New treatments for asthma: From the pathogenic role of prostaglandin D2 to the therapeutic effects of fevipiprant.

Prostaglandin D2 (PGD2) is a pleiotropic mediator, significantly involved in the pathogenesis of type 2 (T2) asthma because of its biologic actions exerted on both immune/inflammatory and airway structural cells. In particular, the pro-inflammatory and pro-remodelling effects of PGD2 are mainly mediated by stimulation of chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). This receptor is the target of the oral competitive antagonist fevipiprant, which on the basis of recent phase II studies is emerging as a potential very promising anti-asthma drug. Indeed, fevipiprant appears to be safe and effective, especially in consideration of its ability to inhibit eosinophilic bronchial inflammation and improve forced expiratory volume in one second (FEV1). Further ongoing phase III trials will definitely clarify if fevipiprant can prospectively become a valid option for an efficacious add-on treatment of moderate-to-severe T2-high asthma.

Real-life rapidity of benralizumab effects in patients with severe allergic eosinophilic asthma: Assessment of blood eosinophils, symptom control, lung function and oral corticosteroid intake after the first drug dose.

Benralizumab is a humanized monoclonal antibody which binds to the α subunit of the interleukin-5 (IL-5) receptor and to the FcγRIIIa receptor expressed by natural killer cells, thus suppressing the pro-eosinophil actions of IL-5 and triggering eosinophil apoptosis via the very effective mechanism of antibody-dependent cell-mediated cytotoxicity (ADCC). Because of its recent approval and introduction in clinical practice for the add-on biological therapy of severe eosinophilic asthma, real-life investigations are still lacking. In this regard, our present real-life study refers to 13 patients with severe allergic eosinophilic asthma, currently under treatment with benralizumab at the Respiratory Unit of "Magna Græcia" University Hospital located in Catanzaro, Italy. Already 4 weeks after the first subcutaneous injection of benralizumab at the dosage of 30 mg, blood eosinophil count rapidly dropped down from 814.7 ±â€¯292.3 cells/µL to 51.3 ±â€¯97.5 cells/µL (p < 0.0001). This relevant hematologic change was associated with quick and significant increases in asthma control test (ACT) score (from 15.31 ±â€¯2.78 to 21.15 ±â€¯3.58; p < 0.0001), pre-bronchodilator forced expiratory volume in 1 s (FEV1) (from 1441 ±â€¯757.9 mL to 1887 ±â€¯837.3 mL; p < 0.001), and morning peak expiratory flow (PEF) (from 4.21 ±â€¯2.20 to 5.33 ±â€¯1.99 L/sec; p < 0.01). Furthermore, the marked improvement in global health status experienced by our patients allowed them to progressively lower and then completely interrupt, within 4 weeks, their daily intake of oral corticosteroids (OCS), which thereby fell from 15.58 ±â€¯8.30 to 0 mg (p < 0.0001) of prednisone. Therefore, such preliminary results suggest that in patients with severe allergic eosinophilic asthma benralizumab can exert, within a real-life context, a very rapid and effective therapeutic action, already detectable 4 weeks after the first drug administration.

Omalizumab lowers asthma exacerbations, oral corticosteroid intake and blood eosinophils: Results of a 5-YEAR single-centre observational study.

