence that PMBL is able to prevent respiratory tract infections. Methods A number of studies investigating randomized comparisons of PMBL (active) with placebo or no treatment (control) were selected for analysis. The primary outcome measure was the prevention of exacerbations or acute respiratory tract infection. The results were expressed as relative risk (RR) and the number of patients needed to treat for one to benefit (NNTB). Results Data from 2557 patients from 15 randomized clinical trials (RCTs) was investigated. PMBL induced a significant reduction of infections vs placebo (RR −0.513; 95% CI; −0.722 – −0.303; p = 0.00). The NNTB was 1.15. The RR was always in favor of PMBL (in recurrent respiratory infections other than COPD, chronic bronchitis and tuberculosis, RR −0.502; 95% CI −0.824 – −0.181; in children RR −2.204; 95% CI −3.260 – −1.147; in COPD or chronic bronchitis, RR −0.404; 95% CI −0.864–0.057; in tuberculosis, RR −0.502; 95% CI −0.890 – −0.114). Conclusions The results of the present meta-analysis suggest that PBML is effective in both in children and in adults in preventing respiratory tract infections. Our current meta-analysis shows that there is a trend with PBML toward clinically significant results in patients with COPD but it did not quite achieve statistical significance due to the small number of COPD studies.

Bronchodilators are the cornerstone of pharmacological management of COPD. For patients whose conditions are not sufficiently controlled by monotherapy, combining bronchodilators of different classes, in particular an inhaled muscarinic antagonist with an inhaled beta(2)-agonist, seems a convenient way of delivering treatment and obtaining superior results. When administered as combination therapy, short-acting bronchodilators provide superior bronchodilation compared with individual agents given alone. More recently, long-acting beta(2)-agonists (LABAs) and muscarinic antagonists (LAMAs) have been introduced, and current guidelines recommend regular use of these agents alone or as concurrent therapy in COPD to maximize bronchodilation. In particular, the combination of a LABA plus LAMA seems to play an important role. This article illustrates the scientific rationale for combining LABAs and LAMAs in COPD, reviews the clinical evidence to support these agents given in combination, and discusses their potential role in the management of patients with COPD.

Pharmacological modulation of beta-adrenoceptor function is one of the critical issues in the treatment of patients with concurrent chronic obstructive pulmonary disease (COPD) and chronic heart failure (CHF). A volume of published evidence sustains the role of long-acting beta(2)-agonists in the treatment of stable COPD, but beta-agonists seem to be detrimental when used for long term in CHF. beta(2)-agonists may exacerbate heart failure and, in any case, they induce adverse cardiac effects in COPD patients with pre-existing cardiovascular disease. The adverse effects of beta(2)-agonists are likely to be exacerbated in COPD patients with coexistent CHF. beta-Blockers are the standard treatment in CHF, but they can worsen FEV(1) and airway hyperresponsiveness and reluctance exists to prescribe these agents to COPD patients, despite the anticipated beneficial cardiovascular effects. Although the literature is reassuring, there are currently no prospective long-term studies on the safety of beta-blockers in COPD. Therefore, although beta-blockers can be introduced in any medical setting for treating patients with concurrent COPD and CHF, it still seems appropriate to only use those beta-blockers that are more selective for the beta(1)-AR but without ISA at the lowest dose and to titrate them slowly with attention to lung function and symptoms, adding an inhaled antimuscarinic agent when bronchodilation is needed.

Some studies suggest that the sympathetic nervous system and the renin-angiotensin system are activated in patients with chronic obstructive pulmonary disease (COPD), potentially resulting in negative cardiopulmonary and muscular effects. The aim of this pilot study was to evaluate the efficacy of an angiotensin converting enzyme (ACE) inhibitor on cardiopulmonary exercise performance in COPD patients. Primary outcome was the effect of treatment on the ventilatory response to exercise (VE/VCO(2) slope). Secondary outcomes were exercise variables evaluated by the cardiopulmonary exercise test, and pulmonary function according to ACE genotyping.4 weeks treatment with enalapril (10 mg od) or placebo was evaluated in 21 COPD patients (FEV(1)60%) and without cardiovascular disease in a double-blind, cross-over study.18 patients completed the study. Enalapril did not exert a significant effect on exercise VE/VCO(2) slope or on peak O(2) consumption. However enalapril significantly improved peak O(2) pulse and work rate compared to placebo. A mild but significant worsening of the diffusion capacity of the lung was observed. ACE genotype did not significantly affect patients' response to treatment, except for a trend toward a more evident effect of treatment in patients with II ACE genotype in terms of O(2) pulse and gas diffusion.In this pilot study, ACE inhibition did not affect the ventilatory response to exercise in COPD patients. However, treatment resulted in improvement in work rate and O(2) pulse, suggesting that ACE inhibitor therapy warrants consideration and may provide beneficial effect on the cardiovascular response to exercise in COPD.

