Asthma control and quality of life in a real-life setting: a cross-sectional study of adult asthma patients in Japan (ACQUIRE-2)

Abstract

Objective: The level of asthma control in adult asthma patients receiving treatment in clinical practice from allergy and/or respiratory specialists in Japan remains unclear. We conducted the ACQUIRE-2 study (NCT02640742) to evaluate level of asthma control, asthma symptoms, health-related quality of life (HR-QoL), and reliever medication use in this setting. Methods: This observational study was undertaken between December 2015 and June 2016 in 58 medical institutions across Japan. We enrolled outpatients aged ≥20 years diagnosed with asthma for ≥1 year who were being managed by specialists. Criteria to evaluate the level of asthma control were based on modified definitions of the Asthma Prevention and Management Guideline 2015, Japan (JGL 2015) and Global Initiative for Asthma (GINA) 2012. Asthma symptoms, HR-QoL, and reliever medication use were also evaluated. Results: Of 1250 enrolled patients, 1175 were analyzed, 62.9% of whom were women. Mean (± standard deviation) age and duration of asthma were 59.7 ± 14.5 years and 16.9 ± 14.0 years, respectively. Using JGL 2015-based criteria, 24.4%, 69.2%, and 6.5% of patients had well-controlled, insufficiently-controlled, and poorly-controlled asthma, respectively. Using GINA-based criteria, 35.1%, 49.8%, and 15.1% of patients had controlled, partly controlled, and uncontrolled asthma, respectively. Daytime and nighttime asthma symptoms were experienced by 51.5% and 44.9% of patients, respectively. The mean MiniAQLQ score was 5.8 ± 1.0 (7-point scale). Conclusions: Asthma was not well-controlled in the majority of patients in this study. To achieve better asthma control, improvements in symptom monitoring and management may be required.

Trial registration: ClinicalTrials.gov identifier: NCT02640742.

Keywords:

• Observational study
• Global Initiative for Asthma (GINA)
• Japan Asthma Prevention and Management Guideline (JGL 2015)
• Asthma Control Questionnaire (ACQ-5)
• patient-reported outcomes
• survey

Introduction

Asthma is a chronic respiratory condition of variable severity characterized by reversible airflow obstruction, airway hyper-responsiveness, and airway inflammation producing symptoms of wheezing, breathlessness, chest tightness, and coughing [1]. In Japan, approximately 3 million people are affected by asthma [2]. Of these, 30% have moderate asthma, while it is estimated that 7% have severe asthma [2].

Poorly controlled asthma has a negative impact on health-related quality of life (HR-QoL) [3]. Moreover, poorly-controlled severe asthma can raise an individual’s risk of exacerbations, hospitalization, and death [4]. This may include restrictions on physical activity, sleep disorder, time off from school or work, poor life satisfaction, or emotional and psychological distress. More than approximately half of all asthma patients experience uncontrolled asthma despite the introduction of global and national disease management guidelines [5–7].

The Asthma Prevention and Management Guideline 2015, Japan (JGL 2015) provides guidance on treatment goals in the management of asthma [8]. These consist of leading a normal and healthy life, preventing the development of irreversible airway remodeling and maintaining normal lung function, preventing asthma attacks throughout the day, preventing death due to asthma, and preventing adverse effects caused by therapeutic agents. Guidelines from many countries [8–10] are based on the Global Initiative for Asthma (GINA) report as they share a common goal: to improve asthma management using the best evidence available from published data [11]. The GINA report, which includes global strategies and key recommendations for asthma diagnosis, management, and prevention [12], is updated and published yearly based on the latest data [11]. As a key strategy, the GINA report recommends using a stepwise approach to control asthma symptoms and reduce risk based on five steps of treatment according to disease severity and other patient characteristics [12].

