Predictors of change in asthma-related quality of life: a longitudinal real-life study in adult asthmatics

We conducted a retrospective longitudinal study on patients (≥ 18 years old at the first visit) recruited from the Liege University Hospital Asthma Clinic (Belgium) between 2011 and 2020. As described in our previous study [11], in accordance with the global initiative for asthma (GINA) criteria [2], the asthma diagnosis was based on the presence of typical symptoms (wheezing, breathlessness, chest tightness, and cough) combined with a 12% and 200 ml forced expiratory volume in 1 s (FEV1) reversibility after inhalation of 400 μg salbutamol, a β2 receptor agonist, and/or a provocative concentration of methacholine, a cholinergic agonist for muscarinic receptor, causing a 20% drop in FEV1 ≤ 16 mg/ml when FEV1 ≥ 70% predicted. We selected patients who had at least two visits at the asthma clinic and completed twice the Asthma Control Test [23] (ACT) and the Mini Asthma Quality of Life Questionnaire [24] (Mini AQLQ). When the patients had more than two visits, we systematically selected the first two visits (n = 290) (Fig. 1). Considering 3, 4, or 5 visits would have led to 20%, 45%, and 65% population attrition. As our intention was to include a large number of parameters in multiple regression analysis, we believed it was preferable to capture the larger number of patients as possible. In addition, selecting the first two visits increases the probability of unraveling relationship between pharmacological treatment and quality of life, as it is usually at the first visit that treatment is initiated or modified.

All the studied variables described below were contained in an electronic database constructed and managed by a data manager of the pneumology department of CHU Liège (Belgium). All the variables were collected as part of the patient routine examination performed in the asthma clinic.

Baseline demographic characteristics are presented in Table 1. Overall, 184 patients were female (63%) and 146 patients were atopic (50%). Median age was 54 years and median age at time of diagnosis was 37 years. Median time interval between the two visits was 7 months.

The comparison between visit 1 and visit 2 is presented in Table 2. Median (IQR) global AQLQ increased from 4.07 (3–5.1) to 4.6 (3.4–5.9) (p < 0.0001) with significant improvement in all dimensions (p < 0.0001), except the environmental one (Fig. 2). An acceptable reliability was found for global AQLQ (ICC = 0.94), AQLQ symptom dimension (ICC = 0.88), AQLQ activity dimension (ICC = 0.92), AQLQ emotional dimension (ICC = 0.83), and AQLQ environmental dimension (ICC = 0.74). There was an increase in median asthma control (ACT) from 13 to 17 (p < 0.0001). The proportion of patients with exacerbation decreased from 58 to 47% (p < 0.01). Pre-bronchodilation median % predicted FEV1 increased from 78 to 80% (p < 0.01). Median pre and post-bronchodilation FEV1/FVC % rose from 71 to 74% (p < 0.0001) and from 75 to 76% (p < 0.05), respectively. Median FeNO levels decreased from 29 to 24 ppb (p < 0.0001) and median sputum eosinophil counts from 85.10³/g to 36.10³/g (p < 0.01). Median blood eosinophils decreased from 243/µl to 189/µl (p < 0.01).

With respect to treatment, the proportion of patients treated by SABA alone fell significantly from 20 to 7% (p < 0.0001), while the proportion of patients receiving a maintenance treatment including ICS/LABA and/or LTRA rose from 53 to 80% (p < 0.05). Overall, the mean (SEM) beclomethasone equivalent increased from 1086 (± 60) μg/d to 1288 (± 56) μg/d (p < 0.0001). The proportion of patients with OCS maintenance decreased from 19% at baseline to 10% at follow-up. Globally, pharmacological treatment changes between baseline and follow-up were classified into 6 categories. Improvement in global AQLQ and all its dimension, except the environmental one, was observed in all categories of treatment changes, except in no treatment to SABA (Table 3).

There was 48% of asthmatics who had an improvement in AQLQ ≥ 0.5 (MCID) , while only 17% had a deterioration with a decrease in AQLQ ≥ 0.5.

