FACTORS RESTRICT TREATMENT EFFICIENCY IN ASTHMA PATIENTS

Background: A number of modifiable factors that contribute to poor asthma control have been identified. We wanted to know how many patients had insufficient therapy, adherence, or major inhaler technique errors, and how they affected asthma control. Methodology: We conducted a cross-sectional multicenter observational research with asthma patients who were referred for the first time from primary to specialized treatment. Adequate prescription according to guidelines, treatment adherence, and illness control were among the data collected. 35.9% of the 1682 patients (age 45-17 years, 64.6 percent men) had insufficient prescriptions, 76.8% had low adherence, and 17 percent had critical inhaler technique errors, with Easyhaler users making significantly fewer critical errors than other dry powder inhaler users (10.3 versus 18.4%; p 0.05). Inadequate prescription (OR: 3.65), non-adherence to therapy (OR: 1.8), and inhaler abuse were all linked to poor asthma control (OR: 3.03). A greater number of risk variables were linked to a greater likelihood of having poorly managed asthma.


Introduction
Asthma is a frequent disease that costs a lot of money in terms of healthcare and lost productivity [1]. Asthma is becoming more common around the world, with about 1000 people dying from it every day, according to a study published in 2015 [2]. According to the most recent data on asthma prevalence worldwide, 334 million people are affected [3]. However, its frequency varies widely between countries, with wealthy countries having the highest prevalence1. Exacerbations are associated with high direct (medications, hospitalization, Emergency Department treatment, etc.) and indirect (school absenteeism, loss of work productivity, etc.) costs. Asthma exacerbations are currently one of the most common reasons of Emergency Department4 visits, highlighting asthmatic patients' poor management. Exacerbations can be caused by a variety of circumstances, including exposure to external stimuli, poor adherence to medication, inadequate therapy, and poor inhaler technique in the case of uncontrollable asthma [4][5][6]. Several studies have found that asthmatic patients had poor medication adherence: 50 percent in children and 30-70 percent in adults, depending on the nation, age, sex, and ethnicity [7,8]. Limited understanding or recognition (among patients and/or physicians), beliefs or side effect worries, inhaler features, and directions for use were all factors that contributed to this difference. As a result, asthma control as a therapeutic goal is still a long way off [9]. Better control would improve not only cost effectiveness but also quality of life, lower school absenteeism, and boost workplace productivity. The same problem can be seen in asthma management in primary care. Several research on asthma in primary care appear to imply that, despite accessible medications, asthma control in practical practice is inadequate. European publications [10,11]. have revealed little apparent improvement in symptom control in recent years. The study's primary goals are to (1) determine the appropriateness of prescribed treatment, as well as the presence of poor adherence and critical errors in inhalation technique in patients referred from primary care to a specialist for the first time, and (2) investigate the relationship between these factors and poor asthma control. This real-life study could help us figure out whether asthma management in primary care has improved in terms of prescription quality, inhaler technique, and patient adherence to treatment in the 30 years since asthma guidelines were implemented in Spain [13][14][15][16][17].

Participants and Study Design
Patients aged 18 years who used any type of inhaler device and were referred from general care to a pneumologist or allergologist for the first time for any reason were included in a cross-sectional multicenter observational study. From September through December 2016, data was gathered. The lack of a signed informed permission and incapacitating illness or mental disease were also exclusion criteria, making participation in the study impossible according to the research requirements. Spirometry and a bronchodilator test were performed on all patients to confirm or rule out asthma [19][20][21][22][23][24].

Study Measurements
The following important characteristics were evaluated: adequate asthma therapy based on GINA recommendations44 (GINA treatment steps 1-5 were used to determine the appropriateness of current patients' treatment based on asthma control at the time of the visit). Treatment adherence according to the MG questionnaire (patients were classified into reliable or not reliable according to a punctuation from 0 to 4, with 0 = reliable and 1 = not reliable) 45 Asthma severity according to the 2015 GINA criteria44, comorbidities (allergy, occupational exposure to allergens or irritants, smoking, etc.), and asthma control according to both GINA and ACT criteria44,48 were all gathered. These factors, according to GINA, were considered: Symptoms of the patients throughout the day and at night (two times per week for daytime symptoms and no nocturnal symptoms). As a result, patients were divided into two groups: wellcontrolled (all previous items) and partially/not-controlled (one to four previous things). Patients were divided into the same two categories by the ACT, but this time through five items from the validated Spanish version of the ACT (21: well controlled, 21: partially/not controlled). All data was gathered in a single visit using an online patient notebook that was suited to the study's needs. The study was approved by the Ethics Committee (Hospital Clinic de Barcelona, Registration number HCB/2016/0647), and it was carried out in accordance with the Helsinki Declaration (1964). All participants gave their informed consent [29-35].

