Effectiveness and Safety of Nebulized Magnesium as Last Line Treatment in Adults with Acute Asthma Attack: A Systematic Review and Meta-Analysis.

BACKGROUND: Asthma is a disease characterized by chronic airway inflammation, however one-third of asthmatic cases did not respond adequately. Inhaled magnesium has been proposed as a treatment for unresponsive asthma cases. However, its role remains controversial. This review evaluates the effectiveness and safety of nebulized magnesium compared to standard therapy (Beta Agonist, Anticholinergic, Corticosteroid) in adults with acute asthma attacks. METHODS: The protocol has been registered in PROSPERO. A literature search was conducted through PubMed/MEDLINE, Cochrane, ProQuest, and Google Scholar, and using the keywords "inhaled magnesium" and "asthma". Manual searches were carried out through data portals. Journal articles included are randomized controlled trials. The assessment risk of bias was performed using Version 2 of the Cochrane risk-of-bias tool for randomized trials. RESULTS: There are five articles included in this review. There is no significant difference in readmission rate and oxygen saturation in the magnesium group compared to control (RR 1; 95% CI 0.92 to 1,08; p= 0,96 and MD 1,82; 95% CI -0.89 to 4.53; p= 0.19, respectively). There is a significant reduction of respiratory rate and clinical severity in magnesium (MD -1,72; 95% CI -3,1 to 0.35; p= 0.01, RR 0.29; 95% CI 0.17 to 0.69; p <0.001, respectively). There was a higher risk of side effects in the magnesium group (HR 1.56; 95%CI 1.05 to 2.32; p= 0.03). However, the side effects are relatively mild such as hypotension and nausea. CONCLUSION: Inhaled magnesium improves the outcome of asthmatic patients, especially in lung function, clinical severity, and respiratory rate. Moreover, inhaled magnesium is safe to be given.

Asthma medication adherence, control, and psychological symptoms: a cross-sectional study.

BACKGROUND: Nonadherence to therapies and psychological disorders are associated with poor asthma control. This study aims to assess the prevalence of anxiety and depressive symptoms, asthma control, and adherence to inhalers and to investigate whether there is an association of anxiety and depressive symptoms with adherence to inhalers and asthma control. METHODS: We measured anxiety and depressive symptoms using the Hospital Anxiety and Depression Scale in patients with asthma. Asthma Control Test and the 10-Item Test of Adherence to Inhalers Scale were used to assess levels of asthma control adherence to inhalers, respectively. Univariate and multivariate regression models assessed the associations of anxiety and depressive symptoms with adherence to inhalers and asthma control. RESULTS: A total of 287 patients completed the study, of whom 72% were female. The mean ± SD age and body mass index of our study population were 44 ± 13 years and 29 ± 7.2 kg/m2, respectively. Poor adherence to inhaler use was highly prevalent (49.8%; 95% CI: 43.8 to 55.7). The prevalence of anxiety, depression and poor asthma control was 27.2% (95% CI: 22.1 to 32.7), 20.9% (95% CI: 16.3 to 26.1), and 22.7% (95% CI: 17.9 to 27.9), respectively. We found a negative relationship between asthma control and anxiety, and depressive symptoms (adjusted ß: -0.25; 95% CI: -0.36 to -0.14; p < 0.001 and adjusted ß: -0.29; 95% CI: -0.40 to -0.18; p < 0.001, respectively). A negative relationship was also observed between adherence to inhalers and anxiety and depressive symptoms (adjusted ß: -0.34; 95% CI: -0.46 to -0.22; p < 0.001 and adjusted ß: -0.36; 95% CI: - 0.48 to - 0.24; p < 0.001, respectively). CONCLUSIONS: The high prevalence of uncontrolled asthma symptoms and poor adherence to inhalers and their impact on anxiety and depression levels among patients with asthma point to the need for early screening for psychological symptoms and recognition of nonadherence as part of asthma assessment and management plan in primary care in Saudi Arabia to avoid further worsening of asthma symptoms. Further studies are needed to explore the effectiveness of specific psychoeducational interventions and investigate the long-term impact of early psychological symptom detection on asthma outcomes.

In severe eosinophilic asthma controlled with benralizumab, tapering high-dose ICS reduced dose while maintaining control.

SOURCE CITATION: Jackson DJ, Heaney LG, Humbert M, et al; SHAMAL Investigators. Reduction of daily maintenance inhaled corticosteroids in patients with severe eosinophilic asthma treated with benralizumab (SHAMAL): a randomised, multicentre, open-label, phase 4 study. Lancet. 2024;403:271-281. 38071986.

