We performed a meta-analysis to compare the impact of triple combination therapy with inhaled corticosteroids (ICS), long-acting β
-agonists (LABAs) and long-acting muscarinic receptor antagonists ...(LAMAs)
LABA/LAMA combination therapy or single long-acting bronchodilator therapy in chronic obstructive pulmonary disease. The ICS/LABA/LAMA combination reduced the risk of exacerbation (relative risk 0.70, 95% CI 0.53-0.94) and improved trough forced expiratory volume in 1 s (mean difference in mL +37.94, 95% CI 18.83-53.89)
LABA/LAMA combination therapy. The protective effect of triple combination therapy
LABA/LAMA combination therapy against risk of exacerbation was greater in patients with blood eosinophil counts ≥300 cells·µL
(relative risk 0.57, 95% CI 0.48-0.68). While ∼38 patients had to be treated for 1 year with ICS/LABA/LAMA combination therapy to prevent one exacerbation compared to LABA/LAMA combination therapy, the number needed to treat (NNT) was ∼21 when compared to single long-acting bronchodilator therapy. The person-based NNT per year of ICS/LABA/LAMA combination therapy
LABA/LAMA combination therapy was significantly (p<0.05) lower in patients with eosinophil counts ≥300 cells·µL
(NNT value: 8.58) than in those with counts <300 cells·µL
(NNT value: 46.28). The risk of pneumonia did not differ between ICS/LABA/LAMA combination therapy and its comparators. The number needed to harm was ∼195. This meta-analysis suggests that patients on single long-acting bronchodilator therapy or LABA/LAMA combination therapy, who still have exacerbations and have blood eosinophil counts ≥300 cells·µL
, could benefit from ICS/LABA/LAMA combination therapy.
Conflicting evidence is currently available concerning the impact on asthma exacerbation of triple inhaled corticosteroid (ICS)/long-acting β
-adrenoceptor agonist (LABA)/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 0.61-0.80) and increasing trough forced expiratory volume in 1 s (from +33 to +114 mL). Triple combination therapies including HD ICS were superior (p<0.05) to MD ICS/LABA/LAMA FDC in preventing severe exacerbation (relative risk 0.46-0.65), 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.
The association of asthma and chronic obstructive pulmonary disease (COPD) in the same patient, which is designated as mixed asthma-COPD phenotype or overlap syndrome (ACOS), remains a controversial ...issue. This is primarily because many conflicting aspects in the definition of ACOS remain, and it is extremely difficult to summarize the distinctive features of this syndrome. Furthermore, we are realizing that asthma, COPD, and ACOS are not single diseases but rather syndromes consisting of several endotypes and phenotypes and, consequently, comprising a spectrum of diseases. The umbrella term ACOS blurs the lines between asthma and COPD and allows an approach that simplifies therapy. However, this approach contradicts the modern concept according to which we must move toward more targeted and personalized therapies to treat patients with these diseases. Therefore we argue that the term ACOS must be abandoned and ultimately replaced when new phenotypes and underlying endotypes are identified and a new taxonomy of airway diseases is generated.
Thymic stromal lymphopoietin (TSLP) is an allarmin cytokine whose importance in human asthma has been repeatedly documented. Accordingly, targeting of TSLP and TSLP-mediated signalling is considered ...as an attractive therapeutic strategy to asthma. Tezepelumab, which is the first-in-class anti-TSLP monoclonal antibodies (mAb), is a fully human IgG2λ mAb that binds human TSLP, prevents interaction with its receptor and, consequently, inhibits multiple downstream inflammatory pathways. Because of the excellent results of Phase II trials, the Food and Drug Administration granted tezepelumab as a ‘breakthrough’ biological drug for the treatment of severe asthma. Several studies with this mAb are ongoing. CSJ117 is an Ab fragment that binds to TSLP and is delivered by inhalation but there is no published information on this biologic agent. Since new information suggests that targeting TSLP may be more likely to improve day-to-day asthma symptoms, in contrast to targeting mediators of the adaptive immune system, approaches that primarily act to ameliorate asthma exacerbations, novel approaches capable of blocking TSLP (for example, fully human single-chain fragment variables against TSLP, bifunctional drugs such as the one that combines an anti-IL-13 mAb with an anti-TSLP mAb, a fusion protein consisting of the ectodomains of TSLPR and IL-7Ra that extend into the extracellular space, also known as a TSLP-trap, fragments capable of disrupting the TSLP:TSLPR complex) are under preclinical investigation. However, some critical aspects remain to be clarified before being able to define this approach as the one that will probably better help patients suffering from severe asthma because of its holistic effects.