In a recent Japanese Internet study, more than half of all patients surveyed experienced asthma symptoms at least once per week [13], suggesting that airway inflammation was not fully controlled in these patients. Moreover, in two other Japanese surveys conducted in real clinical practice, one in which patients were recruited via the Internet and were surveyed by post [7], and another in which patients were surveyed directly by their physicians, who were mostly general practitioners [14], 70–90% of patients surveyed had insufficiently or poorly controlled asthma according to the Asthma Prevention and Management Guideline, Japan [15,16]. These results demonstrate that despite receiving treatment, asthma was not well-controlled in most asthma patients [7]. Because asthma has a variety of complex causes and complex pathophysiology, proper diagnosis and management of the disease require special skill sets from respiratory specialists. However, most of the patients in the previous studies were not treated by an allergy and/or respiratory specialist. Moreover, especially in the Internet surveys, the populations differed from those in actual clinical settings because of biases intrinsic to the study design. Thus, the level of asthma control in patients being treated for asthma by an allergy and/or respiratory specialist in actual clinical settings in Japan is unknown.

Therefore, in this study, we evaluated the level of asthma control in patients who were receiving regular treatment for asthma from an allergy and/or respiratory specialist in Japan. This survey also evaluated asthma symptoms, HR-QoL, and the use of reliever medication in this setting.

Methods

Study design

This was a multi-center, non-interventional, cross-sectional study investigating asthma control, asthma symptoms, HR-QoL, and reliever medication use (the monitoring of which is recommended by the GINA 2017 [12]) among adult asthma patients in Japan who were under the management of an allergy specialist (certified by the Japanese society of Allergology) and/or a respiratory specialist (certified by the Japanese Respiratory Society). The study was registered at ClinicalTrials.gov under the identifier NCT02640742. The study was undertaken between December 2015 and June 2016 across 58 medical institutions in Japan.

The primary objective of this study was to evaluate the proportion of patients with “well-controlled,” “insufficiently-controlled,” and “poorly-controlled” asthma based on a modified definition of the JGL 2015 [8], which is used for asthma prevention and management in Japan. Level of asthma control was also evaluated as “controlled,” “partly controlled,” and “uncontrolled” based on a modified definition of GINA 2012 [17]. Secondary objectives included the evaluation of asthma symptoms (intensity, frequency, limitations on activities, and asthma control questionnaire [ACQ-5] score); HR-QoL; use of reliever medication for asthma attacks; and emotional feelings, including patient attitudes towards asthma medication.

The study was conducted in accordance with the Ethical Guidelines for Medical and Health Research Involving Human Subjects (the Ministry of Education, Culture, Sports, Science and Technology and the Ministry of Health, Labor and Welfare, Japan) and in compliance with accepted ethical principles consistent with the Declaration of Helsinki. Prior to the start of the study, the study protocol was approved by the ethics review board of the Medical Corporation Toukeikai Kitamachi Clinic. Prior to beginning the protocol-defined procedures, the investigator obtained a signed and dated consent form from each patient.

Target population

Outpatients aged ≥20 years who had received a diagnosis of asthma at least 1 year prior to study enrollment and were being managed by allergy and/or respiratory specialists in Japan, were enrolled in the study. Patients were eligible if they had started asthma treatment at least 1 year before enrollment with at least one of the following drugs: inhaled corticosteroid (ICS), long-acting β₂ agonist (LABA), ICS/LABA combination, leukotriene receptor antagonist, sustained-release theophylline, tiotropium bromide hydrate (a long-acting anticholinergic), or omalizumab (an anti-IgE antibody). Patients were excluded if they were participating in another interventional study at the time of consent. Additional exclusion criteria included patients requiring additional treatment to address an exacerbation of asthma symptoms at the time of providing consent; patients scheduled for hospitalization for any reason within 2 weeks of providing consent; and patients considered by their physician to be unsuitable for enrollment owing to an inability to adhere to the procedures, limitations, and requirements of the study.

Data collection and outcome measures

During patient enrollment, and after obtaining written informed consent, the investigators confirmed that patients met all the inclusion criteria and none of the exclusion criteria. Investigators collected patient demographic and clinical data (smoking history, medical history, status of asthma treatment, history of asthma exacerbations, existence of comorbidities, and laboratory variables) retrospectively from medical records. The laboratory variables, including lung function, peripheral eosinophils, total IgE, and fractional exhaled nitric oxide, were obtained when the patient’s asthma condition was stable within the past year.

Patients were requested to complete a patient diary for daytime and nighttime asthma symptoms, sleep disorder, and use of reliever medication, the ACQ-5 (Japanese version) [18], an asthma HR-QoL questionnaire (MiniAQLQ, Japanese version) [19], and a patient questionnaire developed specifically for this study, which were provided to the patients after obtaining informed consent. The patients were then instructed to return the completed items by post.