[Dupilumab : a new treatment for severe T2 high asthma]. / Dupilumab, Dupixent® :un nouveau traitement pour l'asthme sévère avec un profil «T2 high¼.

Severe asthma often features a T2 high profile regulated by cytokines such as interleukins IL-4, IL-5 and IL-13. Dupilumab (Dupixent®) is humanized monoclonal antibody directed against the α subunit of the receptor for IL-4 and IL-13. Here we summarise the immunogical background of severe asthma which supports the use of dupilumab and the pivotal randomised controlled trials which have established the efficacy of dupilumab in treating people with severe asthma. Dupilumab reduces the exacerbation rate, has corticosteroids sparing effect, provides sustained improvement in expiratory flow rates and improved asthma control and quality of life with a reassuring safety profile. Dupilumab reduces the levels of FeNO values and of serum IgE but not those of circulating eosinophils. We also report on a few real life data with dupilumab supporting its clinical effectiveness.

L'asthme sévère est souvent caractérisé par un profil immunologique dit «T2 high¼ régulé par des cytokines telles que les interleukines IL-4, IL-5 et IL-13. Le dupilumab (Dupixent®) est un anticorps monoclonal humanisé dirigé contre la sous-unité α du récepteur à l'IL-4 et à l'IL-13. Nous présentons ici les bases immunologiques qui annoncent son efficacité dans le traitement de l'asthme sévère et les grandes études contrôlées qui ont validé son efficacité. Le dupilumab réduit la fréquence des exacerbations, permet une épargne en corticoïdes systémiques, améliore les débits expiratoires, le contrôle de la maladie et la qualité de vie des personnes asthmatiques, sans donner lieu à des effets secondaires notables. Il réduit le taux de FeNO et des IgE sériques, mais pas celui des éosinophiles circulants. Nous donnons également un aperçu de quelques données obtenues en vie réelle pour souligner son utilité en clinique.

Asthma and pregnancy.

Managing asthma during pregnancy is crucial for both the mother and the developing child. Adequate control lowers risks as do continuation of prescribed medication and maintaining of regular check-ups. Signs of deterioration should not be ignored and treating asthma during pregnancy should follow guidelines for non-pregnant women with asthma as described in this review. Effective medication and counseling are essential for a safe pregnancy, emphasizing that well-controlled asthma is key.

Impact of pharmaceutical care for asthma patients on health-related outcomes: An umbrella review.

Recent systematic reviews suggest that pharmacists' interventions in asthma patients have a positive impact on health-related outcomes. Nevertheless, the association is not well established, and the role of clinical pharmacists is poorly represented. The aim of this overview of systematic reviews is to identify published systematic reviews assessing the impact of pharmacists' interventions on health-related outcomes measured in asthma patients. PubMed, Embase, Scopus, and Cochrane Library were searched from inception to December 2022. Systematic reviews of all study designs and settings were included. Methodological quality was assessed using AMSTAR 2. Two investigators performed study selection, quality assessment and data collection independently. Nine systematic reviews met the inclusion criteria. Methodological quality was rated as high in one, low in two, and critically low in six. Reviews included 51 primary studies reporting mainly quality of life, asthma control, lung capacity, and therapeutic adherence. Only four studies were carried out in a hospital setting and only two reviews stated the inclusion of severe asthma patients. The quality of the systematic reviews was generally low, and this was the major limitation of this overview of systematic reviews. However, solid evidence supports that pharmaceutical care improves health-related outcomes in asthma patients.

Barriers to clinical remission in severe asthma.

Severe asthma is associated with an increased risk for exacerbations, reduced lung function, fixed airflow obstruction, and substantial morbidity and mortality. The concept of remission in severe asthma as a new treatment goal has recently gained attention due to the growing use of monoclonal antibody therapies, which target specific pathologic pathways of inflammation. This review evaluates the current definitions of asthma remission and unveils some of the barriers for achieving this state in the severe asthma population. Although there is no unified definition, the concept of clinical remission in asthma should be based on a sustained period of symptom control, elimination of oral corticosteroid exposure and exacerbations, and stabilization of pulmonary function. The conjugation of these criteria seems a realistic treatment target in a minority of asthmatic patients. Some unmet needs in severe asthma may affect the achievement of clinical remission. Late intervention with targeted therapies in the severe asthma population may increase the risk of corticosteroid exposure and the development of irreversible structural airway changes. Moreover, airway infection is an important component in persistent exacerbations in patients on biologic therapies. Phenotyping exacerbations may be useful to guide therapy decisions and to avoid the liberal use of oral corticosteroids. Another challenge associated with the aim of clinical remission in severe asthma is the multifaceted interaction between the disease and its associated comorbidities. Behavioural factors should be evaluated in case of persistent symptoms despite optimised treatment, and assessing biomarkers and targeting treatable traits may allow for a more objective way of reaching remission. The concept of clinical remission will benefit from an international consensus to establish unifying criteria for its assessment, and it should be addressed in the future management guidelines.

