Asthma is the most common respiratory disease globally. It affects 264.4 million people, and continues to be associated with death and disability even in the anti-inflammatory era.24
The past two decades saw significant progress in diagnosis with the introduction of simple biomarkers such as blood eosinophils and exhaled nitric oxide in routine practice and treatment. The latter included the wide use of inhalation therapy, including rapid onset bronchodilators represented by short-acting inhaled β2-agonists (SABAs), inhaled corticosteroids (ICS), and combinations of ICS with long-acting inhaled β2-agonists (LABA). These advances resulted in “slowing the race” for finding an effective, safe treatment, leading to a significant decrease in clinical trials in the early 2010s.
However, the proportion of patients misdiagnosed with asthma remains high, with overdiagnosis of up to 56% in adults and 54% in children and underdiagnosis of up to 70% in adults and 50% in children.25 These challenges defined the agenda of the asthma and COPD section of the congress, which focused on the search for reliable diagnostic approaches and tools and optimization of therapy.
Knowing the mechanisms behind the disease is crucial to initiate the proper treatment, especially considering the role of small airways in asthma. Small airways are defined as those less than 2 mm in diameter, and their involvement in the disease – so-called “small airway dysfunction” (SAD) – remains an unmet need in asthma diagnosis and management. SAD is already present before asthma is diagnosed and occurs at all severities of asthma and after allergen inhalation or smoking. It is associated with such conditions as hyperresponsiveness, exercise-induced asthma, exacerbations, and poor asthma control.
M. Kraft (USA) presented the results of the ATLANTIS study to determine the role of SAD in the clinical manifestation of asthma and to evaluate which clinical method or combination of methods can best assess this abnormality.26 Most patients had Global Initiative for Asthma Strategy (GINA) steps 3 (26.5% of patients) and 4 (30.5% of patients), and only 4.8% had GINA step 5, the most severe form. 84% used a combination of inhaled corticosteroids.
The study revealed that SAD is present in 91% of the asthma population across all severities, particularly in more severe asthma cases, and can be used to help predict exacerbations. Kraft suggested that small airway lung function tests, including impulse oscillometry, body plethysmography, and spirometry, can be used in clinical practice.
D. Lo (UK) continued the discussion of asthma diagnostic testing.27 None of the tests have perfect diagnostic accuracy, so they are “good for confirming, but not excluding asthma.” Results depend significantly on the timing of testing, and the optimal time to test is during or shortly after an acute attack. Using several methods in combination achieves the best results. These typically include spirometry plus bronchodilator reversibility, fraction of exhaled nitric oxide (FeNO), and peak flow variability tests in the primary care setting and indirect and direct challenge tests in the secondary care facilities.
There is no universal test to diagnose asthma, and despite the availability of effective inhaled therapies, many patients with asthma continue to have poor disease control, resulting in a significant burden on the patient and healthcare system.
The challenges of asthma testing include the costs of tests (approximately 60-100 Euros per test), poor compliance during PEF monitoring, and limited options for testing young children. For example, spirometry can be successfully used in only 78% of 5-year-old children and FeNO in 18%. Spirometry and FeNO can be used in all children starting at age eight.
G. Brusselle (Belgium) spoke about the pathophysiological basis of using biologics in asthma management.28 There are several clinical phenotypes of asthma, including early-onset asthma, with allergy as the main driver of the inflammation, and adult-onset asthma, where allergy does not play the leading role. There are also several inflammatory phenotypes, including eosinophilic inflammation, which can be either allergic or non-allergic, in Type-2-high asthma and neutrophilic asthma in Type 2-low asthma. These two different inflammatory phenotypes define different approaches to therapy based on the pathogenesis but also present a significant challenge for diagnosis.
For instance, non-invasive biomarkers exist for eosinophilic asthma: elevated FeNO and blood eosinophil count, which correlates with sputum eosinophils in asthma. No such biomarkers exist for neutrophilic asthma, and blood neutrophil count does not correlate with sputum neutrophil levels in asthma. Therapeutic targets in eosinophilic asthma are also clearly defined, including corticosteroids, type-2 cytokines, and IgE in allergic eosinophilic severe asthma. The targets are less clear in neutrophilic asthma, with the main ones being pro-inflammatory cytokines such as IL-1β, IL-6, and TNF.
For Type 2-high severe asthma, anti-IL5/IL-5R antibodies (benralizumab, mepolizumab, and reslizumab) reduced asthma exacerbations and improved asthma control and quality of life, predominantly in adult-onset asthma. However, recent studies showed that they might also have some benefit in childhood-onset severe asthma. In children with allergic or Type 2 severe asthma, anti-IgE Omalizumab and anti-IL4R Dupilumab have shown efficacy in clinical trials. In neutrophilic asthma targeting the IL-23/IL-17/TNF axis in severe asthma not only does not provide any benefit but can harm patients, as shown in the Phase 2a risankizumab trial when the drug showed a higher rate of asthma worsening than placebo.29
Tezepelumab targeting the epithelial alarmin RSLP reduced annual asthma exacerbation rates in uncontrolled, severe asthma and was investigated in a Phase 3 study on less than 1000 patients against placebo. The results showed significant improvement in lung function, reduced asthma exacerbations by 56% compared to placebo, and reduced Type 2 biomarkers, including blood eosinophils, FeNO, and serum IgE.30
The use of oral corticosteroids (OCS), particularly in short courses (5-7 days), proved to be an effective and fast-acting treatment option for acute asthma symptoms, including exacerbations. Early administration of OCS for treating severe asthma exacerbations is considered a standard of care.31 E. Heffler (Italy) considers OCS a last resort; while they are effective, they often have multiple side effects, including osteoporosis, obesity, and increased risk of infection.32 He suggested physicians consider adding biologics as an alternative approach for assessing patients for step-up therapy, especially in cases of a high cumulative dose or long-term use of OCS. Approved biologics (mepolizumab, dupilumab, benralizumab) have demonstrated long-term reductions in OCS use.