Case report forms and patient diaries over seven consecutive days were searched for information reflected in the JGL 2015 and GINA 2012 definitions to prospectively evaluate the level of asthma control, which was the primary study outcome. Table 1 shows the evaluation criteria for level of asthma control based on the modified definitions of the JGL 2015 and GINA 2012.

Table 1. Criteria for level of asthma control (adapted from JGL 2015 and GINA 2012).

	Level of asthma control (modified from JGL 2015) [8]
	Well-controlled (Meet all criteria)	Insufficiently-controlled (Meet 1 or 2 criteria)	Poorly-controlled
Asthma symptoms (in the daytime or at night)	None	Once or more a week	Met 3 or more criteria of insufficiently-controlled
Use of reliever	None	Once or more a week
Limitation of activities including exercise	None	Restricted
Exacerbation^a	None	Once or more a year	Once or more a month
	Level of asthma control (modified from GINA 2012) [15]
	Controlled (All of the following)	Partly controlled (Any measure presented)	Uncontrolled
Daytime symptoms	None (twice or less/week)	More than twice/week	Three or more features of “partly controlled asthma”
Limitation of activities	Absent	Present
Nocturnal symptoms/awaking	Absent	Present
Need for reliever/rescue inhaler	None (twice or less/week)	More than twice/week
Exacerbation^b	Absent	Absent	More than once in four weeks

^a Exacerbation was determined based on the clinical record within the past 1 year and the patient diary (recorded for 7 consecutive days).

^b Exacerbations recorded within the previous 4 weeks or the 7 consecutive days in the patient diary were classified as uncontrolled asthma.

JGL: Asthma Prevention and Management Guideline, Japan; GINA: Global Initiative for Asthma.

The ACQ-5, consisting of five questions on symptom control on a 7-point scale (0 = well-controlled, 6 = extremely poorly-controlled), was used to assess asthma control over the previous week. The overall score from the ACQ-5 was the mean of the five responses. Asthma control was defined as well-controlled (≤0.75), insufficiently-controlled (>0.75 to <1.5), or poorly controlled (≥1.5) [18].

The MiniAQLQ was used to assess HR-QoL [19]. The MiniAQLQ includes questions on asthma symptoms (five items), activity limitation (four items), emotional function (three items), and environmental stimuli (three items). Each item was measured on a 7-point scale (7 = no impairment, 1 = maximum impairment). The final score was calculated as the mean of the overall value.

Patient questionnaires were used to assess the level of asthma control during the previous month, use of drugs for asthmatic attack, and emotional feelings, including patient attitudes towards asthma medication.

Statistical methods

The minimum sample size was determined to be the number of patients required to estimate the proportion of patients whose asthma was well-controlled at a sufficient level of accuracy. Ohta et al. [14] reported that the proportion of patients with well-controlled asthma in their study population was 32%. Based on this report, it was assumed that patients whose asthma was well-controlled would account for 30% of the study population. The minimum sample size for attaining a ± 3% width of the 95% confidence interval (CI) was determined to be 897. Assuming a dropout rate of 15%, the minimum sample size was estimated to be 1055. Therefore, a target sample size of 1100 was set for the study.

Categorical variables were presented as frequencies and percentages, while continuous variables were summarized using mean and standard deviation. Level of asthma control was presented as the number and proportion of patients whose asthma was well-controlled, insufficiently controlled, or poorly controlled based on definitions modified from JGL 2015, and controlled, partly controlled, or uncontrolled based on definitions modified from GINA 2012. The 95% CI for the proportion of patients was calculated by the Clopper–Pearson exact method for binominal proportions. For the ACQ-5 score, the numbers/proportions of patients with scores of ≤0.75, >0.75 to <1.5, and ≥1.5 were calculated. A score of ≥1.5 was regarded as indicating poor asthma control. In addition, ACQ-5 scores and MiniAQLQ scores were summarized using descriptive statistics. A MiniAQLQ score of <6 was considered to represent poor HR-QoL [20]. All eligible patients, excluding those who did not submit a completed patient diary or those who were in violation of the protocol, were included in the analysis. All analyses were performed using SAS® Software version 9.3 (SAS Institute Inc., NC, USA).

