Asthma is a chronic disease affecting people of any age characterized by airway hyperresponsiveness (AHR), airway obstruction and inflammation, intermittent airflow and mucus production [1, 2]. Wheezing, cough, chest tightness, and shortness of breath, usually accompanied by airflow limitation, are the most typical symptoms of asthma patients . Asthma is also a common condition: recent estimates report that about 300 million people have asthma worldwide, with prevalence of the disease likely increasing by a further 100 million by 2025 [3–6].
The way asthma has been defined and classified has changed over time. In the past, asthma was considered “a single entity” disease, characterized by abnormal response of T-helper cell Type 2 (Th2) cells and B cells . Today, the term “asthma” is rather intended as a collection of several distinct endotypes (T2-high vs T2-low) and phenotypes (e.g. young atopic, obese middle aged, smokers, late onset, etc.) that can lead to different symptomatology and variable level of airflow obstruction . Particularly in severe asthma, in-depth understanding of asthma pathogenesis and pathophysiology, together with identification of phenotypes, has important implications on treatment decision making.
The pathophysiology of asthma is characterized by the immune response of two CD4 + T-cell subsets, Th1 and Th2 cells. Specifically, the Type 2 asthma endotype (in the past known as “T2-high”) is originated from the complex mechanisms of Type 2 inflammation where two phenotypic components are co-expressed (eosinophilic, allergic, or mixed). Type 2 inflammation is mainly driven by Th2 cell activation, which triggers an abnormal generation of cytokines (interleukin IL-4, IL-5 and IL-13), in response to the detection of different agents (e.g. allergens, pollution, viruses, etc.) [1, 7, 8]. Indeed, further research in the last decades clarified that the underlying mechanism of Type 2 inflammation is much more complex, being mediated by many other players, such as innate lymphoid cells (ILC2s), produced in response to external agents [1, 7, 8]. Th2 and ILC2-derived IL-4, IL-5, and IL-13 generate the typical pathophysiological effects of asthma, including activation and recruitment of eosinophils in the airways, IgE production by activated plasma cells, AHR and airway remodelling.
IL-4 and IL-13 are relatively upstream players in the inflammatory cascade, and they are responsible for various pro-inflammatory activities. IL-13 stimulates the production of eotaxin 1 in airway inflammatory cells, causes airway smooth muscle and goblet cell hyperplasia, transforms fibroblasts into myofibroblasts, increases tracheal-bronchial mucus secretion, collagen production by fibroblasts and subepithelial basal membrane thickening, which are all features of airway remodelling . IL-4 plays a central role in the activation of the whole cytokine cascade in Type 2 inflammation. It acts on mast cells, producing IL-4/13 and IL-5 themselves. Furthermore, IL-4/13 induce isotype class switching of B cells to produce IgE, and directly affect the lung airway structure. In particular, IL-4/13 induce basement membrane thickening, impairment of epithelial integrity and proliferation of M2 macrophages, which directly changes the lung airway structure (e.g. fibrosis). Finally, IL-13 promotes inducible nitric oxide (iNO)-synthase activity and nitric oxide (NO) production, increasing the fraction of exhaled nitric oxide (FeNO) level (Fig. 1).
Type 2 is probably the most common type of asthma: about 50%-70% of people with asthma have an underlying Type 2 inflammation [8, 10, 11]. From a diagnosis standpoint, blood eosinophils (EOS) count has been commonly used as a biomarker to identify Type 2 asthma. Indeed, other biomarkers, such serum immunoglobulin-E (IgE) levels, and more recently FeNO, have been linked to mechanisms involved in Type 2 inflammation [1, 12, 13]. More specifically, FeNO has emerged as an important biomarker, as it informs about the inflammatory state of the airways [9, 14]. Therefore, it has been effectively used as predictive biomarker in several clinical trials evaluating the effectiveness of biological therapies in moderate-severe asthma [15–18]. Furthermore, during the process of allergic inflammation, FeNO is produced by the airway epithelium in excessive amount, because of the nitric oxide synthase upregulation, so elevated FeNO is a good index of Type 2 inflammation.
