Introduction: Asthma is a major non-communicable disease. It affects both children and adults, but is the most common chronic condition among the former. While inhaled controller drugs stabilize the disease in most asthma patients, there are a certain number of people who suffer from severe asthma, which requires treatment escalation. Oral corticosteroids are usually added, but they are associated with various side effects that may limit their application. The introduction of biologicals targeting inflammatory mediators has opened a new era of asthma treatment highlighting the importance of patient characterization.

Aim: The RECOGNISE study sought to provide real-world insight into the characteristics of patients deemed eligible for biological therapy based on the judgment of the clinical investigator in primary and secondary care settings.

Materials and methods: The RECOGNISE study was a multicenter, observational, cross-sectional, one-visit study to characterize those severe asthma patients who are considered eligible for biological therapy among asthma patients in primary and secondary care settings in Bulgaria. Female and male asthma patients over 18 years of age were enrolled at four sites across the country. Severe asthma diagnosis had to be in agreement with the American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines. Patients provided patient-reported outcomes on asthma control and health-related quality of life (HRQoL). Investigators completed specifically designed electronic case report forms (eCRFs), which included demographics and medical history. Medical history included lung function, biomarkers, comorbidities, exacerbations, Healthcare Resource Utilization (HRU), and prescribed asthma medication in the last 12 months as well as adherence to medication.

Results: Ninety-two severe asthma patients were enrolled in the Bulgarian RECOGNISE study (females prevailing – 65.22%). The median age (range) at diagnosis was 40 (18, 74) years. Most patients were never-smokers (n=72, 78.26%). For eligible patients, the median total EOS blood count was 431.0 cells/µl (n=19) and the blood EOS percentage was 5.95% (n=64). Chronic OCS use (treatment maintenance with OCS for ≥50% of the previous year) was documented for 30.1% of eligible patients. The results from the Bulgarian RECOGNISE cohort show that 90.2% of the severe asthma patients from the primary and secondary care sites are eligible for treatment with the approved biologicals.

Conclusions: The current findings emphasize how crucial it is for patients with severe asthma to be monitored by an asthma specialist who can determine when it is time to switch to biologicals.

asthma specialist, biological therapy, eligibility, severe asthma

Asthma is a non-communicable chronic disease characterized by inflammation and narrowing of the small airways. Although it affects both children and adults, the disease is the most prevalent chronic condition in the former. It is estimated that nearly 300 million people in the world have asthma, and in 2019 asthma was the cause of approximately half a million deaths.^{[1, 2]} Across the globe, asthma affects between 1 and 18% of the population of individual countries, with the prevalence being lower in the lowest-income or rural countries. The variable extent of inflammation and airway remodeling in patients results in different combinations of symptoms, which include coughing, wheezing, chest tightness, and airflow limitation.^{[3, 4]} Furthermore, the airways of asthma patients are hyper-responsive to a number of triggers, which include exercise and inhaled irritants. It should be noted that the disease onset and severity are determined by a myriad of genetic and environmental factors.^[5] A satisfactory disease control is established in most patients through administration of controller drugs, which include inhaled corticosteroids (ICSs), long-acting bronchodilator inhalers (LABAs), leukotriene receptor antagonists (LTRAs), and monoclonal antibody (anti-IgE). However, fractions of patients (less than 10%) suffer from severe asthma with an early-childhood onset through multiallergen sensitization. Severe asthma tends to persist throughout the lifetime of affected patients and is associated with the greatest morbidity and healthcare burden due to its difficult clinical management, regardless of treatment.^[5]

The 2014 European Respiratory Society (ERS)/American Thoracic Society (ATS) guidelines define severe asthma as “asthma that requires treatment with high-dose inhaled corticosteroids plus a second controller (and/or systemic corticosteroids) to prevent it from becoming ‘uncontrolled’ or which remains ‘uncontrolled’ despite this therapy”. Misdiagnosis and underdiagnosis of asthma, which result in improper treatment choices, increase the avoidable morbidity and mortality rate and thus present a challenge, especially in the low- and middle-income nations.^[6] This issue has highlighted the necessity for accurate diagnosis and the exclusion of similar conditions, as emphasized in the above-mentioned set of guidelines. Further, asthma is recognized as a highly heterogeneous condition including a number of phenotypes and subphenotypes. The most notable division would be between Th2-type asthma and non-Th2-type asthma, with the former including severe eosinophilic asthma – up to 70% of the patients.^[5–7] The increasing number of novel severe asthma treatment prompted the introduction of these new guidelines, advancing clinical management through disease phenotype identification (clinical as well as molecular) and subsequent evidence-based treatment decisions.^[8]