Background The wide availability of long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) fixed-dose combinations (FDCs) in the absence of head-to-head comparative pragmatic trials ...makes it difficult to choose which combination should be used. Therefore, we carried out a systematic review with meta-analysis that incorporated the data from trials lasting at least 3 months to evaluate the effectiveness of LAMA/LABA FDCs for COPD treatment. Methods Randomized controlled trials were identified by searching different databases of published and unpublished trials. We aimed to assess the influence of LAMA/LABA combinations on trough FEV1 , transitional dyspnea index, St. George's Respiratory Questionnaire, and cardiac safety vs monocomponents. Results Fourteen papers and one congress abstract with 23,168 patients with COPD (combinations, n = 10,328; monocomponents, n = 12,840) were included in this study. Our results showed that all LAMA/LABA combinations were always more effective than the LAMA or LABA alone in terms of the improvement in trough FEV1 . Although there was not significant difference among LAMA/LABA combinations, we identified a gradient of effectiveness among the currently available LAMA/LABA FDCs. LAMA/LABA combinations also improved both transitional dyspnea index and St. George's Respiratory Questionnaire scores, but did not increase the cardiovascular risk when compared with monocomponents. Conclusions The gradient of effectiveness emerging from this meta-analysis is merely a weak indicator of possible differences between the various LAMA/LABA FDCs. Only direct comparisons will document if a specific LAMA/LABA FDC is better than the other. In the meanwhile, we believe it is only proper to consider that dual bronchodilation is better than a LAMA or a LABA alone, regardless of the drugs used.
The impact of comorbidities on severe asthma Rogliani, Paola; Sforza, Maurizia; Calzetta, Luigino
Current opinion in pulmonary medicine,
2020-January, 2020-01-00, 20200101, Letnik:
26, Številka:
1
Journal Article
PURPOSE OF REVIEWSevere asthma is often associated with numerous comorbidities that complicate disease management and affect patientʼs outcomes. They contribute to poor disease control and mimic ...asthma symptoms. Although some comorbidities such as obstructive sleep apnea, bronchiectasis, and chronic obstructive pulmonary disease are generally well recognized, many other may remain undiagnosed but may be detected in an expert specialist setting. The management of comorbidities seems to improve asthma outcomes, and optimizes therapy by avoiding overtreatment. The present review provides recent knowledge regarding the most common comorbidities which are associated with severe asthma.
RECENT FINDINGSComorbidities are more prevalent in severe asthma than in mild-to-moderate disease or in the general population. They can be grouped into two large domainsthe pulmonary domain and the extrapulmonary domain. Pulmonary comorbidities include upper respiratory tract disorders (obstructive sleep apnea, allergic and nonallergic rhinitis, chronic rhinosinusitis, nasal polyposis) and middle/lower respiratory tract disorders (chronic obstructive pulmonary disease, allergic bronchopulmonary aspergillosis and fungal sensitization, bronchiectasis, dysfunctional breathing). Extrapulmonary comorbidities include anxiety, depression, gastro-esophageal reflux disease, obesity, cardiovascular, and metabolic diseases.
SUMMARYThe identification of comorbidities via multidimensional approach is needed to initiate appropriate multidisciplinary management of patients with severe asthma.