Omalizumab is a humanized monoclonal antibody which binds to human immunoglobulins E (IgE), thus preventing their interactions with both high affinity and low affinity IgE receptors. Therefore, omalizumab is currently recommended for add-on biological therapy of uncontrolled allergic asthma, mainly characterized by type 2 airway eosinophilic inflammation. Because omalizumab has been the first, and for a long time the only available monoclonal antibody for add-on treatment of type 2 asthma, some long-term studies have been published which provide a clear evidence of the therapeutic effectiveness of the anti-IgE pharmacological strategy. Within this context, the present single-centre observational study refers to 15 patients with severe allergic asthma, treated with omalizumab for at least 5 years at the Respiratory Unit of "Magna Græcia" University Hospital located in Catanzaro, Italy. In these asthmatic subjects we observed significant increases in asthma control test (ACT) score, with respect to baseline (14.60 ±â€¯2.97), after 1 year (19.20 ±â€¯2.98; p < 0.0001) and 5 years (21.67 ±â€¯2.38; p < 0.0001) of add-on treatment with omalizumab. More importantly, omalizumab significantly lowered the number of annual asthma exacerbations (baseline: 3.66 ±â€¯2.01) after 1 year (0.83 ±â€¯1.14; p < 0.0001) and 5 years (0.63 ±â€¯0.99; p < 0.0001), respectively. This excellent therapeutic outcome made it possible to drastically decrease the daily oral intake of prednisone (baseline: 22.50 ±â€¯5.17 mg) after 1 year (1.83 ±â€¯4.06 mg; p < 0.0001), as well as after 5 years (1.66 ±â€¯3.61 mg; p < 0.0001). With regard to lung function, omalizumab significantly and persistently enhanced FEV1 (baseline: 1636 ±â€¯628.4 mL) after 1 year (2000 ±â€¯679.7 mL; p < 0.05) and 5 years (1929 ±â€¯564.8 mL; p < 0.05), respectively. Such relevant clinical and functional improvements were associated with reductions of blood eosinophil counts (baseline: 646.0 ±â€¯458.9 cells/µl), already detectable after 1 year (512.7 ±â€¯327.8 cells/µl; not significant), which reached the threshold of statistical significance after 5 years (326.0 ±â€¯171.8 cells/µl; p < 0.05). Therefore, these real-life data referring to our single-centre observational investigation further corroborate the long-term therapeutic ability of omalizumab to improve several clinical, functional and haematological signatures of severe type 2 asthma.

Real-life evaluation of the clinical, functional, and hematological effects of mepolizumab in patients with severe eosinophilic asthma: Results of a single-centre observational study.

Mepolizumab is a humanized monoclonal antibody which targets interleukin-5 (IL-5) and is nowadays available in many countries for add-on biological therapy of severe eosinophilic asthma. Although the approval of mepolizumab use in clinical practice has been made possible by several successful pre-marketing controlled trials, so far only a very few studies have been performed in a real-life setting. Within such a context, our present observational investigation refers to 14 patients with refractory eosinophilic asthma, currently treated with mepolizumab at the Respiratory Unit of "Magna Græcia" University Hospital located in Catanzaro, Italy, whose anti-IL-5 treatment began between June 2017 and January 2018. These patients experienced a significant increase in asthma control test (ACT) score, that was evaluated at baseline (13.64 ±â€¯3.00), as well as after 4 weeks (18.86 ±â€¯3.15; p < 0.0001) and 24 weeks (20.07 ±â€¯1.94; p < 0.0001) of add-on therapy with mepolizumab. This relevant improvement in symptom control was paralleled by a dramatic fall of blood eosinophil numbers, counted at baseline (647.1 ±â€¯274.7 cells/µl), and at the 4th (147.8 ±â€¯66.5 cells/µl; p < 0.0001) and 24th week (98.6 ±â€¯40.3 cells/µl; p < 0.0001) after starting add-on treatment with mepolizumab. These changes were associated with significant and stable increases in FEV1, which was recorded at baseline (1389 ±â€¯454.3 mL), as well as after 4 weeks (1711 ±â€¯482.3 mL; p < 0.001) and 24 weeks (1701 ±â€¯456.0 mL; p < 0.01). Moreover, in comparison to the 6 months preceding the beginning of treatment with mepolizumab, after 24 weeks of anti-IL-5 therapy significant decreases were detected with regard to exacerbation numbers (from 3.64 ±â€¯1.86 to 1.0 ±â€¯0.78; p < 0.001) and oral intake of prednisone (from 24.11 ±â€¯10.36 mg/day to 1.78 ±â€¯3.82 mg/day). Therefore, these preliminary data referring to our single-centre observational study corroborate, in a real-life environment, the efficacy of mepolizumab for treatment of patients with exacerbation-prone, corticosteroid-refractory, severe eosinophilic asthma.

Asthma management in a specialist setting: Results of an Italian Respiratory Society survey.

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.

Molecular and cellular mechanisms underlying the therapeutic effects of budesonide in asthma.

