Asthma is a heterogeneous chronic inflammatory disease of the airways that affects approximately 300 million people worldwide. About 5-10% of all asthmatics suffer from severe or uncontrolled asthma, associated with increased mortality and hospitalization, reduced quality of life, and increased health care costs. In recent years, new treatments have become available, and different asthma phenotypes characterized by specific biomarkers have been identified. Biological drugs are currently indicated for patients with severe asthma that is not controlled with recommended treatments. They are mostly directed against inflammatory molecules of the type 2 inflammatory pathway and are effective at reducing exacerbations, maintaining control over asthma symptoms, and reducing systemic steroid use, which is associated with well-known adverse events. Although biological drugs for severe asthma have had a major impact on the management of the disease, there is still a need for head-to-head comparison studies of biologics and to identify new biomarkers for asthma diagnosis, prognosis, and response to treatment. Identifying novel biomarkers could facilitate the development of therapeutic strategies that are precisely tailored to each patient's requirements.

Background and Purpose Airway hyperresponsiveness (AHR) is a central abnormality in asthma. IL‐5 may modulate AHR in animal models of asthma, but the available data is inconsistent on the impact of targeting IL‐5 pathway against AHR. The difference between targeting IL‐5 or the IL‐5 receptor, α subunit (IL‐5Rα) in modulating AHR remains to be investigated in human airways. The aim of this study was to compare the role of the anti‐IL‐5Rα benralizumab and the anti‐IL‐5 mepolizumab against AHR and to assess whether these agents influence the levels of cAMP. Experimental Approach Passively sensitized human airways were treated with benralizumab and mepolizumab. The primary endpoint was the inhibition of AHR to histamine. The secondary endpoints were the protective effect against AHR to parasympathetic activation and mechanical stress, and the tissue modulation of cAMP. Key Results Benralizumab and mepolizumab significantly inhibited the AHR to histamine (maximal effect −134.14 ± 14.93% and −108.29 ± 32.16%, respectively), with benralizumab being 0.73 ± 0.10 logarithm significantly more potent than mepolizumab. Benralizumab and mepolizumab significantly inhibited the AHR to transmural stimulation and mechanical stress. Benralizumab was 0.45 ± 0.16 logarithm significantly more potent than mepolizumab against AHR to parasympathetic activation. The effect of these agents was significantly correlated with increased levels of cAMP. Conclusion and Implications Targeting the IL‐5/IL‐5Rα axis is an effective strategy to prevent the AHR. Benralizumab was more potent than the mepolizumab and the concentration‐dependent beneficial effects of both these monoclonal antibodies were related to improved levels of cAMP in hyperresponsive airways.

To date there are no network meta-analyses comparing the impact of as-needed treatments in asthma, including the single maintenance and reliever therapy (known as SMART or MART – for simplicity SMART will be used hereafter) and the use of inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA) combination exclusively on an as-needed basis. Therefore, we performed a systematic review and network meta-analysis concerning the efficacy and safety of SMART and as-needed therapies in asthma. Data of 32 096 asthmatic patients were extracted from 21 studies, lasting from 6 to 12 months. In adult mild to moderate asthmatic patients low-dose (LD) SMART and as-needed LD ICS/LABA combination were significantly (relative effect <0.78, P<0.05) more effective than the other as-needed therapies in reducing the risk of exacerbation, and both were ranked as the first treatment option reaching the first quartile of the surface under the cumulative ranking curve analysis (SUCRA). In adult moderate to severe asthmatic patients LD to medium-dose (MD) SMART and high-dose (HD) ICS/LABA+as-needed short-acting β2-agonist were equally effective in reducing the risk of severe asthma exacerbation (P>0.05), although only LD to MD SMART was ranked as the first treatment option (first SUCRA quartile). Overall, these treatments were well tolerated and effective also on lung function and disease control. This study supports SMART and as-needed therapies as a suitable therapeutic option for asthma, by providing the most effective positioning of each specific treatment according to the disease severity.

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Conflicting evidence is currently available concerning the impact on asthma exacerbation of triple inhaled corticosteroid (ICS), long-acting β2-adrenoceptor agonist (LABA), and long-acting muscarinic receptor antagonist (LAMA) fixed-dose combination (FDC). Since meta-analyses allow settling controversies of apparently inconsistent results, we performed a network meta-analysis of Phase III randomised controlled trials including 9535 patients to assess the effect of ICS/LABA/LAMA combinations in uncontrolled asthma. Triple combination therapies with an ICS administered at high dose (HD) were more effective (p<0.05) than medium dose (MD) ICS/LABA/LAMA FDC and both MD and HD ICS/LABA FDCs against moderate to severe exacerbation (relative risk [RR] from 0.61 to 0.80) and increasing trough forced expiratory volume in the 1st second (mL from +33 to +114). Triple combination therapies including HD ICS were superior (p<0.05) than MD ICS/LABA/LAMA FDC in preventing severe exacerbation (RR from 0.46 to 0.65), but not with respect to moderate exacerbation (p>0.05). Triple combination therapies were equally effective on asthma control, with no safety concerns. This quantitative synthesis suggests that ICS/LABA/LAMA FDCs are effective and safe in uncontrolled asthma, and that the dose of ICS in the combination represents the discriminating factor to treat patients with a history of moderate or severe exacerbation.

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; p < 0.001), although the efficacy of AZD1222 (62.1%) introduced a significant level of heterogeneity in the meta-analysis (I2 92.17%, p < 0.001). No significant modifying factors resulted from the meta-regression analysis. However, considering the mRNA-based vaccines, a trend toward significance (p = 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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