With the aim to individuate alleles that may reflect a higher susceptibility to the disease, in the present study we analyzed the HLA allele frequency distribution in a group of 99 Italian patients ...affected by a severe or extremely severe form of COVID‐19. After the application of Bonferroni's correction for multiple tests, a significant association was found for HLA‐DRB1*15:01, ‐DQB1*06:02 and ‐B*27:07, after comparing the results to a reference group of 1017 Italian individuals, previously typed in our laboratory. The increased frequencies observed may contribute to identify potential markers of susceptibility to the disease, although controversial results on the role of single HLA alleles in COVID‐19 patients have been recently reported.
Abstract Objectives In airway infections, biofilm formation has been demonstrated to be responsible for both acute and chronic events, and constitutes a genuine challenge in clinical practice. ...Difficulty in eradicating biofilms with systemic antibiotics has led clinicians to consider the possible role of non-antibiotic therapy. The aim of this review is to examine current evidence for the use of N-acetylcysteine (NAC) in the treatment of biofilm-related respiratory infections. Methods Electronic searches of PUBMED up to September 2015 were conducted, searching for ‘biofilm’, ‘respiratory tract infection’, ‘N-acetylcysteine’, ‘cystic fibrosis’, ‘COPD’, ‘bronchiectasis’, ‘otitis’, and ‘bronchitis’ in titles and abstracts. Studies included for review were primarily in English, but a few in Italian were also selected. Results Biofilm formation may be involved in many infections, including ventilator-associated pneumonia, cystic fibrosis, bronchiectasis, bronchitis, and upper respiratory airway infections. Many in vitro studies have demonstrated that NAC is effective in inhibiting biofilm formation, disrupting preformed biofilms (both initial and mature), and reducing bacterial viability in biofilms. There are fewer clinical studies on the use of NAC in disruption of biofilm formation, although there is some evidence that NAC alone or in combination with antibiotics can decrease the risk of exacerbations of chronic bronchitis, chronic obstructive pulmonary disease, and rhinosinusitis. However, the usefulness of NAC in the treatment of cystic fibrosis and bronchiectasis is still matter of debate. Most of the studies published to date have used oral or intramuscular NAC formulations. Conclusions Evidence from in vitro studies indicates that NAC has good antibacterial properties and the ability to interfere with biofilm formation and disrupt biofilms. Results from clinical studies have provided some encouraging findings that need to be confirmed and expanded using other routes of administration of NAC such as inhalation.
: 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.
To date there are no head-to-head studies comparing different mucolytic/antioxidant agents. Considering the inconsistent evidence resulting from the pivotal studies on mucolytic/antioxidant agents ...tested in chronic obstructive pulmonary disease (COPD), and the recent publication of Reducing Exacerbations and Symptoms by Treatment with ORal Erdosteine in COPD (RESTORE) study, we have performed a meta-analysis to compare the efficacy and safety of erdosteine 600 mg/day, carbocysteine 1500 mg/day, and N-acetylcysteine (NAC) 1200 mg/day in COPD.
A pairwise and network meta-analyses were performed to assess the efficacy of erdosteine, carbocysteine, and NAC on acute exacerbation of COPD (AECOPD), duration of AECOPD, and hospitalization. The frequency of adverse events (AEs) was also investigated.
Data obtained from 2753 COPD patients were extracted from 7 RCTs published between 2004 and 2017. In the pairwise meta-analysis mucolytic/antioxidant agents significantly reduced the risk of AECOPD (RR 0.74 95%CI 0.68-0.80). The network meta-analysis provided the following rank of effectiveness: erdosteine>carbocysteine>NAC. Only erdosteine reduced the risk of experiencing at least one AECOPD (P < 0.01) and the risk of hospitalization due to AECOPD (P < 0.05). Erdosteine and NAC both significantly reduced the duration of AECOPD (P < 0.01). The AEs induced by erdosteine, carbocysteine, and NAC were mild in severity and generally well tolerated. The quality of evidence of this quantitative synthesis is moderate.
The overall efficacy/safety profile of erdosteine is superior to that of both carbocysteine and NAC. Future head-to-head studies performed on the same COPD populations are needed to definitely confirm the results of this meta-analysis.
CRD42016053762 .
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