Inhaled glucocorticoids are the mainstay of asthma treatment. Indeed, such therapeutic agents effectively interfere with many pathogenic circuits underpinning asthma. Among these drugs, during the last decades budesonide has been probably the most used molecule in both experimental studies and clinical practice. Therefore, a large body of evidence clearly shows that budesonide, either alone or in combination with long-acting bronchodilators, provides a successful control of asthma in many patients ranging throughout the overall spectrum of disease severity. These excellent therapeutic properties of budesonide basically depend on its molecular mechanisms of action, capable of inhibiting within the airways the activity of multiple immune-inflammatory and structural cells involved in asthma pathobiology.

Cellular mechanisms underlying eosinophilic and neutrophilic airway inflammation in asthma.

Asthma is a phenotypically heterogeneous chronic disease of the airways, characterized by either predominant eosinophilic or neutrophilic, or even mixed eosinophilic/neutrophilic inflammatory patterns. Eosinophilic inflammation can be associated with the whole spectrum of asthma severity, ranging from mild-to-moderate to severe uncontrolled disease, whereas neutrophilic inflammation occurs mostly in more severe asthma. Eosinophilic asthma includes either allergic or nonallergic phenotypes underlying immune responses mediated by T helper (Th)2 cell-derived cytokines, whilst neutrophilic asthma is mostly dependent on Th17 cell-induced mechanisms. These immune-inflammatory profiles develop as a consequence of a functional impairment of T regulatory (Treg) lymphocytes, which promotes the activation of dendritic cells directing the differentiation of distinct Th cell subsets. The recent advances in the knowledge of the cellular and molecular mechanisms underlying asthmatic inflammation are contributing to the identification of novel therapeutic targets, potentially suitable for the implementation of future improvements in antiasthma pharmacologic treatments.

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.

Short-Term Evaluation of Dupilumab Effects in Patients with Severe Asthma and Nasal Polyposis.

BACKGROUND: Having been approved for biological treatment of atopic dermatitis, dupilumab has also been recently licensed as add-on therapy for severe asthma and nasal polyposis. With regard to the latter diseases, few real-life clinical investigations have been carried out to date. OBJECTIVE: The primary end point of this single-center observational study was to evaluate in a real-life setting the short-term therapeutic effects of dupilumab in patients with severe asthma and nasal polyposis. METHODS: At baseline and after 4 weeks of add-on therapy with dupilumab, several clinical and functional parameters were assessed in 20 patients with severe asthma and nasal polyposis, including both allergic and nonallergic subjects. RESULTS: After 4 weeks of treatment with dupilumab, all patients experienced remarkable improvement in both severe asthma and nasal polyposis. In particular, asthma-control test and sinonasal outcome test 22 scores had significantly increased (p<0.0001) and decreased (p<0.0001), respectively. Oral corticosteroid intake got to zero within 4 weeks (p<0.0001). Moreover, in week 4, significant increases were detected with regard to both prebronchodilator forced expiratory volume in the first second (p<0.01) and forced vital capacity (FVC; p<0.05). At the same time point, dupilumab had significantly reduced residual volume (p<0.0001) and total lung capacity (p<0.001), whereas it had enhanced forced midexpiratory flow of 25%-75% FVC (p<0.01) and peak expiratory flow (p<0.01). After 4 weeks of treatment, dupilumab had also lowered levels of fractional exhaled nitric oxide (p<0.0001). CONCLUSION: The results of this real-life study suggest that dupilumab can be utilized in both allergic and nonallergic patients with severe asthma and nasal polyposis as a valuable add-on biological therapy with rapid onset of action.

Effects of the first three doses of benralizumab on symptom control, lung function, blood eosinophils, oral corticosteroid intake, and nasal polyps in a patient with severe allergic asthma.