Results

Demographics

The patient disposition is shown in Figure 1. Of the 1250 patients enrolled from 58 participating centers, including 20 clinics and 38 hospitals, four patients withdrew their consent, and five patients failed to meet the inclusion criteria. Thus, the eligible population included 1241 patients. Sixty-six patients did not submit a patient diary; of the remaining 1175 patients included in the analysis, 183 patients failed to complete their patient diaries; thus, the primary analysis set included 992 patients.

Figure 1. Patient disposition.

Patient demographic and clinical characteristics are summarized in Table 2. In total, women comprised 62.9% of patients. Mean (± standard deviation [SD]) age, body mass index, and duration of asthma were 59.7 ± 14.5 years, 23.4 ± 3.9 kg/m², and 16.9 ± 14.0 years, respectively. Among the 1175 patients, 1168 (99.4%) had used medication for long-term asthma control in the past year. Furthermore, 1163 out of 1175 patients (99.0%) were prescribed an ICS with or without a LABA. The most common comorbidity was allergic rhinitis/pollinosis, which occurred in 534 patients (45.4%), followed by gastroesophageal reflux disease in 99 patients (8.4%).

Table 2. Patient demographic and clinical characteristics.

Patient demographic or clinical characteristic		No. of patients (%) or mean ± SD
Overall		1175 (100.0)
Sex
	Male	436 (37.1)
	Female	739 (62.9)
Age, years		n = 1175
		59.7 ± 14.5
BMI, kg/m^2		n = 1163
		23.4 ± 3.9
Smoking status
	Never smoker	760 (64.7)
	Ex-smoker	358 (30.5)
	Current smoker	57 (4.9)
Smoking history, pack years		n = 415
		25.1 ± 23.2
Duration of asthma, years		n = 1001
		16.9 ± 14.0
History of childhood asthma
	Yes	204 (17.4)
	No	821 (69.9)
	Unknown	150 (12.8)
Family history of asthma
	Yes	262 (22.3)
	No	606 (51.6)
	Unknown	307 (26.1)
Use of controller during the past 1 year		1168 (99.4)
Medications at the time of consent
	ICS or ICS/LABA	1163 (99.0)
	LTRA	486 (41.4)
	Antiallergic agents	269 (22.9)
	Theophylline	232 (19.7)
	Short-acting β2 agonist	197 (16.8)
	Systemic corticosteroids	118 (10.0)
	LAMA	102 (8.7)
	LABA (single agent)	47 (4.0)
	Anti-IgE antibody	24 (2.0)
History of exacerbation in the year prior to enrollment
	Yes	213 (18.1)
	No	962 (81.9)
Comorbidity
	Yes	888 (75.6)
	No	287 (24.4)
Type of comorbidity
	Rhinitis allergic/pollinosis	534 (45.4)
	Gastroesophageal reflux	99 (8.4)
	Chronic sinusitis	85 (7.2)
	Chronic obstructive pulmonary disease	66 (5.6)
	Atopic dermatitis	55 (4.7)
	NSAID sensitive asthma	40 (3.4)
	Food allergy	37 (3.1)
	Eosinophilic sinusitis	23 (2.0)
	Cardiac failure	11 (0.9)
	Eosinophilic otitis media	9 (0.8)
	Eosinophilic granulomatosis with polyangiitis/Churg–Strauss syndrome/allergic granulomatous angiitis	6 (0.5)
	Allergic bronchopulmonary mycosis	6 (0.5)
	Other concomitant conditions not listed above	528 (44.9)

BMI: body mass index; ICS: inhaled corticosteroid; LABA: long-acting β2 agonist; LAMA: long-acting anticholinergic agent; LTRA: leukotriene receptor antagonist; NSAID: nonsteroidal anti-inflammatory drug; SD: standard deviation.

Clinical test results are summarized in Table 3. Of the 578 patients who had lung function test results in their medical records, mean (± SD) forced expiratory volume in 1 s/forced vital capacity (FEV₁/FVC) and FEV₁% predicted were 72.4% ± 11.9%, and 85.3% ± 20.2%, respectively. Fractional exhaled nitric oxide, peripheral blood eosinophils, and total IgE levels were recorded in 335 (28.5%), 262 (22.3%), and 132 (11.2%) patients, respectively. Mean (± SD) values were exhaled nitric oxide, 33.8 ± 29.4 ppb; peripheral blood eosinophils, 318.2 ± 366.8 cells/μL; and total IgE level, 388.7 ± 692.5 IU/mL.