PI3Kγδ inhibition suppresses key disease features in a rat model of asthma.

BACKGROUND: Two isoforms of Phosphoinositide 3-kinase (PI3K), p110γ and p110δ, are predominantly expressed in leukocytes and represent attractive therapeutic targets for the treatment of allergic asthma. The study aim was to assess the impact of administration of an inhaled PI3Kγδ inhibitor (AZD8154) in a rat model of asthma. METHODS: Firstly, we checked that the tool compound, AZD8154, inhibited rat PI3K γ & δ kinases using rat cell-based assays. Subsequently, a time-course study was conducted in a rat model of asthma to assess PI3K activity in the lung and how it is temporally associated with other key transcription pathways and asthma like features of the model. Finally, the impact on lung dosed AZD8154 on target engagement, pathway specificity, airway inflammation and lung function changes was assessed. RESULTS: Data showed that AZD8154 could inhibit rat PI3K γ & δ isoforms and, in a rat model of allergic asthma the PI3K pathway was activated in the lung. Intratracheal administration of AZD8154 caused a dose related suppression PI3K pathway activation (reduction in pAkt) and unlike after budesonide treatment, STAT and NF-κB pathways were not affected by AZD8154. The suppression of the PI3K pathway led to a marked inhibition of airway inflammation and reduction in changes in lung function. CONCLUSION: These data show that a dual PI3Kγδ inhibitor suppress key features of disease in a rat model of asthma to a similar degree as budesonide and indicate that dual PI3Kγδ inhibition may be an effective treatment for people suffering from allergic asthma.

Biological treatments in childhood asthma.

PURPOSE OF REVIEW: The aim is to update the information currently available for the use of biologics in severe asthma in children, in order to facilitate their prescription as far as possible. RECENT FINDINGS: The appearance of biologics for the treatment of severe asthma has meant a revolutionary change in the therapeutic approach to this disease. Currently, five biologics have been approved for severe asthma in children and/or adolescents by the regulatory agencies: omalizumab, mepolizumab, benralizumab, dupilumab and tezepelumab. But despite their positive results in terms of efficacy, there are still relevant points of debate that should induce caution when selecting the most appropriate biologic in a child with severe asthma. Indeed, safety is essential and, for several of the existing treatments, the availability of medium-term to long-term data in this regard is scarce. SUMMARY: The use of biologics can facilitate the therapeutic paradigm shift from pleiotropic treatments to personalized medicine. However, the choice of the most appropriate biologics remains a pending issue. On the other hand, to the extent that several of the biologics have been available for a relatively short time, the most robust evidence in terms of efficacy and safety in children is that of omalizumab.

Biologic agents licensed for severe asthma: a systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: Six biologic agents are now approved for patients with severe asthma. This meta-analysis aimed to assess the efficacy and safety of licensed biologic agents in patients with severe asthma, including the recently approved tezepelumab. METHODS: We searched MEDLINE, Embase and CENTRAL to identify randomised controlled trials involving licensed biologics until 31 January 2023. We used random-effects meta-analysis models for efficacy, including subgroup analyses by individual agents and markers of T2-high inflammation (blood eosinophils and fractional exhaled nitric oxide), and assessed safety. RESULTS: 48 studies with 16 350 patients were included in the meta-analysis. Biologics were associated with a 44% reduction in the annualised rate of asthma exacerbations (rate ratio 0.56, 95% CI 0.51-0.62) and 60% reduction of hospitalisations (rate ratio 0.40, 95% CI 0.27-0.60), a mean increase in the forced expiratory volume in 1 s of 0.11 L (95% CI 0.09-0.14), a reduction in asthma control questionnaire by 0.34 points (95% CI -0.46--0.23) and an increase in asthma quality of life questionnaire by 0.38 points (95% CI 0.26-0.49). There was heterogeneity between different classes of biologics in certain outcomes, with overall greater efficacy in patients with T2 inflammation. Overall, biologics exhibited a favourable safety profile. CONCLUSIONS: This comprehensive meta-analysis demonstrated that licensed asthma biologics reduce exacerbations and hospitalisations, improve lung function, asthma control and quality of life, and limit the use of systemic corticosteroids, with a favourable safety profile. These effects are more prominent in patients with evidence of T2 inflammation.