Severe allergic eosinophilic asthma can be characterized by inadequate control, despite the regular use of high dosages of inhaled corticosteroids/long-acting ß2-adrenergic agonists combinations, and the very frequent utilization of oral corticosteroids. Therefore, under these circumstances, an add-on biological treatment with monoclonal antibodies directed against suitable molecular targets, involved in the pathobiology of type-2 airway inflammation, is very useful. Within such a context, our case report refers to a 46-year-old woman with severe allergic eosinophilic asthma and relapsing nasal polyps, not eligible to add-on biological therapy with omalizumab because of her very high serum levels of immunoglobulins E (IgE). She is currently under treatment with the humanized monoclonal antibody benralizumab (30 mg subcutaneous injection, administered every 4 weeks for the first three doses, and every 8 weeks thereafter), an eosinophil-depleting anti-interleukin-5-receptor biologic. Our patient experienced relevant clinical and functional improvements already after the first dose, and subsequently striking changes were recorded after the second and third doses, including remarkable increases in asthma control test scores and forced expiratory volume in 1 s values, associated with a complete depletion of blood eosinophils and the interruption of oral corticosteroid intake, as well as with the concomitant disappearance of nasal polyps after the second dose. In conclusion, this case study suggests that benralizumab can exert a very rapid and effective therapeutic action in patients with severe eosinophilic asthma and nasal polyposis.

Real-Life effects of benralizumab on exacerbation number and lung hyperinflation in atopic patients with severe eosinophilic asthma.

BACKGROUND: The humanized monoclonal antibody benralizumab targets the α subunit of the interleukin-5 (IL-5) receptor and the FcγRIIIa receptor expressed by natural killer cells. Through this dual mechanism of action, benralizumab neutralizes the pro-eosinophil functions of IL-5 and promotes eosinophil apoptosis. OBJECTIVES AND METHODS: The present real-life study aimed to evaluate, in 22 allergic patients with severe eosinophilic asthma, the effects of benralizumab on asthma exacerbations and lung hyperinflation. RESULTS: In this regard here we show that, after 24 weeks of add-on treatment, benralizumab completely depleted peripheral blood eosinophils (from 810 to 0 cells/µL; p < 0.0001), and significantly decreased both asthma exacerbation number (from 4 to 0; p < 0.0001) and residual volume (from 2720 to 2300 mL; p < 0.01). Moreover, at the same time point (24 weeks) benralizumab also increased pre-bronchodilator FEV1 (from 1295 to 1985 mL; p < 0.0001), FVC (from 2390 to 2974 mL; p < 0.0001), FEF25-75 (from 0.6 to 1.42 L/sec; p < 0.0001), IC (from 1940 to 2460 mL; not significant), and ACT score (from 14.73 to 22.95; p < 0.0001), as well as reduced prednisone intake (from 25 to 0 mg; p < 0.0001). CONCLUSION: In conclusion, our results suggest that via its anti-eosinophil actions benralizumab improved airflow limitation, lung hyperinflation, and respiratory symptoms, as well as lowered asthma exacerbation rate and abrogated OCS consumption in most patients.

Oxygen therapy via high flow nasal cannula in severe respiratory failure caused by Sars-Cov-2 infection: a real-life observational study.

The worldwide spread of coronavirus disease 2019 (COVID-19), caused by the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was declared a pandemic by the World Health Organization (WHO) in March 2020. According to clinical studies carried out in China and Italy, most patients experience mild or moderate symptoms; about a fifth of subjects develop a severe and critical disease, and may suffer from interstitial pneumonia, possibly associated with acute respiratory distress syndrome (ARDS) and death.In patients who develop respiratory failure, timely conventional oxygen therapy through nasal catheter plays a crucial role, but it can be used only in mild forms. Continuous positive airway pressure (CPAP) support or non-invasive mechanical ventilation (NIV) are uncomfortable, and require significant man-machine cooperation. Herein we describe our experience of five patients with COVID-19, who were treated with high-flow nasal cannula (HFNC) after failure of CPAP or NIV, and discuss the role of HFNC in COVID-19 patients. Our findings suggest that HFNC can be used successfully in selected patients with COVID-19-related ARDS.The reviews of this paper are available via the supplemental material section.

Clinical characteristics and predictors of mortality associated with COVID-19 in elderly patients from a long-term care facility.