Table 3. Summary of clinical test results.

Clinical test		No. of patients (%) or mean ± SD
Overall		1175 (100.0)
Lung function		n = 578
	FVC (L)	2.909 ± 0.881
	FEV1 (L)	2.113 ± 0.748
	FEV1/FVC (%)	72.4 ± 11.9
	FEV1 % predicted	85.3 ± 20.2
	Peak expiratory flow rate (L/s)	5.958 ± 2.108
Reversibility		n = 122
	FEV1 reversibility (mL)	107.2 ± 128.6
	Rate of change (%)	6.5 ± 9.3
Fractional exhaled nitric oxide		n = 335
	Overall (ppb)	33.8 ± 29.4
Eosinophils in peripheral blood		n = 262
	Eosinophil ratio (%)	4.8 ± 4.9
	Eosinophils in peripheral blood (cells/μL)	318.2 ± 366.8
Total IgE level (IU/mL)		n = 132
		388.7 ± 692.5
Specific IgE antibodies		n = 52
	Negative	13 (1.1)
	Positive	39 (3.3)

FEV₁: forced expiratory volume in 1 s; FVC: forced vital capacity; SD: standard deviation.

Outcome measures

Primary endpoint

Level of asthma control was evaluated based on definitions modified from the JGL 2015 and GINA 2012 (Table 4). Data of 992 patients (84.4%) were available for these analyses. According to the JGL 2015-based definitions, asthma was well-controlled, insufficiently controlled, and poorly controlled in 242 (24.4%), 686 (69.2%), and 64 patients (6.5%), respectively. When level of asthma control was analyzed by treatment step in accordance with JGL 2015, asthma was well-controlled in 37 (55.2%), 93 (34.1%), 90 (20.0%), and 22 (10.9%) patients on treatment steps 1, 2, 3, and 4, respectively.

Table 4. Level of asthma control.

		JGL 2015-based criteria
		Total	Well-controlled n (%)	Insufficiently-controlled n (%)	Poorly-controlled n (%)
Overall		992	242 (24.4)	686 (69.2)	64 (6.5)
Treatment step (by JGL)
	1	67	37 (55.2)	29 (43.3)	1 (1.5)
	2	273	93 (34.1)	168 (61.5)	12 (4.4)
	3	449	90 (20.0)	334 (74.4)	25 (5.6)
	4	201	22 (10.9)	153 (76.1)	26 (12.9)
	Unknown	2	–	–	–
		GINA 2012-based criteria
		Total	Controlled n (%)	Partly controlled n (%)	Uncontrolled n (%)
Overall		992	348 (35.1)	494 (49.8)	150 (15.1)
Treatment step (by GINA)
	1	0	0	0	0
	2	60	38 (63.3)	20 (33.3)	2 (3.3)
	3	315	144 (45.7)	141 (44.8)	30 (9.5)
	4	554	147 (26.5)	308 (55.6)	99 (17.9)
	5	54	15 (27.8)	21 (38.9)	18 (33.3)
	Unknown	9	–	–	–

JGL: Asthma Prevention and Management Guideline 2015, Japan; GINA: Global Initiative for Asthma 2012.

Using GINA-based definitions, asthma was controlled, partly controlled, and uncontrolled in 348 (35.1%), 494 (49.8%), and 150 (15.1%) patients, respectively. When level of asthma control was analyzed by treatment step in accordance with GINA, asthma was controlled in 38 (63.3%), 144 (45.7%), 147 (26.5%), and 15 (27.8%) patients in treatment steps 2, 3, 4, and 5, respectively.

Secondary endpoints

Asthma symptoms are summarized in Table 5. Of the 992 patients evaluated for asthma symptoms, 511 (51.5%) patients experienced daytime asthma symptoms, 445 (44.9%) experienced nighttime asthma symptoms, and 107 (10.8%) patients experienced nighttime sleep disorder. During the day, 162 (16.3%), 209 (21.1%), and 441 (44.5%) patients experienced wheezing, chest tightness, and cough, respectively; at night, these symptoms were experienced by 159 (16.0%), 158 (15.9%), and 388 (39.1%) patients, respectively. In total, 564 (56.9%) experienced sputum, while 70 (7.1%) of patients experienced restrictions on activities, including exercise.