As stated in the guidelines’ definition, severe asthma may remain uncontrolled even when patients receive the maximally optimized Global Initiative for Asthma (GINA) Step 4 or 5 therapy regimens of medium-/high-dose inhaled corticosteroids with a second controller, in addition to the treatment of contributing factors. To further complicate matter, severe asthma worsens upon decrease or cessation of high-dose regimens.^[3]

Clinicopathological features established as important for asthma diagnosis and prognosis include age at onset, sex, allergy, and history of airflow limitation or exacerbations. Severe asthma pathophysiology is defined by the nature of underlying inflammation, with eosinophilic versus non-eosinophilic inflammation representing an important distinction.^{[9, 10]} Childhood-onset asthma is distinct from an adult-onset disease, with the former being commonly associated with an IgE-dependent sensitization toward an allergen, while the latter develops independently of an allergen. Exacerbation frequency and the extent of airflow limitation represent other phenotyping bases.^[5] Lung function decline and worsening airflow obstruction are particularly prominent in cases of late-onset eosinophilic disease.^[11]

While they have been the mainstay for severe asthma treatment, oral corticosteroids (OCS) are associated with considerable side effects, which include the development of metabolic disease (e.g., obesity and diabetes), osteoporosis, cataracts, cardiovascular complications (e.g., hypertension), and adrenal suppression. Use of OCS is also associated with a psychological burden (e.g., anxiety and depression), further compromising the patients’ quality of life.^[6] Minimization of OCS use has therefore become a major goal within the clinical treatment of asthma, with advances in phenotyping allowing for more precise disease management, particularly through biologicals targeting immune factors, that is, mainly cytokines and cytokine receptors. Milestones in asthma precision medicine include the introduction of humanized monoclonal antibodies against IgE (e.g., omalizumab) for severe allergic asthma as well as IL-5 and IL-5-targeting antibodies (e.g. mepolizumab, benralizumab) for severe eosinophilic disease, in addition to the more recently developed monoclonals targeting IL-4 and IL-13.^{[12, 13]} Early research and clinical trials of anti-IL-5/anti IL-5Rα highlighted the importance of considering immune pathophysiology and disease phenotype stratification.^{[14, 15]} More specifically, anti-IL-5 therapy has been demonstrated as particularly effective in those suffering from severe eosinophilic asthma, when used in conjunction with ICS and LABA.^{[16, 17]} Further, anti-IL-5 allows for reducing OCS intake.^{[18, 19]} As IL-5 is a major mediator of eosinophil activation, blood eosinophil count is an important marker for anti-IL-5 treatment efficacy.^[20] Taken together, advances in asthma treatment are inadvertently dependent on the identification of targetable disease features.

Severe asthma precision medicine is no exception to the necessity for effective patient stratification based on clinicopathological features and biomarkers.^{[21, 22]} Adequate and timely (early) stratification is often limited to specialized centers where such biologicals are administered. However, epidemiological data on severe asthma patients diagnosed and treated in primary care or other non-specialized settings have been limited.

In order to provide real-world evidence on the matter, the RECOGNISE study collected the characteristics of patients diagnosed with severe asthma who were evaluated for eligibility for biologic treatment in primary and secondary care settings. Bulgaria was part of the Phase 1 countries in RECOGNISE, along with the Czech Republic, Germany, Greece, Hungary, Poland, Romania, and Slovenia. Phase 2 countries included France, Italy, the Netherlands, and Spain. The present work presents results from the Bulgarian RECOGNISE cohort.