Severe Asthma or Chronic Obstructive Pulmonary Disease with Eosinophilic Inflammation? From Uncertainty to Remission under Anti IL-5R Therapy.

Background and Objectives: Severe adult-onset eosinophilic asthma and COPD with eosinophilic inflammation are two entities with a similar clinical course and are sometimes difficult to differentiate in clinical practice, especially in patients with a history of smoking. Anti-IL-5 or -IL-5R biological therapy has been shown to be highly effective in severe eosinophilic asthma but has not demonstrated significant benefit in patients with COPD with the eosinophilic phenotype. Our aim was to illustrate this issue in the form of a case report. Materials and Methods: We present the case of a 67-year-old patient who is a former smoker with late-onset severe uncontrolled asthma (ACT score < 15) who experienced frequent exacerbations requiring treatment with systemic corticosteroids. The patient's lung function gradually worsened to a nadir FEV1 = 18%, despite a high dose of ICS in combination with a LABA and intermittent courses of OCS, with negative allergic skin-tests, but with high blood eosinophils level. Biological treatment with an anti-IL5R monoclonal antibody (benralizumab) was initiated, despite the difficulty in the differential diagnosis between asthma and COPD with eosinophilic inflammation. Results: The patient's evolution was favorable; clinical remission was effectively achieved with significant improvement in lung function (FEV1 > 100%), but with persistence of residual mild fixed airway obstructive dysfunction (FEV1/FVC < 0.7). The therapeutic response has been maintained to date. Conclusions: Benralizumab was shown to be very effective in a patient with late-onset severe eosinophilic asthma presenting features of chronic obstructive disease-habitual exposure to tobacco and inhaled noxious substances, and persistent airflow limitation on spirometry.

Remission in asthma.

PURPOSE OF REVIEW: To review the current concepts of remission in asthma. RECENT FINDINGS: Until 2023, asthma guidelines have been promoting the concept of disease control, recommending the step-wise addition of drugs until the best possible disease control is achieved. With the advent of highly effective, anti-inflammatory disease-modifying antiasthmatic drugs (DMAADs), treatment goals of asthma have changed. Several national guidelines have now announced remission as a general treatment goal in asthma. Currently, all guidelines agree that asthma remission is defined by the presence of at least three characteristics over a period of at least one 1 year: absence of exacerbations, no systemic corticosteroid use for the treatment of asthma and minimal asthma-related symptoms. In the future, a generally accepted, evidence-based and easy-to-use definition of remission will be needed for daily clinical practice. It is clear, however, that precise phenotyping (including measurement of biomarkers) is an essential prerequisite to achieve clinical remission in each individual patient. SUMMARY: Remission has been included as the treatment goal in asthma in several national guidelines, reflecting the paradigm shift in asthma, from short-term symptom control to long-term symptom prevention. An international consensus on the criteria for asthma remission is expected in the near future.

Long-term multicenter comparison shows equivalent efficacy of monoclonal antibodies in severe asthma therapy.

BACKGROUND: Monoclonal antibodies (biologics) drastically changed severe asthma therapy. Mepolizumab (anti-interleukin (IL) 5), benralizumab (anti-IL5 receptor alpha), and dupilumab (anti-IL4/13) are the most used biologics in this context. While all biologics are efficient individually, the choice of biologic is complicated by insufficient data on their comparative long-term treatment efficacy. Here, we compare the real-life efficacy of these biologics in asthma therapy over 12 months. METHODS: 280 severe asthma patients treated with mepolizumab (129/280, 46%), benralizumab (83/280, 30%) or dupilumab (68/280, 24%) for one year were analyzed retrospectively. Data were collected at baseline and after 6 and 12 months of therapy. Endpoints were changes pulmonary function (PF), exacerbation rate, oral corticosteroid (OCS) use and dose, asthma control test (ACT) score and fractional exhaled nitric oxide (FeNO) levels as well as responder status measured by the recently published "Biologic Asthma Response Score" (BARS). RESULTS: All biologics led to significant improvements in PF, ACT and OCS dose. Only Mepolizumab and Benralizumab significantly decreased the exacerbation rate, while only Mepolizumab and Dupilumab significantly decreased FeNO. Responder rates measured by BARS were high across all groups: roughly half of all patients achieved full response and most of the remainder achieved at least partial responder status. Overall, outcomes were similar between groups after both 6 and 12 months. CONCLUSIONS: All biologics showed great efficacy in individual parameters and high responder rates measured by BARS without a clinically relevant advantage for any antibody. Response was usually achieved after 6 months and retained at 12 months, emphasizing the utility of early response assessment.