Table 5. Asthma symptoms.

Asthma symptoms, n (%)			n = 992*
Any asthma symptoms
		Daytime	511 (51.5)
		Nighttime	445 (44.9)
Wheezing
		Daytime	162 (16.3)
		Nighttime	159 (16.0)
Chest tightness
		Daytime	209 (21.1)
		Nighttime	158 (15.9)
Cough
		Daytime	441 (44.5)
		Nighttime	388 (39.1)
Sputum			564 (56.9)
Sleep disorder			107 (10.8)
Limitation of activities (including exercise)			70 (7.1)

* Patients with ≥5 days’ worth of entries in their patient diary.

Patient-reported outcomes are summarized in Table 6. Data for patient-reported asthma control (based on ACQ-5 score) over the previous week were collected from 1157 patients (98.5%). Most patients (n = 700, 60.5%) had a score of ≤0.75; 276 patients (23.9%) had a score >0.75 to <1.5; and 181 patients (15.6%) had a score ≥1.5. The HR-QoL of patients with asthma was affected by the disease. Overall, the mean (± SD) MiniAQLQ score was 5.8 ± 1.0 on a 7-point scale. The impairments in HR-QoL were associated with limitations on daily activities (mean ± SD score, 6.1 ± 1.1) and asthma symptoms (6.0 ± 1.0), followed by emotional function (5.8 ± 1.2). Data on asthma control status in the past month (based on patient questionnaire responses) were collected from 1158 patients (98.6%). Of these, asthma was well-controlled, insufficiently controlled, and poorly controlled in 754 (65.1%), 305 (26.3%), and 99 (8.5%) patients, respectively.

Table 6. Summary of patient-reported outcomes.

		No. of patients (%) or mean ± SD
ACQ-5 score^a		n = 1157
	≤0.75 (controlled asthma)	700 (60.5)
	>0.75, <1.5	276 (23.9)
	≥1.5 (not well-controlled asthma)	181 (15.6)
	Mean score	0.7 ± 0.9
MiniAQLQ score		n = 1152
	Mean score	5.8 ± 1.0
	Symptoms	6.0 ± 1.0
	Limitation on activities	6.1 ± 1.1
	Emotional function	5.8 ± 1.2
	Environmental stimuli	5.0 ± 1.6

^a Categories as described in Jia et al [21].

ACQ: asthma control questionnaire; AQLQ: asthma quality of life questionnaire; SD: standard deviation.

A total of 1125 patients provided responses in the patient questionnaire on their use of relievers and emotional feelings. When the 743 patients who had used reliever medication were asked in what situation they used it, 272 patients (36.6%) reported wheezing; 233 patients (31.4%), chest tightness; 175 patients (23.6%), mild attack (dyspnea with somewhat difficult movement but able to lie down); 55 patients (7.4%), moderate attack (dyspnea, barely able to walk, unable to lie down); and 8 patients (1.1%), severe attack (dyspnea, unable to move, difficulty speaking). Of six factors that patients were asked to consider regarding their treatment expectations, the three factors most commonly considered as “very important” were “symptom improvement,” 947 patients (84.2%); “fewer adverse reactions,” 873 patients (77.6%); and “rapid onset of action,” 859 patients (76.4%). This suggests a need for drugs that address each of these factors.

Discussion

This multi-center cross-sectional study sought to evaluate level of asthma control, asthma symptoms, HR-QoL, and the use of reliever medication in patients receiving treatment for asthma under the management of an allergy and/or respiratory specialist in Japan. In this survey, there were more women (62.9%) than men, the mean age was 59.7 years, the mean duration of asthma was 16.9 years, and over half (54.6%) of the patients were aged over 60 years. This sex and age distribution was similar to that in a 2014 survey in Japan [22].

Proportion of patients by level of control (JGL and GINA)

Our results showed that less than a quarter (24.4%) of the patients surveyed had well-controlled asthma based on the modified JGL 2015 criteria, while 69.2% and 6.5% of patients had insufficiently or poorly controlled asthma, despite receiving treatment from an allergy and/or respiratory specialist. However, using the GINA 2012-based definitions of asthma control, roughly a third (35.1%) of the patients had controlled asthma, approximately half (49.8%) of the patients had partly controlled asthma, and 15.1% of patients had uncontrolled asthma.