Elevated biomarker levels, such as EOS, FeNO and IgE, are key clinical indicators of Type 2 inflammation [11, 19]. EOS level is mediated by IL-4, IL-13, and IL-5 and defines eosinophilic asthma [20, 21]. FeNO level correlates with serum IgE and sputum EOS; it is mediated by IL-4 and IL-13 , and correlates also with allergic asthma [20, 21]. Type 2 inflammation is the key driver of all Type 2 asthma phenotypes, including eosinophilic, allergic or mixed (i.e. eosinophilic and allergic are co-expressed) .
Today, clinical guidelines recommend testing severe asthma patients for multiple biomarkers, i.e. blood and sputum EOS, FeNO, IgE (thresholds: blood EOS ≥ 150 cells/µL; FeNO ≥ 20 ppb; IgE ≥ 30 IU/mL) especially in presence of refractory disease with underlying Type 2 inflammation . There is a clear rationale for investigating these biomarkers simultaneously: while in many patients more than one biomarker can be overexpressed, others could have only one increased, independently one from the other . In this latter case, some biomarker expression might have been suppressed by pharmacological treatment, (i.e. oral corticosteroids for blood eosinophils) but asthma would remain clinically uncontrolled [1, 23].
Evaluation of Type 2 inflammation biomarkers is of critical importance to guide treatment decision in severe asthma which is refractory to conventional medical therapy. The standard of care of asthma is based on inhaled corticosteroids (ICS), either as monotherapy or in combination with other treatments, such as long-acting β2-adrenoreceptor agonists (LABAs) and/or cysteinyl-leukotriene type 1 receptor antagonists (LTRAs) [1, 23]. However, treatment is estimated to be ineffective in around 5%-10% of the overall population (i.e. severe patients), who then need escalation to high dose ICS and/or systemic therapy with corticosteroids, associated with uncertain clinical response, high risk of adverse events and long-term contraindications [1, 23, 24]. It is estimated that asthma is not adequately controlled in about half of this severe, refractory population . Furthermore, the clinical picture can be complicated by coexisting Type 2 inflammatory conditions that are commonly observed in these patients: chronic rhinitis and sinusitis, nasal polyps, atopic dermatitis .
Over the last 15–20 years, several biologic therapies have been developed to address the unmet medical need in severe asthma, and many others are under evaluation in clinical trials . Treatment with biologic therapies has improved the prognosis of patients with uncontrolled severe asthma, and concomitantly, the understanding of the complex pathogenesis and pathophysiology mechanisms of the disease, favouring the concept of patient stratification by biomarker . Among biologics, dupilumab (Dupixent), a fully human monoclonal antibody directed against the alpha subunit of the IL-4 receptor (and inhibiting IL-4 and IL-13 signalling) has been shown to be safe and effective in adolescents and adults with severe uncontrolled asthma [28–30]. Recently, dupilumab has been authorized by the European Medicines Agency (EMA) for the “treatment of adults and adolescents 12 years and older as add-on maintenance treatment for severe asthma with Type 2 inflammation, characterised by raised blood EOS and/or raised FeNO” . Therefore, dupilumab is the first biologic approved and specifically indicated for the treatment of uncontrolled severe asthma with Type 2 inflammation: asthma that includes allergic (anti-IgE) and/or eosinophilic (anti-IL5) phenotypes. Instead, the other biologic drugs approved by the EMA are indicated for specific Type 2 severe asthma phenotypes (e.g. “Allergic” for anti-IgE or “Eosinophilic” for anti-IL5) [32–36]. The rationale for this biomarker-related indication comes from the QUEST study, a 52-week placebo-controlled, phase 3 confirmatory study (NCT02414854) enrolling patients aged ≥ 12 years, one of the largest ever-conducted trials characterizing patients in terms of biomarker expression (EOS, FeNO, IgE).
Stratification of patient population by biomarkers to identify the right eligible patients is a crucial task in the “biologic-era”. While personalized treatment of asthma is producing significant benefits for patients, asthma management costs are increasing. Notably, about 50% of the global asthma budget is allocated to severe patients (who account for < 10% of the overall population) [37, 38].
The need for managing resources appropriately and controlling therapeutic expenditure makes biomarker testing even more important, for budget allocation purposes and cost-effective use of high-cost drugs, such as biologics. Quite recently, many studies have been conducted with the objective of estimating the epidemiological and clinical burden of severe asthma in Italy [39–41]. In this paper we aimed to: 1) estimate the number of Type 2 severe asthma patients who would be eligible for dupilumab treatment in Italy, according to its approved indication; and 2) characterize the dupilumab-eligible population by expected biomarker status.