Statistical Analysis
For categorical data, the Pearson's chi-squared test (2) was used, and for continuous data, the analysis of variance test was used. To establish the independence of discovered components, a binary logistic regression was performed (OR). Cohen's k coefficient, Spearman's correlation coefficient, and R square were used to express the relationship and concordance between ACT/GINA regarding asthma control (R2). SPSS 20.0 was used to analyze all of the data [35-40].

Demographics and Clinical Characterization
The trial involved 1682 patients, with men accounting for 64.6 percent of the total. The average age was 45 years and 17 months. Table 1 summarizes the cohort's characteristics [41][42][43][44][45]. In terms of treatment adherence, the Test of Adherence to Inhalers (TAI) questionnaire revealed that 76.8% of patients had poor adherence, while the Morisky-Green (MG) questionnaire revealed that 68.5 percent of patients had poor adherence (Table  2). Furthermore, according to the ACT, 68.8% of patients with poor adherence had poorly managed asthma, whereas 55.1 percent of patients with strong adherence had poorly controlled asthma (OR 1.8, 95 percent CI: 1.42-2.27, p 0.0001; Table 3). According to the extended TAI test, nearly 17% of patients exhibited at least one major error in inhaler technique (errors in the use of the device that jeopardize the effectiveness of inhaled medication) ( Table 2). According to the ACT, 83.2 percent of patients with critical inhaler errors had poorly managed asthma, compared to 62.1 percent of patients with poorly controlled asthma and no critical inhaler errors (OR 3.03, 95 percent CI: 2.18-4.21, p 0.0001; Table 3). Misuse rates varied depending on whether the device was a pressurized metered-dose inhaler (pMDI) or a dry powder inhaler (DPI). As a result (  Each of these risk variables (insufficient prescription, poor adherence, and inhaler abuse) had a statistically significant effect on asthma control (p 0.0001; Table 3). Furthermore, having a higher number of risk factors was linked to having poorly controlled asthma, with a maximum of 93 percent for the ACT and 100 percent for the GINA if all three problems were present, and 46 percent for the ACT and 54 percent for the GINA if none were present. When the GINA score was compared to the ACT questionnaire score, there was a moderate agreement (Kappa = 0.458; Rho = 0.709; r2 = 0.503). Supplementary Tables 1  and 2 and Supplementary Figs 1 and 2 show the relevant tables for the GINA asthma control, which are quite similar to the ACT control.