Results of univariate beta regression mixed models are given in online supplement Table S1, where results for each independent variables after fixing the effect for time and treatment changes group were provided. All the significant factors in the univariate beta regression mixed models for global AQLQ and/or its 4 dimensions were investigated in a multivariate beta regression mixed model (Table 4). Only ACT had a significant impact on global AQLQ (Fig. 3 upper panel) and on its 4 dimensions (p < 0.0001 for all), which increased when ACT increased. When drawing a ROC curve, we found that a change in ACT of 3 was the best threshold to predict an improvement of 0.5 AQLQ (AUC = 0.85; p < 0.0001) (Fig. 3 lower panel). The global AQLQ significantly decreased with increasing BMI (p < 0.01). Change in activity dimension of AQLQ was associated with change in BMI and decreased as BMI increased (p < 0.0001) (Table 4). When fitting the full model including all variables, only ACT and BMI were still significantly associated with global AQLQ in the multivariable model (data not shown).

Global AQLQ and its four dimensions were also transformed to binary variables using cut point 6. The proportion of patients with global AQLQ ≥ 6 rose from 8% in visit 1 to 22% in visit 2 (p < 0.0001) (Table 5).

Results of univariate binary logistic mixed models are given in online supplement Table S2, where results for each independent variables after fixing the effect for time and treatment changes group were provided. All the significant factors in the univariate binary logistic mixed models for converted binary global AQLQ and/or its 4 dimensions were considered in a multivariate binary logistic regression mixed model (Table 6). Increasing ACT over time increased the probability of achieving a high level of global AQLQ and its 4 dimensions over time (p < 0.0001). One unit increase in BMI (p < 0.01) as well as stopping OCS (p < 0.05) compared to no changes level decreased the odds ratio of being in the high level of global AQLQ. Likewise, increasing BMI decreased the probability of achieving a high level in activity dimension of AQLQ (p < 0.01). Finally, a higher FeNO associated with a greater probability of achieving a high level in the activity dimension of AQLQ (p < 0.01) (Table 6).

Many cross-sectional studies have already demonstrated that asthma control is a major factor associated with asthma quality of life [6, 10, 11]. In addition, Chen et al. who conducted a prospective observational cohort study (TENOR study) [29] showed that asthma control was an independent predictor of HRQL in asthma both at baseline and after a 12 months follow-up. Here, using real-world data, we go one step further by demonstrating that changes in asthma control as reflected by changes in ACT, is the main predictor of change in AQLQ. Furthermore, by constructing ROC curve, we found that an increase of three in ACT was the best threshold to predict an increase of 0.5 in AQLQ, which represent the MCID.

Another interesting result that emerged from the current study is the fact that change in BMI was found to be an independent predictor of change in global AQLQ and its activity dimension over time. The impact of high BMI on asthma quality of life and on its activity dimension had already been reported in cross-sectional studies [11, 14, 30]. Dramatic changes in BMI obtained after Bariatric surgery were found to improve asthma control and asthma quality of life [31]. None of our patients had undergone bariatric surgery between the two visits. To the best of our knowledge, we are reporting here for the first time that change in BMI, independent of a bariatric surgery, may be an independent factor of asthma quality of life after adjustment for asthma control. We believe this is an important finding as it would suggest that reducing BMI by providing nutritional counseling and promoting regular physical activity in asthmatics may be a way to improve quality of life independent of asthma control.

