Asthma management with triple ICS/LABA/LAMA combination to reduce the risk of exacerbation: an umbrella review compliant with the PRIOR statement.

INTRODUCTION: According to Global Initiative for Asthma (GINA) guidelines, long-acting muscarinic antagonists (LAMAs) should be considered as add-on therapy in patients with asthma that remains uncontrolled, despite treatment with medium-dose (MD) or high-dose (HD) inhaled corticosteroids (ICS)/long-acting ß2-agonist (LABA) combinations. In patients ≥ 18 years, LAMA may be added in triple combination with an ICS and a LABA. To date, the precise efficacy of triple ICS/LABA/LAMA combination remains uncertain concerning the impact on exacerbation risk in patients with uncontrolled asthma. Therefore, an umbrella review was performed to systematically summarize available data on the effect of triple ICS/LABA/LAMA combination on the risk of asthma exacerbation. METHODS: An umbrella review has been performed according to the PRIOR statement. RESULTS: The overall results obtained from 5 systematic reviews and meta-analyses suggest that triple ICS/LABA/LAMA combination reduces the risk of asthma exacerbation. HD-ICS showed a greater effect particularly in reducing severe asthma exacerbation, especially in patients with evidence of type 2 inflammation biomarkers. CONCLUSIONS: The findings of this umbrella review suggest an optimization of ICS dose in triple ICS/LABA/LAMA combination, based on the severity of exacerbation and type 2 biomarkers expression.

Delivering monoclonal antibodies via inhalation: a systematic review of clinical trials in asthma and COPD.

INTRODUCTION: Advances in understanding the pathophysiology of asthma and chronic obstructive pulmonary disease (COPD) led to investigation of biologic drugs targeting specific inflammatory pathways. No biologics are licensed for COPD while all the approved monoclonal antibodies (mAbs) for severe asthma treatment are systemically administered. Systemic administration is associated with low target tissue exposure and risk of systemic adverse events. Thus, delivering mAbs via inhalation may be an attractive approach for asthma and COPD treatment due to direct targeting of the airways. AREAS COVERED: This systematic review of randomized control trials (RCTs) evaluated the potential role of delivering mAbs via inhalation in asthma and COPD treatment. Five RCTs were deemed eligible for a qualitative analysis. EXPERT OPINION: Compared to systemic administration, delivering mAbs via inhalation is associated with rapid onset of action, greater efficacy at lower doses, minimal systemic exposure, and lower risk of adverse events. Although some of the inhaled mAbs included in this study showed a certain level of efficacy and safety in asthmatic patients, delivering mAbs via inhalation is still challenging and controversial. Further adequately powered and well-designed RCTs are needed to assess the potential role of inhaled mAbs in the treatment of asthma and COPD.

A narrative review on asthma and pest sensitization (cockroach, mouse and rat allergens): a social issue besides the medical problem.

OBJECTIVE: Among animals defined as "pests", cockroaches and rodents (mouse and rat) represent the most common cause of airway allergic sensitization and bronchial asthma worldwide. Their frequency of sensitization has been widely assessed in US and other countries but poorly in Western Europe. This narrative review aims to provide a synthesis of data resulting in MEDLINE concerning allergic sensitization/asthma to pests as well as their related environmental/social risk factors, specifically in the European area. DATA SOURCES: We performed a literature research in MEDLINE for clinical trials, randomized controlled trials, systematic reviews and meta-analyses. STUDY SELECTIONS: We selected studies to the following key words: allergic sensitization, allergic rhinitis, bronchial asthma, cockroach, hypersensitivity, integrated pest management, material hardship, medication compliance, mouse, pest, poverty, rat, rodents. RESULTS: Current evidence indicates that residence in poor and urban areas, exposure to outdoor/indoor pollutants and tobacco smoke, poverty, material hardship, poor-quality housing, differences in health care quality, medication compliance, health care access contribute to increased pest-related allergic sensitization and asthma morbidity. CONCLUSION: Further research should be done on many aspects of pest allergy such as a better characterization of allergens and epidemiological aspects. Relevant social actions should be carried out against poverty, healthcare disparities, psycho-social stress, poor compliance to therapy, with economic contributions to improve private and public living environments. Allergic sensitization to pests and pest-allergic respiratory diseases like asthma are "paradoxical" conditions, as they typically affect the poorest communities but can only be corrected by high-cost (diagnostic and preventive) interventions. We hope that progress can be made in this direction in the future.

Strength of association between comorbidities and asthma: a meta-analysis.

