Chronic oral corticosteroids use and persistent eosinophilia in severe asthmatics from the Belgian severe asthma registry

In a cross-sectional analysis on SA patients enrolled in the BSAR, we compared characteristics of SA patients chronically using OCS with those SA patients who did not. Chronic OCS use was defined as daily use of OCS. Furthermore, we made a comparison of patients with high (≥400/mm³) and low blood eosinophil counts (BEC) under OCS.

We also looked at a small number of severe asthmatics with persistently elevated BEC despite OCS therapy in whom an anti-IL5 monoclonal antibody was started.

Between March 2009 and February 2019, severe asthmatics [1] from 21 Belgian centers were enrolled in the BSAR, utilizing a secured web database which admits password protected anonymized data [10], after gaining fully informed written consent (2008/221). The American Thoracic Society definition of SA [11] was used for patients recruited between 2009 and 2014. As the definition of SA changed in 2014 [1], the BSAR website was adapted accordingly.

Asthma was diagnosed based on symptoms of cough, breathlessness or dyspnea together with the demonstration of airflow variability [12]. The latter was defined by one or more of the following: increase in forced expiratory volume in 1 s (FEV1) of 12% or greater after inhalation of 400 μg of salbutamol or an inhaled concentration of methacholine provoking a 20% fall in FEV1 of less than 16 mg/ml. Methacholine challenges were performed according to a standardized methodology as previously described [13].

Other prerequisites for inclusion were: age ≥ 18 years, asthma follow-up by a respiratory physician for at least 12 months, education on the disease provided to the patient, and compliance thought to be satisfactory in order to include only patients with severe refractory asthma and those in whom comorbidities had been addressed. All the data presented were collected at the time point of recruitment into the registry.

Patients were characterized as atopic if they had at least one positive specific IgE (> 0.35 kU/l; ImmunoCAP system, Phadia AB, Uppsala; Sweden) to at least one common aeroallergen (cat, dog, house dust mites, grass pollen, tree pollen and a mixture of molds) or a positive skin prick test. An exacerbation in the previous year was defined by a course of OCS for at least 3 days for asthma worsening. Emergency room visits, hospitalizations, and intensive care unit stays were also recorded. Presence (or absence) of treatment with long-acting muscarinic antagonists (LAMA), short or long-acting ß2-agonists (SABA, LABA), anti-IgE, anti-IL5 and macrolides was recorded, as well as OCS maintenance doses.

Quality of life was assessed using the self-administered Asthma Quality of Life Questionnaire (AQLQ) [14] and asthma control by both the Juniper Asthma Control Questionnaire (ACQ) [15] and the Asthma Control Test (ACT) [16].

Patients underwent FENO measurement at a flow rate of 50 ml/s according to the ERS/ATS recommendations (NIOX, Aerocrine, Sweden) [17] followed by spirometry with bronchodilation (inhalation of 400 μg salbutamol) and complete pulmonary function tests with evaluation of lung volumes and diffusion capacity.

Tobacco status were recorded. An ex-smoker was defined as someone who had stopped smoking for at least 6 months.

Sputum was induced almost exclusively in Liège and processed as previously reported [18]; 225 sputum samples were collected in the data set (23% of the total population). Cell counts were estimated on samples centrifuged (Cytospin) and stained with Hemacolor® Staining set after counting 500 non-squamous cells (Merck chemical, Overijste, Belgium). Sputum cytology was analyzed and 4 phenotypes were defined: the eosinophilic phenotype with ≥3% sputum eosinophil count (and < 76% neutrophil count), the neutrophilic phenotype with ≥76% sputum neutrophil count (and < 3% eosinophil count), and the mixed granulocytic phenotype being a combination of the above [19]. The fourth was paucigranulocytic phenotype, defined as an inflammatory cell count below these thresholds. Blood samples were drawn for evaluation of total serum IgE levels, specific IgE and BEC.

Nasal polyps and sinusitis were diagnosed by Ear Nose and Throat specialists either by endoscopy or sinus CT scanner. Gastroesophageal reflux was diagnosed either upon anamnesis (symptoms of heartburn), or by the presence of oesophagitis upon gastroscopy or treatment response to PPI. Chest CT imaging was obtained in patients with an atypical presentation of SA and in case of history of smoking. Hospital Anxiety and Depression Scale (HADS) questionnaires [20] were used to assess psychopathology.

Data on vocal cord dysfunction, allergic bronchopulmonary aspergillosis, Aspirin-sensitivity, eosinophilic granulomatosis with polyangiitis (EGPA: formerly called Churg-Strauss syndrome), occupational asthma (asthma acquired in the workplace), premenstrual asthma, and obesity were also collected.

Near-fatal asthma is described as an asthma attack that require intensive care unit stay with mechanical ventilation.

BEC were categorized in 4 groups: < 150/mm³, between 150 and 299/mm³, between 300 and 400/mm³, and > 400/mm³ to evaluate eosinophil levels in patients treated with OCS and the mean dose of OCS in each group.

Finally, an analysis was conducted to compare patients normalizing their BEC (< 400/mm³) under OCS treatment versus those who did not.