Long-term safety, durability of response, cessation and switching of biologics.

PURPOSE OF REVIEW: Severe asthma patients suffer from decreased quality of life, and increased asthma symptoms, exacerbations, hospitalizations, and risk of death. Biologics have revolutionized treatment for severe asthma. However, with multiple biologic agents now available, clinicians must consider initial selection the long-term effectiveness of biologics. Additionally, patients have overlapping eligibilities and clinicians may consider switching between biologics for improved response. Finally, careful assessment of biologics cessation is needed for severe asthma patients who depend on these add-on therapies for asthma control. RECENT FINDINGS: Evidence for long-term durability and safety varies by biologic agent. In general, initial benefits noted from these agents (ex. exacerbation reduction) is, at minimum, sustained with long term use. Rates of adverse events and serious adverse events, including those requiring cessation of a biologics are low with long term use. Further studies are needed to understand the development of antidrug antibodies but currently their prevalence rates are low. Adverse events and insufficient efficacy are common reasons for biologic cessation or switching. Discontinuation maybe associated with waning of benefits but can be considered in certain situations. Biologic switching can be associated with improved asthma control. SUMMARY: Biologics are safe and effective long-term therapies for the management of asthma. Discontinuation must be carefully considered and if possible avoided. Reasons for insufficient efficacy must be evaluated and if needed, biologic switching should be considered.

[IS INHALED CORTICOSTEROID STEP-DOWN RECOMMENDED FOR ADULT ASTHMA PATIENTS HAVE BEEN WELL CONTROLLED OVER THE LONG TERM WITH MODERATE OR HIGH-DOSE INHALED CORTICOSTEROIDS?]

We conducted a systematic review to examine whether step-down of inhaled corticosteroid (ICS) is recommended for adult patients with asthma have been well controlled with moderate or high-dose inhaled corticosteroids for more than 12 weeks. Seven randomized controlled trials were included. ICS step-down did not increase asthma exacerbations requiring systemic steroid therapy and hospitalization. There was no effect on respiratory function, asthma control, or QOL. No significant differences were observed in serious adverse events or steroid-related adverse events, but the observation period was insufficient to assess long-term effects. Based on these results, we weakly recommend ICS step-down in adult patients with asthma have been well controlled with moderate or high-dose inhaled corticosteroids, but long-term asthma control and the incidence of steroid-related adverse events should be further investigated in the future.

Changes in disease burden and treatment reality in patients with severe asthma.

BACKGROUND: Biologics are clinically available for patients with severe asthma, but changes in asthma control over time are unknown. We examined changes in disease burden and treatment in severe asthma patients. METHODS: This retrospective study used a Japanese health insurance database (Cross Fact) and included patients aged ≥16 years treated continuously with an inhaled corticosteroid (ICS) for a diagnosis of asthma in each calendar year from 2015 to 2019. Severe asthma was defined as annual use of high-dose ICS plus one or more asthma controller medications four or more times, oral corticosteroids for ≥183 days, or biologics for ≥16 weeks. Changes in asthma exacerbations, prescriptions, and laboratory testing were examined. RESULTS: Demographic characteristics were similar throughout the study. The number and proportion of patients with severe asthma among those with asthma increased (2724; 15.3% in 2015 vs 4485; 19.0% in 2019). The proportion of severe asthma patients with two or more asthma exacerbations decreased from 24.4% to 21.5%. Odds ratios (95% confidence interval) of ≥2 asthma exacerbations in each year compared with 2015 were 0.96 (0.85-1.08) in 2016 and 0.86 (0.76-0.97) in 2017, with significant reductions observed in subsequent years. Short-acting beta agonists and oral corticosteroid prescriptions for asthma exacerbations decreased and long-acting muscarinic antagonist and biologic prescriptions for maintenance treatment increased. CONCLUSIONS: This study showed improvements in disease burden and treatment in severe asthma patients. There remains an unmet medical need for patients with severe asthma, given the proportion who continue to have asthma exacerbations.