BACKGROUND: The strength of association between comorbidities and asthma has never been ranked in relation to the prevalence of the comorbidity in the nonasthma population. We investigated the strength of association between comorbidities and asthma. METHODS: A comprehensive literature search was performed for observational studies reporting data on comorbidities in asthma and nonasthma populations. A pairwise meta-analysis was performed and the strength of association calculated by anchoring odds ratios and 95% confidence intervals with the rate of comorbidities in nonasthma populations via Cohen's d method. Cohen's d=0.2, 0.5 and 0.8 were cut-off values for small, medium and large effect sizes, respectively; very large effect size resulted for Cohen's d >0.8. The review was registered in the PROSPERO database; identifier number CRD42022295657. RESULTS: Data from 5 493 776 subjects were analysed. Allergic rhinitis (OR 4.24, 95% CI 3.82-4.71), allergic conjunctivitis (OR 2.63, 95% CI 2.22-3.11), bronchiectasis (OR 4.89, 95% CI 4.48-5.34), hypertensive cardiomyopathy (OR 4.24, 95% CI 2.06-8.90) and nasal congestion (OR 3.30, 95% CI 2.96-3.67) were strongly associated with asthma (Cohen's d >0.5 and ≤0.8); COPD (OR 6.23, 95% CI 4.43-8.77) and other chronic respiratory diseases (OR 12.85, 95% CI 10.14-16.29) were very strongly associated with asthma (Cohen's d >0.8). Stronger associations were detected between comorbidities and severe asthma. No bias resulted according to funnel plots and Egger's test. CONCLUSION: This meta-analysis supports the relevance of individualised strategies for disease management that look beyond asthma. A multidimensional approach should be used to assess whether poor symptom control is related to uncontrolled asthma or to uncontrolled underlying comorbidities.

Hypocalcemia is associated with adverse outcomes in patients hospitalized with COVID-19.

PURPOSE: Calcium ions are involved in the regulation of several cellular processes and may also influence viral replication. Hypocalcemia has been frequently reported during infectious diseases and in critically ill patients, including also COVID-19 patients, significantly related with the pro-inflammatory state and mortality. The aim of this study is to investigate the prevalence of hypocalcemia at admission in patients hospitalized for COVID-19 (Coronavirus disease 2019) and to evaluate association of hypocalcemia with in-hospital COVID-19 outcomes. METHODS: Retrospective analysis on 118 consecutive patients, hospitalized for COVID-19 between March and May 2020. Clinical characteristics, inflammation markers, biochemical routine and mineral metabolism parameters at admission were collected. Hypocalcemia was defined as total serum calcium <2.2 mmol/L. Population was stratified by tertiles of total serum calcium. Primary outcome was the composite of in-hospital death or admission to intensive care unit (ICU). Secondary outcomes included in-hospital death, admission to ICU and need for non-invasive ventilation as separate events. Associations were tested by logistic regression and Cox-regression analysis with survival curves. RESULTS: Overall prevalence of hypocalcemia was 76.6%, with just 6.7% of patients reporting levels of 25-(OH)-vitamin D > 30 ng/ml. Total serum calcium was inversely related with selected inflammatory biomarkers (p < 0.05) and poorer outcome of COVID-19 during hospitalization. Lower tertile of total calcium (≤2.02 mmol/L) had increased risk of in-hospital mortality (HR 2.77; 1.28-6.03, p = 0.01) compared with other groups. CONCLUSION: Total serum calcium detected on admission is inversely related with proinflammatory biomarkers of severe COVID-19 and is useful to better define risk stratification for adverse in-hospital outcome.

Beyond Dual Bronchodilation - Triple Therapy, When and Why.

Although pharmacological treatment of COPD is codified in different guidelines and strategy documents, there is abundant evidence of discrepancy between what they suggest and what health professionals prescribe, especially in low-risk groups where there is widespread overprescription of triple therapy. It is therefore necessary to clarify when the use of triple therapy is indicated in COPD patients and when it is preferable to maintain treatment with dual bronchodilation. In this article, we discuss our views based on our experience and what is reported in the literature and try to give answers to these two questions. The evidence generated by pivotal RCTs supports the use of triple therapy in patients who present for the first time and have severe airway obstruction, are symptomatic, have had frequent moderate or severe exacerbations in the previous year, and have peripheral eosinophilia. However, it is difficult to determine whether step-up is useful in all other cases because the available data are quite conflicting. It is likely that the inconsistency in the information generated by the various available studies may explain the prescribing behaviour of many physicians who do not adhere to recommendations of guidelines and strategies. However, it is necessary to establish whether and when the addition of an ICS to the LAMA/LABA combination is effective, to determine whether triple therapy can induce an additional clinical benefit over dual bronchodilation, irrespective of a preventive effect on COPD exacerbations, to establish its value, and to examine whether cost differences can support the use of triple therapy over combined LAMA/LABA therapy in real life.

Advances in understanding of mechanisms related to increased cardiovascular risk in COPD.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) represents a serious global health issue that is commonly associated with cardiovascular (CV) disease (CVD). The close relationship between COPD and CVD could be explained by different factors, first and foremost a chronic low-grade systemic inflammation implicated in the pathogenesis of both diseases and several stimuli enhancing the inflammatory processes and causing a mixed condition with worse outcomes than either disorder alone. AREAS COVERED: The present narrative review considers the mechanisms underlying the increased CV risk in COPD, and it provides insights on biomarkers and predictive models to predict CVD in COPD patients. EXPERT OPINION: COPD patients often remain asymptomatic of CVD, with respiratory symptoms generally attributed to the preexisting pulmonary disease. It is fundamental to understand the mechanistic pathways that underpin the intimate relationship between the two disorders. However, it is still not clear what is the origin of the common background of low-grade systemic inflammation, it could be a 'spillover' or a general inflammatory state. Primary prevention, cross-collaboration between specialists and early detection via predictive biomarkers and validated models are fundamental to stratify COPD patients according to CV risk.

Severe Asthma and Biological Therapy: When, Which, and for Whom.

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.