Since December 2019, coronavirus disease 2019 (COVID-19) pandemic has spread from China all over the world and many COVID-19 outbreaks have been reported in long-term care facilities (LCTF). However, data on clinical characteristics and prognostic factors in such settings are scarce. We conducted a retrospective, observational cohort study to assess clinical characteristics and baseline predictors of mortality of COVID-19 patients hospitalized after an outbreak of SARS-CoV-2 infection in a LTCF. A total of 50 patients were included. Mean age was 80 years (SD, 12 years), and 24/50 (57.1%) patients were males. The overall in-hospital mortality rate was 32%. At Cox regression analysis, significant predictors of in-hospital mortality were: hypernatremia (HR 9.12), lymphocyte count < 1000 cells/µL (HR 7.45), cardiovascular diseases other than hypertension (HR 6.41), and higher levels of serum interleukin-6 (IL-6, pg/mL) (HR 1.005). Our study shows a high in-hospital mortality rate in a cohort of elderly patients with COVID-19 and hypernatremia, lymphopenia, CVD other than hypertension, and higher IL-6 serum levels were identified as independent predictors of in-hospital mortality. Given the small population size as major limitation of our study, further investigations are necessary to better understand and confirm our findings in elderly patients.

Molecular mechanisms underlying airway smooth muscle contraction and proliferation: implications for asthma.

Airway smooth muscle (ASM) plays a key role in bronchomotor tone, as well as in structural remodeling of the bronchial wall. Therefore, ASM contraction and proliferation significantly participate in the development and progression of asthma. Many contractile agonists also behave as mitogenic stimuli, thus contributing to frame a hyperresponsive and hyperplastic ASM phenotype. In this review, the molecular mechanisms and signaling pathways involved in excitation-contraction coupling and ASM cell growth will be outlined. Indeed, the recent advances in understanding the basic aspects of ASM biology are disclosing important cellular targets, currently explored for the implementation of new, more effective anti-asthma therapies.

Benralizumab: From the Basic Mechanism of Action to the Potential Use in the Biological Therapy of Severe Eosinophilic Asthma.

Asthma is a very frequent chronic airway disease that includes many different clinical phenotypes and inflammatory patterns. In particular, eosinophilic bronchial inflammation is often associated with allergic as well as nonallergic asthma. The most important cytokine involved in the induction, maintenance, and amplification of airway eosinophilia in asthma is interleukin-5 (IL-5), released by both T helper 2 (Th2) lymphocytes and group 2 innate lymphoid cells (ILC2). Hence, IL-5 and its receptor are suitable targets for selective biologic drugs which can play a key role in add-on treatment of severe eosinophilic asthma refractory to corticosteroids. Within such a context, the anti-IL-5 monoclonal antibodies mepolizumab and reslizumab have been developed and approved for biological therapy of uncontrolled eosinophilic asthma. In this regard, on the basis of several successful randomized controlled trials, the anti-IL-5 receptor benralizumab has also recently obtained the approval from US Food and Drug Administration (FDA).

Severe eosinophilic asthma: from the pathogenic role of interleukin-5 to the therapeutic action of mepolizumab.

Mepolizumab is an anti-interleukin-5 (IL-5) humanized monoclonal antibody that has been recently approved as an add-on biological treatment for severe eosinophilic asthma, by both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Moreover, mepolizumab is also currently included within the step 5 of the Global Initiative for Asthma guidelines, as an add-on therapy for severe uncontrolled asthma. The relevant therapeutic benefits detectable in patients with refractory eosinophilic asthma receiving mepolizumab depend on the pivotal pathogenic role played by IL-5 in these subjects. Indeed, IL-5 is the key cytokine responsible for maturation, activation, proliferation, and survival of eosinophils. Therefore, IL-5 represents a strategic molecular target for anti-eosinophilic treatments. By selectively inhibiting the biological actions of IL-5, mepolizumab provides a valuable therapeutic option for patients with severe eosinophilic asthma, refractory to standard treatments including inhaled and even systemic corticosteroids. In particular, the very important advantages linked to the use of mepolizumab in these difficult-to-treat asthmatic individuals have been well documented by several different trials performed worldwide.

Role of biologics in severe eosinophilic asthma - focus on reslizumab.

