Asthma is a heterogeneous and complex condition characterized by chronic airway inflammation, which may be clinically stratified into three main phenotypes: type 2 (T2) low, T2-high allergic, and T2-high non-allergic asthma. This real-world study investigated whether phenotyping patients with asthma using non-invasive parameters could be feasible to characterize the T2-low and T2-high asthma phenotypes in clinical practice. This cross-sectional observational study involved asthmatic outpatients (n = 503) referring to the Severe Asthma Centre of the San Luigi Gonzaga University Hospital. Participants were stratified according to the patterns of T2 inflammation and atopic sensitization. Among outpatients, 98 (19.5%) patients had T2-low asthma, 127 (25.2%) T2-high non-allergic, and 278 (55.3%) had T2-high allergic phenotype. In comparison to T2-low, allergic patients were younger (OR 0.945, p < 0.001) and thinner (OR 0.913, p < 0.001), had lower smoke exposure (OR 0.975, p < 0.001) and RV/TLC% (OR 0.950, p < 0.001), higher prevalence of asthma severity grade 5 (OR 2.236, p < 0.05), more frequent rhinitis (OR 3.491, p < 0.001) and chronic rhinosinusitis with (OR 2.650, p < 0.001) or without (OR 1.919, p < 0.05) nasal polyps, but less common arterial hypertension (OR 0.331, p < 0.001). T2-high non-allergic patients had intermediate characteristics. Non-invasive phenotyping of asthmatic patients is possible in clinical practice. Identifying characteristics in the three main asthma phenotypes could pave the way for further investigations on useful biomarkers for precision medicine.

The heterogeneity of asthma makes it challenging to unravel the pathophysiologic mechanisms of the disease. Despite the wealth of research identifying diverse phenotypes, many gaps still remain in our knowledge of the disease's complexity. A crucial aspect is the impact of airborne factors over a lifetime, which often results in a complex overlap of phenotypes associated with type 2 (T2), non-T2 and mixed inflammation. Evidence now shows overlaps between the phenotypes associated with T2, non-T2 and mixed T2/non-T2 inflammation. These interconnections could be induced by different determinants such as recurrent infections, environmental factors, T-helper plasticity and comorbidities, collectively resulting in a complex network of distinct pathways generally considered as mutually exclusive. In this scenario, we need to abandon the concept of asthma as a disease characterised by distinct traits grouped into static segregated categories. It is now evident that there are multiple interplays between the various physiologic, cellular and molecular features of asthma, and the overlap of phenotypes cannot be ignored.

Dupilumab is a fully humanized monoclonal antibody, capable of inhibiting intracellular signaling of both interleukin (IL)-4 and IL-13. These are two molecules that, together with other proinflammatory cytokines such as IL-5 and eotaxins, play a pivotal role in orchestrating the airway inflammatory response defined as Type 2 (T2) inflammation, driven by Th2 or Type 2 innate lymphoid cells, which is the major feature of the T2 high asthma phenotype. The dual inhibition of IL-4 and IL-13 activities is due to the blockade of type II IL-4 receptor through the binding of dupilumab with the subunit IL-4Rα. This results in the repression of STAT6 and in the suppression of subsequent de novo formation of several molecules involved in the T2 inflammatory signature. Several clinical trials tested the efficacy and safety of dupilumab in large populations of uncontrolled severe asthmatics, revealing significant improvements in lung function, asthma control, and exacerbation rate. Similar results were reported when dupilumab was employed in patients harboring pathogenetic processes related to T2 immune response, such as atopic dermatitis and chronic rhinosinusitis. In this review, we provide an overview of the recent research in the field of respiratory medicine about dupilumab mechanism of action and its effects.

Currently, the asthmatic population is divided into Type 2-high and non-Type 2/Type 2-low asthmatics, with 50% of patients belonging to one of the two groups. Differently from T2-high, T2-low asthma has not been clearly defined yet, and the T2-low patients are identified on the basis of the absence or non-predominant expression of T2-high biomarkers. The information about the molecular mechanisms underpinning T2-low asthma is scarce, but researchers have recognized as T2-low endotypes type 1 and type 3 immune response, and remodeling events occurring without inflammatory processes. In addition, the lack of agreed biomarkers reprents a challenge for the research of an effective therapy. The first-choice medication is represented by inhaled corticosteroids despite a low efficacy is reported for/in T2-low patients. However, macrolides and long-acting anti-muscarinic drugs have been recognized as efficacious. In recent years, clinical trials targeting biomarkers playing key roles in T3 and T1 immune pathways, alarmins, and molecules involved in neutrophil recruitment have provided conflicting results probably misleading (or biased) in patients’ selection. However, further studies are warranted to achieve a precise characterization of T2-low asthma with the aim of defining a tailored therapy for each single asthmatic patient.

Background: The possible gender impact on asthma arouses current and outstanding interest, but few studies addressed this issue in the real-world setting. Objective: This cross-sectional study tested the hypothesis of a potential difference between asthmatic males and females in a real-life setting, such as a third-level asthma clinic. Methods: A total of 499 asthmatic outpatients (301 females and 198 males, mean age 58.25 years) were consecutively visited. The visit included history, asthma control, and severity grade, physical examination, lung function, fractional exhaled nitric oxide assessment, and blood sample for biomarkers. Results: There were more females than males (about 3 of 5). Asthmatic females smoked less (p < 0.0001) than males and had higher FEV₁ (p = 0.0022) and FVC (p = 0.0004) values than asthmatic males. Conclusions: Gender difference was associated with smoking and lung function impairment; thus, this issue should be carefully considered in asthmatic patients in daily clinical practice.

Pirfenidone and nintedanib are the only two drugs approved for the treatment of idiopathic pulmonary fibrosis (IPF). Both proved to be safe and well-tolerated in clinical trials, but real-world data and direct comparisons are scarce. This real-life study explored the safety profile of pirfenidone and nintedanib with a prolonged follow-up. We retrospectively collected clinical status, adverse events (AEs), and treatment changes from IPF patients who had started an antifibrotic treatment at our centre from December 2011 to December 2020, including 192 patients treated with pirfenidone and 89 with nintedanib. The majority of patients in both groups experienced one or more AEs during the follow-up. A higher proportion of AEs in the nintedanib group were effectively treated with behavioural modifications or additional medications compared with the pirfenidone group (52.5% vs. 40.6%, p = 0.04). Overall, a difference in the impact of AEs due to nintedanib versus pirfenidone resulted in a lower permanent discontinuation of therapy (8.3% vs. 18.3%, p = 0.02), with the latter being associated with a higher risk of drug discontinuation at 48 months after initiation (OR = 2.52, p = 0.03). Our study confirms the safety profile of antifibrotic drugs in IPF but highlights that AEs due to nintedanib are usually easier to manage and lead to fewer cases of permanent discontinuation of therapy.