Between March 2009 and February 2019, 982 severe asthmatics that fulfilled the definition of SA [1, 11] were enrolled in the BSAR.

In this study, we found that approximately one-fifth of SA patients included in BSAR was treated with maintenance OCS and that a high proportion (44%) of these patients still showed a high BEC. The data indicated that late-onset asthma, frequent exacerbations and non-atopic status are associated with OCS maintenance use in SA. Late-onset asthma was also a predictor for persistently high BEC despite OCS.

At enrollment in the registry, 21% of SA patients were taking maintenance OCS, which is a lower proportion of severe asthmatic than previously described by Chung [1]. A partial explanation for this discrepancy could be that in about 26% of this subpopulation, a biotherapy (either IL-5 inhibitors or anti-IgE) had already been started prior to enrolment in BSAR. Indeed, OCS-sparing effects have been reported to be close to 50% with these biotherapies [21‐23].

Our data confirms the predominance of females in the overall SA population [10]. However, we found a higher proportion of males in severe asthmatics using maintenance OCS when compared to non-OCS treated patients. A higher proportion of males was previously reported in eosinophilic asthma [24, 25] and eosinophilic asthma has been shown to respond well to chronic inhaled corticosteroids and OCS treatment [26‐28].

There are different phenotypes of SA. Among these phenotypes, late-onset non allergic asthma has been found to occur after the age of 40, to be frequently associated with nasal polyps and chronic rhinosinusitis, and to be prone to exacerbations with good response to OCS [25]. In our study, not surprisingly, chronic use of OCS was predicted by late-onset of asthma (≥40 yr), high (≥ 2) exacerbation rates in the previous year, and non-atopic status. Late-onset asthma was also a predictor for high BEC (> 400/mm³) in OCS maintenance treated severe asthmatics. Poor response of eosinophils to OCS in this subpopulation needs to be further investigated.

Although OCS are known to suppress eosinophils, BEC were not different between SA patients using maintenance OCS and the ones that do not. We also noticed a high prevalence of patients with high BEC (> 400/mm³) in the OCS maintenance treated SA patients. In these patients with high BEC despite OCS maintenance, we may now offer anti-IL5 therapy to decrease the risk of exacerbation [29‐31]. Persistently high peripheral blood eosinophils have been previously reported in OCS treated asthmatics [22, 32‐34]. MENSA, DREAM and SIRIUS studies show high BEC (MENSA: 320 ± 938 to 280 ± 987); DREAM: 280 ± 1010 to 230 ± 1200; SIRIUS: 250 ± 1245 to 230 ± 1001) despite variable prevalence (25, 30 and 100%, respectively) of patients on OCS maintenance therapy. Whether poor compliance or adherence [35] to treatment or corticosteroid insensitivity are the reasons for high BEC despite OCS maintenance therapy remains unclear.

The lack of measure of compliance/ adherence to treatment represents the first limitation of our study. Poor adherence to treatment is seen in about 32–56% of severe asthmatics [1]. Although compliance was not objectively measured in these severe asthmatic patients, the BSAR investigators only enrolled their patients in the registry if they considered compliance to have been satisfactory in the previous 12 months. We also cannot be absolutely sure that the reported BEC have been measured while patients were actually taking OCS. Indeed, some investigators of BSAR could have provided historical BEC (before starting chronic OCS) or could have stopped OCS in order to obtain a blood eosinophils level > 300/mm3, required for the reimbursement of anti-IL5 in Belgium. Nevertheless, at least the major contributing centers have confirmed that patients were already on OCS maintenance therapy at the time of blood sample collection. Another limitation of our study is the fairly low number of sputums due to the fact that Liège is the only center to use sputum in routine checkup. This could be skewing the data in favor of neutrophilic phenotype for low BEC group, although it is well established that low BEC can have high sputum eosinophils.

In our study, in a small population of patients with eosinophilia despite OCS treatment, we found normalization of BEC under anti-IL5 therapy. With anti-IL5 therapy, a reduction in blood eosinophils is achieved, even in those patients who presented persistent eosinophilia under OCS therapy [36]. More importantly, the introduction of an anti-IL5 treatment allowed an opportunity to reduce the OCS dose in these patients.

Surprisingly, in a fairly small number of patients of this cohort of severe asthmatics, highly uncontrolled asthma was not associated with a high BEC as we could have expected. Instead, it was characterized by impaired lung function (low FEV₁) and diffusion capacity, and higher rate of emphysema (52%). Emphysema which is associated with lower diffusion capacity, may be a cause of dyspnea, which is a symptom considered in the evaluation of asthma control. These subjects fulfill the profile of patients with Asthma COPD overlap. In contrast, as previously reported [25], some patients with a late-onset eosinophilic phenotype present with low symptom expression despite high inflammation. These are poor perceivers with overestimated asthma control, but are at risk for exacerbations.

Approximately one-fifth of SA patients were treated with maintenance OCS at enrollment in BSAR. We demonstrated a significant association between late-onset, exacerbations, non-atopic status and chronic use of OCS in this population. Almost half of SA patients treated with chronic OCS have BEC ≥400/mm³. Moreover, we show a significant association between high BEC and late-onset asthma in OCS maintenance SA patients.