Discussion
Despite years of asthma guidelines implementation, poor asthma control was found to be highly linked to modifiable variables associated with medication failure in this investigation [60]. According to a recent study, although numerous factors may be implicated in poor asthma control, three factors appear to be the key causes of poor asthma control in primary care. Inadequate prescriptions, poor medication adherence, and poor inhaler technique6, 9,13,14,15 are all factors. Obesity has a negative impact on asthma control, and preliminary evidence suggests that losing weight can improve asthma control and quality of life16. However, whereas diet-induced weight loss is associated with a slew of general health benefits, there is currently little evidence on asthma control; as a result, the authors did not include this factor among the modifiable ones. According to the GINA and the ACT, 71.7 and 65.7 percent of patients in our study had inadequate symptom control, respectively. Several studies in primary care have been undertaken in recent years, with various measured variables and designs16. Despite their differences, they all had a tendency to have poor asthma control. Calvo et al.19, in a recent Spanish article, revealed inadequate asthma control (ACT 20) in 638 asthmatic patients, ranging from 23.4 to 75.6 percent, depending on the patients' medical consultation. Almost half of the patients had poor control on average. According to the authors of another study20, 45 percent of asthmatic patients in Spain who received any sort of treatment had uncontrolled asthma. Other European countries' asthma control isn't much better: a recent Swedish primary care research found that 53.6 percent of patients had uncontrolled asthma (600 doses of short-acting beta agonists and/or 1 exacerbation each year). 21. The Asthma Control Questionnaire was used to assess asthma control in the European LIAISON study22, and the percentage of patients with partially or poorly managed asthma was 56.5 among the 12 nations that took part in the study. In the United States, a similar situation exists: 50 percent of patients who visited primary care for a non-respiratory consultation had uncontrolled asthma (ACT 19)23. When compared to our study, most studies reveal a little lower percentage of poorly managed individuals, which could be due to selection bias, as patients sent to specialist care are not expected to be asymptomatic. More than a third of our patients received inadequate treatment at the time of referral from primary care, which was linked to poor asthma control. Both doctors and patients have a tendency to underestimate the severity of asthma, which may explain why many people are undertreated. Lack of time and financial resources are some of the reasons for inadequate asthma management in primary care24, despite the fact that it is well known that poor diagnosis and treatment have a negative impact on patients' health25, resulting in increased care demand and expense. In this regard, the ACT was developed as a tool for detecting poorly controlled asthma and, as a result, identifying those patients who needed the most effective treatment. When a clinician uses it on a regular basis, it has been found to allow for better treatment adjustments. Electronic devices, which could be the gold standard8, (they are an objective approach to assess patients' adherence), are the best strategy for evaluating adherence, but they are expensive and difficult to use for many patients. As a result, self-reports appear to be the most cost-effective way to assess it7, despite the fact that patients are sometimes unwilling to disclose poor adherence29. Two adherence questionnaires were employed in this study, and the TAI questionnaire appears to be more sensitive than the MG one (76 and 68.5 percent, respectively, have a poor adherence). The TAI has also been demonstrated to have a greater association with patient actual adherence30. Furthermore, when asthma control is assessed using the ACT punctuation and GINA criteria, a statistically significant relationship is found. Similarly, in the REcognize Asthma and LInk to Symptoms and Experience (REALISE) study11, nearly half of the patients had poor adherence to treatment, and in the LIAISON study, patients with poorly controlled asthma had a higher rate of low adherence (according to the MG) than those with well-controlled asthma22. To emphasize the significance of strict adherence, It should be noted that its absence is connected to a higher risk of asthma exacerbations, increased use of oral corticosteroids, the necessity for ER visits and/or hospitalization, deterioration of forced expiratory volume in 1 s values29,31, and lastly, higher expenses and poor quality of life7. Every visit, strategies to promote adherence have been investigated, such as reviewing the inhaler usage method as well as patient adherence. Electronic reminders should also be employed because they are highly effective. 29,30,32,33. In primary care, it has been proven that an educational program can help with adherence, cost control, and cost reduction. After proper training, the program should include medical practitioners as well as nursing services34. In terms of the third major cause of poorly managed asthma, insufficient inhaler technique, this study found that 17% of patients referred from primary care make crucial errors, which is linked to poor asthma control (GINA OR 4.76; ACT OR 3.03). Serious inhaler technique errors are those that have the potential to impede medication uptake and distribution to the lungs. Although the percentage of key errors in some studies (ranging from 50 to 90 percent)35 is higher than in ours, this step is unquestionably important in achieving asthma control. Poor inhaler technique has been linked to an increase in symptoms36, the need for hospitalization12, and, most importantly, less effective asthma control. In a Dutch study, between 47.7% and 64.9 percent of patients referred to primary care had inhaler abuse; a pragmatic intervention improved this factor significantly37. Between inhaler devices, the percentage of major mistakes varies greatly. Patients performed better with the DPI devices than the MDIs in our trial, as expected. When compared to other DPIs, EH was related with a lower number of critical errors (Turbuhaler, Nexthaler, Accuhaler). Previous investigations have shown that the EH device has a higher rate of acceptance and satisfaction38,39, which supports this conclusion. Furthermore, some studies suggest that an explanation of how to use an inhaler, as well as a practical demonstration of patient abilities with the device, are beneficial. Some publications, for example, recommend that before a patient is discharged from the Emergency Department, an explanation of inhaler technique be given. Inadequate prescriptions, treatment adherence, and inhaler technique all contribute to the fact that 73.3 percent of patients have poorly managed asthma (according to GINA criteria) and 65.7 percent of patients have poorly controlled asthma (according to the ACT questionnaire). As already stated These three characteristics are critical for asthma control5,6,9,24, and as additional risk factors are present, control worsens, ranging from 58.4 percent of poor control (ACT 20) when one condition is implicated to 93.5 percent when all conditions are implicated (or 54-100 percent using the GINA criteria). Although the GINA could detect a higher proportion of under controlled individuals than the ACT, our investigation appears to demonstrate such a concordance between the ACT and the GINA criteria for asthma control. Most patients assume that bronchodilators are the major medication for treating asthma and that anti-inflammatory treatment can be stopped during remission times, which is not encouraging. When asthma comprehension is looked at as a predictor of poor asthma control using a binary logistic regression, it appears to be an independent predictor. Patients' adherence is likely influenced by these concerns: in the REALISE study11, half of the patients did not take their maintenance drugs correctly. Even when they experienced severe and persistent symptoms, nearly half of individuals in another study10 reported their asthma was well managed. Patients' understanding and, as a result, adherence to treatment could be improved by educational initiatives.
Our findings reveal that poor asthma management, adherence to therapy, inhaler technique, and asthma knowledge are key factors resulting in poorer asthma control at the primary care level. When referred to a Specialist, many patients do not obtain proper treatment and adherence to therapy is poor. Furthermore, individuals who make major errors in inhaler technique are a common occurrence [79].

Conclusion
This study shows that there is still room for improvement by focusing on these modifiable factors that appear to be key opportunities for improving asthma management at the primary care level, such as optimizing therapy, retraining on inhaler technique, and developing new tools to improve adherence to treatment.