Severe asthma is increasingly recognized as a heterogeneous condition of diverse etiologies and molecular pathophysiology with overlapping symptoms.^{[4-6, 8-10]} The stratification of patients with distinct subtypes based on clinicopathological and asthma-specific biological characteristics is therefore imperative for efficient disease management through the selection of personalized treatment, particularly biological therapy, in an attempt to reduce corticosteroid use and the associated side effects.^[25–29] The RECOGNISE study provides insights into clinical and biological characteristics of patients considered eligible or non-eligible for biological therapy as per the judgment of clinicians from twelve countries and 140 sites across Europe. The Bulgarian RECOGNISE study provided unprecedented insight into the profile of patients deemed eligible/non-eligible for biological therapy and a basis for comparison with overall European data.

In the Bulgarian RECOGNISE cohort, over 90% of patients were considered eligible for biological therapy, while 9.8% were non-eligible. Eligible and non-eligible patients were diagnosed at a similar adult age (median age [Q1–Q3] at diagnosis was 40 [30–54] years in eligible vs. 41 [34–53] years in non-eligible patients). The proportion of female patients was comparable between eligibility-based subgroups (66% vs. 56%). Eosinophilia was more common among eligible patients (median total EOS [Q1–Q3]: 431 [330–540] vs. 360 [250–470] cells/µl; median blood EOS in % [Q1–Q3]: 6 [2.4–8.7] vs. 6 [2.3–10]). In general, differences between eligibility-based groups with regard to age at diagnosis, female patient proportion, and eosinophilia prevalence were in agreement for the Bulgarian and the overall RECOGNISE cohorts.

Of note, a history of atopy was more common among non-eligible patients (78% vs. 50.6%) of the Bulgarian cohort, while the opposite was observed for the overall RECOGNISE cohort (30% vs. 50%). In the Bulgarian cohort, IgE levels were only determined for eight patients, all of which were eligible. Thus, no comparison could be made based on eligibility. Pre-bronchodilator FEV1 was the same between subgroups (median FEV1 in the last 12 months [Q1–Q3]: 1,390 [1,090–1,930] vs. 1,390 [1,220–1,640] ml), suggestive of a comparable exacerbation risk, in agreement with European cohort data. The proportion of patients with exacerbations in the last 12 months was indeed similar (95% vs. 89%) between the two subgroups in the Bulgarian cohort as opposed to the overall RECOGNISE cohort where exacerbations were more common in eligible patients (87% vs. 53%). Chronic OCS use was more common in Bulgarian eligible patients (30% vs. 0%) as was also observed for the overall cohort (28% vs. 18%). The proportion of patients having undergone short courses of systemic corticosteroids was similar between the eligibility-based subgroups (84% vs. 78%) in the Bulgarian cohort, which was different from the tendency observed for the overall cohort where short courses of systemic corticosteroids were more common in eligible patients (77% vs. 45%). Of note, the level of inhaled nitric oxide was not determined for the Bulgarian cohort. In the total European cohort of RECOGNISE, a tendency toward higher exhaled NO was observed in eligible compared to non-eligible patients.

Visits to the asthma specialist within the last 12 months were comparable between eligible and non-eligible patients in the Bulgarian cohort (97.6% vs. 100%), while considerably more common in the former subgroup for the overall RECOGNISE cohort (93% vs. 68%). GP visits were more common for non-eligible patients (44.6% vs. 55.6%), which was in agreement with the overall cohort results (65% vs. 74%). Hospitalizations were equally common between the eligibility-based subgroups of the Bulgarian cohort (55.4% vs. 55.6%), while more common for eligible patients in the overall cohort (21% vs. 13%). In contrast to the overall cohort (19% vs. 9%), emergency visits were more common for non-eligible patients in the Bulgarian cohort (19.3% vs. 44.4%). Sick leave was slightly more common for non-eligible patients in the Bulgarian cohort (18.1% vs. 22.2%), while the opposite was observed for the overall RECOGNISE population (15% vs. 12%). Somewhat lower Charlson scores were observed in eligible Bulgarian patients (ACCI 0–1: 42.2% vs. 33%), which was in agreement with the results for the overall cohort (ACCI 0–1: 44% vs. 37%). Based on the SGRQ, impairment seemed to be lesser in eligible patients, indicating a better HRQoL in this subgroup, while the opposite was observed for the overall cohort. Based on the ACQ-6, asthma was somewhat less well-controlled in eligible patients of the Bulgarian cohort, which was in agreement with data for the overall RECOGNISE cohort.