Brain natriuretic peptide (BNP) relaxes guinea pig tracheal smooth muscle in vitro and is effective in preventing ovalbumin-induced bronchoconstriction and microvascular leakage in guinea pigs in vivo. Nonetheless, published studies on BNP in human airways in vitro are still lacking in the literature. The aim of this study was to investigate the effect of BNP in isolated human bronchi. The relaxant effect of BNP (1 nM to 10 μM) was assessed in nonsensitized and in passively sensitized human bronchial airways pre-contracted with submaximal concentration (EC 70 ) of carbachol or histamine. At the end of the experiment, papaverine (500 μM) was then added. BNP induced a weak relaxant activity on carbachol-contracted bronchi in nonsensitized (relaxation: 4.23 ± 0.51%) and passively sensitized bronchi (relaxation: 11.31 ± 2.22%). On the other hand, BNP induced a relaxant activity on His-contracted bronchi in nonsensitized (relaxation: 42.52 ± 9.03%) and in passively sensitized (relaxation: 60.57 ± 9.58%). All these findings are a clear documentation of the modest relaxant role of BNP in asthma and, likely, COPD.

Knowledge on the effects of the additive bronchodilatory effects of short-acting agents on the top of the effect of long-acting bronchodilators is limited. In this trial, we examined the influence of higher than conventional doses of the short-acting inhaled β 2 -adrenergic agent salbutamol and the short-acting anticholinergic drug ipratropium bromide on bronchodilation induced by a regular treatment with the long-acting anticholinergic drug tiotropium 18 μg/day in 30 patients with stable COPD. On 3 separate days, a dose-response curve to inhaled salbutamol (100 μg puff-1), ipratropium bromide (20 μg puff-1) or placebo was constructed 3 h after inhalation of the last dose of tiotropium, using one puff, one puff, two puffs and two puffs, for a total cumulative dose of 600 μg salbutamol or 120 μg ipratropium bromide. Doses were given at 30-min intervals and measurements made 15 min after each dose. At the highest cumulative dose, salbutamol showed a trend to be more effective than ipratropium bromide in improving FEV1 (0.157 L vs 0.125 L), and reducing sRaw (−4.52 kPa/s vs 3.57 kPa/s), although the differences between the two treatments were always not significant (p > 0.05), whereas there was no substantial difference between the two drugs in changing FVC (0.179 L vs 0.168 L), IC (0.254 L vs 0.240 L), TGV (−0.444 L vs −0.441 L), TLC (−0.334 L vs −0.318 L) and RV (−0.467 L vs −0.498 L). Both drugs did not affect heart rate and SpO2. Our results indicate that there is not much difference in bronchodilation between adding higher than conventional doses of salbutamol or ipratropium bromide to tiotropium in patients with stable COPD. Effective improvement of the pulmonary function may be achieved in such a type of patients by adding salbutamol 600 μg or ipratropium bromide 120 μg to regular tiotropium. These is an interesting finding mainly for those COPD patients suffering from cardiovascular co-morbidities that are at highest risk of myocardial infarction, congestive heart failure , cardiac arrest and sudden cardiac death when treated with elevated doses of a β 2-agonist (EudraCT number: 2007-001597-82).

It has been demonstrated in mammals that the airway hyper-responsiveness, which accompanies viral infections, is the result of increased reflex bronchoconstriction due to inhibition of muscarinic prejunctional receptors, which belong to M2 subtypes. Multiple mechanisms account for virus-induced M2 receptor dysfunction. Viral neuraminidase may deglycosylate the M2 receptor, decreasing acetylcholine affinity. Equine influenza remains a common viral respiratory disease of horses worldwide, which results in loss to the equine industry, by decreasing performance, convalescence time and loss of peak performance due to chronic sequelae, such as airway hyper-responsiveness. The purpose of this study was to evaluate the effect of neuraminidase on equine isolated bronchi, assessed in equine bronchial smooth muscle rings, derived from five healthy equine male lungs. A pretreatment with vehicle did not modify contraction induced by electrical field stimulation (EFS) studies at each frequency tested. A pretreatment with pilocarpine (1-100 microM) significantly reduced, while methoctramine (1-100 microM) significantly increased contraction induced by EFS. Finally, neuraminidase (0.5 UI) significantly increased contraction induced by EFS. These results suggest that airway hyper-responsiveness that follows a viral influenza infection might be related to a dysfunction of muscarinic prejunctional receptors.

Acute exacerbations of chronic bronchitis (AECB) affect a significant proportion of the adult population worldwide and are associated with a substantial socioeconomic burden. The majority of episodes of AECB are bacterial in aetiology and patients are generally treated empirically with orally administered antibacterial agents. Guidelines for the management of AECB have been developed by a number of national health authorities and international organisations, with the aim of promoting rational selection of antibacterial therapy to minimise the risk of treatment failure and subsequent hospitalisation while containing the development and spread of antibacterial resistance. This paper reviews a number of recently published or updated AECB treatment guidelines, focusing on patient stratification strategies, antibacterial treatment recommendations, and newer antibacterial treatment options, including respiratory fluoroquinolones and the ketolide telithromycin, which have recently been added to a number of national treatment guidelines.