Because the symptoms of COPD, eosinophilic granulomatosis with polyangiitis, and allergic bronchopulmonary aspergillosis may affect the evaluation of level of asthma control, we conducted a post hoc analysis of the data excluding patients with these comorbidities. Among the 935 patients included in the re-analysis, asthma was well-controlled, insufficiently controlled, and poorly controlled in 230 (24.6%), 647 (69.2%), and 58 (6.2%) patients, respectively (JGL-based criteria). These proportions were similar to those observed in the primary analysis set, indicating that the above comorbidities did not greatly influence the overall results.

The results based on both sets of criteria highlight that asthma is insufficiently controlled/partly controlled in most patients, and that the proportion of patients with poorly controlled/uncontrolled asthma is notable, regardless of the treatment step they are on and despite receiving long-term (≥1 year) treatment by allergy and/or respiratory specialists. Similarly, in a survey of 8000 European patients with asthma, Price et al. reported that 45.1% of patients had uncontrolled asthma as defined by GINA 2012; however, 90.5% of patients perceived their asthma to be well-controlled [6]. In a Japanese mail-based survey of asthma patients managed and followed up by physicians (not limited to allergy and/or respiratory specialists), high proportions of patients experienced daytime symptoms (87.5%), nocturnal symptoms (62.3%), and limitation on activities (42.9%) [7].

Possible explanations for the current outcomes

There are several possible explanations for the large number of patients with poorly controlled asthma by JGL-based criteria. First, patients may have poor adherence to treatment because they underestimate the severity of their disease [6]. Second, healthcare professionals may not provide adequate instruction regarding correct administration of medication (i.e. proper inhalation technique). It is important to note that in addition to providing in-depth instruction at initial treatment, continuous education is crucial for patients to effectively manage this chronic disease [8]. Moreover, to improve asthma control levels, the selection of appropriate pharmacological and non-pharmacological treatment should be based on regular assessments of control levels, and the application of the GINA control-based management cycle [12]. This cycle involves three main steps: (1) assessment of symptom control and risk factors (including lung function), inhaler technique and adherence, and patient preferences; (2) pharmacological and non-pharmacological treatment adjustment; and (3) review of response based on symptoms, exacerbations, side effects, patient satisfaction, and lung function. Finally, it should be noted that asthma symptoms reported in a daily patient diary differ from those reported in a daily clinical setting.

Generally, the JGL 2015 or GINA 2012 criteria for level of asthma control are consistent. However, numerical discrepancies were observed in this study, which may be attributed to differences between the criteria. The JGL-based criteria for “well-controlled” were defined by a complete lack of asthma symptoms, exacerbations, limitations in exercise and other activities, and reliever medication use for asthma attacks. In the GINA-based questionnaire, patients who used reliever medication ≤2 times/week or experienced daytime asthma symptoms ≤2 times/week were still considered to have “controlled” asthma. Moreover, in the GINA-based criteria, daytime and nighttime asthma symptoms were evaluated as separate items; however, in the JGL-based criteria, both types of asthma symptoms were evaluated together as a single item. In fact, in this survey, nearly half (44.9%) of all patients experienced nighttime asthma symptoms.

Asthma symptoms

Nighttime asthma symptoms and sleep disorder are common in asthma patients and can be detrimental to their HR-QoL [23,24]. Moreover, in the GINA report, the frequency of nighttime asthma symptoms is one of the indexes used to select a patient’s treatment step [12]. We found that cough was the most frequently experienced nighttime symptom with over a third of patients (39.1%) reporting coughing at nighttime; wheezing and chest tightness were experienced by 16.0% and 15.9% of patients, respectively. In other surveys, the frequency of nighttime asthma symptoms in patients with asthma was similar to this survey, ranging from 37% to 47% [25,26]. However, in a survey of ICS-naive asthma patients who were receiving medical treatment in Japan [27], approximately 75% of patients experienced nighttime asthma symptoms.