90.2% of Bulgarian patients were considered eligible for biological therapy by investigators compared to 81% for RECOGNISE Phase 1 countries (Bulgaria included) and 52% for Phase 2 countries (including Germany). Among Phase 1 countries, Bulgaria was second only to Slovenia (91.26%) with regard to the proportion of eligible patients. As per approved EU labels^[25–29], 51% of Bulgarian patients were eligible for biological therapy, relative to 64% for all phase 1 countries and 55% for Phase 2 countries (not incl. Germany).

The major reasons for referral to biological therapy according to the investigator were ‘high-risk patients’, ‘corticosteroid treatment (high dose, long-term use & side effects), and ‘add-on specialist treatment’, which was in line with overall Phase 1 results.

Approximately one-quarter of Bulgarian patients were dependent on chronic OCS use (maintenance OCS for ≥50% of the previous year), which was a similar proportion to that observed for the overall RECOGNISE cohort. These patients tended to have somewhat higher eosinophil levels. While the IgE count of patients with chronic OCS use was considerably lower than that of patients without, a history of atopy was more common in the former subgroup. Short courses of systemic corticosteroids were slightly less common in patients with chronic OCS use in the Bulgarian cohort, while the opposite was observed for the overall RECOGNISE cohort. Exacerbations were more frequent in those frequently using OCS, which was in agreement with overall RECOGNISE results. The same was observed for emergency visits in both the Bulgarian and overall cohorts. Charlson scores were similar between OCS use-based subgroups as were ACQ-6 scores. It should be noted that doctor’s and emergency visits were lowest in Bulgaria out of the countries included in RECOGNISE (both phases). Days in hospital recorded for the Bulgarian cohort were also among the lowest.

All investigators in the Bulgarian RECOGNISE were pulmonologists, which was in agreement with other Phase 1 countries, whether the majority of investigators were of the same specialization. This prevalence of pulmonologists as investigators was associated with the considerably higher proportion of patients deemed eligible (81%) in Phase 1 countries, including Bulgaria (90.2%), as opposed to the proportion in Phase 2 countries (52%), where the majority of specialists involved were general practitioners. This difference highlights the importance of having an asthma specialist to evaluate patients. It should be noted that a lower proportion of Bulgarian participants (51%) were also eligible for biological therapy based on approved EU labels when compared to Phase 1 patients (64%). The heterogeneous nature of the disease may require greater consideration and flexibility upon assessment, which an asthma specialist is able to provide. The Lancet Commission previously suggested that ‘arbitrary’ disease labels should not be the point of focus as opposed to the determination of measurable and treatable disease features.^[30] Further, having the patient’s medical history at their disposal, the pulmonologist should be able to consider various relevant factors that are beyond the competence of the general practitioner.

As an observational real-world study, RECOGNISE has certain limitations inherent to its design. One example would be the relatively small number of inclusion/exclusion criteria as compared to criteria employed in randomized controlled trials. However, it should be noted that the employed criteria were sufficient for minimizing the enrolment of patients with a misdiagnosis of asthma. As the local study teams selected study sites, site selection bias also cannot be excluded as a possibility. Since patients were recruited at hospitals, a bias toward patients with more frequent HRU is quite possible. This would also imply a bias toward patients suffering from more severe disease. It should be noted that source data verification was carried out only for two sites per country. For the Bulgarian RECOGNISE study, this would mean 50%, which was highest among the proportion across all countries from both study phases (21%). A limitation specific to the Bulgarian RECOGNISE study was the lack of data on FeNO, which, along with IgE and eosinophils, is considered an important factor for the characterization of patient inflammatory profiles.

Taken together, the findings of the Bulgarian RECOGNISE study indicate that a considerable proportion of severe asthma patients may benefit from biological therapy (e.g., mepolizumab, reslizumab, benralizumab, omalizumab, and dupilumab) to improve disease management, allowing for a lower need for systemic corticosteroids and less associated side effects. The current study also highlights the importance of observation by a specialist, who is able to consider the intricacies of asthma as a condition that is considered ever more heterogeneous and complex.

We thank all practitioners and patients for their participation. This study was funded by AstraZeneca. Writing support was provided by Alex Prodan, M.Sc. and funded by AstraZeneca.