In this study, changes in lung function and airway eosinophilic inflammation were not found as independent factors associated with changes in AQLQ. We believe however that these factors were determinants in improving asthma control, as previously demonstrated in both cross-sectional and longitudinal studies [32, 33]. Therefore, asthma control mediates the effect of improving lung function and reducing inflammation on asthma quality of life. A surprising finding of the current study is the fact that a rise in FeNO is an independent predictor of the probability of achieving an optimal AQLQ in its activity dimension. This is in keeping with our recently published cross-sectional study [11], where we demonstrated that FeNO level was an independent predictor positively associated the activity dimension of AQLQ. High FeNO has traditionally been seen as a bad outcome reflecting an eosinophilic inflammation [34]. Roberts et al.[35] showed that quality of life declines with increasing FeNO as a result of pollen allergen exposure. Our population is far from being exclusively atopic, thereby limiting the relationship between allergen exposure and subsequent rise in FeNO leading to deterioration in asthma quality of life. The reason why rise in FeNO might increase the probability of achieving an excellent AQLQ in its activity dimension in our study remains to be investigated but it is worth noting that NO is a potent mediator of vasodilation, a physiological process critical in skeletal muscle O2 supply. Our multivariate statistical analysis revealed that patient perspective measured through PROM may actually question the interpretation of FeNO level in asthma and suggest that FeNO and eosinophils, although being correlated, may actually have different effects on asthma quality of life.

One important finding of our study is the fact that asthma quality of life improves between the first passage at the asthma clinic and the follow-up visit, whichever the pharmacological treatment change. If the proportion of patients on SABA alone decreased from 20 to 6% and the proportion of patients with maintenance treatment ICS/LABA or LTRA increased from 50 to 83% between baseline and follow-up providing a pharmacological rationale for the improvement in quality of life, there was also decreased treatment burden in other patients with either stopping maintenance OCS or reducing the dose of ICS. This suggests that some patients are over treated, and that decreasing corticoids exposure might be beneficial in some circumstances. The dedicated chest physicians to our asthma clinic are using markers of T2 inflammation including sputum eosinophils, FeNO, and blood eosinophils to initiate or adjust the dose of ICS [36‐38]. Therefore, the existence/ persistence of T2 biomarkers is an impetus to start or increase the dose of ICS but a decrease in corticoids may be proposed to the patients who combine low eosinophils and low FeNO, which may result in an improvement of asthma quality of life [22]. Why quality of life also improved in those patients with no treatment change may be explained by several factors and is in keeping with a previous study [39]. First, as it is a real-life retrospective study, we cannot assume that adherence to treatment was optimal at baseline. We can anticipate that time dedicated to the patient and investigations by health care professionals during the passage at the asthma clinic (approximately 60–80 min) would have increased health literacy and adhesion to the pharmacological treatment strategy [40]. Therefore, an improved adherence to usual treatment and/or a better handling of aerosol devices by the patient might have led to a better asthma control and quality of life [41]. Second, we have also to consider non-pharmacological factors such as an engagement of the patient toward a better nutrition or regular physical activity [42, 43] as it is generally advised by the health care professionals working in our asthma clinic. Our finding is supported by the demonstration that providing patient with information about the disease, particularly by increasing patients’ knowledge of how to treat their symptoms, may improve asthma control and quality of life [44]. Indeed, this reinforcement of knowledge on the disease and on the techniques of taking bronchodilators is part of therapeutic patient education recognized as contributing to an improvement of quality of life, although this practice is still not formalized and institutionalized in Belgium [45].

One strength of this study is the fact that our cohort encompassed a wide variety of asthmatics with whom healthcare professionals have to deal in their everyday clinical practice including moderate-to-severe asthma but also some milder form of the disease. This gives confidence that our finding may be of relevance to a global asthma population and there is increased recognition of the importance of real-life studies to support the findings of randomized control trials (RCT) [46].Other strengths are the extensive clinical characterization of the patients and the use of scientifically validated PROMs (ACT and Mini-AQLQ). Nevertheless, the current study has several limitations. First, the absence of sociodemographic characteristics—such as the level of instruction or the occupation—is regrettable when it is known that they may influence HRQL [6, 10]. Second, we limited our analysis by comparing only two visits and it would have been interesting to see whether quality of life further improved with recurrent passages at asthma clinic. Third, among those who attended twice, some did not complete ACT and AQLQ at the second visit (52/342 = 15%) (see Fig. 1). A fourth limitation is the fact that our analysis did not include several comorbidities—such as rhinosinusitis or gastroesophageal reflux—known to impact the asthma quality of life [47, 48].