In this survey, 10.8% of patients reported nighttime sleep disorder. However, in previously published surveys, approximately a half to two-thirds of patients reported that they experienced sleep disorder due to their asthma [28,29]. This survey evaluated nighttime asthma symptoms and nighttime sleep disorder based on a short, 1-week patient diary; thus, if no sleep disturbance occurred during this timeframe, this may have led to the low reported frequency of nighttime sleep disorder. Among 107 patients who had sleep disorder, 98 patients also suffered daytime asthma symptoms. The assessment and alleviation of sleep disorder should be an important consideration in asthma treatment.

During the daytime, approximately half of the patients surveyed experienced asthma symptoms (51.5%). Cough was a common symptom during daytime, with 44.5% of patients reporting coughing. HR-QoL based on the MiniAQLQ scores was also affected, with limitations in daily activities and asthma symptoms reported as the greatest impairments.

When comparing the proportions of patients with well-controlled asthma between JGL/GINA-based criteria (24.4%/35.1%) and ACQ-5/questionnaire-based criteria (60.5%), we noted a discrepancy. This can be explained by the fact that the ACQ-5 evaluates only symptoms, whereas the modified JGL/GINA criteria are based not only on symptoms but also on information of reliever medication use, limitation of activities, and exacerbations. This type of discrepancy was common in certain settings [21].

Sputum was the most frequently experienced asthma symptom with more than half (56.9%) of the patients surveyed reporting sputum either during the day and/or at night. The presence of excessive sputum in patients with chronic asthma is associated with airway obstruction, reduced lung function, and high rates of hospitalization and mortality [30,31]. Targeting the inflammatory responses that drive sputum production through the use of corticosteroids is key in the treatment of asthma [31].

Limitations

Our study had several limitations. First, as this was a cross-sectional study, a causal relationship between the level of asthma control and asthma treatment could not be established. For the same reason, it is difficult to make any further conclusions regarding the effect of the level of control on patient-centered outcomes. Second, adherence and inhaler technique were not evaluated. However, this survey only included patients receiving continuous treatment from an allergy and/or respiratory specialist; thus, the treatment of asthma was likely to be consistent with recent guidelines, and patients were monitored predominantly by these specialists. Third, the criteria used to assess asthma control in the present study were based on modified definitions of the JGL 2015 and GINA 2012, but we did not include data of pulmonary function to determine asthma control, which are present in the original JGL/GINA guidelines.

Conclusions

In summary, this study revealed that among patients under the care of an allergy and/or respiratory specialist in real clinical practice, 75.6% of patients had insufficiently /poorly controlled asthma according to JGL 2015-based criteria, and 64.9% of patients had partly controlled/uncontrolled asthma according to GINA 2012-based criteria. To achieve better asthma control, improvements in symptom monitoring and management may be required. Daytime and nighttime symptoms were reported by 51.5% and 44.9% of asthma patients, respectively, suggesting that appropriate assessment of asthma symptoms should be considered in daily clinical practice.

Declaration of interest

MA received funds from Toa Pharmaceuticals Co., Ltd., and Kyowa Hakko Kirin Co., Ltd., for advisory roles, as well as honoraria from Astellas Pharma Inc., AstraZeneca K.K., GlaxoSmithKline K.K., Kyorin Pharmaceutical Co., Ltd., MSD K.K., and Nippon Boehringer Ingelheim Co., Ltd. SH received honoraria from Astellas Pharma Inc., Novartis Pharma K.K., AstraZeneca K.K., Nippon Boehringer Ingelheim Co., Ltd., Kyorin Pharmaceutical Co., Ltd., Teijin Pharma Ltd., Sanofi K.K, Torii Pharmaceutical Co., Ltd., and MSD K.K. AY and TJ are full-time employees of AstraZeneca K.K. GT received honoraria from AstraZeneca K.K. and Nippon Boehringer Ingelheim Co., Ltd., and research funding from Nippon Boehringer Ingelheim Co., Ltd. MN has no conflicts of interest to declare.

Author contributions

AY and TJ contributed to the study conception and data analysis. TJ contributed to the data acquisition. All authors contributed to the study design, interpretation of data, and reviewing the manuscript. All authors read and approved the final manuscript.

Additional information

Funding

The authors would like to acknowledge Emma Donadieu, MSc, and Keyra Martinez Dunn, MD, of Edanz Medical Writing for medical writing support, which was funded by AstraZeneca K.K., Osaka, Japan. The study was funded by AstraZeneca K.K., Osaka, Japan.