A. Bourdin (France) drew attention to improving long-term outcomes while reducing OCS use. From his experience, patients use excessive doses of OCS – as high as up to 70 mg/day while GINA recommends ≤7.5 mg/day as a maximum.33 This trend has led to a high prevalence of side effects, with 93% of patients with severe asthma having at least one condition related to OCS use which influences their quality of life, including depression, pain sensitization, weight gain, and sleep disturbance.
A promising alternative to OCS therapeutic use is Dupilumab, which demonstrated continued reduction of OCS use over three years of follow-up in the TRAVERSE study, an open-label extension study of the long-term safety and efficacy of dupilumab.34
At the end of the initial VENTURE study, only 29.9% in the placebo arm were free of OCS, compared with 53.3% in the dupilumab group. The dupilumab group also showed a sustained improvement in lung function and maintained improvement in asthma control and quality of life.34 46% of patients in the study had mixed phenotypes, and after three years of therapy, total IgE decreased by 77-79%, which supports the mechanism of action but also supports the fact that this effect is sustained through time.
FeNO levels decreased by 48% after 52 weeks of therapy (≥20% changes in FeNO levels are considered clinically meaningful). There were no new safety signals after an additional two years of therapy, and side effects were comparable to placebo.35
The current trend is to establish more ambitious endpoints for patients with severe asthma. Clinical remission is defined as the sustained absence of significant asthma symptoms based on a validated instrument for 12 months or more, the optimization and stabilization of lung function, agreement by both the patient and HCP regarding disease remission, and the absence of systemic CS therapy for exacerbation treatment or long-term disease control.36 To characterize remission, researchers need to collect long-term follow-up data and consider such parameters as symptom control, OCS use, biomarkers, and occurrence of exacerbations.
In discussing treatment options, the goals and endpoints of therapy must be considered. The definition of goals in clinics will influence the definition of endpoints in clinical trials.
Asthma is one of the most common chronic diseases among children worldwide, affecting 11-14% of children aged 6-14 years.37 2-10% of asthmatic children have severe asthma.38 Roughly two-thirds of children with severe asthma have poor disease control. Pediatric asthma leads to reduced lung function, impaired lung growth, and frequent exacerbations and negatively impacts the child’s and caregiver’s quality of life. The major unmet need in managing pediatric asthma is the limited availability of non-steroid therapies, especially in children under six.
There were several presentations about the use of dupilumab in pediatric treatment. L. Bacharier (USA) tried to find biomarkers for dupilumab response and showed that in the dupilumab group, the asthma exacerbation rate (AER) was low and independent of baseline values of FeNO and blood eosinophils.39 Conversely, higher baseline FeNO and blood eosinophils were associated with a higher asthma exacerbation rate in the placebo group. In the dupilumab group, higher values of FeNO and blood eosinophils were associated with a greater improvement in ppFEV1.
The authors concluded that elevated FeNO or blood eosinophil count could identify children with uncontrolled moderate to severe asthma who are likely to respond to dupilumab. In another study, a group of investigators assessed the long-term safety and efficacy of dupilumab in children with uncontrolled, moderate to severe asthma and showed that it was well tolerated, with the efficacy sustained over an additional 52 weeks in patients with Type 2 asthma.40 The rate of asthma exacerbations was significantly lower, with an average of 0.118-0.124 events/year over 2.16-2.56 events/year at baseline. There were no new safety signals in children >6 years of age.
While the goal for COPD disease progression is to mitigate the frequency and severity of exacerbations, flare-ups can often be unavoidable, resulting in a progressive decline in lung function, comorbidities, and quality of life, as well as an increase in mortality. Systemic corticosteroids are the universal treatment for COPD exacerbations. However, the drugs are known to have severe side effects; studies show that cumulative doses of oral corticosteroids in COPD patients are associated with an increased risk of death.
The single-center BEAT-COPD study suggested using peripheral blood eosinophils during a moderate COPD exacerbation to direct oral corticosteroid therapy safely.41 The Stratified Treatment to Reduce Risk in COPD (STARR2) trial reported by M. Bafadhel (UK) confirmed this approach.42 The trial showed that eosinophil-guided prescription in primary care is safe and is not associated with worsening outcomes. Bafadhel noted that although the investigators have not performed an economic analysis to determine how many adverse events might be avoided using the biomarker-guided approach, “we do know that some of these patients who are given prednisolone, their comorbidities of diabetes worsened.”
The ABACOPD study investigated whether antibiotics are required in patients with acute moderate COPD exacerbations.43 In one subgroup, it appeared antibiotics could be ruled out. The ABACOPD trial randomized 294 patients presenting at 28 different sites in Germany to either five days of sultamicillin or a placebo. 70% of the patients were treated in the hospital. All received standard of care, including prednisone 40 mg for 7–10 days, oxygen as needed, and continued inhalation therapy.
The treatment failure rate among those receiving five days of sultamicillin was 15.3% vs. 25% in those who received a placebo, falling outside the bounds of noninferiority (9.97% between-group difference, 95% confidence interval [CI], 0.7-19.23). The proportion of patients reporting at least one adverse event (AE) was higher in the antibiotic group vs. the placebo group (53% vs. 42%; p=0.0453), but no differences were seen for serious AEs. Based on these results, the authors concluded that antibiotics are in GOLD stages I/II but they cannot be withheld in GOLD stages III/IV despite their more frequent adverse events.