Within the context of the heterogeneous phenotypic stratification of asthmatic population, many patients are characterized by moderate-to-severe eosinophilic asthma, not adequately controlled by relatively high dosages of inhaled and even oral corticosteroids. Therefore, these subjects can obtain significant therapeutic benefits by additional biologic treatments targeting interleukin-5 (IL-5), given the key pathogenic role played by this cytokine in maturation, activation, proliferation, and survival of eosinophils. In particular, reslizumab is a humanized anti-IL-5 monoclonal antibody that has been found to be an effective and safe add-on therapy, capable of decreasing asthma exacerbations and significantly improving disease control and lung function in patients experiencing persistent allergic or nonallergic eosinophilic asthma, despite the regular use of moderate-to-high doses of inhaled corticosteroids. These important therapeutic effects of reslizumab, demonstrated by several controlled clinical trials, have led to the recent approval by US Food and Drug Administration of its use, together with other antiasthma medications, for the maintenance treatment of patients suffering from severe uncontrolled asthma.

Anti-IgE therapy with omalizumab for severe asthma: current concepts and potential developments.

The humanized monoclonal anti-IgE antibody omalizumab is currently the only biologic drug approved for asthma treatment. Omalizumab inhibits allergic responses by binding to serum immunoglobulins E (IgE), thus preventing their interactions with cellular IgE receptors. Omalizumab is also capable of down-regulating the expression of high affinity IgE receptors on inflammatory cells, as well as the numbers of eosinophils in both peripheral blood and induced sputum. The clinical effects of omalizumab include relevant improvements in respiratory symptoms and quality of life, paralleled by a marked reduction of asthma exacerbations, emergency room visits, and use of systemic corticosteroids and rescue bronchodilators. Moreover, some recent studies suggest potential benefits of omalizumab also in non allergic phenotypes of severe asthma. Very interesting are also further recent reports referring to the potential inhibitory effect of omalizumab with regard to bronchial structural changes, especially occurring in severe asthma and globally defined as airway remodeling. Omalizumab is relatively well tolerated, and only very rarely induces anaphylactic reactions. Therefore, this drug represents a valid option as add-on therapy for patients with severe persistent asthma, inadequately controlled by high doses of standard inhaled treatments.

Pharmacologic rationale underlying the therapeutic effects of tiotropium/olodaterol in COPD.

Bronchodilators are the most important drugs used for the treatment of chronic obstructive pulmonary disease (COPD). In particular, these therapeutic agents are mostly long-acting compounds utilized via inhalation, and include LAMA (long-acting muscarinic receptor antagonists) and LABA (long-acting ß2-adrenoceptor agonists). Because LAMA and LABA induce bronchodilation by distinct mechanisms of action, LABA/LAMA combinations provide a reciprocal potentiation of the pharmacological effects caused by each component. Hence, many COPD patients who do not achieve a satisfactory control of their symptoms using a single, either LAMA or LABA bronchodilator, can experience relevant benefits with the use of LAMA/LABA fixed combinations. Many different LAMA/LABA combinations have been recently developed and evaluated in randomized clinical trials. In this context, our review focuses on the pharmacological mechanisms underpinning the bronchodilation elicited by the LAMA tiotropium bromide and the LABA olodaterol. We also discuss the results of the most important clinical studies carried out in COPD patients to assess the efficacy and safety of tiotropium/olodaterol combinations.

Application of proteomics and peptidomics to COPD.

Chronic obstructive pulmonary disease (COPD) is a complex disorder involving both airways and lung parenchyma, usually associated with progressive and poorly reversible airflow limitation. In order to better characterize the phenotypic heterogeneity and the prognosis of patients with COPD, there is currently an urgent need for discovery and validation of reliable disease biomarkers. Within this context, proteomic and peptidomic techniques are emerging as very valuable tools that can be applied to both systemic and pulmonary samples, including peripheral blood, induced sputum, exhaled breath condensate, bronchoalveolar lavage fluid, and lung tissues. Identification of COPD biomarkers by means of proteomic and peptidomic approaches can thus also lead to discovery of new molecular targets potentially useful to improve and personalize the therapeutic management of this widespread respiratory disease.